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data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-00b6a3f3-21f2-48f5-a9b7-c8c7308ad51e NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-00b6a3f3-21f2-48f5-a9b7-c8c7308ad51e Main Human Susceptibility Loci for Sleep Disorders uuid-00b6a3f3-21f2-48f5-a9b7-c8c7308ad51e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-00b6a3f3-21f2-48f5-a9b7-c8c7308ad51e PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: mesenchymal stem cell Description: Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-00e26e82-75ff-4776-a66d-f9d3a780ed65 NodeType: Group Organ: oncogenic Organ_System: oncogenic PMID: 16082183 PMID: 19242414 PMID: 23348381 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-group:uuid-00e26e82-75ff-4776-a66d-f9d3a780ed65 Metastasis Suppressors uuid-00e26e82-75ff-4776-a66d-f9d3a780ed65 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType mesenchymal stem cell PS:Description Group is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-00e26e82-75ff-4776-a66d-f9d3a780ed65 PS:NodeType Group PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 16082183 PS:PMID 19242414 PS:PMID 23348381 PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-086158b9-58eb-49ed-b144-822311f4fe17 NodeType: Group Notes: Mutations in this genes leading to lack or dysfunction of corresponding proteins were shown to be associated with several forms of hypothyroidism. Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-086158b9-58eb-49ed-b144-822311f4fe17 Genes with Mutations Associated with Hypothyroidism uuid-086158b9-58eb-49ed-b144-822311f4fe17 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-086158b9-58eb-49ed-b144-822311f4fe17 PS:NodeType Group PS:Notes Mutations in this genes leading to lack or dysfunction of corresponding proteins were shown to be associated with several forms of hypothyroidism. PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-09f62fc0-4779-4f72-b190-76db8a331820 NodeType: Group Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-09f62fc0-4779-4f72-b190-76db8a331820 Genes with Mutations and Deletions Associated with Male Infertility uuid-09f62fc0-4779-4f72-b190-76db8a331820 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-09f62fc0-4779-4f72-b190-76db8a331820 PS:NodeType Group PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-0de8431e-a2e3-48f8-a40c-8e5c049ba9bb NodeType: Group Organ: stomach Organ_System: digestive system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-group:uuid-0de8431e-a2e3-48f8-a40c-8e5c049ba9bb Proteins of Helicobacter Pylori with Pathogenic Potential uuid-0de8431e-a2e3-48f8-a40c-8e5c049ba9bb PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-0de8431e-a2e3-48f8-a40c-8e5c049ba9bb PS:NodeType Group PS:Organ stomach PS:Organ_System digestive system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-0ed71ee2-a5a2-495a-b615-ac344b4977c4 NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-0ed71ee2-a5a2-495a-b615-ac344b4977c4 Genes with Mutations Associated with Glaucoma (Including Congenital Eye Dysgenesis Syndromes) uuid-0ed71ee2-a5a2-495a-b615-ac344b4977c4 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-0ed71ee2-a5a2-495a-b615-ac344b4977c4 PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-113dc13f-d68a-4c88-b27e-22d160231508 NodeType: Group Organ: Tooth Organ_System: digestive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-113dc13f-d68a-4c88-b27e-22d160231508 Genes with Mutations Associated with Hereditary Abnormalities of Enamel uuid-113dc13f-d68a-4c88-b27e-22d160231508 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-113dc13f-d68a-4c88-b27e-22d160231508 PS:NodeType Group PS:Organ Tooth PS:Organ_System digestive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-121f8b09-4a74-4932-9c3f-b7ba74a90fff NodeType: Group Organ: heart Organ_System: cardiovascular system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-121f8b09-4a74-4932-9c3f-b7ba74a90fff Genes with Mutations Associated with Hypertrophic Cardiomyopathy uuid-121f8b09-4a74-4932-9c3f-b7ba74a90fff PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-121f8b09-4a74-4932-9c3f-b7ba74a90fff PS:NodeType Group PS:Organ heart PS:Organ_System cardiovascular system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-122631d2-173b-4ac5-b0a9-8c723a1ed340 NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-122631d2-173b-4ac5-b0a9-8c723a1ed340 Genes with Mutations Associated with Usher Syndromes uuid-122631d2-173b-4ac5-b0a9-8c723a1ed340 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-122631d2-173b-4ac5-b0a9-8c723a1ed340 PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-128f6d1c-1733-436d-9575-c01277bfa79b NodeType: Group PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-group:uuid-128f6d1c-1733-436d-9575-c01277bfa79b Protein cofactors uuid-128f6d1c-1733-436d-9575-c01277bfa79b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-128f6d1c-1733-436d-9575-c01277bfa79b PS:NodeType Group PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-135bf918-2eb3-4e8b-9edb-fbc09e8afc99 NodeType: Group Organ: bone Organ_System: skeletal system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-135bf918-2eb3-4e8b-9edb-fbc09e8afc99 Genes with Mutations Associated with Osteoporosis uuid-135bf918-2eb3-4e8b-9edb-fbc09e8afc99 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-135bf918-2eb3-4e8b-9edb-fbc09e8afc99 PS:NodeType Group PS:Organ bone PS:Organ_System skeletal system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-177f0ce2-ab21-4c26-a772-5b7af9bc756a NodeType: Group Organ_System: endocrine system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-177f0ce2-ab21-4c26-a772-5b7af9bc756a Genes with Mutations Associated with Tyrosinemia uuid-177f0ce2-ab21-4c26-a772-5b7af9bc756a PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-177f0ce2-ab21-4c26-a772-5b7af9bc756a PS:NodeType Group PS:Organ_System endocrine system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1846f8fe-d4b8-4057-bd4b-298115d92796 NodeType: Group Notes: Alternative lengthening of telomeres is a TERT-independent mechanism of telomere length maintenance in cancer cells. Organ: oncogenic Organ_System: oncogenic PMID: 20937668 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-group:uuid-1846f8fe-d4b8-4057-bd4b-298115d92796 Proteins Related to Alternative Lengthening of Telomeres in Cancer uuid-1846f8fe-d4b8-4057-bd4b-298115d92796 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Group is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1846f8fe-d4b8-4057-bd4b-298115d92796 PS:NodeType Group PS:Notes Alternative lengthening of telomeres is a TERT-independent mechanism of telomere length maintenance in cancer cells. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20937668 PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-19e6a535-91fd-4c81-b7a8-02c43e5eabc3 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-19e6a535-91fd-4c81-b7a8-02c43e5eabc3 Genes with Mutations Associated with Amyotrophic Lateral Sclerosis uuid-19e6a535-91fd-4c81-b7a8-02c43e5eabc3 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-19e6a535-91fd-4c81-b7a8-02c43e5eabc3 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1b0bb52a-bf83-45e2-83d6-393bec700b37 NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-1b0bb52a-bf83-45e2-83d6-393bec700b37 Genes with Susceptibility Loci Associated with Age-Related Macular Degeneration uuid-1b0bb52a-bf83-45e2-83d6-393bec700b37 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1b0bb52a-bf83-45e2-83d6-393bec700b37 PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1bd7679f-cbba-49fe-a1ea-a05817ed9a94 NodeType: Group Organ: liver Organ_System: digestive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-1bd7679f-cbba-49fe-a1ea-a05817ed9a94 Genes with Mutations Associated with Hepatocellular Carcinoma uuid-1bd7679f-cbba-49fe-a1ea-a05817ed9a94 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1bd7679f-cbba-49fe-a1ea-a05817ed9a94 PS:NodeType Group PS:Organ liver PS:Organ_System digestive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1c97dc53-51a3-4bc9-99f9-6e50832ec4cc NodeType: Group Organ: ear Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-1c97dc53-51a3-4bc9-99f9-6e50832ec4cc Genes with Mutations Associated with Hereditary Hearing Loss, Mitochondrial uuid-1c97dc53-51a3-4bc9-99f9-6e50832ec4cc PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1c97dc53-51a3-4bc9-99f9-6e50832ec4cc PS:NodeType Group PS:Organ ear PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Source Description: Mutations in UCHL1, PARK2, SNCA, and LRRK2 genes cause an autosomal dominant and in PARK7, PINK1, and ATP13A2 genes an autosomal recessive forms of Parkinson's disease. Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1cde126e-51bf-4a08-9d09-67946bc6840e NodeType: Group Notes: Mutations in UCHL1, PARK2, SNCA, and LRRK2 genes cause an autosomal dominant and in PARK7, PINK1, and ATP13A2 genes an autosomal recessive forms of Parkinson's disease. Organ: brain Organ_System: nervous system Source: Diseases urn:agi-group:uuid-1cde126e-51bf-4a08-9d09-67946bc6840e Genes with Mutations Associated with Parkinson's Disease uuid-1cde126e-51bf-4a08-9d09-67946bc6840e PS:Description Mutations in UCHL1, PARK2, SNCA, and LRRK2 genes cause an autosomal dominant and in PARK7, PINK1, and ATP13A2 genes an autosomal recessive forms of Parkinson's disease. Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1cde126e-51bf-4a08-9d09-67946bc6840e PS:NodeType Group PS:Notes Mutations in UCHL1, PARK2, SNCA, and LRRK2 genes cause an autosomal dominant and in PARK7, PINK1, and ATP13A2 genes an autosomal recessive forms of Parkinson's disease. PS:Organ brain PS:Organ_System nervous system PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1d7f6fe9-f3c8-4ad8-ad99-04df02ac0e0c NodeType: Group Organ_System: endocrine system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-1d7f6fe9-f3c8-4ad8-ad99-04df02ac0e0c Genes with Mutations Associated with Obesity uuid-1d7f6fe9-f3c8-4ad8-ad99-04df02ac0e0c PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1d7f6fe9-f3c8-4ad8-ad99-04df02ac0e0c PS:NodeType Group PS:Organ_System endocrine system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: neuron Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1f6528b8-c42c-494c-8f35-4620fdcfe28e NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-1f6528b8-c42c-494c-8f35-4620fdcfe28e Genes Associated with Mental Retardation and Brain Malformations in Epilepsy uuid-1f6528b8-c42c-494c-8f35-4620fdcfe28e PS:CellType neuron PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1f6528b8-c42c-494c-8f35-4620fdcfe28e PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1f72f79d-b4d4-455f-a00d-6cc074070303 NodeType: Group Organ: ovary Organ_System: reproductive system Source: Diseases urn:agi-group:uuid-1f72f79d-b4d4-455f-a00d-6cc074070303 Genes with Mutations Associated with Polycystic Ovary Syndrome uuid-1f72f79d-b4d4-455f-a00d-6cc074070303 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-1f72f79d-b4d4-455f-a00d-6cc074070303 PS:NodeType Group PS:Organ ovary PS:Organ_System reproductive system PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-209a58ee-6b49-48ac-a3c1-7896ac3bed4f NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-209a58ee-6b49-48ac-a3c1-7896ac3bed4f Genes Associated with Ulcerative Colitis uuid-209a58ee-6b49-48ac-a3c1-7896ac3bed4f PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-209a58ee-6b49-48ac-a3c1-7896ac3bed4f PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: cancer cell CellType: lymphocyte Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-24233e55-323d-4048-8669-0d4d1483aacf NodeType: Group Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-24233e55-323d-4048-8669-0d4d1483aacf Genes Frequently Hypermethylated in Follicular Lymphoma uuid-24233e55-323d-4048-8669-0d4d1483aacf PS:CellType cancer cell PS:CellType lymphocyte PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-24233e55-323d-4048-8669-0d4d1483aacf PS:NodeType Group PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-24cda4fa-6705-4292-88ed-91acbc9758d7 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-24cda4fa-6705-4292-88ed-91acbc9758d7 Genes with Mutations Associated with Splenic Marginal Zone Lymphoma uuid-24cda4fa-6705-4292-88ed-91acbc9758d7 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-24cda4fa-6705-4292-88ed-91acbc9758d7 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2861aa57-a3e7-4869-8ecf-46403643d127 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-2861aa57-a3e7-4869-8ecf-46403643d127 Genes Hypermethylated in Medulloblastoma uuid-2861aa57-a3e7-4869-8ecf-46403643d127 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2861aa57-a3e7-4869-8ecf-46403643d127 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2dcab306-fc6a-4294-a25f-0e3f3738bbd4 NodeType: Group Organ: oncogenic Organ_System: oncogenic PMID: 23073633 PMID: 24493750 PMID: 25445667 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-group:uuid-2dcab306-fc6a-4294-a25f-0e3f3738bbd4 Ion Channels and Aquaporins Involved in Cancer Cell Migration uuid-2dcab306-fc6a-4294-a25f-0e3f3738bbd4 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Group is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2dcab306-fc6a-4294-a25f-0e3f3738bbd4 PS:NodeType Group PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 23073633 PS:PMID 24493750 PS:PMID 25445667 PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2fa78d8d-1e3e-4c48-907e-98f2a593fed9 NodeType: Group Organ_System: lymphatic system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-group:uuid-2fa78d8d-1e3e-4c48-907e-98f2a593fed9 Alternative End Joining Regulation uuid-2fa78d8d-1e3e-4c48-907e-98f2a593fed9 PS:CellType B-cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-2fa78d8d-1e3e-4c48-907e-98f2a593fed9 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3288e530-1b9d-4c0a-9cfb-26e04877020e NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-3288e530-1b9d-4c0a-9cfb-26e04877020e Genes with Mutations Associated with Retinitis Pigmentosa uuid-3288e530-1b9d-4c0a-9cfb-26e04877020e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3288e530-1b9d-4c0a-9cfb-26e04877020e PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3341c7ab-cb84-473c-9175-1f748780837b NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-3341c7ab-cb84-473c-9175-1f748780837b Genes with Mutations Associated with Lamellar Ichthyosis uuid-3341c7ab-cb84-473c-9175-1f748780837b PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3341c7ab-cb84-473c-9175-1f748780837b PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3486006a-b4d3-4bcc-8074-7045f63e20d7 NodeType: Group Organ: ovary Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-3486006a-b4d3-4bcc-8074-7045f63e20d7 Genes with Mutations Associated with Primary Ovarian Insufficiency uuid-3486006a-b4d3-4bcc-8074-7045f63e20d7 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3486006a-b4d3-4bcc-8074-7045f63e20d7 PS:NodeType Group PS:Organ ovary PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-34c7027d-0fd9-46d9-ac54-aa9d029ff58b NodeType: Group Organ_System: nervous system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-34c7027d-0fd9-46d9-ac54-aa9d029ff58b Proteins Involved in Cowden Syndrome uuid-34c7027d-0fd9-46d9-ac54-aa9d029ff58b PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-34c7027d-0fd9-46d9-ac54-aa9d029ff58b PS:NodeType Group PS:Organ_System nervous system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-34df31b9-01d1-4ea7-814d-c83fce330239 NodeType: Group Organ: oncogenic Organ_System: oncogenic PMID: 20457567 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-group:uuid-34df31b9-01d1-4ea7-814d-c83fce330239 Cadherins Involved in Cancer Invasion and Metastasis uuid-34df31b9-01d1-4ea7-814d-c83fce330239 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Group is built manually using published studies. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-384ff60e-12d0-4464-9530-b0c82332e627 PS:NodeType Group PS:Organ joint PS:Organ kidney PS:Organ_System skeletal system PS:Organ_System urinary tract PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-387416e5-15a1-416b-afbe-35c42c70428d NodeType: Group Organ: kidney Organ_System: urinary tract Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-387416e5-15a1-416b-afbe-35c42c70428d Genes with Mutations Associated with Glomerulonephritis and Nephrotic Syndrome uuid-387416e5-15a1-416b-afbe-35c42c70428d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-387416e5-15a1-416b-afbe-35c42c70428d PS:NodeType Group PS:Organ kidney PS:Organ_System urinary tract PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-398a706d-2612-4733-ae9c-c172a6944494 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-398a706d-2612-4733-ae9c-c172a6944494 Genes with Mutations Associated with Glioma uuid-398a706d-2612-4733-ae9c-c172a6944494 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-398a706d-2612-4733-ae9c-c172a6944494 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3a5e8b68-c718-4c49-855c-0bcfbe03c989 NodeType: Group Organ: pancreas Organ_System: digestive system Organ_System: endocrine system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-3a5e8b68-c718-4c49-855c-0bcfbe03c989 Genes with Mutations Associated with Pancreatic Cancer uuid-3a5e8b68-c718-4c49-855c-0bcfbe03c989 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3a5e8b68-c718-4c49-855c-0bcfbe03c989 PS:NodeType Group PS:Organ pancreas PS:Organ_System digestive system PS:Organ_System endocrine system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3fae68aa-98df-4872-bc3a-054cc47bfee2 NodeType: Group Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-group:uuid-3fae68aa-98df-4872-bc3a-054cc47bfee2 COVID19 complications uuid-3fae68aa-98df-4872-bc3a-054cc47bfee2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-3fae68aa-98df-4872-bc3a-054cc47bfee2 PS:NodeType Group PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-442b7310-29cb-4857-84ca-70457e24e852 NodeType: Group Organ: ear Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-442b7310-29cb-4857-84ca-70457e24e852 Genes with Mutations Associated with Hereditary Hearing Loss, Nonsyndromic, X-Linked uuid-442b7310-29cb-4857-84ca-70457e24e852 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-442b7310-29cb-4857-84ca-70457e24e852 PS:NodeType Group PS:Organ ear PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-44798114-2342-4bec-b645-9586246c3223 NodeType: Group Organ: pancreas Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-44798114-2342-4bec-b645-9586246c3223 Genes with Mutations Associated with Neonatal Diabetes Mellitus uuid-44798114-2342-4bec-b645-9586246c3223 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-44798114-2342-4bec-b645-9586246c3223 PS:NodeType Group PS:Organ pancreas PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell CellType: lymphoblast Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-44ab904c-44d5-42f6-a3bf-74925b034b77 NodeType: Group Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-44ab904c-44d5-42f6-a3bf-74925b034b77 Proteins Involved in B-Cell Acute Lymphoblastic Leukemia uuid-44ab904c-44d5-42f6-a3bf-74925b034b77 PS:CellType B-cell PS:CellType cancer cell PS:CellType lymphoblast PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-44ab904c-44d5-42f6-a3bf-74925b034b77 PS:NodeType Group PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-46c69da0-cd87-42c6-8bf0-0c95235ccaeb NodeType: Group Organ_System: lymphatic system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-group:uuid-46c69da0-cd87-42c6-8bf0-0c95235ccaeb Immunoglobulin Class-Switch Recombination Regulation uuid-46c69da0-cd87-42c6-8bf0-0c95235ccaeb PS:CellType B-cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-46c69da0-cd87-42c6-8bf0-0c95235ccaeb PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-48d810e9-8801-4ce7-8b2f-8eb026005c45 NodeType: Group Organ: kidney Organ_System: urinary tract Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-48d810e9-8801-4ce7-8b2f-8eb026005c45 Proteins under Expressed in Pyelonephritis uuid-48d810e9-8801-4ce7-8b2f-8eb026005c45 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-48d810e9-8801-4ce7-8b2f-8eb026005c45 PS:NodeType Group PS:Organ kidney PS:Organ_System urinary tract PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-48ecb602-c641-413e-97bc-8e14604d6728 NodeType: Group Organ: Parathyroid gland Organ_System: endocrine system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-48ecb602-c641-413e-97bc-8e14604d6728 Genes with Mutations Associated with Hypoparathyroidism uuid-48ecb602-c641-413e-97bc-8e14604d6728 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-48ecb602-c641-413e-97bc-8e14604d6728 PS:NodeType Group PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-4a957e47-2f90-4281-b794-dd12c2bf8818 NodeType: Group Organ: prostate Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-4a957e47-2f90-4281-b794-dd12c2bf8818 Genes with Mutations Associated with Prostate Cancer uuid-4a957e47-2f90-4281-b794-dd12c2bf8818 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-4a957e47-2f90-4281-b794-dd12c2bf8818 PS:NodeType Group PS:Organ prostate PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-4c76569d-bacc-4aac-88bc-06eef6c9f369 NodeType: Group Organ: pancreas Organ_System: endocrine system Source: Diseases urn:agi-group:uuid-4c76569d-bacc-4aac-88bc-06eef6c9f369 Genes with Mutations Associated with Maturity Onset Diabetes of the Young (MODY) uuid-4c76569d-bacc-4aac-88bc-06eef6c9f369 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-4c76569d-bacc-4aac-88bc-06eef6c9f369 PS:NodeType Group PS:Organ pancreas PS:Organ_System endocrine system PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-50bd61b9-49eb-4e2a-b365-32e6474587e9 NodeType: Group Organ: ear Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-50bd61b9-49eb-4e2a-b365-32e6474587e9 Genes with Mutations Associated with Hereditary Hearing Loss, Nonsyndromic, Autosomal Dominant uuid-50bd61b9-49eb-4e2a-b365-32e6474587e9 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-50bd61b9-49eb-4e2a-b365-32e6474587e9 PS:NodeType Group PS:Organ ear PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5410beee-3603-4c43-b9c6-0e24658d4183 NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-5410beee-3603-4c43-b9c6-0e24658d4183 Genes with Mutations Associated with Ulcerative Colitis uuid-5410beee-3603-4c43-b9c6-0e24658d4183 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5410beee-3603-4c43-b9c6-0e24658d4183 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-55cf9b49-dd8a-4861-a6c5-3623abcb9b85 NodeType: Group Organ: blood vessel Organ_System: cardiovascular system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-55cf9b49-dd8a-4861-a6c5-3623abcb9b85 Genes with Mutations Associated with Atherosclerosis uuid-55cf9b49-dd8a-4861-a6c5-3623abcb9b85 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-55cf9b49-dd8a-4861-a6c5-3623abcb9b85 PS:NodeType Group PS:Organ blood vessel PS:Organ_System cardiovascular system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-56a0ccd6-16b8-4dba-8971-86856159ca08 NodeType: Group Organ: bronchus Organ: lung Organ_System: respiratory system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-56a0ccd6-16b8-4dba-8971-86856159ca08 Genes with Mutations in GWA Studies of Asthma uuid-56a0ccd6-16b8-4dba-8971-86856159ca08 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-56a0ccd6-16b8-4dba-8971-86856159ca08 PS:NodeType Group PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: epithelial cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-579622f6-8f2e-441d-a90c-997fc3b0804b NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-579622f6-8f2e-441d-a90c-997fc3b0804b Proteins and Lipids of Drusen Associated with Age-Related Macular Degeneration uuid-579622f6-8f2e-441d-a90c-997fc3b0804b PS:CellType epithelial cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-579622f6-8f2e-441d-a90c-997fc3b0804b PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-58a67d27-373e-4e7e-81e7-dca2b60f16f0 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-58a67d27-373e-4e7e-81e7-dca2b60f16f0 Genes with Mutations Associated with Mantle Cell Lymphoma uuid-58a67d27-373e-4e7e-81e7-dca2b60f16f0 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-58a67d27-373e-4e7e-81e7-dca2b60f16f0 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-58d66930-173b-45ec-86c6-df8e4c30a04f NodeType: Group Organ: bone Organ: joint Organ_System: skeletal system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-58d66930-173b-45ec-86c6-df8e4c30a04f Genes with Mutations Associated with Psoriatic Arthritis uuid-58d66930-173b-45ec-86c6-df8e4c30a04f PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-58d66930-173b-45ec-86c6-df8e4c30a04f PS:NodeType Group PS:Organ bone PS:Organ joint PS:Organ_System skeletal system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5a51ba70-33b2-4170-bf67-9f7309c995f3 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-5a51ba70-33b2-4170-bf67-9f7309c995f3 Genes with Mutations Associated with Follicular Lymphoma uuid-5a51ba70-33b2-4170-bf67-9f7309c995f3 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5a51ba70-33b2-4170-bf67-9f7309c995f3 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: generic Description: From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5c2a4c73-255b-45cf-93a3-3e45235e0917 NodeType: Group Organ: generic Organ_System: generic Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-group:uuid-5c2a4c73-255b-45cf-93a3-3e45235e0917 Genes with Mutations Associated with Human Longevity uuid-5c2a4c73-255b-45cf-93a3-3e45235e0917 PS:CellType generic PS:Description From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5c2a4c73-255b-45cf-93a3-3e45235e0917 PS:NodeType Group PS:Organ generic PS:Organ_System generic PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5d3b7f4d-6a82-43ae-96a1-76a6dd6da5ff NodeType: Group Organ: Tooth Organ_System: digestive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-5d3b7f4d-6a82-43ae-96a1-76a6dd6da5ff Genes with Mutations Associated with Hereditary Syndromes with Abnormalities of Size, Shape and Number of Teeth uuid-5d3b7f4d-6a82-43ae-96a1-76a6dd6da5ff PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5d3b7f4d-6a82-43ae-96a1-76a6dd6da5ff PS:NodeType Group PS:Organ Tooth PS:Organ_System digestive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5d4fdc91-f692-4de5-9dcb-8f4f7471cecc NodeType: Group Organ: Parathyroid gland Organ_System: endocrine system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-5d4fdc91-f692-4de5-9dcb-8f4f7471cecc Genes with Mutations Associated with Hypogonadotropic Hypogonadism (Including Kallmann Syndrome) uuid-5d4fdc91-f692-4de5-9dcb-8f4f7471cecc PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5d4fdc91-f692-4de5-9dcb-8f4f7471cecc PS:NodeType Group PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5db0eb02-078d-4667-822c-5ec24758b729 NodeType: Group Organ: heart Organ_System: cardiovascular system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-5db0eb02-078d-4667-822c-5ec24758b729 Genes with Mutations Associated with Myocarditis uuid-5db0eb02-078d-4667-822c-5ec24758b729 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5db0eb02-078d-4667-822c-5ec24758b729 PS:NodeType Group PS:Organ heart PS:Organ_System cardiovascular system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5dea1e48-3f45-4d5b-aebb-b1b8d1a4a5aa NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-5dea1e48-3f45-4d5b-aebb-b1b8d1a4a5aa Genes with Mutations Associated with Primary Glioblastoma uuid-5dea1e48-3f45-4d5b-aebb-b1b8d1a4a5aa PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-5dea1e48-3f45-4d5b-aebb-b1b8d1a4a5aa PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-60750c20-2584-4736-8934-f8faa2b4dfb4 NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-60750c20-2584-4736-8934-f8faa2b4dfb4 Genes with Mutations Associated with Usher Syndrome and Retinitis Pigmentosa uuid-60750c20-2584-4736-8934-f8faa2b4dfb4 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-60750c20-2584-4736-8934-f8faa2b4dfb4 PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-611779f8-b05e-483c-9b5e-1c4b4e00baa4 NodeType: Group Organ_System: hematological system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-611779f8-b05e-483c-9b5e-1c4b4e00baa4 Genes with Mutations Associated with HIV Type 1 Infection Resistance uuid-611779f8-b05e-483c-9b5e-1c4b4e00baa4 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-611779f8-b05e-483c-9b5e-1c4b4e00baa4 PS:NodeType Group PS:Organ_System hematological system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-62c1b54e-0157-42f1-bf24-4fd0ed78d8ff NodeType: Group Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-62c1b54e-0157-42f1-bf24-4fd0ed78d8ff Genes with Mutations Associated with Phenylketonuria uuid-62c1b54e-0157-42f1-bf24-4fd0ed78d8ff PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-62c1b54e-0157-42f1-bf24-4fd0ed78d8ff PS:NodeType Group PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-63714ad6-11e0-4629-9cb2-7bf2ab578041 NodeType: Group Organ: blood vessel Organ_System: cardiovascular system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-63714ad6-11e0-4629-9cb2-7bf2ab578041 Genes with Mutations Associated with Familial and Idiopathic Pulmonary Arterial Hypertension uuid-63714ad6-11e0-4629-9cb2-7bf2ab578041 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-63714ad6-11e0-4629-9cb2-7bf2ab578041 PS:NodeType Group PS:Organ blood vessel PS:Organ_System cardiovascular system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell CellType: lymphocyte Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6386d28e-b54b-413d-a4f7-a9f71f17af3c NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-6386d28e-b54b-413d-a4f7-a9f71f17af3c Genes Frequently Hypomethylated in Mantle Cell Lymphoma (Epigenetic Changes) uuid-6386d28e-b54b-413d-a4f7-a9f71f17af3c PS:CellType cancer cell PS:CellType lymphocyte PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6386d28e-b54b-413d-a4f7-a9f71f17af3c PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-63a89c29-405d-437d-a115-65ad5e2e7cbf NodeType: Group Organ: pancreas Organ_System: digestive system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-63a89c29-405d-437d-a115-65ad5e2e7cbf Genes Highly-Expressed on Surface of Human Primary beta-Cell According to PMID:22460761 uuid-63a89c29-405d-437d-a115-65ad5e2e7cbf PS:CellType insulin-secreting cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-63a89c29-405d-437d-a115-65ad5e2e7cbf PS:NodeType Group PS:Organ pancreas PS:Organ_System digestive system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6447c72b-1028-49d1-9950-4c181f77c730 NodeType: Group Organ: colon Organ: intestine Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-6447c72b-1028-49d1-9950-4c181f77c730 Genes with Mutations Associated with Acute Myeloid Leukemia uuid-6447c72b-1028-49d1-9950-4c181f77c730 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6447c72b-1028-49d1-9950-4c181f77c730 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-65f82eb6-a718-42f9-9f16-85be8a35783d NodeType: Group Organ: brain Organ: pituitary gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-65f82eb6-a718-42f9-9f16-85be8a35783d Proteins Involved in Hypopituitarism uuid-65f82eb6-a718-42f9-9f16-85be8a35783d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-65f82eb6-a718-42f9-9f16-85be8a35783d PS:NodeType Group PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:Pathway_Author PS:Source Description: Mutations in CD40LG, XHIGM, CD40, UNG genes. Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-68239d7d-904c-429a-8dc5-7f30c62ab78f NodeType: Group Notes: Mutations of the CD40LG gene. T cells cannot tell B cells to switch classes. X-linked (XHIGM). Mutations of the AICDA gene. B cells cannot recombine genetic material to change heavy chain production, which is a required step in switching classes. Mutations of the CD40 gene. B cells cannot receive the signal from T cells to switch classes. Mutations of the UNG gene. It does not impair Somatic Hypermutation. Mutations in NEMO cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Organ_System: hematological system Organ_System: lymphatic system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-group:uuid-68239d7d-904c-429a-8dc5-7f30c62ab78f Genes with Mutations Associated with Hyper IgM Syndrome uuid-68239d7d-904c-429a-8dc5-7f30c62ab78f PS:Description Mutations in CD40LG, XHIGM, CD40, UNG genes. Group is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-68239d7d-904c-429a-8dc5-7f30c62ab78f PS:NodeType Group PS:Notes Mutations of the CD40LG gene. T cells cannot tell B cells to switch classes. X-linked (XHIGM). Mutations of the AICDA gene. B cells cannot recombine genetic material to change heavy chain production, which is a required step in switching classes. Mutations of the CD40 gene. B cells cannot receive the signal from T cells to switch classes. Mutations of the UNG gene. It does not impair Somatic Hypermutation. Mutations in NEMO cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). PS:Organ_System hematological system PS:Organ_System lymphatic system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-695eeb03-13d7-48c5-a9de-d6f85791c9a5 NodeType: Group Organ: kidney Organ_System: urinary tract Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-695eeb03-13d7-48c5-a9de-d6f85791c9a5 Genes with Mutations Associated with Cystic Kidney Disease uuid-695eeb03-13d7-48c5-a9de-d6f85791c9a5 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-695eeb03-13d7-48c5-a9de-d6f85791c9a5 PS:NodeType Group PS:Organ kidney PS:Organ_System urinary tract PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6f566f81-fb4c-4a6d-8a19-2608cfb85a8e NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-6f566f81-fb4c-4a6d-8a19-2608cfb85a8e Genes Hypermethylated in Glioma uuid-6f566f81-fb4c-4a6d-8a19-2608cfb85a8e PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6f566f81-fb4c-4a6d-8a19-2608cfb85a8e PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6ff490a8-1a75-426a-befe-e79ad7d10933 NodeType: Group Organ_System: hematological system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-6ff490a8-1a75-426a-befe-e79ad7d10933 MicroRNA Involved in Systemic Lupus Erythematosus uuid-6ff490a8-1a75-426a-befe-e79ad7d10933 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-6ff490a8-1a75-426a-befe-e79ad7d10933 PS:NodeType Group PS:Organ_System hematological system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-747bebd7-71c8-4cfd-9c58-3b2ed6690e8e NodeType: Group Organ_System: musculoskeletal system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-group:uuid-747bebd7-71c8-4cfd-9c58-3b2ed6690e8e Gene with Mutations Assosiated with Muscular Dystrophy, Facioscapulohumeral uuid-747bebd7-71c8-4cfd-9c58-3b2ed6690e8e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-747bebd7-71c8-4cfd-9c58-3b2ed6690e8e PS:NodeType Group PS:Organ_System musculoskeletal system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: neuron Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-77276298-9ffe-4c5e-8091-571016c33ef2 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-77276298-9ffe-4c5e-8091-571016c33ef2 Genes Associated with in Epileptic Encephalopathies uuid-77276298-9ffe-4c5e-8091-571016c33ef2 PS:CellType neuron PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-77276298-9ffe-4c5e-8091-571016c33ef2 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-78021817-2c03-4bdf-99c3-05b4076e1e76 NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-78021817-2c03-4bdf-99c3-05b4076e1e76 Genes with Mutations Associated with Inflammatory Bowel Diseases uuid-78021817-2c03-4bdf-99c3-05b4076e1e76 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-78021817-2c03-4bdf-99c3-05b4076e1e76 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-785c156c-c924-4ca4-9960-e5c61f3b839e NodeType: Group Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-785c156c-c924-4ca4-9960-e5c61f3b839e Genes with Mutations Associated with Graves Disease uuid-785c156c-c924-4ca4-9960-e5c61f3b839e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-785c156c-c924-4ca4-9960-e5c61f3b839e PS:NodeType Group PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7b9eb945-5d39-4092-8c4b-fe87bb5cf9b9 NodeType: Group Organ_System: nervous system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-7b9eb945-5d39-4092-8c4b-fe87bb5cf9b9 Proteins Involved in Li-Fraumeni Syndrome uuid-7b9eb945-5d39-4092-8c4b-fe87bb5cf9b9 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7b9eb945-5d39-4092-8c4b-fe87bb5cf9b9 PS:NodeType Group PS:Organ_System nervous system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7bae5ebb-84d3-482d-9622-40511456aeec NodeType: Group Organ: blood vessel Organ_System: cardiovascular system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-7bae5ebb-84d3-482d-9622-40511456aeec Genes with Mutations Associated with Arterial Hypertension uuid-7bae5ebb-84d3-482d-9622-40511456aeec PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7bae5ebb-84d3-482d-9622-40511456aeec PS:NodeType Group PS:Organ blood vessel PS:Organ_System cardiovascular system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: generic Description: From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7cb85e70-5cb2-4abb-8f36-55d85c24ded0 NodeType: Group Organ: generic Organ_System: generic Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-group:uuid-7cb85e70-5cb2-4abb-8f36-55d85c24ded0 Genes with Mutations Associated with Ageing (non-Mammalian Animal Model) uuid-7cb85e70-5cb2-4abb-8f36-55d85c24ded0 PS:CellType generic PS:Description From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7cb85e70-5cb2-4abb-8f36-55d85c24ded0 PS:NodeType Group PS:Organ generic PS:Organ_System generic PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: neuron Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7f9cf644-f33a-44f9-b751-9ed836b25ae7 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-7f9cf644-f33a-44f9-b751-9ed836b25ae7 Genes Associated with Syndromic Epilepsy uuid-7f9cf644-f33a-44f9-b751-9ed836b25ae7 PS:CellType neuron PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-7f9cf644-f33a-44f9-b751-9ed836b25ae7 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-80d8a2b9-0eee-423e-ae01-a553325c652d NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-80d8a2b9-0eee-423e-ae01-a553325c652d Genes with Mutations Associated with Hodgkin Lymphoma uuid-80d8a2b9-0eee-423e-ae01-a553325c652d PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-80d8a2b9-0eee-423e-ae01-a553325c652d PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-847c8076-4101-430c-beb3-c7249d2725fd NodeType: Group Organ: bronchus Organ: lung Organ_System: respiratory system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-847c8076-4101-430c-beb3-c7249d2725fd Genes with Mutations in Linkage Studies and Positional Cloning Associated with Asthma uuid-847c8076-4101-430c-beb3-c7249d2725fd PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-847c8076-4101-430c-beb3-c7249d2725fd PS:NodeType Group PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: neuron Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-854159fd-f760-433e-b704-d6490973273d NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-854159fd-f760-433e-b704-d6490973273d Genes Associated with Inherited Errors of Metabolism in Epilepsy uuid-854159fd-f760-433e-b704-d6490973273d PS:CellType neuron PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-854159fd-f760-433e-b704-d6490973273d PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-85567a80-1a11-44d1-841d-0bbae477ae33 NodeType: Group Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-85567a80-1a11-44d1-841d-0bbae477ae33 Genes with Mutations Associated with Diffuse Large-B-Cell Lymphoma, ABC Subtype uuid-85567a80-1a11-44d1-841d-0bbae477ae33 PS:CellType B-cell PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-85567a80-1a11-44d1-841d-0bbae477ae33 PS:NodeType Group PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-895ac203-239c-482a-b2fa-09642f24a959 NodeType: Group Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-895ac203-239c-482a-b2fa-09642f24a959 Genes with Mutations Associated with Diffuse Large-B-Cell Lymphoma, PMBL Subtype uuid-895ac203-239c-482a-b2fa-09642f24a959 PS:CellType B-cell PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-895ac203-239c-482a-b2fa-09642f24a959 PS:NodeType Group PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-897d975f-2866-4c63-ad85-b13bbd22b694 NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-897d975f-2866-4c63-ad85-b13bbd22b694 Genes with Mutations Associated with Atopic Dermatitis uuid-897d975f-2866-4c63-ad85-b13bbd22b694 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-897d975f-2866-4c63-ad85-b13bbd22b694 PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8d7cc5e3-d1b9-4b5b-b532-66c7ab1cd886 NodeType: Group Organ: uterus Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-8d7cc5e3-d1b9-4b5b-b532-66c7ab1cd886 Genes with Mutations Associated with Endometriosis uuid-8d7cc5e3-d1b9-4b5b-b532-66c7ab1cd886 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8d7cc5e3-d1b9-4b5b-b532-66c7ab1cd886 PS:NodeType Group PS:Organ uterus PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8d9dd998-cef1-45be-ad8c-d488caeb121a NodeType: Group Organ_System: hematological system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-8d9dd998-cef1-45be-ad8c-d488caeb121a Genes with Mutations Associated with Chronic Myeloid Leukemia uuid-8d9dd998-cef1-45be-ad8c-d488caeb121a PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8d9dd998-cef1-45be-ad8c-d488caeb121a PS:NodeType Group PS:Organ_System hematological system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8ea540e9-095b-4e93-b9e8-61b7ece5b2bd NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-8ea540e9-095b-4e93-b9e8-61b7ece5b2bd Genes with Mutations Associated with Psoriasis uuid-8ea540e9-095b-4e93-b9e8-61b7ece5b2bd PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8ea540e9-095b-4e93-b9e8-61b7ece5b2bd PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8f3a22f4-acad-4e26-8e6e-ee665f2145b7 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-group:uuid-8f3a22f4-acad-4e26-8e6e-ee665f2145b7 Genes with Mutations Associated with Multiple Sclerosis uuid-8f3a22f4-acad-4e26-8e6e-ee665f2145b7 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-8f3a22f4-acad-4e26-8e6e-ee665f2145b7 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-919762fa-b63f-4df8-b576-0813cc77b52f NodeType: Group Organ: eye Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-919762fa-b63f-4df8-b576-0813cc77b52f Genes with Mutations Associated with Bardet-Biedl Syndrome and Retinitis Pigmentosa uuid-919762fa-b63f-4df8-b576-0813cc77b52f PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-919762fa-b63f-4df8-b576-0813cc77b52f PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-91c7327a-0d48-4d3b-95ad-fc44cc3a750e NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-91c7327a-0d48-4d3b-95ad-fc44cc3a750e Genes with Mutations Associated with Melanoma uuid-91c7327a-0d48-4d3b-95ad-fc44cc3a750e PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-91c7327a-0d48-4d3b-95ad-fc44cc3a750e PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9889f9f5-f997-460f-a6b2-a262684b5a6d NodeType: Group Organ: eye Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-9889f9f5-f997-460f-a6b2-a262684b5a6d Genes with Mutations Associated with Graves Ophthalmopathy uuid-9889f9f5-f997-460f-a6b2-a262684b5a6d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9889f9f5-f997-460f-a6b2-a262684b5a6d PS:NodeType Group PS:Organ eye PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-99b4a66f-2aba-4274-bbb6-0010954f5ec0 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-99b4a66f-2aba-4274-bbb6-0010954f5ec0 Genes with Mutations Associated with Neuroblastoma uuid-99b4a66f-2aba-4274-bbb6-0010954f5ec0 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-99b4a66f-2aba-4274-bbb6-0010954f5ec0 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-99f7f578-19e7-4f27-88cf-588374a429a2 NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-99f7f578-19e7-4f27-88cf-588374a429a2 Genes with Mutations Associated with Peutz-Jeghers Syndrome uuid-99f7f578-19e7-4f27-88cf-588374a429a2 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-99f7f578-19e7-4f27-88cf-588374a429a2 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9d30d0b1-2ae9-471a-b8ab-3ad725594e33 NodeType: Group Organ: testis Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-9d30d0b1-2ae9-471a-b8ab-3ad725594e33 Genes with Mutations Associated with Gonadal Dysgenesis uuid-9d30d0b1-2ae9-471a-b8ab-3ad725594e33 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9d30d0b1-2ae9-471a-b8ab-3ad725594e33 PS:NodeType Group PS:Organ testis PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9ea3c338-d506-4b4b-b7e9-cc6f9653d278 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-9ea3c338-d506-4b4b-b7e9-cc6f9653d278 Genes with Mutations Associated with Astrocytoma uuid-9ea3c338-d506-4b4b-b7e9-cc6f9653d278 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-9ea3c338-d506-4b4b-b7e9-cc6f9653d278 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a0432b8b-664f-412a-9a5d-1782107cca67 NodeType: Group Organ_System: hematological system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-a0432b8b-664f-412a-9a5d-1782107cca67 Genes Associated with Systemic Lupus Erythematosus uuid-a0432b8b-664f-412a-9a5d-1782107cca67 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a0432b8b-664f-412a-9a5d-1782107cca67 PS:NodeType Group PS:Organ_System hematological system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a08f4c65-3e81-4018-b058-601bc583939d NodeType: Group Organ_System: lymphatic system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-group:uuid-a08f4c65-3e81-4018-b058-601bc583939d V(D)J Recombination Regulation uuid-a08f4c65-3e81-4018-b058-601bc583939d PS:CellType B-cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a08f4c65-3e81-4018-b058-601bc583939d PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a1508305-8363-48df-b03c-eae547af5cec NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-a1508305-8363-48df-b03c-eae547af5cec Genes with Mutations Associated with Crohn's Disease uuid-a1508305-8363-48df-b03c-eae547af5cec PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a1508305-8363-48df-b03c-eae547af5cec PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a163ef0b-d931-4654-b4d0-0ca5642f3185 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-a163ef0b-d931-4654-b4d0-0ca5642f3185 Genes with Mutations Associated with B-Cell Chronic Lymphocytic Leukemia uuid-a163ef0b-d931-4654-b4d0-0ca5642f3185 PS:CellType B-cell PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a163ef0b-d931-4654-b4d0-0ca5642f3185 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a6b4b8f9-96cc-4125-b3ff-5f0e58811d99 NodeType: Group Organ_System: reproductive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-a6b4b8f9-96cc-4125-b3ff-5f0e58811d99 Genes with Mutations Associated with Cowden Syndrome uuid-a6b4b8f9-96cc-4125-b3ff-5f0e58811d99 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a6b4b8f9-96cc-4125-b3ff-5f0e58811d99 PS:NodeType Group PS:Organ_System reproductive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a859ec1c-1978-455a-896b-88aa679d0b34 NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-a859ec1c-1978-455a-896b-88aa679d0b34 Genes with Mutations Associated with Hirschsprung Disease uuid-a859ec1c-1978-455a-896b-88aa679d0b34 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a859ec1c-1978-455a-896b-88aa679d0b34 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a864899d-0fa6-4976-b55c-59c8859e1aa7 NodeType: Group Organ: eye Organ_System: sensory system Source: Diseases urn:agi-group:uuid-a864899d-0fa6-4976-b55c-59c8859e1aa7 Genes with Mutations Associated with Cataract uuid-a864899d-0fa6-4976-b55c-59c8859e1aa7 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a864899d-0fa6-4976-b55c-59c8859e1aa7 PS:NodeType Group PS:Organ eye PS:Organ_System sensory system PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: B-cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a8737853-e763-4259-a4da-be22b095e224 NodeType: Group Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-a8737853-e763-4259-a4da-be22b095e224 Genes with Mutations Associated with Diabetes Mellitus Type 1 uuid-a8737853-e763-4259-a4da-be22b095e224 PS:CellType B-cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-a8737853-e763-4259-a4da-be22b095e224 PS:NodeType Group PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Group is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-aa648fd4-ac95-4033-8f13-8b884704cb3b NodeType: Group Organ: oncogenic Organ_System: oncogenic PMID: 21779009 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-group:uuid-aa648fd4-ac95-4033-8f13-8b884704cb3b Chemokines, Growth Factors and Receptors Involved in Cancer Cells Chemotaxis uuid-aa648fd4-ac95-4033-8f13-8b884704cb3b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Group is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-aa648fd4-ac95-4033-8f13-8b884704cb3b PS:NodeType Group PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21779009 PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ab6fbe06-f998-44ff-ab83-d384e24b0549 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-ab6fbe06-f998-44ff-ab83-d384e24b0549 Genes with Mutations Associated with Mucosa Lymphoid Tissue (MALT) Lymphoma uuid-ab6fbe06-f998-44ff-ab83-d384e24b0549 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ab6fbe06-f998-44ff-ab83-d384e24b0549 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ab9457c8-52d5-4c94-a0d1-565074042218 NodeType: Group Organ: pancreas Organ_System: digestive system PMID: 21912665 Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-ab9457c8-52d5-4c94-a0d1-565074042218 Genomic Human beta-Cell Selective Markers uuid-ab9457c8-52d5-4c94-a0d1-565074042218 PS:CellType insulin-secreting cell PS:Description From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Group is built using manually curated ResNet data. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ad57895b-5624-46b3-9d9d-27634abfda23 PS:NodeType Group PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ad7a7424-3b1f-41aa-a8be-aa5caaee2a2d NodeType: Group Organ: Parathyroid gland Organ_System: endocrine system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-ad7a7424-3b1f-41aa-a8be-aa5caaee2a2d Genes with Mutations Associated with Hyperparathyroidism uuid-ad7a7424-3b1f-41aa-a8be-aa5caaee2a2d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ad7a7424-3b1f-41aa-a8be-aa5caaee2a2d PS:NodeType Group PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-b1deccab-779c-481d-89b3-9db346cb007c NodeType: Group Organ_System: hematological system Organ_System: lymphatic system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-b1deccab-779c-481d-89b3-9db346cb007c Genes with Mutations Associated with Systemic Scleroderma uuid-b1deccab-779c-481d-89b3-9db346cb007c PS:Description Group is built using manually curated ResNet data. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-bd3f339d-e0b5-45ca-8cd6-4b16ec0ac9cc PS:NodeType Group PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-c267dc4c-f266-48d3-92ef-4f848ece322a NodeType: Group Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-c267dc4c-f266-48d3-92ef-4f848ece322a Genes with Mutations Associated with Diffuse Large-B-Cell Lymphoma, GCB Subtype uuid-c267dc4c-f266-48d3-92ef-4f848ece322a PS:CellType B-cell PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-c5f067a2-64d6-405f-a290-b57dceab50e7 PS:NodeType Group PS:Organ breast PS:Organ ovary PS:Organ_System reproductive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-c7559416-d38b-4dc8-909e-c4a9e1d2c439 NodeType: Group Organ: ear Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-c7559416-d38b-4dc8-909e-c4a9e1d2c439 Genes with Mutations Associated with Hereditary Hearing Loss, Nonsyndromic, Autosomal Recessive uuid-c7559416-d38b-4dc8-909e-c4a9e1d2c439 PS:Description Group is built using manually curated ResNet data. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-c8f949e3-9d94-4897-a0b2-1e92f7b34484 PS:NodeType Group PS:Organ ear PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cac9a88d-7614-42dc-80ca-e8dc8019c06f NodeType: Group Organ: heart Organ_System: cardiovascular system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-cac9a88d-7614-42dc-80ca-e8dc8019c06f Genes with Mutations Associated with Dilated Cardiomyopathy uuid-cac9a88d-7614-42dc-80ca-e8dc8019c06f PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cac9a88d-7614-42dc-80ca-e8dc8019c06f PS:NodeType Group PS:Organ heart PS:Organ_System cardiovascular system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cd125883-4cea-4b2a-a3ed-e27b20cffa6d NodeType: Group Organ: ear Organ_System: sensory system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-cd125883-4cea-4b2a-a3ed-e27b20cffa6d Genes with Mutations Associated with Hereditary Hearing Loss, Syndromic uuid-cd125883-4cea-4b2a-a3ed-e27b20cffa6d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cd125883-4cea-4b2a-a3ed-e27b20cffa6d PS:NodeType Group PS:Organ ear PS:Organ_System sensory system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cd5b26c3-440b-4c6c-aa3a-8d69f3136c1d NodeType: Group Organ: bone Organ_System: skeletal system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-cd5b26c3-440b-4c6c-aa3a-8d69f3136c1d Genes with Mutations Associated with Osteopetrosis uuid-cd5b26c3-440b-4c6c-aa3a-8d69f3136c1d PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cd5b26c3-440b-4c6c-aa3a-8d69f3136c1d PS:NodeType Group PS:Organ bone PS:Organ_System skeletal system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cd9d081f-968c-473c-abc9-6b320bb31680 NodeType: Group Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-cd9d081f-968c-473c-abc9-6b320bb31680 Genes with Mutations Associated with Thyroid Dysgenesis and Hypothyroidism uuid-cd9d081f-968c-473c-abc9-6b320bb31680 PS:Description Group is built using manually curated ResNet data. 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PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ce52863a-bc7a-4cc5-af17-16ffd5a2f900 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cf081bff-6acd-4a67-b778-16cb275de78e NodeType: Group Organ_System: nervous system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-cf081bff-6acd-4a67-b778-16cb275de78e Proteins Involved in Mood Deviation Caused by Hypothyroidism uuid-cf081bff-6acd-4a67-b778-16cb275de78e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-cf081bff-6acd-4a67-b778-16cb275de78e PS:NodeType Group PS:Organ_System nervous system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d10f0406-3aa9-4d44-b6b4-aaf630f58c89 NodeType: Group Organ_System: endocrine system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-d10f0406-3aa9-4d44-b6b4-aaf630f58c89 Genes with Mutations Associated with Prolactinoma uuid-d10f0406-3aa9-4d44-b6b4-aaf630f58c89 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d10f0406-3aa9-4d44-b6b4-aaf630f58c89 PS:NodeType Group PS:Organ_System endocrine system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d2f2e59c-e903-4037-ba60-badac0868375 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-d2f2e59c-e903-4037-ba60-badac0868375 Genes with Mutations Associated with Secondary Glioblastoma uuid-d2f2e59c-e903-4037-ba60-badac0868375 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d2f2e59c-e903-4037-ba60-badac0868375 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d39e0971-8198-455f-8421-30f0d786bd0e NodeType: Group Organ: eye Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-d39e0971-8198-455f-8421-30f0d786bd0e Proteins Involved in Graves Ophthalmopathy uuid-d39e0971-8198-455f-8421-30f0d786bd0e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d39e0971-8198-455f-8421-30f0d786bd0e PS:NodeType Group PS:Organ eye PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: generic Description: From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d3b5beff-7453-4917-a4e7-1f90001ec4a5 NodeType: Group Organ: generic Organ_System: generic Pathway_Author: A. 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Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-d8eb78e4-2d66-4778-86e6-5abe45de38c6 Genes with Mutations Associated with Osteoartritis uuid-d8eb78e4-2d66-4778-86e6-5abe45de38c6 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-d8eb78e4-2d66-4778-86e6-5abe45de38c6 PS:NodeType Group PS:Organ bone PS:Organ_System skeletal system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Source CellType: neuron Description: Group is built using manually curated ResNet data. 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Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-dc23134c-8775-42ff-b666-2ac15c6d4d7a NodeType: Group Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-dc23134c-8775-42ff-b666-2ac15c6d4d7a Genes with Mutations Associated with Myasthenia Gravis uuid-dc23134c-8775-42ff-b666-2ac15c6d4d7a PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-dc23134c-8775-42ff-b666-2ac15c6d4d7a PS:NodeType Group PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Source Description: Group is built using manually curated ResNet data. 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Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-dcdf011c-6a85-4765-af84-7bb1136d7935 NodeType: Group Organ: colon Organ: intestine Organ_System: digestive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-dcdf011c-6a85-4765-af84-7bb1136d7935 Genes with Mutations Associated with Colorectal Cancer uuid-dcdf011c-6a85-4765-af84-7bb1136d7935 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-dcdf011c-6a85-4765-af84-7bb1136d7935 PS:NodeType Group PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-de4f7b73-bb83-4806-bb6b-837ae815071c NodeType: Group Organ: bone Organ_System: skeletal system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-de4f7b73-bb83-4806-bb6b-837ae815071c Genes with Mutations Assosiated with Rheumatoid Arthritis uuid-de4f7b73-bb83-4806-bb6b-837ae815071c PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-de4f7b73-bb83-4806-bb6b-837ae815071c PS:NodeType Group PS:Organ bone PS:Organ_System skeletal system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-de662a0d-11f5-4004-bc0c-456c33e8ab7e NodeType: Group Organ_System: nervous system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-de662a0d-11f5-4004-bc0c-456c33e8ab7e Genes with Mutations Associated with Li-Fraumeni Syndrome uuid-de662a0d-11f5-4004-bc0c-456c33e8ab7e PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-de662a0d-11f5-4004-bc0c-456c33e8ab7e PS:NodeType Group PS:Organ_System nervous system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e1241ec4-9519-4672-8c42-aca7c8618f47 NodeType: Group Organ: kidney Organ_System: urinary tract Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-e1241ec4-9519-4672-8c42-aca7c8618f47 Genes with Mutation Associated with Urolithiasis uuid-e1241ec4-9519-4672-8c42-aca7c8618f47 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e1241ec4-9519-4672-8c42-aca7c8618f47 PS:NodeType Group PS:Organ kidney PS:Organ_System urinary tract PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e5586f8d-55ad-4fab-aecc-98ac4d61eb1a NodeType: Group Organ_System: nervous system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-e5586f8d-55ad-4fab-aecc-98ac4d61eb1a Proteins Involved in Mental Retardation Caused by Hypothyroidism uuid-e5586f8d-55ad-4fab-aecc-98ac4d61eb1a PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e5586f8d-55ad-4fab-aecc-98ac4d61eb1a PS:NodeType Group PS:Organ_System nervous system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e578aedf-84fc-4c69-9241-0410e309cd60 NodeType: Group Organ: kidney Organ: lung Organ: skin Organ_System: respiratory system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-e578aedf-84fc-4c69-9241-0410e309cd60 Genes with Mutations Associated with Cystic Fibrosis uuid-e578aedf-84fc-4c69-9241-0410e309cd60 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-e578aedf-84fc-4c69-9241-0410e309cd60 PS:NodeType Group PS:Organ kidney PS:Organ lung PS:Organ skin PS:Organ_System respiratory system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. 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Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-eb81aa42-3180-4a64-b83d-c8a07eaffad2 NodeType: Group Organ: thyroid gland Organ_System: endocrine system Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-group:uuid-eb81aa42-3180-4a64-b83d-c8a07eaffad2 Proteins with Altered Function Involved in Hyperthyroidism uuid-eb81aa42-3180-4a64-b83d-c8a07eaffad2 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-eb81aa42-3180-4a64-b83d-c8a07eaffad2 PS:NodeType Group PS:Organ thyroid gland PS:Organ_System endocrine system PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ed75a7cd-7ebc-4a2b-b831-e0d57cda5d76 NodeType: Group Organ: testis Organ_System: reproductive system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-ed75a7cd-7ebc-4a2b-b831-e0d57cda5d76 Genes with Mutations Associated with Ambiguous Genitalia Development Or Sex Reversal uuid-ed75a7cd-7ebc-4a2b-b831-e0d57cda5d76 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ed75a7cd-7ebc-4a2b-b831-e0d57cda5d76 PS:NodeType Group PS:Organ testis PS:Organ_System reproductive system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ef5ebc8c-2dc5-48ee-989d-b6036a6a4c7d NodeType: Group Organ: ovary Organ_System: reproductive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-ef5ebc8c-2dc5-48ee-989d-b6036a6a4c7d Genes with Mutations Associated with Ovarian Cancer uuid-ef5ebc8c-2dc5-48ee-989d-b6036a6a4c7d PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ef5ebc8c-2dc5-48ee-989d-b6036a6a4c7d PS:NodeType Group PS:Organ ovary PS:Organ_System reproductive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f036dd14-c928-4dbd-9911-e8d2851d7d75 NodeType: Group Organ: heart Organ_System: cardiovascular system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-f036dd14-c928-4dbd-9911-e8d2851d7d75 Genes with Mutations Associated with Arrhythmogenic Right Ventricular Cardiomyopathy uuid-f036dd14-c928-4dbd-9911-e8d2851d7d75 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f036dd14-c928-4dbd-9911-e8d2851d7d75 PS:NodeType Group PS:Organ heart PS:Organ_System cardiovascular system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f20ee7a2-bfe1-4818-bb54-e0fba34eb9fa NodeType: Group Organ_System: cardiovascular system Organ_System: hematological system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-f20ee7a2-bfe1-4818-bb54-e0fba34eb9fa Genes with Mutations Associated with Hereditary Thrombophilia uuid-f20ee7a2-bfe1-4818-bb54-e0fba34eb9fa PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f20ee7a2-bfe1-4818-bb54-e0fba34eb9fa PS:NodeType Group PS:Organ_System cardiovascular system PS:Organ_System hematological system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f3bb68af-7936-49cb-a6c0-f1abbd6a11a7 NodeType: Group PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-group:uuid-f3bb68af-7936-49cb-a6c0-f1abbd6a11a7 ACPs uuid-f3bb68af-7936-49cb-a6c0-f1abbd6a11a7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f3bb68af-7936-49cb-a6c0-f1abbd6a11a7 PS:NodeType Group PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f424e564-a1c9-4054-91fd-d91e22e79517 NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-group:uuid-f424e564-a1c9-4054-91fd-d91e22e79517 Genes with Mutations Associated with Congenital Ichthyosiform Erythroderma uuid-f424e564-a1c9-4054-91fd-d91e22e79517 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f424e564-a1c9-4054-91fd-d91e22e79517 PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f53cf248-57df-4fcb-b28e-2eff97740c47 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-f53cf248-57df-4fcb-b28e-2eff97740c47 Genes with Mutations Associated with Medulloblastoma uuid-f53cf248-57df-4fcb-b28e-2eff97740c47 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f53cf248-57df-4fcb-b28e-2eff97740c47 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f6d332d1-71ab-48cd-acfc-9f2f53060465 NodeType: Group Organ_System: lymphatic system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-f6d332d1-71ab-48cd-acfc-9f2f53060465 Genes with Mutations Associated with T-Cell Acute Lymphoblastic Leukemia uuid-f6d332d1-71ab-48cd-acfc-9f2f53060465 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-f6d332d1-71ab-48cd-acfc-9f2f53060465 PS:NodeType Group PS:Organ_System lymphatic system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-fabcd693-7b06-41bb-888f-7993b0fd7dd9 NodeType: Group Organ: brain Organ_System: nervous system Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-group:uuid-fabcd693-7b06-41bb-888f-7993b0fd7dd9 Genes with Polymorphisms Associated with Migraine uuid-fabcd693-7b06-41bb-888f-7993b0fd7dd9 PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-fabcd693-7b06-41bb-888f-7993b0fd7dd9 PS:NodeType Group PS:Organ brain PS:Organ_System nervous system PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-fd074975-76f1-4e3e-bf11-a72dda0758af NodeType: Group Organ: skin Organ_System: integumentary system Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-group:uuid-fd074975-76f1-4e3e-bf11-a72dda0758af Genes Hypermethylated in Melanoma uuid-fd074975-76f1-4e3e-bf11-a72dda0758af PS:CellType cancer cell PS:CellType melanocyte PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-fd074975-76f1-4e3e-bf11-a72dda0758af PS:NodeType Group PS:Organ skin PS:Organ_System integumentary system PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source CellType: cancer cell Description: Group is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ff45aa49-c9a4-4b7d-9a3d-3389cd1363c1 NodeType: Group Organ: breast Organ_System: reproductive system Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-group:uuid-ff45aa49-c9a4-4b7d-9a3d-3389cd1363c1 Genes with Mutations Associated with Breast Cancer uuid-ff45aa49-c9a4-4b7d-9a3d-3389cd1363c1 PS:CellType cancer cell PS:Description Group is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-group:uuid-ff45aa49-c9a4-4b7d-9a3d-3389cd1363c1 PS:NodeType Group PS:Organ breast PS:Organ_System reproductive system PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0020e883-47c7-4322-af5a-f1db26be6e58 NodeType: Pathway Notes: A well-balanced airway surface liquid (ASL) system is required for normal mucus clearance. In asthma, fluids overflow into the lumen increasing ASL thickness leading to airway dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-0020e883-47c7-4322-af5a-f1db26be6e58 3_2_Regulation of airway surface liquid (ASL) thickness uuid-0020e883-47c7-4322-af5a-f1db26be6e58 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0020e883-47c7-4322-af5a-f1db26be6e58 PS:NodeType Pathway PS:Notes A well-balanced airway surface liquid (ASL) system is required for normal mucus clearance. In asthma, fluids overflow into the lumen increasing ASL thickness leading to airway dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-004d4abd-a8a3-4aeb-a321-095708ded90c NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-004d4abd-a8a3-4aeb-a321-095708ded90c Mevalonate Pathway uuid-004d4abd-a8a3-4aeb-a321-095708ded90c PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-004d4abd-a8a3-4aeb-a321-095708ded90c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: In humans, the majority of beta cell replication occurs in early childhood. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00694a24-5c30-4efb-bab5-e2d15515fa55 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: In humans, the majority of beta cell replication occurs in early childhood. Some studies suggest that in adults there is no evidence of any beta cell replication. The expansion of beta cells has been detected only in certain conditions including pregnancy, obesity and the neonatal period. A number of factors such as insulin or incretin hormones (GCG and GIP) increase beta-cell mass via the enhanced IGF1R/PI3K/AKT1 signaling. In vitro, IGF1 and IGF2 were shown to enhance beta-cell proliferation in rat islets and insulinoma cell lines. PRL/PRLR triggers beta-cell proliferation through the JAK2/STAT5A signaling pathway resulting in direct activation of the CCND2 expression and adaptive beta-cell hyperplasia during pregnancy. MLXIPL mediates glucose-stimulated proliferation in pancreatic beta cells. Furthermore, BGLAP has been shown to have direct effects on the expression of insulin and beta-cell cycle mediators such as CCND2 and CDK4. WNT has been shown to induce beta-cell proliferation. Further, TCF7L2 is an effector of the WNT signaling pathway in beta-cells. Mutations in TCF7L2 have been linked to type 2 diabetes. The Ca2+/calcineurin/ NFATC1 signaling pathway positively regulates proliferation in rodent beta-cells. Lastly, moderate glucose elevation and incretins promote pancreatic beta-cell survival via the CREB1-mediated induction of IRS2. In mice, under high-fat diet conditions and during pregnancy, incretins induce beta-cell proliferation via the transactivation of EGFR. Outcome effects: Beta-cell mass is regulated by a number of signaling routes. PI3K/AKT1 signaling is a central pathway in the regulation of beta-cell mass. Organ: pancreas Organ_System: endocrine system PMID: 19196831 PMID: 24594290 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-00694a24-5c30-4efb-bab5-e2d15515fa55 beta-Cell Mass Regulation uuid-00694a24-5c30-4efb-bab5-e2d15515fa55 PS:CellType insulin-secreting cell PS:Description In humans, the majority of beta cell replication occurs in early childhood. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00694a24-5c30-4efb-bab5-e2d15515fa55 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: In humans, the majority of beta cell replication occurs in early childhood. Some studies suggest that in adults there is no evidence of any beta cell replication. The expansion of beta cells has been detected only in certain conditions including pregnancy, obesity and the neonatal period. A number of factors such as insulin or incretin hormones (GCG and GIP) increase beta-cell mass via the enhanced IGF1R/PI3K/AKT1 signaling. In vitro, IGF1 and IGF2 were shown to enhance beta-cell proliferation in rat islets and insulinoma cell lines. PRL/PRLR triggers beta-cell proliferation through the JAK2/STAT5A signaling pathway resulting in direct activation of the CCND2 expression and adaptive beta-cell hyperplasia during pregnancy. MLXIPL mediates glucose-stimulated proliferation in pancreatic beta cells. Furthermore, BGLAP has been shown to have direct effects on the expression of insulin and beta-cell cycle mediators such as CCND2 and CDK4. WNT has been shown to induce beta-cell proliferation. Further, TCF7L2 is an effector of the WNT signaling pathway in beta-cells. Mutations in TCF7L2 have been linked to type 2 diabetes. The Ca2+/calcineurin/ NFATC1 signaling pathway positively regulates proliferation in rodent beta-cells. Lastly, moderate glucose elevation and incretins promote pancreatic beta-cell survival via the CREB1-mediated induction of IRS2. In mice, under high-fat diet conditions and during pregnancy, incretins induce beta-cell proliferation via the transactivation of EGFR. Outcome effects: Beta-cell mass is regulated by a number of signaling routes. PI3K/AKT1 signaling is a central pathway in the regulation of beta-cell mass. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19196831 PS:PMID 24594290 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00774dce-d3bd-40b5-9d41-3f9fdc9467ad NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-00774dce-d3bd-40b5-9d41-3f9fdc9467ad TLR4 -> AP-1 Expression Targets uuid-00774dce-d3bd-40b5-9d41-3f9fdc9467ad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00774dce-d3bd-40b5-9d41-3f9fdc9467ad PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Hypertrophic cardiomyopathy is the most common monogenically inherited form of heart disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0085aea1-c028-4d59-ad7f-4a603bd2e9a0 NodeType: Pathway Notes: Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Signaling description: Mutations in more than 20 genes may induce HCM. Most of these genes encode for sarcomeric proteins, however non-sarcomeric protein genes may also be mutated. Beta-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) are the three most common causal genes for HCM and collectively account for approximately 75% of all HCM cases. The mutated sarcomeric protein genes are cardiac troponin I (TNNI3), cardiac troponin C (TNNC1), cardiac alpha-actin (ACTC1), alpha-tropomyosin (TPM1), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), and alpha-myosin heavy chain (MYH6). In addition, HCM-causing mutations have been identified in several genes encoding Z disk proteins including telethonin (TCAP), myozenin 2 (MYOZ2), cardiac muscle LIM protein (CSRP3), and ankyrin repeat and KH domain-containing protein 1 (ANKRD1,) as well as genes coding for proteins that connect plasma membrane and the sarcomere such as vinculin (VCL), junctophilin 2 (JPH2), and caveolin 3 (CAV3). Titin (TTN) spreading from Z- to M-disk may also be mutated. Mutations in both sarcomeric and non-sarcomeric proteins lead to impaired sarcomere assembly and impaired myofibrillar contractile function. These events lead to compensatory hypertrophy. Calcium (Ca2+) also has an important role in the pathogenesis of HCM. Normally, during action potential, Ca2+ enters the cardiomyocyte through the voltage-gated L-type Ca2+ channels (CACNA1C), which are responsible for Ca2+ influx and to a lesser extent via the Na+/Ca2+ exchanger (SLC8A1), thereby triggering Ca2+-induced Ca2+ release through cardiac ryanodine receptor (RYR2) from the sarcoplasmic reticulum (SR). This Ca2+ binds TNNC1 and activates the myofilaments during systole leading to contraction. During diastole, Ca2+ is taken back up into the SR by cardiac muscle Ca2+ transporting ATPase (ATP2A2) and is pumped out of the cells by SLC8A1, which results in relaxation. The increase in intracellular Ca2+ in HCM is a result of two distinct mechanisms. The mutated sarcomeric proteins use more adenosine triphosphate (ATP) to produce the same force of contraction. Therefore, it compromises Ca2+ reuptake by the ATP2A2 transporter into the SR and more Ca2+ becomes available inside the cells. Conversely, the activation of a number of different receptor classes leads to an increase in intracellular Ca2+. Angiotensin II (AGT), endothelin-1 (EDN1), TNF, and IL6 are released in response to reduced contractility and mediate contractile adaptation through increased Ca2+ release from the SR. Outcome effects: The increase in intracellular Ca2+ activates calmodulin-calcineurin and CAMK-histone deacetylase pathways triggering the transcription of MEF2A, GATA4, and NFATC1, which induces hypertrophy through the expression of contractile proteins. They also induce the expression of fetal isoforms of proteins such as natriuretic peptide A (NPPA), natriuretic peptide B (NPPB), and skeletal muscle actin alpha 1 (ACTA1). AGT, EDN1, TNF, and IL6 activate NF-kB, STAT, JUN/FOS, and SMAD and thereby drive the increase of TIMP1, TIMP2, MMP2, and MMP9 transcription and remodeling of the extracellular matrix. MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP2 and MMP9) can form complexes with TIMPs when the enzymes are in the latent form. In addition, increased myocardial fibrosis occurs due to the increased production of TGFB1 by cardiomyocytes and increased fibroblast proliferation and function. In conclusion, the final morphological events are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis which all result in diastolic dysfunction and heart failure. Organ: heart Organ_System: cardiovascular system PMID: 12775656 PMID: 19136482 PMID: 20438756 PMID: 21415408 PMID: 21700950 PMID: 21825071 PMID: 22027658 PMID: 22796258 PMID: 22874472 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-0085aea1-c028-4d59-ad7f-4a603bd2e9a0 Hypertrophic Cardiomyopathy uuid-0085aea1-c028-4d59-ad7f-4a603bd2e9a0 PS:CellType cardiac myocyte PS:Description Hypertrophic cardiomyopathy is the most common monogenically inherited form of heart disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0085aea1-c028-4d59-ad7f-4a603bd2e9a0 PS:NodeType Pathway PS:Notes Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Signaling description: Mutations in more than 20 genes may induce HCM. Most of these genes encode for sarcomeric proteins, however non-sarcomeric protein genes may also be mutated. Beta-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) are the three most common causal genes for HCM and collectively account for approximately 75% of all HCM cases. The mutated sarcomeric protein genes are cardiac troponin I (TNNI3), cardiac troponin C (TNNC1), cardiac alpha-actin (ACTC1), alpha-tropomyosin (TPM1), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), and alpha-myosin heavy chain (MYH6). In addition, HCM-causing mutations have been identified in several genes encoding Z disk proteins including telethonin (TCAP), myozenin 2 (MYOZ2), cardiac muscle LIM protein (CSRP3), and ankyrin repeat and KH domain-containing protein 1 (ANKRD1,) as well as genes coding for proteins that connect plasma membrane and the sarcomere such as vinculin (VCL), junctophilin 2 (JPH2), and caveolin 3 (CAV3). Titin (TTN) spreading from Z- to M-disk may also be mutated. Mutations in both sarcomeric and non-sarcomeric proteins lead to impaired sarcomere assembly and impaired myofibrillar contractile function. These events lead to compensatory hypertrophy. Calcium (Ca2+) also has an important role in the pathogenesis of HCM. Normally, during action potential, Ca2+ enters the cardiomyocyte through the voltage-gated L-type Ca2+ channels (CACNA1C), which are responsible for Ca2+ influx and to a lesser extent via the Na+/Ca2+ exchanger (SLC8A1), thereby triggering Ca2+-induced Ca2+ release through cardiac ryanodine receptor (RYR2) from the sarcoplasmic reticulum (SR). This Ca2+ binds TNNC1 and activates the myofilaments during systole leading to contraction. During diastole, Ca2+ is taken back up into the SR by cardiac muscle Ca2+ transporting ATPase (ATP2A2) and is pumped out of the cells by SLC8A1, which results in relaxation. The increase in intracellular Ca2+ in HCM is a result of two distinct mechanisms. The mutated sarcomeric proteins use more adenosine triphosphate (ATP) to produce the same force of contraction. Therefore, it compromises Ca2+ reuptake by the ATP2A2 transporter into the SR and more Ca2+ becomes available inside the cells. Conversely, the activation of a number of different receptor classes leads to an increase in intracellular Ca2+. Angiotensin II (AGT), endothelin-1 (EDN1), TNF, and IL6 are released in response to reduced contractility and mediate contractile adaptation through increased Ca2+ release from the SR. Outcome effects: The increase in intracellular Ca2+ activates calmodulin-calcineurin and CAMK-histone deacetylase pathways triggering the transcription of MEF2A, GATA4, and NFATC1, which induces hypertrophy through the expression of contractile proteins. They also induce the expression of fetal isoforms of proteins such as natriuretic peptide A (NPPA), natriuretic peptide B (NPPB), and skeletal muscle actin alpha 1 (ACTA1). AGT, EDN1, TNF, and IL6 activate NF-kB, STAT, JUN/FOS, and SMAD and thereby drive the increase of TIMP1, TIMP2, MMP2, and MMP9 transcription and remodeling of the extracellular matrix. MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP2 and MMP9) can form complexes with TIMPs when the enzymes are in the latent form. In addition, increased myocardial fibrosis occurs due to the increased production of TGFB1 by cardiomyocytes and increased fibroblast proliferation and function. In conclusion, the final morphological events are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis which all result in diastolic dysfunction and heart failure. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 12775656 PS:PMID 19136482 PS:PMID 20438756 PS:PMID 21415408 PS:PMID 21700950 PS:PMID 21825071 PS:PMID 22027658 PS:PMID 22796258 PS:PMID 22874472 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00866d78-2661-4c38-b549-828c6d57c9ed NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-00866d78-2661-4c38-b549-828c6d57c9ed Galactose Metabolism uuid-00866d78-2661-4c38-b549-828c6d57c9ed PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00866d78-2661-4c38-b549-828c6d57c9ed PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Concepts of psoriasis and psoriatic arthritis pathogenesis are changing due to new knowledge of their immunopathology. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00c9b654-115f-4409-b076-f7d7862bc0c0 NodeType: Pathway Notes: Headnote: Psoriatic arthritis refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and psoriatic arthritis pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis was originally considered a disease of abnormal keratinocyte function. At the same time, keratinocytes, key skin cells mediating many of the functional properties of the skin, can respond to proinflammatory cytokines and generate pro-inflammatory activation loops. Signaling description: Cytokines IFNgamma, IL-17 and TNFalpha cooperate to induce the production of anti-microbial peptides (AMPs) and chemokines by keratinocytes, thereby enhancing immune-cell recruitment and inflammation in lesions. TNF alpha is found to be at a higher concentration in psoriatic lesions compared to uninvolved skin. Outcome effects: Collectively, the cytokines IL-17, IFN-gamma, IL-22, and TNF promote keratinocyte activation via a number of signaling routes. IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits keratinocyte terminal differentiation, and promotes antimicrobial protein. TNF alpha increases the production of proinflammatory cytokines IL-6, IL-8, and the adhesion molecules ICAM-1, thus enabling leukocyte infiltration into the skin. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: skeletal system PMID: 15708932 PMID: 17446902 PMID: 22541888 PMID: 23291100 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-00c9b654-115f-4409-b076-f7d7862bc0c0 Keratinocyte Activation in Psoriatic Arthritis uuid-00c9b654-115f-4409-b076-f7d7862bc0c0 PS:CellType keratinocyte PS:Description Concepts of psoriasis and psoriatic arthritis pathogenesis are changing due to new knowledge of their immunopathology. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00c9b654-115f-4409-b076-f7d7862bc0c0 PS:NodeType Pathway PS:Notes Headnote: Psoriatic arthritis refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and psoriatic arthritis pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis was originally considered a disease of abnormal keratinocyte function. At the same time, keratinocytes, key skin cells mediating many of the functional properties of the skin, can respond to proinflammatory cytokines and generate pro-inflammatory activation loops. Signaling description: Cytokines IFNgamma, IL-17 and TNFalpha cooperate to induce the production of anti-microbial peptides (AMPs) and chemokines by keratinocytes, thereby enhancing immune-cell recruitment and inflammation in lesions. TNF alpha is found to be at a higher concentration in psoriatic lesions compared to uninvolved skin. Outcome effects: Collectively, the cytokines IL-17, IFN-gamma, IL-22, and TNF promote keratinocyte activation via a number of signaling routes. IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits keratinocyte terminal differentiation, and promotes antimicrobial protein. TNF alpha increases the production of proinflammatory cytokines IL-6, IL-8, and the adhesion molecules ICAM-1, thus enabling leukocyte infiltration into the skin. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System skeletal system PS:PMID 15708932 PS:PMID 17446902 PS:PMID 22541888 PS:PMID 23291100 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Metastatic reactions occur in 50-70 percent of patients with colorectal cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00e53790-de4a-4903-9810-7e76a1b6bfb0 NodeType: Pathway Notes: Metastatic reactions occur in 50-70% of patients with colorectal cancer. Highlighted proteins: Oncogenes are highlighted in orange, and tumor suppressors are highlighted in green. Organ: colon Organ: intestine Organ_System: integumentary system PMID: 21752724 PMID: 26216840 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-00e53790-de4a-4903-9810-7e76a1b6bfb0 Metastatic Colorectal Cancer uuid-00e53790-de4a-4903-9810-7e76a1b6bfb0 PS:CellType cancer cell PS:Description Metastatic reactions occur in 50-70 percent of patients with colorectal cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00e53790-de4a-4903-9810-7e76a1b6bfb0 PS:NodeType Pathway PS:Notes Metastatic reactions occur in 50-70% of patients with colorectal cancer. Highlighted proteins: Oncogenes are highlighted in orange, and tumor suppressors are highlighted in green. PS:Organ colon PS:Organ intestine PS:Organ_System integumentary system PS:PMID 21752724 PS:PMID 26216840 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00f92da1-ec73-453f-a73f-ef0a7f4b935e NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-00f92da1-ec73-453f-a73f-ef0a7f4b935e Elevated Receptors -> Expression Targets in Ear uuid-00f92da1-ec73-453f-a73f-ef0a7f4b935e PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-00f92da1-ec73-453f-a73f-ef0a7f4b935e PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-010ba5c8-b451-44cf-8d26-ca8690e679d9 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-010ba5c8-b451-44cf-8d26-ca8690e679d9 Vascular Endothelial Cell Vasodilation in Brain uuid-010ba5c8-b451-44cf-8d26-ca8690e679d9 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-010ba5c8-b451-44cf-8d26-ca8690e679d9 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-011a7c8a-455a-4445-848a-2970c03ed26e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-011a7c8a-455a-4445-848a-2970c03ed26e Erythropoietin -> STAT Expression Targets uuid-011a7c8a-455a-4445-848a-2970c03ed26e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-011a7c8a-455a-4445-848a-2970c03ed26e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: leukocyte Description: The initiating factor in the activation of the immune response durinf multiple sclerosis to MBP is the activation of matrix metallopeptidase 25 through FURIN convertase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01228ebd-e828-4c68-b839-e70f33e7e981 NodeType: Pathway Notes: The activation of matrix metallopeptidase 25 through FURIN convertase is the initiating event in the MPB-related complement cascade activation in multiple sclerosis. Organ_System: lymphatic system PMID: 19726693 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-01228ebd-e828-4c68-b839-e70f33e7e981 MPB-Related Complement Cascade Activation uuid-01228ebd-e828-4c68-b839-e70f33e7e981 PS:CellType leukocyte PS:Description The initiating factor in the activation of the immune response durinf multiple sclerosis to MBP is the activation of matrix metallopeptidase 25 through FURIN convertase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01228ebd-e828-4c68-b839-e70f33e7e981 PS:NodeType Pathway PS:Notes The activation of matrix metallopeptidase 25 through FURIN convertase is the initiating event in the MPB-related complement cascade activation in multiple sclerosis. PS:Organ_System lymphatic system PS:PMID 19726693 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-013087e8-1e97-463c-9a4e-a7f16554f581 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-013087e8-1e97-463c-9a4e-a7f16554f581 GLP1R -> ARRB1 Signaling uuid-013087e8-1e97-463c-9a4e-a7f16554f581 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-013087e8-1e97-463c-9a4e-a7f16554f581 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01579bd6-4085-4373-97bb-2842d72d06a3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-01579bd6-4085-4373-97bb-2842d72d06a3 NSP2 interactions uuid-01579bd6-4085-4373-97bb-2842d72d06a3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01579bd6-4085-4373-97bb-2842d72d06a3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0163528c-1882-474b-9b59-51855ae64d4b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-0163528c-1882-474b-9b59-51855ae64d4b ABA storage and degradation template uuid-0163528c-1882-474b-9b59-51855ae64d4b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0163528c-1882-474b-9b59-51855ae64d4b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: generic Description: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-017581da-7f04-4e6c-9929-249b1daafd65 NodeType: Pathway Notes: Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. It plays a crucial role in carbohydrate, fat, and protein metabolism in insulin-dependent tissues. Insulin promotes lipogenesis in hepatocytes and adipocytes resulting in the storage of triglycerides in adipocytes and low density lipoprotein (LDL) in hepatocytes. Signaling description: Intracellular fat is formed from free fatty acids (FFA) delivered by lipoproteins and glycerol-3-P. Insulin involvement in lipogenesis appears in the regulation of glycerol-3-P synthesis and increasing the level of lipoprotein lipase (LPL) mRNA. The hormone causes GLUT (SLC2A1 and SLC2A4) translocation into the membrane surface involving INSR/IRS mechanism promoting glucose influx through it. Intracellular glucose converts to dihydroxyacetone-P during glycolysis which is transformed into glycerol-3-P by glycerol-3-phosphate dehydrogenase (NAD ). In hepatocytes, glycerol-3-P may also be produced from glycerol released from lipoproteins by glycerol kinase. LPL releases FFA from chylomicrons and VLDL which transport FFA from the intestine to the adipose tissue and liver. FFA binds to its receptor, CD36. In the cell, fatty acids are transformed into fatty acyl CoA by ACSL1. Fatty acyl CoA and glycerol-3-P are used to form phosphatidic acid by AGPAT9. Phosphatidic acid is converted into diacylglycerol by phosphatidate phosphatase. Next, the binding of an additional fatty acyl CoA to diacylglycerol results in the formation of triglycerides. In hepatocytes, triglycerides with phospholipids, cholesterol, and APOB are packaged into VLDL. Compound with elevated level is highlighted in red. Organ: generic Organ_System: generic PMID: 10227847 PMID: 11742412 PMID: 18537611 PMID: 20817607 PMID: 9932214 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-017581da-7f04-4e6c-9929-249b1daafd65 Insulin Influence on Lipogenesis uuid-017581da-7f04-4e6c-9929-249b1daafd65 PS:CellType generic PS:Description Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-017581da-7f04-4e6c-9929-249b1daafd65 PS:NodeType Pathway PS:Notes Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. It plays a crucial role in carbohydrate, fat, and protein metabolism in insulin-dependent tissues. Insulin promotes lipogenesis in hepatocytes and adipocytes resulting in the storage of triglycerides in adipocytes and low density lipoprotein (LDL) in hepatocytes. Signaling description: Intracellular fat is formed from free fatty acids (FFA) delivered by lipoproteins and glycerol-3-P. Insulin involvement in lipogenesis appears in the regulation of glycerol-3-P synthesis and increasing the level of lipoprotein lipase (LPL) mRNA. The hormone causes GLUT (SLC2A1 and SLC2A4) translocation into the membrane surface involving INSR/IRS mechanism promoting glucose influx through it. Intracellular glucose converts to dihydroxyacetone-P during glycolysis which is transformed into glycerol-3-P by glycerol-3-phosphate dehydrogenase (NAD ). In hepatocytes, glycerol-3-P may also be produced from glycerol released from lipoproteins by glycerol kinase. LPL releases FFA from chylomicrons and VLDL which transport FFA from the intestine to the adipose tissue and liver. FFA binds to its receptor, CD36. In the cell, fatty acids are transformed into fatty acyl CoA by ACSL1. Fatty acyl CoA and glycerol-3-P are used to form phosphatidic acid by AGPAT9. Phosphatidic acid is converted into diacylglycerol by phosphatidate phosphatase. Next, the binding of an additional fatty acyl CoA to diacylglycerol results in the formation of triglycerides. In hepatocytes, triglycerides with phospholipids, cholesterol, and APOB are packaged into VLDL. Compound with elevated level is highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 10227847 PS:PMID 11742412 PS:PMID 18537611 PS:PMID 20817607 PS:PMID 9932214 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: osteoclast Description: Elevated levels of IL6, IL1B, and TNFSF11 in rheumatoid arthritis contribute to osteoclast proliferation, differentiation, and decreased apoptosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-019b6a8a-14d2-4984-92b1-f44537ae5a60 NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: Elevated levels of IL6, IL1B, and TNFSF11 in RA contribute to osteoclast proliferation, differentiation, and decreased apoptosis. TNFSF11, also known as RANKL initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. The signaling involves TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 proteins and affects NF-kB and MAPK signaling. IL6 initiates NF-kB activation through the JAK-STAT pathway. IL1B also affects NF-kB pathway through the MYD88/IRAK4/IRAK1/TRAF6 axis. Outcome effects: The described signaling leads to osteoclast differentiation and cell survival. In addition, TNFSF11 promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 16824621 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-019b6a8a-14d2-4984-92b1-f44537ae5a60 Osteoclast Activation in Rheumatoid Arthritis uuid-019b6a8a-14d2-4984-92b1-f44537ae5a60 PS:CellType osteoclast PS:Description Elevated levels of IL6, IL1B, and TNFSF11 in rheumatoid arthritis contribute to osteoclast proliferation, differentiation, and decreased apoptosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-019b6a8a-14d2-4984-92b1-f44537ae5a60 PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: Elevated levels of IL6, IL1B, and TNFSF11 in RA contribute to osteoclast proliferation, differentiation, and decreased apoptosis. TNFSF11, also known as RANKL initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. The signaling involves TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 proteins and affects NF-kB and MAPK signaling. IL6 initiates NF-kB activation through the JAK-STAT pathway. IL1B also affects NF-kB pathway through the MYD88/IRAK4/IRAK1/TRAF6 axis. Outcome effects: The described signaling leads to osteoclast differentiation and cell survival. In addition, TNFSF11 promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 16824621 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Tissue bone tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-019df76a-ea1a-46d0-abbd-1ade8469d686 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: bone Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-019df76a-ea1a-46d0-abbd-1ade8469d686 Elevated Receptors -> Expression Targets in Bone Marrow uuid-019df76a-ea1a-46d0-abbd-1ade8469d686 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-019df76a-ea1a-46d0-abbd-1ade8469d686 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ bone PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01a852e8-2832-4549-9d54-90fbfd07935b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-01a852e8-2832-4549-9d54-90fbfd07935b steroids-|oxidative stress in DMD uuid-01a852e8-2832-4549-9d54-90fbfd07935b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01a852e8-2832-4549-9d54-90fbfd07935b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: eosinophil Description: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01a88387-f7d5-4d6a-b458-29319caa3eb8 NodeType: Pathway Notes: Headnote: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. In healthy humans, eosinophils comprise 1-6% of all white blood cells. Eosinophils circulate in the blood for several hours, however in lung, skin, and several other organs, eosinophils appear only in the case of disease such as allergy or helminth invasion and survive up to 12 days. The products of eosinophil degranulation are toxic to parasites and decrease the intensity of allergic reactions.+I128 Signaling description: The maturation of eosinophils generally occurs in bone marrow, but can also be completed in the spleen. The differentiation of eosinophils is initiated by cytokines of Th2 type lymphocytes such as IL3, IL5, and CSF2. IL3 and CSF2 result in the proliferation and differentiation of stem cells to the multipotent myeloid and eosinophil progenitor cells, while IL5 supports the expansion, terminal differentiation, and functional activation of eosinophils. IL5 results in the phosphorylation of JAK2, as well as LYN kinases, which decreases BAX translocation and ultimately reduced apoptosis and promotes eosinophil survival. CSF2 appears to have a strong role in inhibiting eosinophil apoptosis at the tissue level via STAT3-dependent BAD inhibition. It is possible that IL5 triggers the differentiation of eosinophils through activation of the transcription factor SOX4. GATA1 and IRF8 are other crucial factors in eosinophil development. The details of regulation of eosinophil differentiation are not well known. Other cytokines play important roles in eosinophil maturation. IL33 induces helper T-cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding to the IL1RL1 receptor. IL33 markedly enhances eosinophil survival and upregulates the cell surface expression of ICAM1 on eosinophils, but suppresses ICAM3 and L-selectin. In addition, IL33 mediates the significant release of proinflammatory cytokine IL6 and the chemokines IL8 and CCL2. In addition, leptin (LEP) has been shown to be an eosinophil survival factor. Outcome effects: LEP upregulates the cell surface expression of adhesion molecules including ICAM1 and CD18 on eosinophils. LEP can also induce the release of inflammatory cytokines IL6, IL8, and CCL2. The precise mechanisms of activation of these proteins are unknown, but may involve the activation of NF-kB and MAPK1 cascades. LEP initiates a signaling cascade through MAPK-dependent pathway in eosinophils and blocks eosinophil apoptosis. Lastly, IL15 reduces spontaneous apoptosis in human eosinophils. The effect of IL15 on spontaneous eosinophil apoptosis possibly requires NF-kB activation and autocrine production of CSF2. In addition, IL9 activates eosinophils, but the mechanism of this is not well established. In addition, IL27 may play a crucial role in allergic diseases by activating eosinophils via differential intracellular signaling cascades. The details of these cascades are poorly studied. TNF induces eosinophil survival and degranulation, which is mediated through the activation of NF-kB pathway. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-01a88387-f7d5-4d6a-b458-29319caa3eb8 Eosinophil Survival by Cytokine Signaling uuid-01a88387-f7d5-4d6a-b458-29319caa3eb8 PS:CellType eosinophil PS:Description Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01a88387-f7d5-4d6a-b458-29319caa3eb8 PS:NodeType Pathway PS:Notes Headnote: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. In healthy humans, eosinophils comprise 1-6% of all white blood cells. Eosinophils circulate in the blood for several hours, however in lung, skin, and several other organs, eosinophils appear only in the case of disease such as allergy or helminth invasion and survive up to 12 days. The products of eosinophil degranulation are toxic to parasites and decrease the intensity of allergic reactions.+I128 Signaling description: The maturation of eosinophils generally occurs in bone marrow, but can also be completed in the spleen. The differentiation of eosinophils is initiated by cytokines of Th2 type lymphocytes such as IL3, IL5, and CSF2. IL3 and CSF2 result in the proliferation and differentiation of stem cells to the multipotent myeloid and eosinophil progenitor cells, while IL5 supports the expansion, terminal differentiation, and functional activation of eosinophils. IL5 results in the phosphorylation of JAK2, as well as LYN kinases, which decreases BAX translocation and ultimately reduced apoptosis and promotes eosinophil survival. CSF2 appears to have a strong role in inhibiting eosinophil apoptosis at the tissue level via STAT3-dependent BAD inhibition. It is possible that IL5 triggers the differentiation of eosinophils through activation of the transcription factor SOX4. GATA1 and IRF8 are other crucial factors in eosinophil development. The details of regulation of eosinophil differentiation are not well known. Other cytokines play important roles in eosinophil maturation. IL33 induces helper T-cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding to the IL1RL1 receptor. IL33 markedly enhances eosinophil survival and upregulates the cell surface expression of ICAM1 on eosinophils, but suppresses ICAM3 and L-selectin. In addition, IL33 mediates the significant release of proinflammatory cytokine IL6 and the chemokines IL8 and CCL2. In addition, leptin (LEP) has been shown to be an eosinophil survival factor. Outcome effects: LEP upregulates the cell surface expression of adhesion molecules including ICAM1 and CD18 on eosinophils. LEP can also induce the release of inflammatory cytokines IL6, IL8, and CCL2. The precise mechanisms of activation of these proteins are unknown, but may involve the activation of NF-kB and MAPK1 cascades. LEP initiates a signaling cascade through MAPK-dependent pathway in eosinophils and blocks eosinophil apoptosis. Lastly, IL15 reduces spontaneous apoptosis in human eosinophils. The effect of IL15 on spontaneous eosinophil apoptosis possibly requires NF-kB activation and autocrine production of CSF2. In addition, IL9 activates eosinophils, but the mechanism of this is not well established. In addition, IL27 may play a crucial role in allergic diseases by activating eosinophils via differential intracellular signaling cascades. The details of these cascades are poorly studied. TNF induces eosinophil survival and degranulation, which is mediated through the activation of NF-kB pathway. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: lymphocyte Description: WHIM syndrome results from autosomal dominant mutations in CXCR4 gene. CXCR4 is endowed with potent chemotactic properties for the lymphocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01cf0dc1-4b28-4b03-abfa-cab5a2590a26 NodeType: Pathway Notes: Headnote: Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia. WHIM patients exhibit increased susceptibility to bacterial and viral infections, especially from human papilloma virus common serotypes, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels are often deficient. Signaling description: WHIM syndrome results from autosomal dominant mutations in the CXCR4 gene. CXCR4 protein possesses potent chemotactic properties towards lymphocytes and is expressed on most mature human leukocyte subtypes and hematopoietic progenitor cells. CXCR4 ligand (CXCL12) is important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. When CXCL12 binds to CXCR4, signal transduction activates G-proteins which activate the downstream effectors. This process is regulated by desensitization whereby ADRBK2 mediates the phosphorylation of the C-terminus of the CXCR4 cytoplasmic domain. This leads to the recruitment of ARRB2 to prevent further G-protein activation which subsequently results in receptor internalization and ubiquitination. This signaling plays a critical role in bone marrow homing in addition to myelopoiesis and lymphopoiesis. Point mutations in CXCR4 gene leads to a premature stop codon, thus causing a truncation within the last 10-19 amino acids of the C-end of CXCR4. Additional CXCR4 signaling steps have been suggested to be involved in WHIM syndrome. ADRBK2 plays a role as a regulator of CXCL12-promoted desensitization of CXCR4. In the presence of a truncating mutation of the C-terminal domain of CXCR4, the enhanced binding of ARRB2 to other regions of the receptor paradoxically resulted in prolonged activation of the receptor and failure to internalize it via endocytosis. Outcome effects: Activated downstream effectors of CXCR4 such as paxillin (PXN), AKT1, and MAPK3/MAPK1 and calcium (Ca2) flux trigger adhesion and cell migration. In cells of patients with WHIM syndrome, mutations result in the enhanced production of IP3 and prolonged ligand-stimulated release of intracellular Ca2 flux in response to CXCL12 binding. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: lymphatic system PMID: 21178277 PMID: 24111611 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-01cf0dc1-4b28-4b03-abfa-cab5a2590a26 WHIM Syndrome uuid-01cf0dc1-4b28-4b03-abfa-cab5a2590a26 PS:CellType lymphocyte PS:Description WHIM syndrome results from autosomal dominant mutations in CXCR4 gene. CXCR4 is endowed with potent chemotactic properties for the lymphocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01cf0dc1-4b28-4b03-abfa-cab5a2590a26 PS:NodeType Pathway PS:Notes Headnote: Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia. WHIM patients exhibit increased susceptibility to bacterial and viral infections, especially from human papilloma virus common serotypes, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels are often deficient. Signaling description: WHIM syndrome results from autosomal dominant mutations in the CXCR4 gene. CXCR4 protein possesses potent chemotactic properties towards lymphocytes and is expressed on most mature human leukocyte subtypes and hematopoietic progenitor cells. CXCR4 ligand (CXCL12) is important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. When CXCL12 binds to CXCR4, signal transduction activates G-proteins which activate the downstream effectors. This process is regulated by desensitization whereby ADRBK2 mediates the phosphorylation of the C-terminus of the CXCR4 cytoplasmic domain. This leads to the recruitment of ARRB2 to prevent further G-protein activation which subsequently results in receptor internalization and ubiquitination. This signaling plays a critical role in bone marrow homing in addition to myelopoiesis and lymphopoiesis. Point mutations in CXCR4 gene leads to a premature stop codon, thus causing a truncation within the last 10-19 amino acids of the C-end of CXCR4. Additional CXCR4 signaling steps have been suggested to be involved in WHIM syndrome. ADRBK2 plays a role as a regulator of CXCL12-promoted desensitization of CXCR4. In the presence of a truncating mutation of the C-terminal domain of CXCR4, the enhanced binding of ARRB2 to other regions of the receptor paradoxically resulted in prolonged activation of the receptor and failure to internalize it via endocytosis. Outcome effects: Activated downstream effectors of CXCR4 such as paxillin (PXN), AKT1, and MAPK3/MAPK1 and calcium (Ca2) flux trigger adhesion and cell migration. In cells of patients with WHIM syndrome, mutations result in the enhanced production of IP3 and prolonged ligand-stimulated release of intracellular Ca2 flux in response to CXCL12 binding. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 21178277 PS:PMID 24111611 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01e29c0d-d9f7-4f02-a8a5-f9aeebb3431f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-01e29c0d-d9f7-4f02-a8a5-f9aeebb3431f SARS helicase (NSP13) inhibitors uuid-01e29c0d-d9f7-4f02-a8a5-f9aeebb3431f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01e29c0d-d9f7-4f02-a8a5-f9aeebb3431f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: Deletion of FOXO3 (or PTEN) in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01e8c47f-712b-4096-a468-062625ae41e3 NodeType: Pathway Notes: Headnote: Primordial follicles are long-lived structures assembled early in life. The mechanisms that control the balance between the conservation and activation of primordial follicles are critically important for fertility and dictate the onset of menopause. FOXO3 plays an essential role in these processes by suppressing the growth of primordial follicles, thereby preserving them until later in life. Signaling description: Deletion of FOXO3 (or PTEN) in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). These findings raised the possibility that mutations or naturally occurring polymorphisms of the human orthologue FOXO3 might contribute to POF or idiopathic primary amenorrhea. Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 16979636 PMID: 17616716 PMID: 17959613 PMID: 18827065 PMID: 18989304 PMID: 20219431 PMID: 21245654 PMID: 23673628 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-01e8c47f-712b-4096-a468-062625ae41e3 FOXO3 and PTEN Inactivation in Premature Ovarian Failure (Mouse Model) uuid-01e8c47f-712b-4096-a468-062625ae41e3 PS:CellType oocyte PS:Description Deletion of FOXO3 (or PTEN) in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-01e8c47f-712b-4096-a468-062625ae41e3 PS:NodeType Pathway PS:Notes Headnote: Primordial follicles are long-lived structures assembled early in life. The mechanisms that control the balance between the conservation and activation of primordial follicles are critically important for fertility and dictate the onset of menopause. FOXO3 plays an essential role in these processes by suppressing the growth of primordial follicles, thereby preserving them until later in life. Signaling description: Deletion of FOXO3 (or PTEN) in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). These findings raised the possibility that mutations or naturally occurring polymorphisms of the human orthologue FOXO3 might contribute to POF or idiopathic primary amenorrhea. Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 16979636 PS:PMID 17616716 PS:PMID 17959613 PS:PMID 18827065 PS:PMID 18989304 PS:PMID 20219431 PS:PMID 21245654 PS:PMID 23673628 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-023049b2-f059-45ec-9825-2850975fd930 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-023049b2-f059-45ec-9825-2850975fd930 Huntington's Disease Anatomy and Molecular Biomarkers uuid-023049b2-f059-45ec-9825-2850975fd930 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-023049b2-f059-45ec-9825-2850975fd930 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: gastrin-secreting cell Description: Gastrin secretion by G-cell under control of nutrients, SST and GRP. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-023ebd14-0103-46e5-a16c-ed46b6afb4cf NodeType: Pathway Notes: Headnote: Gastrin is one of the major signaling peptides in the digestive process. The expression and secretion of gastrin by stomach G-cells is regulated by a number of nutrients and signals from the parasympathetic nervous system and also by certain enteroendocrine cells (e.g. D-cells) of the digestive system. Signaling description: The lysophosphatidic acid (LPAR5) and L-amino acid (GPRC6A) receptors are the major D-cell receptor in the lumen of the stomach. These receptors via G-proteins activate two signaling pathways: cAMP/PKA and phospholipase C (PLCE1) dependent signaling. cAMP induced PKA activation leads to the activation of GAST transcription. PKA inhibits the repressor of GAST transcription (MEN1) and activates SP1 and CTNNB1, which bind to the promoter of GAST gene and activate its transcription. Phospholipase C synthesizes inositol P3 and diacylglycerol, which leads to the accumulation of intracellular calcium and PKC activation, respectively. In turn, PKC activates L-type calcium channels which leads to extracellular calcium influx and gastrin secretion. GAST propeptide is cleaved by carboxypeptidase B2 (CPB2) and proprotein convertase subtilisin/kexin type 2 (PCSK2). Processed gastrins can be hydrolyzed in plasma by plasma membrane-bound oligomer of MEP1B activated by PKC. The release of gastrins is also activated by gastrin releasing peptide (GRP) secreted by post-ganglionic fibers of the vagus nerve. The inhibition of GAST expression occurs due to an activation of SSTR2 by somatostatin (SST) which blocks cAMP signaling via G-proteins GNAI3 and GNAO1. Outcome effects: Gastrin synthesis and secretion by G-cell is under the control of nutrients and GRP. In ECL-cells, gastrin signaling leads to histamine secretion and activation of stomach secretion (including stomach acid secretion). Organ: stomach Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-023ebd14-0103-46e5-a16c-ed46b6afb4cf G-cell: Gastrin Secretion uuid-023ebd14-0103-46e5-a16c-ed46b6afb4cf PS:CellType gastrin-secreting cell PS:Description Gastrin secretion by G-cell under control of nutrients, SST and GRP. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-023ebd14-0103-46e5-a16c-ed46b6afb4cf PS:NodeType Pathway PS:Notes Headnote: Gastrin is one of the major signaling peptides in the digestive process. The expression and secretion of gastrin by stomach G-cells is regulated by a number of nutrients and signals from the parasympathetic nervous system and also by certain enteroendocrine cells (e.g. D-cells) of the digestive system. Signaling description: The lysophosphatidic acid (LPAR5) and L-amino acid (GPRC6A) receptors are the major D-cell receptor in the lumen of the stomach. These receptors via G-proteins activate two signaling pathways: cAMP/PKA and phospholipase C (PLCE1) dependent signaling. cAMP induced PKA activation leads to the activation of GAST transcription. PKA inhibits the repressor of GAST transcription (MEN1) and activates SP1 and CTNNB1, which bind to the promoter of GAST gene and activate its transcription. Phospholipase C synthesizes inositol P3 and diacylglycerol, which leads to the accumulation of intracellular calcium and PKC activation, respectively. In turn, PKC activates L-type calcium channels which leads to extracellular calcium influx and gastrin secretion. GAST propeptide is cleaved by carboxypeptidase B2 (CPB2) and proprotein convertase subtilisin/kexin type 2 (PCSK2). Processed gastrins can be hydrolyzed in plasma by plasma membrane-bound oligomer of MEP1B activated by PKC. The release of gastrins is also activated by gastrin releasing peptide (GRP) secreted by post-ganglionic fibers of the vagus nerve. The inhibition of GAST expression occurs due to an activation of SSTR2 by somatostatin (SST) which blocks cAMP signaling via G-proteins GNAI3 and GNAO1. Outcome effects: Gastrin synthesis and secretion by G-cell is under the control of nutrients and GRP. In ECL-cells, gastrin signaling leads to histamine secretion and activation of stomach secretion (including stomach acid secretion). PS:Organ stomach PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02568410-7474-43ac-ad8c-c80a494d8934 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-02568410-7474-43ac-ad8c-c80a494d8934 IGF2+>Keratocytes uuid-02568410-7474-43ac-ad8c-c80a494d8934 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02568410-7474-43ac-ad8c-c80a494d8934 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-025f587f-c121-45ad-ab43-60c81e509c06 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-025f587f-c121-45ad-ab43-60c81e509c06 ROS Metabolism uuid-025f587f-c121-45ad-ab43-60c81e509c06 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-025f587f-c121-45ad-ab43-60c81e509c06 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-026a9048-301e-4f39-b383-127e20755527 NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: HIV uses CD4 and CXCR4 as receptors for entry. Also, HIV envelope glycoprotein Gp120 (env) binds to CD4 to promote FAS synthesis. CD4, through LCK and ZAP70, activates LAT which results in Jun/Fos activation first through PLCG1/ PRKCQ which leads to NF-kB activation, and secondly through GRB2/SOS1/Ras/RAF1/ERK (MAPK). Outcome effects: NF-kB and Jun/Fos promote FAS transcription which after final editing is translocated and integrated into the membrane. At the same time, env protein binds to CCR5 on the macrophage surface and through JAK/STAT pathway promotes FASLG synthesis. Macrophage-released FASLG binds to FAS of CD4 T-cells causing cell apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 12810858 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-026a9048-301e-4f39-b383-127e20755527 CD4+ T-Cell Death in HIV uuid-026a9048-301e-4f39-b383-127e20755527 PS:CellType T-cell PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-026a9048-301e-4f39-b383-127e20755527 PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: HIV uses CD4 and CXCR4 as receptors for entry. Also, HIV envelope glycoprotein Gp120 (env) binds to CD4 to promote FAS synthesis. CD4, through LCK and ZAP70, activates LAT which results in Jun/Fos activation first through PLCG1/ PRKCQ which leads to NF-kB activation, and secondly through GRB2/SOS1/Ras/RAF1/ERK (MAPK). Outcome effects: NF-kB and Jun/Fos promote FAS transcription which after final editing is translocated and integrated into the membrane. At the same time, env protein binds to CCR5 on the macrophage surface and through JAK/STAT pathway promotes FASLG synthesis. Macrophage-released FASLG binds to FAS of CD4 T-cells causing cell apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 12810858 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: trophoblast Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02860fdb-2e49-4ae2-931d-02951a11a698 NodeType: Pathway Notes: Headnote: The trophoblast is the peripheral part of the human conceptus, which exerts a crucial role in implantation and placentation. Antiphospholipid antibodies (aPL) increase the risk of recurrent miscarriage, intrauterine growth restriction and preterm birth. It is associated with decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways. Signaling description: aPL are preferentially targeted to the trophoblast cells of the placenta where they activate complement through the classical pathway. The complement cascade is initiated; C3 and, subsequently, C5 are activated. C5a is generated, which attracts and activates neutrophils and monocytes and stimulates the release of inflammatory mediators, including reactive oxidants, proteolytic enzymes, chemokines and cytokines, which results in further influx of inflammatory cells and, ultimately, fetal injury.Intraplacental thrombosis is considered one of the main pathogenic mechanism mediating foetal loss in antiphospholipid syndrome (APS). This (Hypothesis) of placental damage was supported by the finding of thrombosis and infarction in placentas from women with APS and by the demonstration of aPL capability to induce a procoagulant state in vitro through several mechanisms including the ability of the aPL antibodies (specifically, Aanti-beta-2GPI / anti-APOH antibodies) to disrupt the anticoagulant annexin A5 (ANXA5) shield on trophoblast and endothelial cell monolayers. Normally ANXA5 forms a shield around negatively-charged phospholipid molecules, thus reducing their availability for coagulation. Outcome Effects; anti-ANXA5 antibodies increase phospholipid-dependent coagulation steps. ANXA5 expression is decreased on trophoblasts of preeclamptic placentas. Organ: uterus Organ_System: reproductive system PMID: 17334336 PMID: 17418423 PMID: 20822807 PMID: 21556027 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-02860fdb-2e49-4ae2-931d-02951a11a698 Trophoblast Damage in Infertility (Hypothesis) uuid-02860fdb-2e49-4ae2-931d-02951a11a698 PS:CellType trophoblast PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02860fdb-2e49-4ae2-931d-02951a11a698 PS:NodeType Pathway PS:Notes Headnote: The trophoblast is the peripheral part of the human conceptus, which exerts a crucial role in implantation and placentation. Antiphospholipid antibodies (aPL) increase the risk of recurrent miscarriage, intrauterine growth restriction and preterm birth. It is associated with decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways. Signaling description: aPL are preferentially targeted to the trophoblast cells of the placenta where they activate complement through the classical pathway. The complement cascade is initiated; C3 and, subsequently, C5 are activated. C5a is generated, which attracts and activates neutrophils and monocytes and stimulates the release of inflammatory mediators, including reactive oxidants, proteolytic enzymes, chemokines and cytokines, which results in further influx of inflammatory cells and, ultimately, fetal injury.Intraplacental thrombosis is considered one of the main pathogenic mechanism mediating foetal loss in antiphospholipid syndrome (APS). This (Hypothesis) of placental damage was supported by the finding of thrombosis and infarction in placentas from women with APS and by the demonstration of aPL capability to induce a procoagulant state in vitro through several mechanisms including the ability of the aPL antibodies (specifically, Aanti-beta-2GPI / anti-APOH antibodies) to disrupt the anticoagulant annexin A5 (ANXA5) shield on trophoblast and endothelial cell monolayers. Normally ANXA5 forms a shield around negatively-charged phospholipid molecules, thus reducing their availability for coagulation. Outcome Effects; anti-ANXA5 antibodies increase phospholipid-dependent coagulation steps. ANXA5 expression is decreased on trophoblasts of preeclamptic placentas. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 17334336 PS:PMID 17418423 PS:PMID 20822807 PS:PMID 21556027 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02968168-6bb1-4b9f-b129-1602971275d0 NodeType: Pathway Notes: Headnote: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. ANGPT1/TEK is known to regulate both vascular quiescence and angiogenesis. The pathology of angiogenic switch in tumors is characterized by exit from quiescence state by endothelial cells (ECs), cell proliferation and migration with the formation of new blood vessels. Maintenance of vascular quiescence keeps in with the absence of pro-angiogenic stimuli and ANGPT1/TEK "trans-association" state. The acquisition of this quiescence state by ECs is regarded as a potential anti-cancer therapeutic target. Signaling description: At the cell-cell contacts, oligomerized ANGPT1 bridges TEK expressed in adjoining cells, resulting in the formation of homophilic TEK trans-association. The core of ANGPT1/TEK related signaling, through PI3K and TNIP2, promotes inhibition of ECs activation or apoptosis. The precise mechanism of molecular signaling shown on this pathway is well known and is associated with the activation of AKT and NF-kB. Outcome effects: KDR, VEGFA, ANGPT2, DLL4, CXCL8 are changing their expression due to AKT signaling activation. Their altered expression leads to ECs quiescence and inhibition of angiogenesis. The inhibition of pro-apoptotic proteins CASP3 and CASP9 and anti-apoptotic BIRC5 activation leads to the suppression of apoptosis and cell survival. Animal data: The majority of the data on ANGPT/TEK and their role in angiogenesis were revealed from animal model (mice) experiments. Organ: blood vessel wall Organ_System: cardiovascular system PMID: 17634421 PMID: 20054809 PMID: 20651738 PMID: 22841837 PMID: 23908119 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-02968168-6bb1-4b9f-b129-1602971275d0 ANGPT/TEK Maintains Endothelial Cell Quiescence in Cancer uuid-02968168-6bb1-4b9f-b129-1602971275d0 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02968168-6bb1-4b9f-b129-1602971275d0 PS:NodeType Pathway PS:Notes Headnote: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. ANGPT1/TEK is known to regulate both vascular quiescence and angiogenesis. The pathology of angiogenic switch in tumors is characterized by exit from quiescence state by endothelial cells (ECs), cell proliferation and migration with the formation of new blood vessels. Maintenance of vascular quiescence keeps in with the absence of pro-angiogenic stimuli and ANGPT1/TEK "trans-association" state. The acquisition of this quiescence state by ECs is regarded as a potential anti-cancer therapeutic target. Signaling description: At the cell-cell contacts, oligomerized ANGPT1 bridges TEK expressed in adjoining cells, resulting in the formation of homophilic TEK trans-association. The core of ANGPT1/TEK related signaling, through PI3K and TNIP2, promotes inhibition of ECs activation or apoptosis. The precise mechanism of molecular signaling shown on this pathway is well known and is associated with the activation of AKT and NF-kB. Outcome effects: KDR, VEGFA, ANGPT2, DLL4, CXCL8 are changing their expression due to AKT signaling activation. Their altered expression leads to ECs quiescence and inhibition of angiogenesis. The inhibition of pro-apoptotic proteins CASP3 and CASP9 and anti-apoptotic BIRC5 activation leads to the suppression of apoptosis and cell survival. Animal data: The majority of the data on ANGPT/TEK and their role in angiogenesis were revealed from animal model (mice) experiments. PS:Organ blood vessel wall PS:Organ_System cardiovascular system PS:PMID 17634421 PS:PMID 20054809 PS:PMID 20651738 PS:PMID 22841837 PS:PMID 23908119 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: neutrophil Description: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02b2c791-d142-42f0-b73c-e2bde6559ae6 NodeType: Pathway Notes: Headnote: The acute phase response (APR) is a prominent systemic reaction of the organism to an infection and tissue injury. One of the mechanisms of APR is increased values of adrenocorticotrophic hormone (ACTH) and glucocorticoids via the activation of hypothalamic-pituitary-adrenal (HPA) axis. Signaling description: Glucocorticoids mediate anti-inflammatory effects in the body. Hypothalamic hormone CRH induces ACTH production by adenohypophysis and then ACTH stimulates the secretion of glucocorticoids by the adrenal cortex. The expression of neurohormones CRH and ACTH are stress-induced. During inflammation, IL1, IL6, and TNF as well as neurotransmitters and neuropeptides such as serotonin, acetylcholine, histamine, and noradrenaline stimulate CRH production. Histamine is one of the few central nervous system neurotransmitters that can cause consistent blood-brain barrier opening. Transport systems from blood to the central nervous system (CNS) have been identified for IL1, IL6, and TNF. PGE2 also plays an important role in IL1B-induced upregulation of CRH. CRH provides an anti-inflammatory response by CRHR1 signaling in the adrenal gland and stimulation of ACTH release. ACTH is a melanocortin that is derived from proopiomelanocortin (POMC) proteolytic cleavage by PCSK1. MC2R is the specific receptor for ACTH in the adrenal gland where it leads to the production and release of steroids. MC2R requires the expression of MRAP, which interacts with MC2R and facilitates MC2R cell surface expression. The classical signaling pathway for MCRs passes through G-proteins, which activate adenylate cyclase (ADCY), increase intracellular cAMP production, and activate PKA. The stimulation of all MCRs leads to the activation of MAPK3/MAPK1. The activation of PKA has been shown to counteract Ras/RAF1/ MAPK3/MAPK1 signaling pathway. RAPGEF4/RAPGEF3 is a RAP1A/RAP2A-specific GEF, which translates cAMP signal to MAPKs via BRAF pathway in a PKA- and Ras-independent manner. BRAF is the dominant molecular switch that permits differential cAMP-dependent regulation of MAPKs. Outcome effects: Glucocorticoids are produced in the adrenal gland and exert potent anti-inflammatory effects by inhibiting IL2 gene expression by lymphocytes, IL1 gene expression by macrophages, MHC class II antigen expression, and phospholipase A2 activity. Glucocorticoids activate the expression of TSC22D3, a protein whose mechanism of action is unclear, but it is known that it interacts with and inhibits the function of NF-kB, Jun/Fos, and ANXA1. Furthermore, glucocorticoids have been shown to inhibit T-cell binding to endothelial cells by modulating the expression of adhesion molecules. Organ: adrenal gland Organ: brain Organ_System: endocrine system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-02b2c791-d142-42f0-b73c-e2bde6559ae6 Hypothalamic-Pituitary-Adrenal Axis in Acute Phase Response uuid-02b2c791-d142-42f0-b73c-e2bde6559ae6 PS:CellType neutrophil PS:Description The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02b2c791-d142-42f0-b73c-e2bde6559ae6 PS:NodeType Pathway PS:Notes Headnote: The acute phase response (APR) is a prominent systemic reaction of the organism to an infection and tissue injury. One of the mechanisms of APR is increased values of adrenocorticotrophic hormone (ACTH) and glucocorticoids via the activation of hypothalamic-pituitary-adrenal (HPA) axis. Signaling description: Glucocorticoids mediate anti-inflammatory effects in the body. Hypothalamic hormone CRH induces ACTH production by adenohypophysis and then ACTH stimulates the secretion of glucocorticoids by the adrenal cortex. The expression of neurohormones CRH and ACTH are stress-induced. During inflammation, IL1, IL6, and TNF as well as neurotransmitters and neuropeptides such as serotonin, acetylcholine, histamine, and noradrenaline stimulate CRH production. Histamine is one of the few central nervous system neurotransmitters that can cause consistent blood-brain barrier opening. Transport systems from blood to the central nervous system (CNS) have been identified for IL1, IL6, and TNF. PGE2 also plays an important role in IL1B-induced upregulation of CRH. CRH provides an anti-inflammatory response by CRHR1 signaling in the adrenal gland and stimulation of ACTH release. ACTH is a melanocortin that is derived from proopiomelanocortin (POMC) proteolytic cleavage by PCSK1. MC2R is the specific receptor for ACTH in the adrenal gland where it leads to the production and release of steroids. MC2R requires the expression of MRAP, which interacts with MC2R and facilitates MC2R cell surface expression. The classical signaling pathway for MCRs passes through G-proteins, which activate adenylate cyclase (ADCY), increase intracellular cAMP production, and activate PKA. The stimulation of all MCRs leads to the activation of MAPK3/MAPK1. The activation of PKA has been shown to counteract Ras/RAF1/ MAPK3/MAPK1 signaling pathway. RAPGEF4/RAPGEF3 is a RAP1A/RAP2A-specific GEF, which translates cAMP signal to MAPKs via BRAF pathway in a PKA- and Ras-independent manner. BRAF is the dominant molecular switch that permits differential cAMP-dependent regulation of MAPKs. Outcome effects: Glucocorticoids are produced in the adrenal gland and exert potent anti-inflammatory effects by inhibiting IL2 gene expression by lymphocytes, IL1 gene expression by macrophages, MHC class II antigen expression, and phospholipase A2 activity. Glucocorticoids activate the expression of TSC22D3, a protein whose mechanism of action is unclear, but it is known that it interacts with and inhibits the function of NF-kB, Jun/Fos, and ANXA1. Furthermore, glucocorticoids have been shown to inhibit T-cell binding to endothelial cells by modulating the expression of adhesion molecules. PS:Organ adrenal gland PS:Organ brain PS:Organ_System endocrine system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02b7098a-09f4-4201-99ef-85aad8c2be83 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-02b7098a-09f4-4201-99ef-85aad8c2be83 TGFA -> CREB/CREBBP/ELK-SRF/MYC Expression Targets uuid-02b7098a-09f4-4201-99ef-85aad8c2be83 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02b7098a-09f4-4201-99ef-85aad8c2be83 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02c30309-05c7-4557-a69e-a6987201cf7b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-02c30309-05c7-4557-a69e-a6987201cf7b EGFR/ERBB2 -> TP53 Signaling uuid-02c30309-05c7-4557-a69e-a6987201cf7b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02c30309-05c7-4557-a69e-a6987201cf7b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: Hepatocellular carcinoma (HCC) is the third most cause of cancer-related death worldwide. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02ce8b6e-a796-4ecc-95da-ec3dbc926e76 NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: HCC is characterized by the overexpression of growth factors and their receptors including EGFRs, VEGFRs, MET, and IGF1R in addition to mutations in MET, PTEN, KRAS, BRAF, HRAS, and PIK3CA genes. The ERBB family of receptor tyrosine kinases consists of four related members including EGFR, ERBB2, ERBB3, and ERBB4. The family of vascular endothelial growth factor receptors consists of FLT1, KDR, and FLT4. Ligand-bound EGFRs, VEGFRs, MET, TGFBR1, and IGF1R activate PIK3CA via SRC and IRS1 proteins. PIK3CA, via PIP3 and PDPK1, activates AKT1. Activated AKT1 promotes several essential pathways. PTEN normally dephosphorylates PIP3 and suppresses AKT1-mediated signaling; however mutations in PTEN gene lead to the constitutive activation of AKT1 which phosphorylates and activates MTOR and inhibits TP53. Further, AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1). In addition, activated AKT1 inhibits FOXO1 and FOXO3. AKT1 also phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c (CYCS) from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. Finally, growth factor receptors mediate JAK1/2 (Janus kinases 1/2) which are involved in cell growth and activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: The described alterations associated with HCC cause constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, proliferation, and migration of epithelial pancreatic cells. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. In the nucleus, activated beta-catenin interacts with TCF4 and LEF1 to induce the expression of downstream target genes which are involved in cell proliferation, differentiation, and migration. BRAF activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 20175032 PMID: 22212931 PMID: 22652888 PMID: 23426905 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-02ce8b6e-a796-4ecc-95da-ec3dbc926e76 Growth Factor Signaling in Hepatocellular Carcinoma uuid-02ce8b6e-a796-4ecc-95da-ec3dbc926e76 PS:CellType cancer cell PS:CellType hepatocyte PS:Description Hepatocellular carcinoma (HCC) is the third most cause of cancer-related death worldwide. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02ce8b6e-a796-4ecc-95da-ec3dbc926e76 PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: HCC is characterized by the overexpression of growth factors and their receptors including EGFRs, VEGFRs, MET, and IGF1R in addition to mutations in MET, PTEN, KRAS, BRAF, HRAS, and PIK3CA genes. The ERBB family of receptor tyrosine kinases consists of four related members including EGFR, ERBB2, ERBB3, and ERBB4. The family of vascular endothelial growth factor receptors consists of FLT1, KDR, and FLT4. Ligand-bound EGFRs, VEGFRs, MET, TGFBR1, and IGF1R activate PIK3CA via SRC and IRS1 proteins. PIK3CA, via PIP3 and PDPK1, activates AKT1. Activated AKT1 promotes several essential pathways. PTEN normally dephosphorylates PIP3 and suppresses AKT1-mediated signaling; however mutations in PTEN gene lead to the constitutive activation of AKT1 which phosphorylates and activates MTOR and inhibits TP53. Further, AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1). In addition, activated AKT1 inhibits FOXO1 and FOXO3. AKT1 also phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c (CYCS) from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. Finally, growth factor receptors mediate JAK1/2 (Janus kinases 1/2) which are involved in cell growth and activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: The described alterations associated with HCC cause constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, proliferation, and migration of epithelial pancreatic cells. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. In the nucleus, activated beta-catenin interacts with TCF4 and LEF1 to induce the expression of downstream target genes which are involved in cell proliferation, differentiation, and migration. BRAF activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 20175032 PS:PMID 22212931 PS:PMID 22652888 PS:PMID 23426905 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author PS:Source CellType: epithelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02d5d8d8-5b03-4f18-85c1-dab8353ac7e5 NodeType: Pathway Organ: eye PMID: 18501660 PMID: 21293732 PMID: 24165276 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-02d5d8d8-5b03-4f18-85c1-dab8353ac7e5 Corneal deturgesence by endothelium uuid-02d5d8d8-5b03-4f18-85c1-dab8353ac7e5 PS:CellType epithelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02d5d8d8-5b03-4f18-85c1-dab8353ac7e5 PS:NodeType Pathway PS:Organ eye PS:PMID 18501660 PS:PMID 21293732 PS:PMID 24165276 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02d81e70-76a2-41c5-8ade-e882bdc43ade NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-02d81e70-76a2-41c5-8ade-e882bdc43ade Nicotinate and Nicotinamide Metabolism uuid-02d81e70-76a2-41c5-8ade-e882bdc43ade PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02d81e70-76a2-41c5-8ade-e882bdc43ade PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02f25103-88fb-44c2-a674-a619bcf148cc NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-02f25103-88fb-44c2-a674-a619bcf148cc TENs kill tumor cells uuid-02f25103-88fb-44c2-a674-a619bcf148cc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02f25103-88fb-44c2-a674-a619bcf148cc PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02f6f3bd-9f94-468e-a0a1-d2779041c45d NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-02f6f3bd-9f94-468e-a0a1-d2779041c45d FGFR -> AP-1/CREB/CREBBP/ELK/SRF/MYC Signaling uuid-02f6f3bd-9f94-468e-a0a1-d2779041c45d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02f6f3bd-9f94-468e-a0a1-d2779041c45d PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: B cells - key components of humoral immunity - are sensitive to such toxic compounds as dioxin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02fdf572-fd10-4bdb-8b06-37f11aa6db21 NodeType: Pathway Notes: Headnote: B-cells, key components of humoral immunity, are sensitive to such toxic compounds as dioxin. Signaling description: AHR is an important mediator of the effects of dioxin on B-cells. Dioxin induces AHR expression and results in inhibition of IgM secretion. Changes in B-cell differentiation and antibody production may depend on BACH2, a direct target of AHR. Outcome effects: BACH2 expression in response to dioxin-AHR binding inhibits PRDM1 and regulates the suppressive effects of BCL6 and PAX5. In addition, it was shown that IL4 causes AHR expression and activation in B-cells. IL4 can also induce AHR expression in a STAT6-dependent manner and translocate the induced AHR to the nuclei in both mouse and human B-cells. AhR activated by IL4 induces the expression of a xenobiotic-metabolizing gene, CYP1A1, and dioxin synergistically acts on the induction of this gene by IL4. Organ_System: lymphatic system PMID: 15899923 PMID: 20952503 PMID: 21296099 PMID: 23580432 PMID: 23942720 PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: bone marrow urn:agi-pathway:uuid-02fdf572-fd10-4bdb-8b06-37f11aa6db21 B-Cell Differentiation Inhibition by Dioxin uuid-02fdf572-fd10-4bdb-8b06-37f11aa6db21 PS:CellType B-cell PS:Description B cells - key components of humoral immunity - are sensitive to such toxic compounds as dioxin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-02fdf572-fd10-4bdb-8b06-37f11aa6db21 PS:NodeType Pathway PS:Notes Headnote: B-cells, key components of humoral immunity, are sensitive to such toxic compounds as dioxin. Signaling description: AHR is an important mediator of the effects of dioxin on B-cells. Dioxin induces AHR expression and results in inhibition of IgM secretion. Changes in B-cell differentiation and antibody production may depend on BACH2, a direct target of AHR. Outcome effects: BACH2 expression in response to dioxin-AHR binding inhibits PRDM1 and regulates the suppressive effects of BCL6 and PAX5. In addition, it was shown that IL4 causes AHR expression and activation in B-cells. IL4 can also induce AHR expression in a STAT6-dependent manner and translocate the induced AHR to the nuclei in both mouse and human B-cells. AhR activated by IL4 induces the expression of a xenobiotic-metabolizing gene, CYP1A1, and dioxin synergistically acts on the induction of this gene by IL4. PS:Organ_System lymphatic system PS:PMID 15899923 PS:PMID 20952503 PS:PMID 21296099 PS:PMID 23580432 PS:PMID 23942720 PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: granulosa cell CellType: theca cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0304650c-dc99-4c1f-a44a-b0d31c704704 NodeType: Pathway Notes: Headnote: Follicle stimulating hormone (FSH) and lutenising hormone (LH) are produced in the anterior lobe of pituitary gland and their function in gonads is mediated over distinct FSH and LH receptors (FSHR and LHCGR), respectively. LH receptors are found on both granulosa and thecal cells; the expression of FSH receptors is restricted to the granulose cells. Signaling description: LH stimulates female progesterone synthesis and ovulation and also theca cell androgen production. FSH is required for follicle maturation and stimulation of ovarian estrogen production. During the process of folliculogenesis, the conversion of cholesterol into ovarian hormones takes place. Conversion of steroids to androgens occurs within the theca cells. Androgens and are converted to estrogens by aromatase enzyme (CYP19A1) in the granulosa cells. NR5A1 is a key transcriptional regulator involved in production of key steroidogenic enzymes and transporters, including STAR, CYP11A1, CYP17A1, and CYP19A. Organ: ovary Organ_System: reproductive system PMID: 18703422 PMID: 20362963 PMID: 20364094 PMID: 20382564 PMID: 24365330 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-0304650c-dc99-4c1f-a44a-b0d31c704704 LH and FSH Signaling and Steroidogenesis uuid-0304650c-dc99-4c1f-a44a-b0d31c704704 PS:CellType granulosa cell PS:CellType theca cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0304650c-dc99-4c1f-a44a-b0d31c704704 PS:NodeType Pathway PS:Notes Headnote: Follicle stimulating hormone (FSH) and lutenising hormone (LH) are produced in the anterior lobe of pituitary gland and their function in gonads is mediated over distinct FSH and LH receptors (FSHR and LHCGR), respectively. LH receptors are found on both granulosa and thecal cells; the expression of FSH receptors is restricted to the granulose cells. Signaling description: LH stimulates female progesterone synthesis and ovulation and also theca cell androgen production. FSH is required for follicle maturation and stimulation of ovarian estrogen production. During the process of folliculogenesis, the conversion of cholesterol into ovarian hormones takes place. Conversion of steroids to androgens occurs within the theca cells. Androgens and are converted to estrogens by aromatase enzyme (CYP19A1) in the granulosa cells. NR5A1 is a key transcriptional regulator involved in production of key steroidogenic enzymes and transporters, including STAR, CYP11A1, CYP17A1, and CYP19A. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18703422 PS:PMID 20362963 PS:PMID 20364094 PS:PMID 20382564 PS:PMID 24365330 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-030f83cb-3ccc-4124-bc92-9d2708b0f6f5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-030f83cb-3ccc-4124-bc92-9d2708b0f6f5 FGF1 -> RUNX Expression Targets uuid-030f83cb-3ccc-4124-bc92-9d2708b0f6f5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-030f83cb-3ccc-4124-bc92-9d2708b0f6f5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0315367b-4867-48c3-bbc7-5443dd2d9ce9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-0315367b-4867-48c3-bbc7-5443dd2d9ce9 Purine metabolism template uuid-0315367b-4867-48c3-bbc7-5443dd2d9ce9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0315367b-4867-48c3-bbc7-5443dd2d9ce9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-032b7304-27ef-466b-a11e-ff513e62cb93 NodeType: Pathway Organ_System: hematological system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-032b7304-27ef-466b-a11e-ff513e62cb93 Proteins Involved in Systemic Lupus Erythematosus uuid-032b7304-27ef-466b-a11e-ff513e62cb93 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-032b7304-27ef-466b-a11e-ff513e62cb93 PS:NodeType Pathway PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The plasminogen activation system is mostly recognized for its fibrinolytic activity and ability to dissolve blood clots but it is also involved in inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-033417b5-a6ca-437f-b7d3-cbc45b8bfdb8 NodeType: Pathway Notes: Headnote: The plasminogen activation system is mostly recognized for its fibrinolytic activity and ability to dissolve blood clots, but it is also involved in inflammation. The interaction between coagulation and inflammation is a bidirectional process. Coagulation factors and plasminogen (PLG) are important players in inflammation. Signaling description: PLG is an inactive precursor of plasmin that is released from the liver. Upon binding to the cell surface, PLG is converted into active plasmin by PLAT, PLAU, KNG1, F12, and others. Fibrin is a cofactor for PLG activation by PLAT. There are several points of plasmin participation in inflammation. PLG influences inflammatory cell migration. Plasmin degrades a variety of matrix proteins (FN1 and laminin complex) and activates certain matrix metalloproteases (MMP1, MMP3, and MMP13) thereby facilitating cell migration through the extracellular matrix (ECM). The contribution of PLG to inflammatory cell recruitment is dependent upon its tethering to the surface of cells. The binding of PLG to cell surfaces is mediated by different receptors, collectively known as PLG-R. For example, ENO1 and ANXA2 are expressed on monocytoid cells and are directly implicated in macrophage recruitment. PLG also participates in the release or processing of various chemokines/cytokines. For instance, PLG triggers complement activation by classical pathway and triggers monocytes to release TGFB1 and leukotriene B4 (LTB4), thereby promoting an inflammatory response. PLG can also trigger intracellular signaling events in macrophages and neutrophils. Outcome effects: Plasmin may activate multiple signaling pathways including JAK1/TYK2/STAT3, p38 MAPK, and NF-kB pathway. Plasmin also activates MAPK3/MAPK1. Since a functional plasmin receptor has yet to be identified, the exact mechanisms of signaling pathways activated by PLG are not well known. In addition, macrophages share with monocytes the ANXA2/S100A10 heterotetramer, which can act as a signaling plasmin receptor. In contrast to thrombin (F2), which activates F2R and PARD3 and triggers an increase in Ca2+ and inositol 1,4,5-trisphosphate in monocytes, plasmin acts in a different manner. Monocytes express F2R, F2RL1, and PARD3, but it has been suggested that F2RL1 is not involved in monocyte activation. The pathway shows the probable mechanisms of transferring signals from receptors to transcription factors. As with LPS, plasmin preferentially induces the activation of IKBKB in monocytes. Plasmin-induced activation of JAK1, p38, MAPK3/MAPK1, and NF-kB is needed for cytokine expression in macrophages. Plasmin triggers monocytes for the rapid expression of TNF, IL1A, IL1B, and TF on the cell membrane. Plasmin also activates NF-kB and JUN/FOS resulting in CCL2 and CCL20 expression that causes monocytes and neutrophils to migrate into inflammatory foci. With NF-kB and JUN/FOS activation, plasmin leads to CD40 expression which is necessary for T-cell activation. Organ: generic Organ_System: hematological system PMID: 22561604 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-033417b5-a6ca-437f-b7d3-cbc45b8bfdb8 Plasmin Effects in Inflammation uuid-033417b5-a6ca-437f-b7d3-cbc45b8bfdb8 PS:CellType generic PS:Description The plasminogen activation system is mostly recognized for its fibrinolytic activity and ability to dissolve blood clots but it is also involved in inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-033417b5-a6ca-437f-b7d3-cbc45b8bfdb8 PS:NodeType Pathway PS:Notes Headnote: The plasminogen activation system is mostly recognized for its fibrinolytic activity and ability to dissolve blood clots, but it is also involved in inflammation. The interaction between coagulation and inflammation is a bidirectional process. Coagulation factors and plasminogen (PLG) are important players in inflammation. Signaling description: PLG is an inactive precursor of plasmin that is released from the liver. Upon binding to the cell surface, PLG is converted into active plasmin by PLAT, PLAU, KNG1, F12, and others. Fibrin is a cofactor for PLG activation by PLAT. There are several points of plasmin participation in inflammation. PLG influences inflammatory cell migration. Plasmin degrades a variety of matrix proteins (FN1 and laminin complex) and activates certain matrix metalloproteases (MMP1, MMP3, and MMP13) thereby facilitating cell migration through the extracellular matrix (ECM). The contribution of PLG to inflammatory cell recruitment is dependent upon its tethering to the surface of cells. The binding of PLG to cell surfaces is mediated by different receptors, collectively known as PLG-R. For example, ENO1 and ANXA2 are expressed on monocytoid cells and are directly implicated in macrophage recruitment. PLG also participates in the release or processing of various chemokines/cytokines. For instance, PLG triggers complement activation by classical pathway and triggers monocytes to release TGFB1 and leukotriene B4 (LTB4), thereby promoting an inflammatory response. PLG can also trigger intracellular signaling events in macrophages and neutrophils. Outcome effects: Plasmin may activate multiple signaling pathways including JAK1/TYK2/STAT3, p38 MAPK, and NF-kB pathway. Plasmin also activates MAPK3/MAPK1. Since a functional plasmin receptor has yet to be identified, the exact mechanisms of signaling pathways activated by PLG are not well known. In addition, macrophages share with monocytes the ANXA2/S100A10 heterotetramer, which can act as a signaling plasmin receptor. In contrast to thrombin (F2), which activates F2R and PARD3 and triggers an increase in Ca2+ and inositol 1,4,5-trisphosphate in monocytes, plasmin acts in a different manner. Monocytes express F2R, F2RL1, and PARD3, but it has been suggested that F2RL1 is not involved in monocyte activation. The pathway shows the probable mechanisms of transferring signals from receptors to transcription factors. As with LPS, plasmin preferentially induces the activation of IKBKB in monocytes. Plasmin-induced activation of JAK1, p38, MAPK3/MAPK1, and NF-kB is needed for cytokine expression in macrophages. Plasmin triggers monocytes for the rapid expression of TNF, IL1A, IL1B, and TF on the cell membrane. Plasmin also activates NF-kB and JUN/FOS resulting in CCL2 and CCL20 expression that causes monocytes and neutrophils to migrate into inflammatory foci. With NF-kB and JUN/FOS activation, plasmin leads to CD40 expression which is necessary for T-cell activation. PS:Organ generic PS:Organ_System hematological system PS:PMID 22561604 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-034a980c-20df-4c3b-a171-f06c9661419b NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-034a980c-20df-4c3b-a171-f06c9661419b Proteins Involved in Multiple Myeloma uuid-034a980c-20df-4c3b-a171-f06c9661419b PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-034a980c-20df-4c3b-a171-f06c9661419b PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0356c9d6-36e7-4f4e-8517-e04535b36dd5 NodeType: Pathway Notes: THR activates many specific cellular processes. The main target organ for thyroid hormones is the heart, and noticeable changes in cardiac function occur in patients with hypo- and hyperthyroidism. Also, thyroid hormones play a crucial role in cholesterol and lipid metabolism in the liver, in skeletal growth, and in the maintenance of bone mass. T3 plays a principal role in skeletal homeostasis and bone remodeling. Pathway 2. Effects of thyroid hormone deficiency: Cell-specific effects of thyroid hormone action (Fig. 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-0356c9d6-36e7-4f4e-8517-e04535b36dd5 2_2_Effects of thyroid hormone deficiency: cell-specific effects of thyroid hormone action uuid-0356c9d6-36e7-4f4e-8517-e04535b36dd5 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0356c9d6-36e7-4f4e-8517-e04535b36dd5 PS:NodeType Pathway PS:Notes THR activates many specific cellular processes. The main target organ for thyroid hormones is the heart, and noticeable changes in cardiac function occur in patients with hypo- and hyperthyroidism. Also, thyroid hormones play a crucial role in cholesterol and lipid metabolism in the liver, in skeletal growth, and in the maintenance of bone mass. T3 plays a principal role in skeletal homeostasis and bone remodeling. Pathway 2. Effects of thyroid hormone deficiency: Cell-specific effects of thyroid hormone action (Fig. 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Reed Sternberg cell CellType: cancer cell Description: Classical HL is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells, which are transformed post-germinal center B-cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-037e2c70-b0f5-470b-aa15-d86985cf0301 NodeType: Pathway Notes: Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). Classical HL, based on histological features, is further subdivided into 4 groups: 1) nodular sclerosis, 2) mixed cellularity HL, 3) lymphocyte depletion HL and 4) lymphocyte-rich HL. Nodular sclerosis HL accounts for about 60% of cases. Signaling description: Classical HL is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells, which are transformed post-germinal center B-cells destined for apoptosis since they have not undergone successful immunoglobulin gene rearrangement. Several mechanisms which are not clearly understood allow these cells to survive. HRS cells account for only about 1% of cells in the tumor tissue. The majority of cells in HL lesions are a mixed infiltrate of various types of cells of the immune system (T-cells, neutrophils, eosinophils, mast cells, and others). This microenvironment promotes the survival of HRS cells and helps them escape attack from cytotoxic T or natural killer (NK) cells. Classical HL is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. They have lost expression of most B cell-typical genes (B cell receptor (BCR), immunoglobulins, and many B-cell specific CD markers) and acquired expression of multiple genes typical for T-cells, myeloid cells, mast cells, and dendritic cells.Multiple signaling pathways and transcription factors show deregulated activity in HRS cells: NF-kB, JAK-STAT, PI3K/Akt, RAS-MAPK, NOTCH 1 and receptor tyrosine kinases. HRS cells also show constitutive activity of both the classical (canonical) and alternative (or non-canonical) NF-kB signaling pathways, which is regarded as the major pathogenetic mechanism in HL.NF-kB activity in HRS cells is mediated by diverse mechanisms: receptor signaling through CD40, TNFRSF8 (CD30), TNFRSF11A (RANK), TNFRSF17 (BCMA), and TNFRSF13B (TACI), genomic REL amplification, inactivating mutations in NFKBIA and NFKBIE, and signaling through the EBV protein LMP1. EBV is found in HRS cells in about 40% of classical HL. In pediatric HL, this association can be up to 90% and HL in patients with AIDS show EBV-infected HRS cells in nearly all cases. EBV proteins such as LMP1, LMP2A, and EBNA1 play a role in the pathophysiology of HL. LMP1 mimics an active CD40 receptor, thereby inducing constitutive NF-kB activation and can also activate JUN/FOS, PI3K, and JAK/STAT signaling. LMP2A can replace the function of an active BCR and mimic BCR signaling. EBNA1 blocks SMAD2, thereby interrupting TGF-beta receptor (TGFBR) signaling and decreasing the level of PTPRK, a member of the protein tyrosine phosphatase (PTP) family. The role of EBV in HL is important, but facultative, as 60% of patients develop the disease without EBV. In conclusion, the treatment of HL has been proven to be successful with the current treatment protocols involving multi-agent chemotherapy and/or radiotherapy (bleomycin, etoposide, Cytoxan, vincristine, procarbazine, and prednisone) and achieve cure rates of 80-90%. Outcome effects: The down-regulation of B-cell commitment genes such as PAX-5, EBF-1, and TCF-3 is responsible for the expression of myeloid and T-cell markers and loss of expression of most B-cell markers. In addition, the down-regulation of POU2AF1, POU2F2, and SPI1 genes is responsible for the block of immunoglobulins synthesis. Prominent lymph node fibrosis is a typical feature of most types of HL and originates from HRS cell-mediated fibroblast activation. Highlighted proteins: Viral proteins are shown in grey. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 14700604 PMID: 15086409 PMID: 16304386 PMID: 19078975 PMID: 20008234 PMID: 22224767 PMID: 23023715 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-037e2c70-b0f5-470b-aa15-d86985cf0301 Hodgkin Lymphoma uuid-037e2c70-b0f5-470b-aa15-d86985cf0301 PS:CellType Reed Sternberg cell PS:CellType cancer cell PS:Description Classical HL is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells, which are transformed post-germinal center B-cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-037e2c70-b0f5-470b-aa15-d86985cf0301 PS:NodeType Pathway PS:Notes Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). Classical HL, based on histological features, is further subdivided into 4 groups: 1) nodular sclerosis, 2) mixed cellularity HL, 3) lymphocyte depletion HL and 4) lymphocyte-rich HL. Nodular sclerosis HL accounts for about 60% of cases. Signaling description: Classical HL is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells, which are transformed post-germinal center B-cells destined for apoptosis since they have not undergone successful immunoglobulin gene rearrangement. Several mechanisms which are not clearly understood allow these cells to survive. HRS cells account for only about 1% of cells in the tumor tissue. The majority of cells in HL lesions are a mixed infiltrate of various types of cells of the immune system (T-cells, neutrophils, eosinophils, mast cells, and others). This microenvironment promotes the survival of HRS cells and helps them escape attack from cytotoxic T or natural killer (NK) cells. Classical HL is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. They have lost expression of most B cell-typical genes (B cell receptor (BCR), immunoglobulins, and many B-cell specific CD markers) and acquired expression of multiple genes typical for T-cells, myeloid cells, mast cells, and dendritic cells.Multiple signaling pathways and transcription factors show deregulated activity in HRS cells: NF-kB, JAK-STAT, PI3K/Akt, RAS-MAPK, NOTCH 1 and receptor tyrosine kinases. HRS cells also show constitutive activity of both the classical (canonical) and alternative (or non-canonical) NF-kB signaling pathways, which is regarded as the major pathogenetic mechanism in HL.NF-kB activity in HRS cells is mediated by diverse mechanisms: receptor signaling through CD40, TNFRSF8 (CD30), TNFRSF11A (RANK), TNFRSF17 (BCMA), and TNFRSF13B (TACI), genomic REL amplification, inactivating mutations in NFKBIA and NFKBIE, and signaling through the EBV protein LMP1. EBV is found in HRS cells in about 40% of classical HL. In pediatric HL, this association can be up to 90% and HL in patients with AIDS show EBV-infected HRS cells in nearly all cases. EBV proteins such as LMP1, LMP2A, and EBNA1 play a role in the pathophysiology of HL. LMP1 mimics an active CD40 receptor, thereby inducing constitutive NF-kB activation and can also activate JUN/FOS, PI3K, and JAK/STAT signaling. LMP2A can replace the function of an active BCR and mimic BCR signaling. EBNA1 blocks SMAD2, thereby interrupting TGF-beta receptor (TGFBR) signaling and decreasing the level of PTPRK, a member of the protein tyrosine phosphatase (PTP) family. The role of EBV in HL is important, but facultative, as 60% of patients develop the disease without EBV. In conclusion, the treatment of HL has been proven to be successful with the current treatment protocols involving multi-agent chemotherapy and/or radiotherapy (bleomycin, etoposide, Cytoxan, vincristine, procarbazine, and prednisone) and achieve cure rates of 80-90%. Outcome effects: The down-regulation of B-cell commitment genes such as PAX-5, EBF-1, and TCF-3 is responsible for the expression of myeloid and T-cell markers and loss of expression of most B-cell markers. In addition, the down-regulation of POU2AF1, POU2F2, and SPI1 genes is responsible for the block of immunoglobulins synthesis. Prominent lymph node fibrosis is a typical feature of most types of HL and originates from HRS cell-mediated fibroblast activation. Highlighted proteins: Viral proteins are shown in grey. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 14700604 PS:PMID 15086409 PS:PMID 16304386 PS:PMID 19078975 PS:PMID 20008234 PS:PMID 22224767 PS:PMID 23023715 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0388b15f-63cb-429e-a198-5ff40d0e2518 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-0388b15f-63cb-429e-a198-5ff40d0e2518 CRH -> Synthesis of Corticosteroids uuid-0388b15f-63cb-429e-a198-5ff40d0e2518 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0388b15f-63cb-429e-a198-5ff40d0e2518 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-039595b9-799c-4904-9ac7-b09d08ae9e24 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-039595b9-799c-4904-9ac7-b09d08ae9e24 NTF3 Expression Targets uuid-039595b9-799c-4904-9ac7-b09d08ae9e24 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-039595b9-799c-4904-9ac7-b09d08ae9e24 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03a4e910-8cff-433f-b33f-6a1dec82d16c NodeType: Pathway Notes: MTHFR converts folate to its active form, 5-methyltetrahydrofolate, which is a necessary co-factor in methionine cycle and is involved in the production of universal methyl donor S-adenosylmethionine. The decreased production of 5-methyltetrahydrofolate due to an altered MTHFR function may lead to the accumulation of non-metabolized Hcy, which may cause cell senescence. Organ: generic Organ_System: generic PMID: 18065414 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-03a4e910-8cff-433f-b33f-6a1dec82d16c MTHFR Activity Regulation uuid-03a4e910-8cff-433f-b33f-6a1dec82d16c PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03a4e910-8cff-433f-b33f-6a1dec82d16c PS:NodeType Pathway PS:Notes MTHFR converts folate to its active form, 5-methyltetrahydrofolate, which is a necessary co-factor in methionine cycle and is involved in the production of universal methyl donor S-adenosylmethionine. The decreased production of 5-methyltetrahydrofolate due to an altered MTHFR function may lead to the accumulation of non-metabolized Hcy, which may cause cell senescence. PS:Organ generic PS:Organ_System generic PS:PMID 18065414 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03a5843a-8abc-4adf-be5c-03d87ad849e3 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-03a5843a-8abc-4adf-be5c-03d87ad849e3 Rett Syndrome Mutated Genes uuid-03a5843a-8abc-4adf-be5c-03d87ad849e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03a5843a-8abc-4adf-be5c-03d87ad849e3 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell CellType: T-cell Description: Thyroid follicle damage might be provoked by self-antigen presentation and specific T lymphocyte activation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03b73de4-4f5e-4937-8827-515ae2e281c5 NodeType: Pathway Notes: Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. Thyroid follicle damage in HT may be provoked by self-antigen presentation by antigen-presenting cells (APCs) and specific T-lymphocyte activation. Signaling description: The central phase of HT is characterized by an apparent uncontrolled production of autoreactive CD4 T cells, CD8 cytotoxic T-cells, and immunoglobulin G autoantibodies. Studies involving HT patients indicate a strong association between TAb production and three CTLA4 single nucleotide polymorphisms (SNPs) including -318C/T in the promoter, 49A/G, and CT60. The SNP of the PTPN22 gene, resulting in arginine to tryptophan substitution at codon 620 (R620W), has been demonstrated to be a risk factor for many autoimmune diseases including HT. VDR-FokI SNP in exon 2 has also been identified in HT. The C allele of tumor necrosis factor (TNF)-beta -1031T/C SNP inhibitor of cytokine production is also associated with HT. Accordingly, in patients with HT, serum levels of TGFB1 were lower than in controls which did not change following treatment with levothyroxine. Outcome effects: In HT, thyrocytes with an aberrant expression of human leukocyte antigen (HLA) class II molecules may act as APCs capable of presenting thyroid autoantigens and initiating autoimmune thyroid disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: lymphatic system PMID: 10874534 PMID: 15762980 PMID: 17143095 PMID: 18752454 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-03b73de4-4f5e-4937-8827-515ae2e281c5 Immune Sustem Activation in Hashimoto's Thyroiditis uuid-03b73de4-4f5e-4937-8827-515ae2e281c5 PS:CellType B-cell PS:CellType T-cell PS:Description Thyroid follicle damage might be provoked by self-antigen presentation and specific T lymphocyte activation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03b73de4-4f5e-4937-8827-515ae2e281c5 PS:NodeType Pathway PS:Notes Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. Thyroid follicle damage in HT may be provoked by self-antigen presentation by antigen-presenting cells (APCs) and specific T-lymphocyte activation. Signaling description: The central phase of HT is characterized by an apparent uncontrolled production of autoreactive CD4 T cells, CD8 cytotoxic T-cells, and immunoglobulin G autoantibodies. Studies involving HT patients indicate a strong association between TAb production and three CTLA4 single nucleotide polymorphisms (SNPs) including -318C/T in the promoter, 49A/G, and CT60. The SNP of the PTPN22 gene, resulting in arginine to tryptophan substitution at codon 620 (R620W), has been demonstrated to be a risk factor for many autoimmune diseases including HT. VDR-FokI SNP in exon 2 has also been identified in HT. The C allele of tumor necrosis factor (TNF)-beta -1031T/C SNP inhibitor of cytokine production is also associated with HT. Accordingly, in patients with HT, serum levels of TGFB1 were lower than in controls which did not change following treatment with levothyroxine. Outcome effects: In HT, thyrocytes with an aberrant expression of human leukocyte antigen (HLA) class II molecules may act as APCs capable of presenting thyroid autoantigens and initiating autoimmune thyroid disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System lymphatic system PS:PMID 10874534 PS:PMID 15762980 PS:PMID 17143095 PS:PMID 18752454 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03bfae20-2c53-4767-a679-2f1bc13fddc0 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-03bfae20-2c53-4767-a679-2f1bc13fddc0 CD38/CD19 -> JUN/FOS/NF-kB Signaling in B-cell Proliferation uuid-03bfae20-2c53-4767-a679-2f1bc13fddc0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03bfae20-2c53-4767-a679-2f1bc13fddc0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03c093f9-dc73-43ff-a70c-670065e136c7 NodeType: Pathway Notes: The chronic hyperglycemia characteristic of diabetes causes damage to the microvessels (microangiopathy), resulting in impaired nutrition of peripheral nerve fibers. The limited vascular supply to peripheral nerves also makes nerves fibers susceptible to ischemia/hypoxia. Damage to the perineurium microvessels is likely the most critical factor in neuronal injury and dysfunction in DN. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-03c093f9-dc73-43ff-a70c-670065e136c7 1_Microangiopathy in diabetic neuropathy uuid-03c093f9-dc73-43ff-a70c-670065e136c7 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03c093f9-dc73-43ff-a70c-670065e136c7 PS:NodeType Pathway PS:Notes The chronic hyperglycemia characteristic of diabetes causes damage to the microvessels (microangiopathy), resulting in impaired nutrition of peripheral nerve fibers. The limited vascular supply to peripheral nerves also makes nerves fibers susceptible to ischemia/hypoxia. Damage to the perineurium microvessels is likely the most critical factor in neuronal injury and dysfunction in DN. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03ef019f-1d46-45da-8edd-c91f2c62698c NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-03ef019f-1d46-45da-8edd-c91f2c62698c alpha Oxidation of Phytanic Acid uuid-03ef019f-1d46-45da-8edd-c91f2c62698c PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-03ef019f-1d46-45da-8edd-c91f2c62698c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-041dc6d2-785b-4d5d-babc-8c5cdf2d3c97 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-041dc6d2-785b-4d5d-babc-8c5cdf2d3c97 Trehalose cycle template uuid-041dc6d2-785b-4d5d-babc-8c5cdf2d3c97 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-041dc6d2-785b-4d5d-babc-8c5cdf2d3c97 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: It is widely understood that cannabinoids modulate the sleep-wake cycle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-041ffac0-f52a-4fdc-8b3b-36acd9b96a40 NodeType: Pathway Notes: Headnote: It is widely accepted that cannabinoids modulate the sleep-wake cycle. Signaling description: Postsynaptic neurons synthesize and release endocannabinoids including anandamide and 2-arachidonylglycerol (2-AG). Anandamide is synthesized by NAPEPLD, while 2-AG is synthesized by PLCB1 and diacylglycerol lipases (DAGLs). Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic cannabinoid receptor 1 (CNR1) coupled to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+ channels. This reduces membrane depolarization and exocytosis, thereby inhibiting the release of neurotransmitters such as glutamate. MGLL inactivates 2-AG in presynaptic neurons. Fatty acid amide hydrolase (FAAH) inactivates anandamide in postsynaptic neurons. The transport of endocannabinoids facilitates both endocannabinoid release and re-uptake. Outcome effects: The development of drugs aimed to block CNR1 may be considered as new candidates for treating excessive somnolence. Moreover, the use of drugs that block the anandamide membrane transporter or inhibit FAAH activity may represent an opportunity to treat insomnia by enhancing the endogenous levels of anandamide. Organ: brain Organ_System: nervous system PMID: 14746372 PMID: 15340387 PMID: 18313952 PMID: 18514375 PMID: 21919868 PMID: 24520411 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-041ffac0-f52a-4fdc-8b3b-36acd9b96a40 Endocannabinoids Role in Sleep Regulation uuid-041ffac0-f52a-4fdc-8b3b-36acd9b96a40 PS:CellType neuron PS:Description It is widely understood that cannabinoids modulate the sleep-wake cycle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-041ffac0-f52a-4fdc-8b3b-36acd9b96a40 PS:NodeType Pathway PS:Notes Headnote: It is widely accepted that cannabinoids modulate the sleep-wake cycle. Signaling description: Postsynaptic neurons synthesize and release endocannabinoids including anandamide and 2-arachidonylglycerol (2-AG). Anandamide is synthesized by NAPEPLD, while 2-AG is synthesized by PLCB1 and diacylglycerol lipases (DAGLs). Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic cannabinoid receptor 1 (CNR1) coupled to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+ channels. This reduces membrane depolarization and exocytosis, thereby inhibiting the release of neurotransmitters such as glutamate. MGLL inactivates 2-AG in presynaptic neurons. Fatty acid amide hydrolase (FAAH) inactivates anandamide in postsynaptic neurons. The transport of endocannabinoids facilitates both endocannabinoid release and re-uptake. Outcome effects: The development of drugs aimed to block CNR1 may be considered as new candidates for treating excessive somnolence. Moreover, the use of drugs that block the anandamide membrane transporter or inhibit FAAH activity may represent an opportunity to treat insomnia by enhancing the endogenous levels of anandamide. PS:Organ brain PS:Organ_System nervous system PS:PMID 14746372 PS:PMID 15340387 PS:PMID 18313952 PS:PMID 18514375 PS:PMID 21919868 PS:PMID 24520411 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-042f79ca-b38b-4ca1-8def-97731a53d3e3 NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The nucleosome remodeling factor (NURF) complex is an imitation switch (ISWI)-containing chromatin remodeling complex that catalyzes ATP-dependent nucleosome sliding. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. The ISWI family of ATPases contains a SANT domain adjacent to a SLIDE domain that forms a nucleosome recognition module that binds to an unmodified histone tail and DNA. Outcome effects: NURF has the ability to alter chromatin structure and regulate transcription by nucleosome sliding. Mammalian NURF is composed of BPTF, ATPase subunit (SMARCA1), RBBP4, and RBBP7. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-042f79ca-b38b-4ca1-8def-97731a53d3e3 NURF in Chromatin Remodeling uuid-042f79ca-b38b-4ca1-8def-97731a53d3e3 PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-042f79ca-b38b-4ca1-8def-97731a53d3e3 PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The nucleosome remodeling factor (NURF) complex is an imitation switch (ISWI)-containing chromatin remodeling complex that catalyzes ATP-dependent nucleosome sliding. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. The ISWI family of ATPases contains a SANT domain adjacent to a SLIDE domain that forms a nucleosome recognition module that binds to an unmodified histone tail and DNA. Outcome effects: NURF has the ability to alter chromatin structure and regulate transcription by nucleosome sliding. Mammalian NURF is composed of BPTF, ATPase subunit (SMARCA1), RBBP4, and RBBP7. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-045dd18c-e732-4dea-9ecb-ef382d593591 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: IL33 can induce the release of IL13 independent of IgE stimulation and without mast cell degranulation. IL33 promotes cytokine production via MYD88-dependent pathway. This may suggest a potential role for IL33 in mast cell and Th2 cytokine-associated immune responses and disorders. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-045dd18c-e732-4dea-9ecb-ef382d593591 Mast-Cell Activation without Degranulation through IL33/IL1RL1 Signaling uuid-045dd18c-e732-4dea-9ecb-ef382d593591 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-045dd18c-e732-4dea-9ecb-ef382d593591 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: IL33 can induce the release of IL13 independent of IgE stimulation and without mast cell degranulation. IL33 promotes cytokine production via MYD88-dependent pathway. This may suggest a potential role for IL33 in mast cell and Th2 cytokine-associated immune responses and disorders. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04659cf0-895a-4b2d-a7dc-ab49bc05186c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-04659cf0-895a-4b2d-a7dc-ab49bc05186c Chlorophyllide biosynthesis template uuid-04659cf0-895a-4b2d-a7dc-ab49bc05186c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04659cf0-895a-4b2d-a7dc-ab49bc05186c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: hepatocyte Description: SHBG is the key circulating protein which controls the bioavailability of testosterone. IGFBP1 is the protein which binds free IGF1 preventing its action. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04679a1a-66d9-40ea-8475-b81d0ee0ed23 NodeType: Pathway Notes: Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. The origin of hyperandrogenemia arises from excessive luteinizing hormone (LH) stimulation of follicle theca cells. Signaling description: SHBG and IGFBP1 are proteins involved in the pathogenesis of polycystic ovary syndrome. SHBG is a key circulating protein, which controls the bioavailability of testosterone; whereas IGFBP1 is the protein, which binds free IGF1, thus preventing its action. Insulin (INS) can augment ovarian steroidogenesis indirectly by reducing the production of IGFBP1 in the liver and therefore elevating the levels of free IGF1 and reducing hepatic biosynthesis of SHBG. The mechanism of SHBG downregulation remains elusive. The mechanism of insulin-induced inhibition of IGFBP1 synthesis includes the initiation of the PI3K pathway leading to AKT1 activation. Outcome effects: Activated AKT1 phosphorylates and inhibits FOXO1 which is a positive regulator of IGFBP1 transcription. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: liver Organ_System: digestive system PMID: 19078868 PMID: 21606667 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-04679a1a-66d9-40ea-8475-b81d0ee0ed23 SHBG and IGFBP1 Synthesis Decline in Polycystic Ovary Syndrome uuid-04679a1a-66d9-40ea-8475-b81d0ee0ed23 PS:CellType hepatocyte PS:Description SHBG is the key circulating protein which controls the bioavailability of testosterone. IGFBP1 is the protein which binds free IGF1 preventing its action. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04679a1a-66d9-40ea-8475-b81d0ee0ed23 PS:NodeType Pathway PS:Notes Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. The origin of hyperandrogenemia arises from excessive luteinizing hormone (LH) stimulation of follicle theca cells. Signaling description: SHBG and IGFBP1 are proteins involved in the pathogenesis of polycystic ovary syndrome. SHBG is a key circulating protein, which controls the bioavailability of testosterone; whereas IGFBP1 is the protein, which binds free IGF1, thus preventing its action. Insulin (INS) can augment ovarian steroidogenesis indirectly by reducing the production of IGFBP1 in the liver and therefore elevating the levels of free IGF1 and reducing hepatic biosynthesis of SHBG. The mechanism of SHBG downregulation remains elusive. The mechanism of insulin-induced inhibition of IGFBP1 synthesis includes the initiation of the PI3K pathway leading to AKT1 activation. Outcome effects: Activated AKT1 phosphorylates and inhibits FOXO1 which is a positive regulator of IGFBP1 transcription. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ liver PS:Organ_System digestive system PS:PMID 19078868 PS:PMID 21606667 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04695630-52f0-4ab9-b0e5-f0a6ad76de79 NodeType: Pathway Notes: Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Mutant HTT disrupt binding of the HAP1/ DCTN1 complex to microtubules and motor complexes and thereby can depress BDNF axonal transport and release. Organ: brain Organ_System: nervous system PMID: 16339760 PMID: 16699508 PMID: 19262167 PMID: 20152113 PMID: 21882412 PMID: 22633949 PMID: 22921535 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: nerve tissue urn:agi-pathway:uuid-04695630-52f0-4ab9-b0e5-f0a6ad76de79 Axonal Transport uuid-04695630-52f0-4ab9-b0e5-f0a6ad76de79 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04695630-52f0-4ab9-b0e5-f0a6ad76de79 PS:NodeType Pathway PS:Notes Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Mutant HTT disrupt binding of the HAP1/ DCTN1 complex to microtubules and motor complexes and thereby can depress BDNF axonal transport and release. PS:Organ brain PS:Organ_System nervous system PS:PMID 16339760 PS:PMID 16699508 PS:PMID 19262167 PS:PMID 20152113 PS:PMID 21882412 PS:PMID 22633949 PS:PMID 22921535 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-047ca988-624f-4829-8859-652296d1bd99 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-047ca988-624f-4829-8859-652296d1bd99 Cellulose biosynthesis template uuid-047ca988-624f-4829-8859-652296d1bd99 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-047ca988-624f-4829-8859-652296d1bd99 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-048e8b8e-bdb9-4cd1-b2d9-7292b8ffc348 NodeType: Pathway Notes: Chondrocytes dye through a combination of apoptosis, necrosis, autophagy, and chondroptosis. Proinflammatory cytokines may promote chondrocyte death together ECM damage, oxidative, and mechanical stress. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-048e8b8e-bdb9-4cd1-b2d9-7292b8ffc348 2_Chondrocyte death in osteoarthritis uuid-048e8b8e-bdb9-4cd1-b2d9-7292b8ffc348 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-048e8b8e-bdb9-4cd1-b2d9-7292b8ffc348 PS:NodeType Pathway PS:Notes Chondrocytes dye through a combination of apoptosis, necrosis, autophagy, and chondroptosis. Proinflammatory cytokines may promote chondrocyte death together ECM damage, oxidative, and mechanical stress. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Annexins are a group of proteins that contain a conserved structural element, known as an annexin repeat, and are capable of binding to negatively charged phospholipids in a Ca2 -dependent manner. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-049ea356-a710-40a2-bcdf-0a9696e408cc NodeType: Pathway Notes: Headnote: Annexins are a group of proteins that contain a conserved structural element, known as the annexin repeat, and are capable of binding to negatively charged phospholipids in a Ca2+ -dependent manner. ANXA1 is the central annexin involved in anti-inflammatory responses. Signaling description: In resting polymorphonuclear leukocytes (PMN), approximately 60% of intracellular ANXA1 is localized in gelatinase and azurophilic granules. PMN adhesion to endothelial cell monolayers provokes the rapid mobilization of ANXA1 onto the cell surface. The engagement of FPR2/ lipoxin A4 by selective agonists may induce ANXA1 phosphorylation and mobilization in human PMNs. The mobilization of ANXA1 is downstream of PKC activation. Glucocorticoids regulate the synthesis and function of ANXA1 possibly through non-genomic processes, depending on the cell type and the time of induction. Interestingly, studies on the cytokine responsiveness of the ANXA1 promoter have revealed that the gene is induced by IL6. Outcome effects: ANXA1 and its derived peptides display potent proinflammatory activity and activate neutrophils in vitro by acting on FPR1. In contrast, other studies have shown that these peptides use FPR2 for their anti-inflammatory actions. ANXA1 was the first identified inhibitor of phospholipase A2. ANXA1 binds to F-actin and also interacts with profilin, a G-actin binding protein and regulator of actin polymerization. ANXA5 affects the mechanisms of coagulation and has been observed to relocate to the membrane cytoskeleton following platelet activation. This relocation appears to involve both binding to the plasma membrane and to a specific actin isoform, ACTG1. This is paralleled by an association with the platelet membrane of cytosolic phospholipase A2 which suggests an interaction between this phospholipase and ANXA5. The expression of ANXA2 on the cell surface is believed to serve as a receptor for plasminogen (PLG), which functions to produce plasmin. The production of plasmin counteracts fibrinolysis by promoting the degradation of fibrin. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-049ea356-a710-40a2-bcdf-0a9696e408cc Annexins in Inflammation Resolution uuid-049ea356-a710-40a2-bcdf-0a9696e408cc PS:CellType generic PS:Description Annexins are a group of proteins that contain a conserved structural element, known as an annexin repeat, and are capable of binding to negatively charged phospholipids in a Ca2 -dependent manner. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-049ea356-a710-40a2-bcdf-0a9696e408cc PS:NodeType Pathway PS:Notes Headnote: Annexins are a group of proteins that contain a conserved structural element, known as the annexin repeat, and are capable of binding to negatively charged phospholipids in a Ca2+ -dependent manner. ANXA1 is the central annexin involved in anti-inflammatory responses. Signaling description: In resting polymorphonuclear leukocytes (PMN), approximately 60% of intracellular ANXA1 is localized in gelatinase and azurophilic granules. PMN adhesion to endothelial cell monolayers provokes the rapid mobilization of ANXA1 onto the cell surface. The engagement of FPR2/ lipoxin A4 by selective agonists may induce ANXA1 phosphorylation and mobilization in human PMNs. The mobilization of ANXA1 is downstream of PKC activation. Glucocorticoids regulate the synthesis and function of ANXA1 possibly through non-genomic processes, depending on the cell type and the time of induction. Interestingly, studies on the cytokine responsiveness of the ANXA1 promoter have revealed that the gene is induced by IL6. Outcome effects: ANXA1 and its derived peptides display potent proinflammatory activity and activate neutrophils in vitro by acting on FPR1. In contrast, other studies have shown that these peptides use FPR2 for their anti-inflammatory actions. ANXA1 was the first identified inhibitor of phospholipase A2. ANXA1 binds to F-actin and also interacts with profilin, a G-actin binding protein and regulator of actin polymerization. ANXA5 affects the mechanisms of coagulation and has been observed to relocate to the membrane cytoskeleton following platelet activation. This relocation appears to involve both binding to the plasma membrane and to a specific actin isoform, ACTG1. This is paralleled by an association with the platelet membrane of cytosolic phospholipase A2 which suggests an interaction between this phospholipase and ANXA5. The expression of ANXA2 on the cell surface is believed to serve as a receptor for plasminogen (PLG), which functions to produce plasmin. The production of plasmin counteracts fibrinolysis by promoting the degradation of fibrin. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a18590-35f6-4f46-9b2d-058562d0799d NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-04a18590-35f6-4f46-9b2d-058562d0799d IL12R -> STAT Signaling uuid-04a18590-35f6-4f46-9b2d-058562d0799d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a18590-35f6-4f46-9b2d-058562d0799d PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a4caab-bd1f-4896-8ccd-7d1072bf61d5 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-04a4caab-bd1f-4896-8ccd-7d1072bf61d5 Serotonin Release in Nociception uuid-04a4caab-bd1f-4896-8ccd-7d1072bf61d5 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a4caab-bd1f-4896-8ccd-7d1072bf61d5 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuroglia CellType: neuron Description: Monomeric Abeta is soluble while oligomeric and cross linked Abeta is not, ultimately generating highly insoluble and stable plaques. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a7033c-8922-458a-9f07-2aeb598dae81 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The key aspect of the amyloidogenic (Hypothesis) of AD pathogenesis is the toxic effect of amyloid fibrils that are assembled in the extracellular space of a patient's brain. Signaling description: Abeta can exist in multiple assembly states: monomers, oligomers, protofibrils, and fibrils. Monomeric Abeta is soluble, while oligomeric and cross linked Abeta is not, ultimately generating highly insoluble and stable plaques. Diffuse senile plaques have been shown to consist of mainly Abeta 42(43), and classic senile plaques contain both Abeta 40 and Abeta 42(43), which is less soluble and forms fibrils faster than the shorter isoforms. Amyloid fibrils have toxic effects on the brain, at the same time soluble forms of Abeta can also produce neurotoxic effects. The mechanism by which nonfibrillar oligomers cause the loss of neurons is not yet clear, but the experimental evidence points to its toxicity at the synapses.The degradation of fibrillar Abeta can be accomplished via two major pathways: proteolytic degradation and receptor-mediated transport. In case of degradation, Abeta can be internalized and degraded by activated microglia in the brain. Low-density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycosylation end products (AGER) are both involved in receptor-mediated flux of Abeta across the blood-brain barrier. Outcome effects: Once Abeta enters the bloodstream, it can either reenter the brain via AGER receptor, or be delivered to peripheral sites of degradation (e.g. liver and kidney) by chaperone molecules such as APOE or A2M. Chaperones such as clusterin (CLU) and APOE are required for soluble amyloid trafficking into neurons and astrocytes. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 18549781 PMID: 21350608 PMID: 22248099 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-04a7033c-8922-458a-9f07-2aeb598dae81 Amyloid beta Traffic and Degradation in Extracellular Matrix in Alzheimer's Disease uuid-04a7033c-8922-458a-9f07-2aeb598dae81 PS:CellType astrocyte PS:CellType neuroglia PS:CellType neuron PS:Description Monomeric Abeta is soluble while oligomeric and cross linked Abeta is not, ultimately generating highly insoluble and stable plaques. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04a7033c-8922-458a-9f07-2aeb598dae81 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The key aspect of the amyloidogenic (Hypothesis) of AD pathogenesis is the toxic effect of amyloid fibrils that are assembled in the extracellular space of a patient's brain. Signaling description: Abeta can exist in multiple assembly states: monomers, oligomers, protofibrils, and fibrils. Monomeric Abeta is soluble, while oligomeric and cross linked Abeta is not, ultimately generating highly insoluble and stable plaques. Diffuse senile plaques have been shown to consist of mainly Abeta 42(43), and classic senile plaques contain both Abeta 40 and Abeta 42(43), which is less soluble and forms fibrils faster than the shorter isoforms. Amyloid fibrils have toxic effects on the brain, at the same time soluble forms of Abeta can also produce neurotoxic effects. The mechanism by which nonfibrillar oligomers cause the loss of neurons is not yet clear, but the experimental evidence points to its toxicity at the synapses.The degradation of fibrillar Abeta can be accomplished via two major pathways: proteolytic degradation and receptor-mediated transport. In case of degradation, Abeta can be internalized and degraded by activated microglia in the brain. Low-density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycosylation end products (AGER) are both involved in receptor-mediated flux of Abeta across the blood-brain barrier. Outcome effects: Once Abeta enters the bloodstream, it can either reenter the brain via AGER receptor, or be delivered to peripheral sites of degradation (e.g. liver and kidney) by chaperone molecules such as APOE or A2M. Chaperones such as clusterin (CLU) and APOE are required for soluble amyloid trafficking into neurons and astrocytes. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 18549781 PS:PMID 21350608 PS:PMID 22248099 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04cc8adc-fab5-44bd-a8f1-47939eca3f2e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-04cc8adc-fab5-44bd-a8f1-47939eca3f2e Cytoplasm-mitochondria interactions uuid-04cc8adc-fab5-44bd-a8f1-47939eca3f2e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04cc8adc-fab5-44bd-a8f1-47939eca3f2e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04d05c19-5f0f-4d9b-af68-71afbca251f1 NodeType: Pathway Notes: Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol non-genomic actions are described as the activation of C and phospholipase A2, PI3K, and the rapid generation of Ca2+, cyclic AMP, fatty acids and 3-phosphoinositides which lead to the activation of several protein kinases. Calcitriol also can open Ca2+ and Cl- channels. Organ: generic Organ_System: generic PMID: 26950144 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-04d05c19-5f0f-4d9b-af68-71afbca251f1 non-Genomic Rapid Actions of Vitamin D in Vitamin D Biology uuid-04d05c19-5f0f-4d9b-af68-71afbca251f1 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04d05c19-5f0f-4d9b-af68-71afbca251f1 PS:NodeType Pathway PS:Notes Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol non-genomic actions are described as the activation of C and phospholipase A2, PI3K, and the rapid generation of Ca2+, cyclic AMP, fatty acids and 3-phosphoinositides which lead to the activation of several protein kinases. Calcitriol also can open Ca2+ and Cl- channels. PS:Organ generic PS:Organ_System generic PS:PMID 26950144 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: About 40 percent of acute monocytic leukemia (AML-M5) patients have FLT3 and KIT mutations. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04d1b2e4-0bdc-4fbf-9678-c6d7b308f6a3 NodeType: Pathway Notes: Headnote: Acute monocytic leukemia (AML-M5) accounts for 10% of adult acute myeloid leukemia. Based on World Health Organization (WHO) criteria, AML-M5 is diagnosed when more than 80% of leukemic blasts are of the monocytic lineage. A further subclassification (M5a and M5b) depends on whether the monocytic cells are predominantly monoblasts (>80%) (acute monoblastic leukemia) or a mixture of monoblasts and promonocytes (<80% blasts). Signaling description: About 40% of AML-M5 patients have FLT3 and KIT mutations. MLL gene translocations occur in up to 50% of cases of AML in infants and in 80% of monoblastic variants of AML in infants and young children. MLL translocations are also found in approximately 10% of AML cases in adults. FLT3 and KIT are hematopoietic growth factor receptors of the same family of tyrosine kinases and are crucial mediators of stem-and progenitor-cell proliferation and survival. The major signal transduction pathways leading from FLT3 and KIT include PI3K/AKT1 and RAS/MAPK. One of the most frequent MLL gene translocation is MLL-AF10.MLL regulates target HOXA9 and MEIS1 gene expression through direct binding to promoter sequences Outcome effects: The expression of target genes leads to the inhibition of myeloblast differentiation and apoptosis while activating cell cycle and proliferation. MLL regulated HOXA9 and MEIS1 gene expression leads to the block of differentiation, stimulation of proliferation, and self-renewal of leukemic population. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. References: 1). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia. Hematology Education:the education program for the annual congress of the European Hematology Association.5:27-35. 2). Tallman MS, et al. (2004) Acute monocytic leukemia (French-American-British classification M5) does not have a worse prognosis than other subtypes of acute myeloid leukemia: a report from the Eastern Cooperative Oncology Group. J Clin Oncol. 22(7):1276-86. Organ_System: hematological system PMID: 14970186 PMID: 17658267 PMID: 19540337 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-04d1b2e4-0bdc-4fbf-9678-c6d7b308f6a3 FLT3/KIT/MLL Signaling in Leukemia uuid-04d1b2e4-0bdc-4fbf-9678-c6d7b308f6a3 PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description About 40 percent of acute monocytic leukemia (AML-M5) patients have FLT3 and KIT mutations. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04d1b2e4-0bdc-4fbf-9678-c6d7b308f6a3 PS:NodeType Pathway PS:Notes Headnote: Acute monocytic leukemia (AML-M5) accounts for 10% of adult acute myeloid leukemia. Based on World Health Organization (WHO) criteria, AML-M5 is diagnosed when more than 80% of leukemic blasts are of the monocytic lineage. A further subclassification (M5a and M5b) depends on whether the monocytic cells are predominantly monoblasts (>80%) (acute monoblastic leukemia) or a mixture of monoblasts and promonocytes (<80% blasts). Signaling description: About 40% of AML-M5 patients have FLT3 and KIT mutations. MLL gene translocations occur in up to 50% of cases of AML in infants and in 80% of monoblastic variants of AML in infants and young children. MLL translocations are also found in approximately 10% of AML cases in adults. FLT3 and KIT are hematopoietic growth factor receptors of the same family of tyrosine kinases and are crucial mediators of stem-and progenitor-cell proliferation and survival. The major signal transduction pathways leading from FLT3 and KIT include PI3K/AKT1 and RAS/MAPK. One of the most frequent MLL gene translocation is MLL-AF10.MLL regulates target HOXA9 and MEIS1 gene expression through direct binding to promoter sequences Outcome effects: The expression of target genes leads to the inhibition of myeloblast differentiation and apoptosis while activating cell cycle and proliferation. MLL regulated HOXA9 and MEIS1 gene expression leads to the block of differentiation, stimulation of proliferation, and self-renewal of leukemic population. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. References: 1). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia. Hematology Education:the education program for the annual congress of the European Hematology Association.5:27-35. 2). Tallman MS, et al. (2004) Acute monocytic leukemia (French-American-British classification M5) does not have a worse prognosis than other subtypes of acute myeloid leukemia: a report from the Eastern Cooperative Oncology Group. J Clin Oncol. 22(7):1276-86. PS:Organ_System hematological system PS:PMID 14970186 PS:PMID 17658267 PS:PMID 19540337 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04eb184f-9831-4daf-9355-55047f68da08 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-04eb184f-9831-4daf-9355-55047f68da08 IAA activation from amide conjugates template uuid-04eb184f-9831-4daf-9355-55047f68da08 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-04eb184f-9831-4daf-9355-55047f68da08 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:NodeType PS:Notes PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Notes: Read the description in the book: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Source: Atlas urn:agi-pathway:uuid-0519a422-719d-4973-a6d0-3075a11e1e98 3_single type network (autism associated transcriptional factors) uuid-0519a422-719d-4973-a6d0-3075a11e1e98 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Notes Read the description in the book: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: Parathyroid hormone (PTH) is a protein hormone synthesized and secreted by the parathyroid chief cells in response to changes in serum Ca2 levels. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05203e20-248b-421f-947d-220f18b4ed0c NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Parathyroid hormone (PTH) is a protein hormone synthesized, processed, and secreted by the parathyroid chief cells in response to changes in serum ionized calcium (Ca2+) levels. The reduction in serum Ca2+ levels triggers the secretion of PTH, whereas, a rise in vitamin D (calcitriol) levels suppresses PTH secretion. Insufficient Ca2+ intake and lack of calcitriol lead to secondary hyperparathyroidism, which increases the rate of bone remodeling in order to to maintain a normal serum Ca2+ level. Signaling description: The mechanism of bone resorption mediated by excessive PTH action involves the imbalance of the TNFSF11/TNFRSF11B ratio. Both ligands are produced by osteoblasts, and have the opposite functions. TNFSF11 induces osteoclast activation through its signaling, while TNFRSF11B terminates bone resorption by blocking TNFSF11. PTH causes CREB1 phosphorylation through PKA activation by promoting its binding to the promoter region of the TNFSF11 gene. At the same time, PTH down-regulates TNFRSF11B expression by an unknown mechanism. Outcome effects: The imbalance of the TNFSF11/TNFRSF11B ratio causes increased osteoclast activation and bone loss. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. References: 1). Kennedy P, Jain A, Srinivasan R, Chaudhry S (2010) Calcium homeostasis and osteoporosis. Clin J Am Soc Nephrol.5 Suppl 1:S23-30. Organ: bone Organ_System: skeletal system PMID: 16322775 PMID: 19171108 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-05203e20-248b-421f-947d-220f18b4ed0c Hyperparathyroidism, Secondary Effect uuid-05203e20-248b-421f-947d-220f18b4ed0c PS:CellType osteoblast PS:Description Parathyroid hormone (PTH) is a protein hormone synthesized and secreted by the parathyroid chief cells in response to changes in serum Ca2 levels. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05203e20-248b-421f-947d-220f18b4ed0c PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Parathyroid hormone (PTH) is a protein hormone synthesized, processed, and secreted by the parathyroid chief cells in response to changes in serum ionized calcium (Ca2+) levels. The reduction in serum Ca2+ levels triggers the secretion of PTH, whereas, a rise in vitamin D (calcitriol) levels suppresses PTH secretion. Insufficient Ca2+ intake and lack of calcitriol lead to secondary hyperparathyroidism, which increases the rate of bone remodeling in order to to maintain a normal serum Ca2+ level. Signaling description: The mechanism of bone resorption mediated by excessive PTH action involves the imbalance of the TNFSF11/TNFRSF11B ratio. Both ligands are produced by osteoblasts, and have the opposite functions. TNFSF11 induces osteoclast activation through its signaling, while TNFRSF11B terminates bone resorption by blocking TNFSF11. PTH causes CREB1 phosphorylation through PKA activation by promoting its binding to the promoter region of the TNFSF11 gene. At the same time, PTH down-regulates TNFRSF11B expression by an unknown mechanism. Outcome effects: The imbalance of the TNFSF11/TNFRSF11B ratio causes increased osteoclast activation and bone loss. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. References: 1). Kennedy P, Jain A, Srinivasan R, Chaudhry S (2010) Calcium homeostasis and osteoporosis. Clin J Am Soc Nephrol.5 Suppl 1:S23-30. PS:Organ bone PS:Organ_System skeletal system PS:PMID 16322775 PS:PMID 19171108 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-052d9828-a681-4595-938e-7697ae8c4880 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: generic urn:agi-pathway:uuid-052d9828-a681-4595-938e-7697ae8c4880 Hutchinson-Gilford Progeria Syndrome uuid-052d9828-a681-4595-938e-7697ae8c4880 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-052d9828-a681-4595-938e-7697ae8c4880 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-054cfcd8-fa60-41d1-84ff-628737ca15d5 NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-054cfcd8-fa60-41d1-84ff-628737ca15d5 SWI/SNF BRG1/BAF in Chromatin Remodeling uuid-054cfcd8-fa60-41d1-84ff-628737ca15d5 PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-054cfcd8-fa60-41d1-84ff-628737ca15d5 PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0571dabb-9b72-4e8a-bd85-2e38ba8b8e32 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-0571dabb-9b72-4e8a-bd85-2e38ba8b8e32 microRNAs -| TGFB uuid-0571dabb-9b72-4e8a-bd85-2e38ba8b8e32 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0571dabb-9b72-4e8a-bd85-2e38ba8b8e32 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05a8d64a-68e5-4026-988e-832af1d4b08b NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-05a8d64a-68e5-4026-988e-832af1d4b08b GABA Release in Nociception uuid-05a8d64a-68e5-4026-988e-832af1d4b08b PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05a8d64a-68e5-4026-988e-832af1d4b08b PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05c26b1d-6c3a-4c18-9b49-89800c8b8c0a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-05c26b1d-6c3a-4c18-9b49-89800c8b8c0a NGF -> CREB/CEBPB/MEF2A Expression Targets uuid-05c26b1d-6c3a-4c18-9b49-89800c8b8c0a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05c26b1d-6c3a-4c18-9b49-89800c8b8c0a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Ulcerative colitis belongs to a subgroup of inflammatory bowel diseases, is characterized as chronic inflammation, and has become a global health threat. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05df7322-d44b-426b-835a-103f78d218c0 NodeType: Pathway Notes: Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 21530742 PMID: 21616044 PMID: 25028192 PMID: 25133031 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-05df7322-d44b-426b-835a-103f78d218c0 T-Cell Cytotoxic Response in Ulcerative Colitis uuid-05df7322-d44b-426b-835a-103f78d218c0 PS:CellType natural killer cell PS:Description Ulcerative colitis belongs to a subgroup of inflammatory bowel diseases, is characterized as chronic inflammation, and has become a global health threat. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05df7322-d44b-426b-835a-103f78d218c0 PS:NodeType Pathway PS:Notes Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 21530742 PS:PMID 21616044 PS:PMID 25028192 PS:PMID 25133031 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: generic Description: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05ee7891-63d5-47e3-adff-214444e22825 NodeType: Pathway Notes: Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Insulin is an anabolic hormone that reduces the level of circulating glucose by allowing its entry into muscle cells and hepatocytes and through its conversion to a storage molecule called glycogen which is metabolized during an energy deficiency. Signaling description: Insulin (INS) binds to its receptor, INSR and the signal is transduced to IRS which activates PI3K. PI3K-generated PIP3 activates AKT1 leading to TBC1D4 phosphorylation and thus GLUT4 (SLC2A4) translocation into the membrane. Activated by PDPK1, PRKCH induces the same reaction. GLUT1 (SLC2A1) is the specific glucose transporter promoting the entry of glucose into the cell. Subsequently, glucose is converted into glycogen through several stages. The first stage is glucose phosphorylation by hexokinase. As a result, glucose-6-P is formed and then undergoes isomerization by phosphoglucomutase. The translocation of a phosphate group to the first position leads to glucose-1-P formation. UGP2 converts glucose-1-P to UDP-glucose. The last reaction is the addition of UDP-glucose molecules to chains of glycogen catalyzed by glycogen synthase 2 (GYS2). GYS2 activation is also obliged to insulin action through two mechanisms such as AKT1 inhibition of GYS2 inhibitor (GSK3B) and GYS2 phosphorylation by PPP1CC through SHC1/GRB2/ MAPK. Compounds with elevated level are highlighted in red. Organ: generic Organ_System: generic PMID: 10227847 PMID: 11780752 PMID: 18537611 PMID: 21498522 PMID: 9932214 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-05ee7891-63d5-47e3-adff-214444e22825 Insulin Influence on Glycogenesis uuid-05ee7891-63d5-47e3-adff-214444e22825 PS:CellType generic PS:Description Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-05ee7891-63d5-47e3-adff-214444e22825 PS:NodeType Pathway PS:Notes Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Insulin is an anabolic hormone that reduces the level of circulating glucose by allowing its entry into muscle cells and hepatocytes and through its conversion to a storage molecule called glycogen which is metabolized during an energy deficiency. Signaling description: Insulin (INS) binds to its receptor, INSR and the signal is transduced to IRS which activates PI3K. PI3K-generated PIP3 activates AKT1 leading to TBC1D4 phosphorylation and thus GLUT4 (SLC2A4) translocation into the membrane. Activated by PDPK1, PRKCH induces the same reaction. GLUT1 (SLC2A1) is the specific glucose transporter promoting the entry of glucose into the cell. Subsequently, glucose is converted into glycogen through several stages. The first stage is glucose phosphorylation by hexokinase. As a result, glucose-6-P is formed and then undergoes isomerization by phosphoglucomutase. The translocation of a phosphate group to the first position leads to glucose-1-P formation. UGP2 converts glucose-1-P to UDP-glucose. The last reaction is the addition of UDP-glucose molecules to chains of glycogen catalyzed by glycogen synthase 2 (GYS2). GYS2 activation is also obliged to insulin action through two mechanisms such as AKT1 inhibition of GYS2 inhibitor (GSK3B) and GYS2 phosphorylation by PPP1CC through SHC1/GRB2/ MAPK. Compounds with elevated level are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 10227847 PS:PMID 11780752 PS:PMID 18537611 PS:PMID 21498522 PS:PMID 9932214 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-060a33ec-6353-49df-b7ef-a38a9bdc818e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-060a33ec-6353-49df-b7ef-a38a9bdc818e PAF Expression Targets uuid-060a33ec-6353-49df-b7ef-a38a9bdc818e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-060a33ec-6353-49df-b7ef-a38a9bdc818e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-061051ce-62b1-4917-be85-1e180a68d793 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-061051ce-62b1-4917-be85-1e180a68d793 EGFR -> AP-1/CREB/ELK/SRF/MYC Signaling uuid-061051ce-62b1-4917-be85-1e180a68d793 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-061051ce-62b1-4917-be85-1e180a68d793 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0612d7e2-61ed-4693-9100-7d2d99a1623e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0612d7e2-61ed-4693-9100-7d2d99a1623e FGF4 -> AP-1/MYC Expression Targets uuid-0612d7e2-61ed-4693-9100-7d2d99a1623e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0612d7e2-61ed-4693-9100-7d2d99a1623e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: stem cell Description: Oncogene-induced senescence (OIS) is anti-proliferative response within the cell. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06364bec-fb61-4f66-94c8-25baa54b1ecb NodeType: Pathway Notes: Headnote: Oncogene-induced senescence (OIS) is anti-proliferative response within the cell as a result of activating mutation of an oncogene, or the inactivation of a tumor-suppressor gene (Chandeck C, 2010). Pathology of OIS is characterized with proliferative arrest and tumor suppression, cellular dysfunction of normal physiological functions, impact on other cells by secreting soluble factors such as cytokines, growth factors and proteases. Signaling description: Altered forms of PTEN , NF1 and KRAS cause changes in RAF/RAS and AKT1 downstream signalings. The core of AKT1 related signaling through MTOR regulates cell growth and autophagy. The core of RAS/RAF related signaling through MAPK cascade regulates cell cycle and mitosis. Precise mechanism of the molecular signaling on this pathway is well known and is associated with activation and accumulation of JUN/FOS, TP53 and CDKN2A. RB1 lies downstream JUN/FOS, TP53 and its persistent inhibition in OIS leads to mitosis arrest. Activated TP53 also is involved in DNA damage response regulation. Outcome effects: A lot of proteins are changing their expression due to signaling activation in OIS. Specificity of changing in protein expression profile is depends of cell type. Lysosome protein GLB1 accumulation in cytoplasm is proposed to be one of the common marker for altered senescent cell morphology. Altered regulation of histone methyltransferase SUV39H1 in OIS could lead to changes in chromatin and transcriptional repression due to formation of senescence-associated heterochromatic foci (SAHFs). Highlighted proteins: NF1 and SPRED1 with blue highlights have reduced expression/activity in human neurofibromas. LMNB1 with blue highlights has reduced expression/activity in human OIS fibroblasts, melanocytes and in liver of irradiated mice. For references see "Proteins with Altered Expression in Aging" pathway. Organ: generic Organ_System: generic PMID: 18193093 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-06364bec-fb61-4f66-94c8-25baa54b1ecb Oncogene Induced Cellular Senescence uuid-06364bec-fb61-4f66-94c8-25baa54b1ecb PS:CellType stem cell PS:Description Oncogene-induced senescence (OIS) is anti-proliferative response within the cell. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06364bec-fb61-4f66-94c8-25baa54b1ecb PS:NodeType Pathway PS:Notes Headnote: Oncogene-induced senescence (OIS) is anti-proliferative response within the cell as a result of activating mutation of an oncogene, or the inactivation of a tumor-suppressor gene (Chandeck C, 2010). Pathology of OIS is characterized with proliferative arrest and tumor suppression, cellular dysfunction of normal physiological functions, impact on other cells by secreting soluble factors such as cytokines, growth factors and proteases. Signaling description: Altered forms of PTEN , NF1 and KRAS cause changes in RAF/RAS and AKT1 downstream signalings. The core of AKT1 related signaling through MTOR regulates cell growth and autophagy. The core of RAS/RAF related signaling through MAPK cascade regulates cell cycle and mitosis. Precise mechanism of the molecular signaling on this pathway is well known and is associated with activation and accumulation of JUN/FOS, TP53 and CDKN2A. RB1 lies downstream JUN/FOS, TP53 and its persistent inhibition in OIS leads to mitosis arrest. Activated TP53 also is involved in DNA damage response regulation. Outcome effects: A lot of proteins are changing their expression due to signaling activation in OIS. Specificity of changing in protein expression profile is depends of cell type. Lysosome protein GLB1 accumulation in cytoplasm is proposed to be one of the common marker for altered senescent cell morphology. Altered regulation of histone methyltransferase SUV39H1 in OIS could lead to changes in chromatin and transcriptional repression due to formation of senescence-associated heterochromatic foci (SAHFs). Highlighted proteins: NF1 and SPRED1 with blue highlights have reduced expression/activity in human neurofibromas. LMNB1 with blue highlights has reduced expression/activity in human OIS fibroblasts, melanocytes and in liver of irradiated mice. For references see "Proteins with Altered Expression in Aging" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 18193093 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Mechanism of apoptosis induced by Coxsackievirus B3 (CVB3) in cardiomyocyte cells is likely through multiple converging pathways. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-067fda39-928a-46cc-8407-1a92bcc54b14 NodeType: Pathway Notes: Most probably, the coxsackievirus B3 (CVB3) induces apoptosis in cardiomyocyte cells through multiple converging pathways. One of them involves the induction of the death-receptor-mediated pathway by CVB3 through the activation of caspase-8 and cleavage of Bid. Organ: heart Organ_System: cardiovascular system PMID: 17195095 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-067fda39-928a-46cc-8407-1a92bcc54b14 Apoptosis of Myocyte uuid-067fda39-928a-46cc-8407-1a92bcc54b14 PS:CellType cardiac myocyte PS:Description Mechanism of apoptosis induced by Coxsackievirus B3 (CVB3) in cardiomyocyte cells is likely through multiple converging pathways. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-067fda39-928a-46cc-8407-1a92bcc54b14 PS:NodeType Pathway PS:Notes Most probably, the coxsackievirus B3 (CVB3) induces apoptosis in cardiomyocyte cells through multiple converging pathways. One of them involves the induction of the death-receptor-mediated pathway by CVB3 through the activation of caspase-8 and cleavage of Bid. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 17195095 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a1fe48-951a-45ac-8f45-fae423be5b73 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-06a1fe48-951a-45ac-8f45-fae423be5b73 AVP/Gs -> STAT Expression Targets uuid-06a1fe48-951a-45ac-8f45-fae423be5b73 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a1fe48-951a-45ac-8f45-fae423be5b73 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a45b6d-1940-4231-be90-a87b2021de57 NodeType: Pathway Notes: Headnote: The diversification of the antibody repertoire in addition to the variety of T-cell receptor (TCR) forms are obtained by the largely random recombination of variable (V), diversity (D), and joining (J) gene segments on the heavy chain locus and V and J segments on the light chain locus, immunoglobulin, and TCR genes. V(D)J recombination provides the versatility that is essential to normal immune functioning.A Signaling description: During the process of V(D)J recombination, rearrangement is initiated by double-stranded breaks (DSBs) in the 12 and 23 bp spaced recombination signal sequences (RSS). DSBs are initiated by RAG1 and RAG2 proteins. The activation of transcription of RAG1 and RAG2 genes is up- and downregulated at each B-cell or T-cell stage. Interleukin 7 (IL7) is the main activator of RAG1 and RAG2 expression, but other interleukins that induce T- and B-cell development are also necessary. FLT3 signaling strongly activates STAT5 and PAX5-mediated RAG1 and RAG2 expression during B-cell development. In addition, CD40 and related intracytoplasmic signaling implicate adaptor proteins (such as BLNK), phospholipase activation (PLCG2), and increased concentration of secondary messengers (calcium). These pathways recruit transcription factors involved in the activation of RAG expression. Outcome effects: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig) in somatic cell lines. These genes encode a unique receptor or Ig structure on each T or B-lymphocyte, respectively. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-06a45b6d-1940-4231-be90-a87b2021de57 V(D)J Recombination Activation uuid-06a45b6d-1940-4231-be90-a87b2021de57 PS:CellType B-cell PS:Description V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a45b6d-1940-4231-be90-a87b2021de57 PS:NodeType Pathway PS:Notes Headnote: The diversification of the antibody repertoire in addition to the variety of T-cell receptor (TCR) forms are obtained by the largely random recombination of variable (V), diversity (D), and joining (J) gene segments on the heavy chain locus and V and J segments on the light chain locus, immunoglobulin, and TCR genes. V(D)J recombination provides the versatility that is essential to normal immune functioning.A Signaling description: During the process of V(D)J recombination, rearrangement is initiated by double-stranded breaks (DSBs) in the 12 and 23 bp spaced recombination signal sequences (RSS). DSBs are initiated by RAG1 and RAG2 proteins. The activation of transcription of RAG1 and RAG2 genes is up- and downregulated at each B-cell or T-cell stage. Interleukin 7 (IL7) is the main activator of RAG1 and RAG2 expression, but other interleukins that induce T- and B-cell development are also necessary. FLT3 signaling strongly activates STAT5 and PAX5-mediated RAG1 and RAG2 expression during B-cell development. In addition, CD40 and related intracytoplasmic signaling implicate adaptor proteins (such as BLNK), phospholipase activation (PLCG2), and increased concentration of secondary messengers (calcium). These pathways recruit transcription factors involved in the activation of RAG expression. Outcome effects: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig) in somatic cell lines. These genes encode a unique receptor or Ig structure on each T or B-lymphocyte, respectively. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a6bf82-cf9a-448b-8d37-4d105d8d0635 NodeType: Pathway Notes: High levels of glutamate in the synaptic cleft are found in each type of a hemiplegic migraine (familial and sporadic). Excess glutamate triggers the synthesis of high levels of prostaglandin E2 (PGE2) and nitric oxide (NO) by both neurons and astrocytes in migraines. Increased amounts of PGE2 were detected in patients prior to and during a migraine attack. Synthesized in neurons and astrocytes, PGE2 and NO in turn induce the synthesis of NO in endothelial cells and smooth muscle cells in dura meter. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-06a6bf82-cf9a-448b-8d37-4d105d8d0635 1_1_Glutamate overload enforced prostaglandins and NO synthesis in neurons uuid-06a6bf82-cf9a-448b-8d37-4d105d8d0635 PS:CellType neuron PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06a6bf82-cf9a-448b-8d37-4d105d8d0635 PS:NodeType Pathway PS:Notes High levels of glutamate in the synaptic cleft are found in each type of a hemiplegic migraine (familial and sporadic). Excess glutamate triggers the synthesis of high levels of prostaglandin E2 (PGE2) and nitric oxide (NO) by both neurons and astrocytes in migraines. Increased amounts of PGE2 were detected in patients prior to and during a migraine attack. Synthesized in neurons and astrocytes, PGE2 and NO in turn induce the synthesis of NO in endothelial cells and smooth muscle cells in dura meter. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: NKT-like cell CellType: enterocyte Description: In Celiac disease intraepithelial cytotoxic T lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cell. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06c2d242-cf7e-4060-856a-64cc7ad1da6e NodeType: Pathway Notes: Headnote: Celiac disease (CeD) is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals worldwide. CeD is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Immunodominant 33-mer peptide from a-gliadin translocates into the lamina propria via IFN? dependent transcytosis, which suggests involvement of the transcellular route. Protected transport pathway, which is driven by retrotranscytosis of secretory IgA through transferrin receptor CD71, promotes the influx of intact, and thus harmful, gluten peptides. Intestinal epithelium plays a central role in Celiac disease pathogenesis. It modulates the intestinal immune system that is acutely altered by gliadin. This indicates that gliadin can gain access to the basal surface of the epithelium, and therefore interact directly with the immune system, via both trans- and paracellular routes of absorption. Gluten peptides can be transported across the intestinal epithelium either paracellularly as a consequence of impaired mucosal integrity attributable to increased release of zonulin upon 19 mer gliadin binding to chemokine (C-X-C motif) receptor 3 (CXCR3 receptor). Outcome effects: Zonulin induces a protein kinase C-mediated rearrangement of the cytoskeleton, downregulation of ZO-1 and occludin, and disruption of tight junction complex integrity, increasing epithelial permeability. Interleukin 15 (IL-15)-induced perforin/granzyme and homodimeric natural killer-activating receptor-major histocompatibility-class I chain-related gene A complex (NKG2D-MICA) signaling pathways promote increased cytotoxicity of intraepithelial lymphocytes. Intestinal epithelial cells express high levels of interleukin-15, along with MICs and HLA-E. IL-15 causes upregulation of NKG2D expression by intraepithelial cytotoxic T-lymphocytes and the cytotoxic signalling pathway associated with this receptor. Consequently, intraepithelial cytotoxic T-lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cells. Description of highlighted proteins; IL15, HP, KLRK1 and gliadin are highlighted in red in order to emphasize their increased expression and violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease. TJP1 and OCLN are highlighted in blue in order to display decrease of the intestine barrier and the tight junction assembly, resulting in Celiac disease.Description of Mutated genes: MICA gene in white out style has genetic variants which increase susceptibility to Celiac disease. Organ_System: digestive system Organ_System: lymphatic system PMID: 17053448 PMID: 19935805 PMID: 20301720 PMID: 23155333 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-06c2d242-cf7e-4060-856a-64cc7ad1da6e Enterocyte Mediated Mucosal Damage in Celiac Disease uuid-06c2d242-cf7e-4060-856a-64cc7ad1da6e PS:CellType NKT-like cell PS:CellType enterocyte PS:Description In Celiac disease intraepithelial cytotoxic T lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cell. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06c2d242-cf7e-4060-856a-64cc7ad1da6e PS:NodeType Pathway PS:Notes Headnote: Celiac disease (CeD) is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals worldwide. CeD is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Immunodominant 33-mer peptide from a-gliadin translocates into the lamina propria via IFN? dependent transcytosis, which suggests involvement of the transcellular route. Protected transport pathway, which is driven by retrotranscytosis of secretory IgA through transferrin receptor CD71, promotes the influx of intact, and thus harmful, gluten peptides. Intestinal epithelium plays a central role in Celiac disease pathogenesis. It modulates the intestinal immune system that is acutely altered by gliadin. This indicates that gliadin can gain access to the basal surface of the epithelium, and therefore interact directly with the immune system, via both trans- and paracellular routes of absorption. Gluten peptides can be transported across the intestinal epithelium either paracellularly as a consequence of impaired mucosal integrity attributable to increased release of zonulin upon 19 mer gliadin binding to chemokine (C-X-C motif) receptor 3 (CXCR3 receptor). Outcome effects: Zonulin induces a protein kinase C-mediated rearrangement of the cytoskeleton, downregulation of ZO-1 and occludin, and disruption of tight junction complex integrity, increasing epithelial permeability. Interleukin 15 (IL-15)-induced perforin/granzyme and homodimeric natural killer-activating receptor-major histocompatibility-class I chain-related gene A complex (NKG2D-MICA) signaling pathways promote increased cytotoxicity of intraepithelial lymphocytes. Intestinal epithelial cells express high levels of interleukin-15, along with MICs and HLA-E. IL-15 causes upregulation of NKG2D expression by intraepithelial cytotoxic T-lymphocytes and the cytotoxic signalling pathway associated with this receptor. Consequently, intraepithelial cytotoxic T-lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cells. Description of highlighted proteins; IL15, HP, KLRK1 and gliadin are highlighted in red in order to emphasize their increased expression and violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease. TJP1 and OCLN are highlighted in blue in order to display decrease of the intestine barrier and the tight junction assembly, resulting in Celiac disease.Description of Mutated genes: MICA gene in white out style has genetic variants which increase susceptibility to Celiac disease. PS:Organ_System digestive system PS:Organ_System lymphatic system PS:PMID 17053448 PS:PMID 19935805 PS:PMID 20301720 PS:PMID 23155333 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06d02b91-1cb9-465f-9fe9-1fc951c53ada NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-06d02b91-1cb9-465f-9fe9-1fc951c53ada Pyruvate Metabolism uuid-06d02b91-1cb9-465f-9fe9-1fc951c53ada PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06d02b91-1cb9-465f-9fe9-1fc951c53ada PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06ef67ec-dcd9-4650-a84a-6b56c1d25f9c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-06ef67ec-dcd9-4650-a84a-6b56c1d25f9c Aberrant macrophage activation in COVID19 uuid-06ef67ec-dcd9-4650-a84a-6b56c1d25f9c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06ef67ec-dcd9-4650-a84a-6b56c1d25f9c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f24348-aee1-46fb-9946-bda26448dbe8 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-06f24348-aee1-46fb-9946-bda26448dbe8 Glucocorticoids in Insulin Resistance in Skeletal Muscles uuid-06f24348-aee1-46fb-9946-bda26448dbe8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f24348-aee1-46fb-9946-bda26448dbe8 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Bextra (valdecoxib) is a prescription drug used for the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f369f1-416b-4eee-b44c-2b09fa5a0131 NodeType: Pathway Notes: Headnote: Bextra (valdecoxib) is a prescription drug used for the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is classified as a nonsteroidal anti-inflammatory drug (NSAIDs). Signaling description: In 2005, Bextra was removed from the U.S. market due to concerns about the possible increased risk of heart infarction and stroke. Valdecoxib is a direct inhibitor of prostaglandin synthase (PTGS2), which produces prostaglandin E2 (PGE2). Prostaglandins are secreted and bound to one out of four receptors depending on the cell type. Particularly, PGE2 is bound to PTGER4, which is essential for the late phase of ischemic preconditioning. In addition, PTGER4-induced cAMP synthesis is associated with increased degradation of AGTR1 mRNA. This receptor mediates angiotensin (AGT)-induced vasoconstriction. Outcome effects: Bextra treatment, especially while recovering from heart surgery, significantly increases the risk of heart ischemic disease and blood flow aberrations, which in turn increase the risk of brain ischemia. Organ: heart Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-06f369f1-416b-4eee-b44c-2b09fa5a0131 Valdecoxib Induced Ischemic Disease uuid-06f369f1-416b-4eee-b44c-2b09fa5a0131 PS:Description Bextra (valdecoxib) is a prescription drug used for the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f369f1-416b-4eee-b44c-2b09fa5a0131 PS:NodeType Pathway PS:Notes Headnote: Bextra (valdecoxib) is a prescription drug used for the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is classified as a nonsteroidal anti-inflammatory drug (NSAIDs). Signaling description: In 2005, Bextra was removed from the U.S. market due to concerns about the possible increased risk of heart infarction and stroke. Valdecoxib is a direct inhibitor of prostaglandin synthase (PTGS2), which produces prostaglandin E2 (PGE2). Prostaglandins are secreted and bound to one out of four receptors depending on the cell type. Particularly, PGE2 is bound to PTGER4, which is essential for the late phase of ischemic preconditioning. In addition, PTGER4-induced cAMP synthesis is associated with increased degradation of AGTR1 mRNA. This receptor mediates angiotensin (AGT)-induced vasoconstriction. Outcome effects: Bextra treatment, especially while recovering from heart surgery, significantly increases the risk of heart ischemic disease and blood flow aberrations, which in turn increase the risk of brain ischemia. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f8129a-db8a-4284-a9bd-8c4b5d050e86 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-06f8129a-db8a-4284-a9bd-8c4b5d050e86 Proteins with Altered Expression in Hyper IgM Syndrome uuid-06f8129a-db8a-4284-a9bd-8c4b5d050e86 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-06f8129a-db8a-4284-a9bd-8c4b5d050e86 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0708c5be-81a7-486e-9453-da093a01625d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0708c5be-81a7-486e-9453-da093a01625d Adenosine Expression Targets uuid-0708c5be-81a7-486e-9453-da093a01625d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0708c5be-81a7-486e-9453-da093a01625d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07167258-f3e2-44ed-9663-b12f514fab2f NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-07167258-f3e2-44ed-9663-b12f514fab2f GALR1/2/3 -> POMC/NPY Production uuid-07167258-f3e2-44ed-9663-b12f514fab2f PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07167258-f3e2-44ed-9663-b12f514fab2f PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-071ffc0d-a272-41df-b4f3-b040d06b313f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-071ffc0d-a272-41df-b4f3-b040d06b313f IL10 Expression Targets uuid-071ffc0d-a272-41df-b4f3-b040d06b313f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-071ffc0d-a272-41df-b4f3-b040d06b313f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07251fd7-d65e-43dc-951a-c4550e6c3685 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-07251fd7-d65e-43dc-951a-c4550e6c3685 EGFR -> SMAD1 Signaling uuid-07251fd7-d65e-43dc-951a-c4550e6c3685 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07251fd7-d65e-43dc-951a-c4550e6c3685 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-072fe474-904c-4611-afcf-906191b2e860 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-072fe474-904c-4611-afcf-906191b2e860 Coronavirus-CSF3-Kawasaki uuid-072fe474-904c-4611-afcf-906191b2e860 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-072fe474-904c-4611-afcf-906191b2e860 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07622630-0c02-4e64-9908-526c1fa0de74 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-07622630-0c02-4e64-9908-526c1fa0de74 EFNA1 -> STAT Expression Target uuid-07622630-0c02-4e64-9908-526c1fa0de74 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07622630-0c02-4e64-9908-526c1fa0de74 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-076de15e-e62d-4670-b95d-38ceb9b2b1c0 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: endocrine system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-076de15e-e62d-4670-b95d-38ceb9b2b1c0 Lipodystrophy, Familial Partial uuid-076de15e-e62d-4670-b95d-38ceb9b2b1c0 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-076de15e-e62d-4670-b95d-38ceb9b2b1c0 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System endocrine system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: The Humoral immune reaction has been implicated in vitiligo through the detection of circulating antibodies. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-077182a8-1ba9-4778-a960-a32825e8b684 NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Signaling description: Humoral immune response is implicated in vitiligo pathogenesis. Antibodies against melanocyte-derived antigens were found to be present in the serum of vitiligo patients. Outcome effects: The disease-related antibodies in vitiligo are thought to be involved in melanocyte destruction by yet to be identified mechanism. . Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 11121127 PMID: 23425123 PMID: 23668538 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-077182a8-1ba9-4778-a960-a32825e8b684 Humoral Immunity in Vitiligo uuid-077182a8-1ba9-4778-a960-a32825e8b684 PS:CellType B-cell PS:Description The Humoral immune reaction has been implicated in vitiligo through the detection of circulating antibodies. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-077182a8-1ba9-4778-a960-a32825e8b684 PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Signaling description: Humoral immune response is implicated in vitiligo pathogenesis. Antibodies against melanocyte-derived antigens were found to be present in the serum of vitiligo patients. Outcome effects: The disease-related antibodies in vitiligo are thought to be involved in melanocyte destruction by yet to be identified mechanism. . Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 11121127 PS:PMID 23425123 PS:PMID 23668538 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: A-cell (X-like) Description: Synthesis and release of Nesfatin-1 and Ghrelin by A-cells (X-like) due to taste receptors activation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07b2475d-51f1-4634-9b6c-405813d2b039 NodeType: Pathway Notes: Headnote: The activation of A-cells (stomach enteroendocrine cells similar to X-cells) is part of the digestive process. Activation of A-cells leads to the expression and release of ghrelin and nesfatin-1 and initiates interaction of nutrients with taste receptors. Signaling description: The core of taste receptor related signaling leads to NUCB2 transcription activation and repression of GHR genes through two signaling pathways: PLCbeta/Ca2+ and cAMP signaling. The mechanisms of activation ghrelin expression and release are still not known. The taste receptor signaling pathways lead to the repression of ghrelin synthesis and nesfatin-1 release. Notably, ghrelin is released in the first wave of secretion, and nesfatin-1 in the second wave (10-20 minutes following ghreli release). The precise mechanism of this process is poorly understood. One of hypotheses is depicted on the pathway. Outcome effects: Ghrelin expression stimulates pancreatic juice secretion, gastric motility activation and growth hormone release; also, ghrelin blocks the sense of satiety. Nesfatin-1 expression leads to satiety and blocks gastric motility. Organ: stomach Organ_System: digestive system PMID: 24061204 PMID: 24381790 PMID: 27754932 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-07b2475d-51f1-4634-9b6c-405813d2b039 A-cell (X-like): Ghrelin and Nesfatin-1 Synthesis uuid-07b2475d-51f1-4634-9b6c-405813d2b039 PS:CellType A-cell (X-like) PS:Description Synthesis and release of Nesfatin-1 and Ghrelin by A-cells (X-like) due to taste receptors activation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07b2475d-51f1-4634-9b6c-405813d2b039 PS:NodeType Pathway PS:Notes Headnote: The activation of A-cells (stomach enteroendocrine cells similar to X-cells) is part of the digestive process. Activation of A-cells leads to the expression and release of ghrelin and nesfatin-1 and initiates interaction of nutrients with taste receptors. Signaling description: The core of taste receptor related signaling leads to NUCB2 transcription activation and repression of GHR genes through two signaling pathways: PLCbeta/Ca2+ and cAMP signaling. The mechanisms of activation ghrelin expression and release are still not known. The taste receptor signaling pathways lead to the repression of ghrelin synthesis and nesfatin-1 release. Notably, ghrelin is released in the first wave of secretion, and nesfatin-1 in the second wave (10-20 minutes following ghreli release). The precise mechanism of this process is poorly understood. One of hypotheses is depicted on the pathway. Outcome effects: Ghrelin expression stimulates pancreatic juice secretion, gastric motility activation and growth hormone release; also, ghrelin blocks the sense of satiety. Nesfatin-1 expression leads to satiety and blocks gastric motility. PS:Organ stomach PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 24381790 PS:PMID 27754932 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Microtubules, the principal component of the cytoskeleton, are represented by rigid hollow rods with a diameter of approximately 25nm. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07b37fe9-6a3a-4b26-b64e-ac1be3eda5d4 NodeType: Pathway Notes: Headnote: Microtubules, the principal component of the cytoskeleton, are represented by rigid hollow rods with a diameter of approximately 25nm. Microtubules possess various functions including determining cell shape and participating in a variety of cell movements from organelle locomotion to cellular motility. Signaling description: Microtubules are composed of a single type of globular protein known as tubulin. The alpha- and beta-tubulin dimers polymerize end-to-end in protofilaments. Typically, the microtubule is formed by thirteen associated protofilaments. Microtubules, such as actin filaments, are polar structures with two distinct ends including a fast-growing plus end and a slow-growing minus end. The protofilaments bundle parallel to one another, so in a microtubule, there is one end, the ( ) end, with only beta subunits exposed while the other end, the (-) end, only has alpha subunits exposed. The elongation of the microtubule occurs from the ( ) end since the (-) end is capped. During polymerization, both the alpha- and beta-subunits of the tubulin dimer are bound to a molecule of GTP. While the GTP bound to alpha-tubulin is stable, the GTP bound to beta-tubulin may be hydrolyzed to GDP shortly after assembly. In animal cells, the major microtubule-organizing center is the centrosome which is located adjacent to the nucleus near the center of interphase (non-dividing) cells. The centrosome serves as the initiation site for the assembly of microtubules, which grow outward from the centrosome toward the periphery of the cell. The key protein in the centrosome that nucleates the assembly of microtubules is the gamma tubulin ring complex. Kinesins and dyneins are members of two large families of motor proteins that are responsible for powering the variety of movements in which microtubules participate. Kinesins move microtubules in toward the plus end and dyneins toward the minus end. As for actin filaments, movement along microtubules is based on the action of motor proteins that utilize energy derived from ATP hydrolysis to produce force and movement. The dynein family of related proteins cooperates with another protein complex, dynactin, to move towards the minus end of microtubules. Most kinesin family members move towards the plus end of microtubules and only KIF14 moves towards the minus end to serve a vital function during mitosis and chromosome separation. Outcome effects: Different types of proteins bind to microtubules such as MAPT, MAP2, and MAP4 which act as stabilizers and spacers between microtubules. In addition, MAPT binds to the microtubule surface through electrostatic interactions to increase the stability of the microtubule and favor microtubule elongation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-07b37fe9-6a3a-4b26-b64e-ac1be3eda5d4 Microtubule Cytoskeleton uuid-07b37fe9-6a3a-4b26-b64e-ac1be3eda5d4 PS:CellType generic PS:Description Microtubules, the principal component of the cytoskeleton, are represented by rigid hollow rods with a diameter of approximately 25nm. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07b37fe9-6a3a-4b26-b64e-ac1be3eda5d4 PS:NodeType Pathway PS:Notes Headnote: Microtubules, the principal component of the cytoskeleton, are represented by rigid hollow rods with a diameter of approximately 25nm. Microtubules possess various functions including determining cell shape and participating in a variety of cell movements from organelle locomotion to cellular motility. Signaling description: Microtubules are composed of a single type of globular protein known as tubulin. The alpha- and beta-tubulin dimers polymerize end-to-end in protofilaments. Typically, the microtubule is formed by thirteen associated protofilaments. Microtubules, such as actin filaments, are polar structures with two distinct ends including a fast-growing plus end and a slow-growing minus end. The protofilaments bundle parallel to one another, so in a microtubule, there is one end, the ( ) end, with only beta subunits exposed while the other end, the (-) end, only has alpha subunits exposed. The elongation of the microtubule occurs from the ( ) end since the (-) end is capped. During polymerization, both the alpha- and beta-subunits of the tubulin dimer are bound to a molecule of GTP. While the GTP bound to alpha-tubulin is stable, the GTP bound to beta-tubulin may be hydrolyzed to GDP shortly after assembly. In animal cells, the major microtubule-organizing center is the centrosome which is located adjacent to the nucleus near the center of interphase (non-dividing) cells. The centrosome serves as the initiation site for the assembly of microtubules, which grow outward from the centrosome toward the periphery of the cell. The key protein in the centrosome that nucleates the assembly of microtubules is the gamma tubulin ring complex. Kinesins and dyneins are members of two large families of motor proteins that are responsible for powering the variety of movements in which microtubules participate. Kinesins move microtubules in toward the plus end and dyneins toward the minus end. As for actin filaments, movement along microtubules is based on the action of motor proteins that utilize energy derived from ATP hydrolysis to produce force and movement. The dynein family of related proteins cooperates with another protein complex, dynactin, to move towards the minus end of microtubules. Most kinesin family members move towards the plus end of microtubules and only KIF14 moves towards the minus end to serve a vital function during mitosis and chromosome separation. Outcome effects: Different types of proteins bind to microtubules such as MAPT, MAP2, and MAP4 which act as stabilizers and spacers between microtubules. In addition, MAPT binds to the microtubule surface through electrostatic interactions to increase the stability of the microtubule and favor microtubule elongation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07dfbc6f-2680-4b74-8cef-81b77daf204d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-07dfbc6f-2680-4b74-8cef-81b77daf204d GH1/GHR -> NF-kB/ELK/SRF/MYC Expression Targets uuid-07dfbc6f-2680-4b74-8cef-81b77daf204d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07dfbc6f-2680-4b74-8cef-81b77daf204d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: epithelial cell CellType: leukocyte CellType: mast cell CellType: monocyte Description: NOD-like receptors (NLRs) are cytoplasmic proteins that may bind to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07fc7dc2-d5ec-40ff-a193-add5101fd788 NodeType: Pathway Notes: Headnote: NOD-like receptors (NLRs) are cytoplasmic proteins that may bind to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). NLRs are involved in the regulation of inflammatory and apoptotic responses. Signaling description: The NLR family consists of several proteins that are divided into subfamilies based on their N-terminal protein-interacting domains. NLRC is a subfamily of NLRs, which includes intracellular receptors that contain a CARD-domain (caspase recruiting domain), namely NOD1 and NOD2. Both NOD1 and NOD2 recognize bacterial molecules produced during peptidoglycan (PGN) synthesis in gram-negative bacteria and in some gram-positive bacteria such as Listeria monocytogenes and Bacillus sp. NOD1 recognizes D-gamma-glutamyl-meso- diaminopimelic acid dipeptide (iE-DAP) found in the PGN of all gram-negative and certain gram-positive bacteria, whereas NOD2 recognizes the muramyl dipeptide (MDP) structure found in almost all bacteria. Thus, NOD2 acts as a general sensor of PGN, while NOD1 is involved in the recognition of a specific subset of bacteria. In addition, ligand bound NOD1 and NOD2 oligomerize and activate signaling via RIPK2. Once activated, RIPK2 mediates the ubiquitination of IKBKG leading to the activation of NF-kB and the production of inflammatory cytokines. Furthermore, poly-ubiquitinated RIPK2 recruits TAK1 (MAP3K7), which leads to IKBKG complex activation and the activation of MAPKs. Also, NOD2 signaling has been shown to involve the adapter protein, CARD9 to mediate MAPK p38 and JNK (MAPK8) signaling through RIPK2. NLRC4 also belongs to the NLRC subfamily. Caspase-1 (CASP1) activation induced by cytosolic flagellin has been shown to be NLRC4-dependent. AIM2 acts as a cytosolic DNA sensor that responds to the release of type I interferon and proinflammatory cytokines. AIM2 also acts through inflammasomes to activate CASP1. The NLRP subfamily consists of 14 members characterized by their PYD effector domains. NLPR3 and NLPR1 are the most studied receptors in this subfamily. NLRP1 oligomerization induced by MDP requires ATP. NLRP3 activation is induced by a wide variety of stimuli including whole bacteria (Listeria monocytogenes and Staphylococcus aureus), bacterial RNA, uric acid crystals, amyloid beta, extracellular ATP, and pore-forming toxins (nigericin and maitotoxin). Outcome effects: NLRPs form a multiprotein complex called an inflammasome. NLRP1 and NLRP3 recruit PYCARD, which in turn interacts with CASP1 via a CARD-CARD interaction. CASP1 activation in inflammasomes leads to the maturation and activation of IL1B, IL18, and IL33. These cytokines activate macrophages and T-cells. Lastly, NOD9 (NLRX1) is the first NLR protein shown to be localized at the mitochondria. NLRX1 blocks antiviral inflammatory responses via the MAVS-related pathway. Organ: generic Organ_System: generic PMID: 19748439 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-07fc7dc2-d5ec-40ff-a193-add5101fd788 NOD-like Receptors uuid-07fc7dc2-d5ec-40ff-a193-add5101fd788 PS:CellType dendritic cell PS:CellType epithelial cell PS:CellType leukocyte PS:CellType mast cell PS:CellType monocyte PS:Description NOD-like receptors (NLRs) are cytoplasmic proteins that may bind to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-07fc7dc2-d5ec-40ff-a193-add5101fd788 PS:NodeType Pathway PS:Notes Headnote: NOD-like receptors (NLRs) are cytoplasmic proteins that may bind to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). NLRs are involved in the regulation of inflammatory and apoptotic responses. Signaling description: The NLR family consists of several proteins that are divided into subfamilies based on their N-terminal protein-interacting domains. NLRC is a subfamily of NLRs, which includes intracellular receptors that contain a CARD-domain (caspase recruiting domain), namely NOD1 and NOD2. Both NOD1 and NOD2 recognize bacterial molecules produced during peptidoglycan (PGN) synthesis in gram-negative bacteria and in some gram-positive bacteria such as Listeria monocytogenes and Bacillus sp. NOD1 recognizes D-gamma-glutamyl-meso- diaminopimelic acid dipeptide (iE-DAP) found in the PGN of all gram-negative and certain gram-positive bacteria, whereas NOD2 recognizes the muramyl dipeptide (MDP) structure found in almost all bacteria. Thus, NOD2 acts as a general sensor of PGN, while NOD1 is involved in the recognition of a specific subset of bacteria. In addition, ligand bound NOD1 and NOD2 oligomerize and activate signaling via RIPK2. Once activated, RIPK2 mediates the ubiquitination of IKBKG leading to the activation of NF-kB and the production of inflammatory cytokines. Furthermore, poly-ubiquitinated RIPK2 recruits TAK1 (MAP3K7), which leads to IKBKG complex activation and the activation of MAPKs. Also, NOD2 signaling has been shown to involve the adapter protein, CARD9 to mediate MAPK p38 and JNK (MAPK8) signaling through RIPK2. NLRC4 also belongs to the NLRC subfamily. Caspase-1 (CASP1) activation induced by cytosolic flagellin has been shown to be NLRC4-dependent. AIM2 acts as a cytosolic DNA sensor that responds to the release of type I interferon and proinflammatory cytokines. AIM2 also acts through inflammasomes to activate CASP1. The NLRP subfamily consists of 14 members characterized by their PYD effector domains. NLPR3 and NLPR1 are the most studied receptors in this subfamily. NLRP1 oligomerization induced by MDP requires ATP. NLRP3 activation is induced by a wide variety of stimuli including whole bacteria (Listeria monocytogenes and Staphylococcus aureus), bacterial RNA, uric acid crystals, amyloid beta, extracellular ATP, and pore-forming toxins (nigericin and maitotoxin). Outcome effects: NLRPs form a multiprotein complex called an inflammasome. NLRP1 and NLRP3 recruit PYCARD, which in turn interacts with CASP1 via a CARD-CARD interaction. CASP1 activation in inflammasomes leads to the maturation and activation of IL1B, IL18, and IL33. These cytokines activate macrophages and T-cells. Lastly, NOD9 (NLRX1) is the first NLR protein shown to be localized at the mitochondria. NLRX1 blocks antiviral inflammatory responses via the MAVS-related pathway. PS:Organ generic PS:Organ_System generic PS:PMID 19748439 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0813ef72-533c-4ad9-a6ba-283e4c02668d NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: epididymis Organ: testis Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-0813ef72-533c-4ad9-a6ba-283e4c02668d Elevated Receptors -> Expression Targets in Epididymis uuid-0813ef72-533c-4ad9-a6ba-283e4c02668d PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0813ef72-533c-4ad9-a6ba-283e4c02668d PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ epididymis PS:Organ testis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Acid secretion is one of the most important functions of the collecting duct segment of the kidney nephron. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0823be29-79a0-492c-8dea-d12fa1d9fdfa NodeType: Pathway Notes: Headnote: Acid secretion is one of the most important functions of the collecting duct segment of the kidney nephron. Signaling description: As daily food intake loads acid into the body, urinary acid excretion is essential. The alpha-intercalated cell of the collecting duct is mainly responsible for hydrogen secretion into the urine. Carbon dioxide (CO2), which is generated in the cell and enters from the blood, is converted to carbonic acid. Carbonic acid is divided into hydrogen ion (H+) and bicarbonate ion (HCO3-). Intracellular carbonic anhydrase II (CA2) catalyzes the formation of these ions. Outcome effects: Hydrogen ions are secreted into the lumen by H -transporting two-sector ATPase and H /K -exchanging ATPase. The bicarbonate ion is transported to the blood side by the anion exchanger type 1 (SLC4A1). Organ: kidney Organ_System: urinary tract PMID: 17164835 PMID: 19948674 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-0823be29-79a0-492c-8dea-d12fa1d9fdfa Acid Secretion by Collecting Duct of Kidney Nephron uuid-0823be29-79a0-492c-8dea-d12fa1d9fdfa PS:Description Acid secretion is one of the most important functions of the collecting duct segment of the kidney nephron. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0823be29-79a0-492c-8dea-d12fa1d9fdfa PS:NodeType Pathway PS:Notes Headnote: Acid secretion is one of the most important functions of the collecting duct segment of the kidney nephron. Signaling description: As daily food intake loads acid into the body, urinary acid excretion is essential. The alpha-intercalated cell of the collecting duct is mainly responsible for hydrogen secretion into the urine. Carbon dioxide (CO2), which is generated in the cell and enters from the blood, is converted to carbonic acid. Carbonic acid is divided into hydrogen ion (H+) and bicarbonate ion (HCO3-). Intracellular carbonic anhydrase II (CA2) catalyzes the formation of these ions. Outcome effects: Hydrogen ions are secreted into the lumen by H -transporting two-sector ATPase and H /K -exchanging ATPase. The bicarbonate ion is transported to the blood side by the anion exchanger type 1 (SLC4A1). PS:Organ kidney PS:Organ_System urinary tract PS:PMID 17164835 PS:PMID 19948674 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0830ca6c-7eb1-4c4a-a797-e005d5dd3d18 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-0830ca6c-7eb1-4c4a-a797-e005d5dd3d18 Cytokine->IR uuid-0830ca6c-7eb1-4c4a-a797-e005d5dd3d18 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0830ca6c-7eb1-4c4a-a797-e005d5dd3d18 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08517acc-9da6-4c40-9928-9fb9ac6c4e04 NodeType: Pathway Organ: generic Organ_System: generic PMID: 21167873 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-08517acc-9da6-4c40-9928-9fb9ac6c4e04 ERK5/MAPK7 Signaling uuid-08517acc-9da6-4c40-9928-9fb9ac6c4e04 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08517acc-9da6-4c40-9928-9fb9ac6c4e04 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21167873 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085714e4-3f5f-48f2-adad-5a012991dc22 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-085714e4-3f5f-48f2-adad-5a012991dc22 TNF -> AP-1 Expression Targets uuid-085714e4-3f5f-48f2-adad-5a012991dc22 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085714e4-3f5f-48f2-adad-5a012991dc22 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085dcc7a-451d-4541-9959-5320b7356788 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-085dcc7a-451d-4541-9959-5320b7356788 Proteins Involved in Lesch-Nyhan Syndrome uuid-085dcc7a-451d-4541-9959-5320b7356788 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085dcc7a-451d-4541-9959-5320b7356788 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085de9db-2a8b-4ecb-bd32-5defe59ee076 NodeType: Pathway Notes: Mutations in the proteins, which regulate mitochondrial function, endocytosis and the degradation of misfolded proteins, or RNA metabolism, can lead to the accumulation of toxic protein aggregates in neurons, which initiate neuron apoptosis. The accumulation of misfolded proteins in neurons triggers mitochondrial dysfunction, which includes the overloading of endoplasmic reticulum–associated degradation of proteins (ERAD), the unfolded protein response (UPR), and the impairment of autophagy. The mitochondrial dysfunction prominent in ALS neurons initiates apoptosis. All this leads to the further accumulation of insoluble protein aggregates, a reduction of transcription, and diminished DNA repair leading to neuron death. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-085de9db-2a8b-4ecb-bd32-5defe59ee076 2_Mutations in SOD1 and associated proteins cause motor neuron death in familial ALS uuid-085de9db-2a8b-4ecb-bd32-5defe59ee076 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-085de9db-2a8b-4ecb-bd32-5defe59ee076 PS:NodeType Pathway PS:Notes Mutations in the proteins, which regulate mitochondrial function, endocytosis and the degradation of misfolded proteins, or RNA metabolism, can lead to the accumulation of toxic protein aggregates in neurons, which initiate neuron apoptosis. The accumulation of misfolded proteins in neurons triggers mitochondrial dysfunction, which includes the overloading of endoplasmic reticulum–associated degradation of proteins (ERAD), the unfolded protein response (UPR), and the impairment of autophagy. The mitochondrial dysfunction prominent in ALS neurons initiates apoptosis. All this leads to the further accumulation of insoluble protein aggregates, a reduction of transcription, and diminished DNA repair leading to neuron death. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-086391c6-6fec-4707-ba12-99fbaf784bb0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-086391c6-6fec-4707-ba12-99fbaf784bb0 SARS-| glycosylation quality control and ERAD uuid-086391c6-6fec-4707-ba12-99fbaf784bb0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-086391c6-6fec-4707-ba12-99fbaf784bb0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08700efc-83a8-4a74-b2c0-94541d1339f7 NodeType: Pathway Notes: The Gram-positive bacterium S. pneumoniae, Gram-negative bacteria nontypable H. influenza (NTHi) and M. catarrhalis synergistically induce the activation of mucus production in the middle ear effusion of patients with chronic otitis media. The viscous mucus of the middle ear is a heterogeneous mixture of secreted polypeptides, mainly mucins. The rise of mucin production is a vital defense response against invading microbes (also see Asthma). Excess mucin production, however, results in a conductive hearing loss observed in otitis media. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-08700efc-83a8-4a74-b2c0-94541d1339f7 2_Pathogens stimulate mucins expression in the middle ear uuid-08700efc-83a8-4a74-b2c0-94541d1339f7 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08700efc-83a8-4a74-b2c0-94541d1339f7 PS:NodeType Pathway PS:Notes The Gram-positive bacterium S. pneumoniae, Gram-negative bacteria nontypable H. influenza (NTHi) and M. catarrhalis synergistically induce the activation of mucus production in the middle ear effusion of patients with chronic otitis media. The viscous mucus of the middle ear is a heterogeneous mixture of secreted polypeptides, mainly mucins. The rise of mucin production is a vital defense response against invading microbes (also see Asthma). Excess mucin production, however, results in a conductive hearing loss observed in otitis media. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08a0f8de-e1b2-43be-850e-24d4f692c17b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-08a0f8de-e1b2-43be-850e-24d4f692c17b CCL3L1 Expression Target uuid-08a0f8de-e1b2-43be-850e-24d4f692c17b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08a0f8de-e1b2-43be-850e-24d4f692c17b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ae2bbb-b4b5-49ec-bb3d-05a1f7750a76 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-08ae2bbb-b4b5-49ec-bb3d-05a1f7750a76 SELE -> ELK-SRF Signaling uuid-08ae2bbb-b4b5-49ec-bb3d-05a1f7750a76 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ae2bbb-b4b5-49ec-bb3d-05a1f7750a76 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vasodilation is the widening of blood vessels due to the relaxation of vascular smooth muscle cells within the vessel walls. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08cf71e7-e7dd-4cd7-8aff-133323dda90a NodeType: Pathway Notes: Headnote: Vasodilation is the widening of blood vessels due to the relaxation of vascular smooth muscle cells within the vessel walls. Signaling description: During inflammation, vascular vasodilation causes the engorgement of blood vessels, increase in blood flow, and redness and swelling from injury. Two different mechanisms modulate the relaxation of vascular smooth muscle cells including Gs-protein (GNAS)-coupled pathway and nitric oxide (NO)-cGMP pathway. GNAS-coupled pathway in vascular smooth muscle cells stimulates ADCY, which catalyzes the formation of cAMP. Outcome effects: Unlike the heart, an increase in cAMP in vascular smooth muscle cells causes reduced contraction and increased relaxation. The reason for this is that MYLK is inhibited by cAMP. MYLK phosphorylates myosin and causes contraction. The most potent vasodilators, which act through GNAS signaling, are epinephrine, adenosine, PGI2, PGD2, PGE2, and histamine. Another mechanism that regulates vascular smooth muscle tone is the NO/cGMP pathway. Vascular endothelial cells normally produce NO which diffuses from endothelial cells to adjacent smooth muscle cells and activates guanylyl cyclase (sGC) leading to the increased formation of cGMP and vasodilation. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-08cf71e7-e7dd-4cd7-8aff-133323dda90a Vasodilation Activation uuid-08cf71e7-e7dd-4cd7-8aff-133323dda90a PS:CellType endothelial cell PS:Description Vasodilation is the widening of blood vessels due to the relaxation of vascular smooth muscle cells within the vessel walls. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08cf71e7-e7dd-4cd7-8aff-133323dda90a PS:NodeType Pathway PS:Notes Headnote: Vasodilation is the widening of blood vessels due to the relaxation of vascular smooth muscle cells within the vessel walls. Signaling description: During inflammation, vascular vasodilation causes the engorgement of blood vessels, increase in blood flow, and redness and swelling from injury. Two different mechanisms modulate the relaxation of vascular smooth muscle cells including Gs-protein (GNAS)-coupled pathway and nitric oxide (NO)-cGMP pathway. GNAS-coupled pathway in vascular smooth muscle cells stimulates ADCY, which catalyzes the formation of cAMP. Outcome effects: Unlike the heart, an increase in cAMP in vascular smooth muscle cells causes reduced contraction and increased relaxation. The reason for this is that MYLK is inhibited by cAMP. MYLK phosphorylates myosin and causes contraction. The most potent vasodilators, which act through GNAS signaling, are epinephrine, adenosine, PGI2, PGD2, PGE2, and histamine. Another mechanism that regulates vascular smooth muscle tone is the NO/cGMP pathway. Vascular endothelial cells normally produce NO which diffuses from endothelial cells to adjacent smooth muscle cells and activates guanylyl cyclase (sGC) leading to the increased formation of cGMP and vasodilation. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08e4784d-bf43-4072-81a4-68bdae6fee4f NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-08e4784d-bf43-4072-81a4-68bdae6fee4f Muscular Facioscapulohumeral Dystrophy Drugs uuid-08e4784d-bf43-4072-81a4-68bdae6fee4f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08e4784d-bf43-4072-81a4-68bdae6fee4f PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: In aged people the higher protein level of SIRT1 was observed. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08e83dbe-4214-4143-ba1b-40a7a7625f6f NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. In aged people the higher protein level of SIRT1 was observed. SNV in SIRT1 was found to be significantly associated with longevity and telomere length. Signaling description: SIRT1 is a deacetylase which has a wide array of targets in the nucleus and cytoplasm. SIRT1 requires NAD+ for its function. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. Outcome effects: Activated SIRT1 can play protective role in cell stress response by decreasing transcription or protein synthesis and reducing oxidative stress. NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. Highlighted proteins: SIRT1 with red highlights have increased expression/activity in some older people (above 55 years) compared with younger people. See all references in "Proteins with Altered Expression in Aging" pathway. Mutated proteins: SNV (rs7896005) in SIRT1 was found to be significantly associated with longevity and telomere length. See all references in ""Genes with Mutations Associated with Aging"" pathway. Organ: generic Organ_System: generic PMID: 19478080 PMID: 25785999 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-08e83dbe-4214-4143-ba1b-40a7a7625f6f SIRT1 Signaling in Aging uuid-08e83dbe-4214-4143-ba1b-40a7a7625f6f PS:CellType generic PS:Description In aged people the higher protein level of SIRT1 was observed. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08e83dbe-4214-4143-ba1b-40a7a7625f6f PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. In aged people the higher protein level of SIRT1 was observed. SNV in SIRT1 was found to be significantly associated with longevity and telomere length. Signaling description: SIRT1 is a deacetylase which has a wide array of targets in the nucleus and cytoplasm. SIRT1 requires NAD+ for its function. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. Outcome effects: Activated SIRT1 can play protective role in cell stress response by decreasing transcription or protein synthesis and reducing oxidative stress. NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. Highlighted proteins: SIRT1 with red highlights have increased expression/activity in some older people (above 55 years) compared with younger people. See all references in "Proteins with Altered Expression in Aging" pathway. Mutated proteins: SNV (rs7896005) in SIRT1 was found to be significantly associated with longevity and telomere length. See all references in ""Genes with Mutations Associated with Aging"" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 19478080 PS:PMID 25785999 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ea1e64-cbe1-409b-a4b4-33c3cb9370b3 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-08ea1e64-cbe1-409b-a4b4-33c3cb9370b3 PTPRC -> STAT6 Signaling uuid-08ea1e64-cbe1-409b-a4b4-33c3cb9370b3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ea1e64-cbe1-409b-a4b4-33c3cb9370b3 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ff05a2-0c9c-43c1-b58f-8e97024a29b9 NodeType: Pathway Notes: Headnote: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Splenic MZL (SMZL) is an indolent B-cell neoplasm involving spleen, bone marrow, and rarely peripheral blood. Signaling description: The pathogenesis of SMZL is not well known, however, clinical data point to an association with hepatitis C virus. The infection rate of SMZL does not exceed 15-20%. NF-kB is constitutively activated in 60% of SMZL cases due to TNFAIP3, IKBKB, TRAF3, MAP3K14, and BIRC3 mutations. Activating lesions of MYD88 and CARD11 are found in Toll-like receptor (TLR) and B-cell receptor (BCR) pathways. TP53 disruption is found in 10-15% of cases. Outcome effects: The clinical course of SMZL is heterogeneous, although the majority of cases show an indolent course with a median survival of approximately ten years. Roughly 10% of cases undergo transformation to diffuse large B-cell lymphoma. The therapeutic options for SMZL include a "watch and wait" approach, splenectomy, chemotherapy, and B-cell-depleting therapy with rituximab. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: spleen Organ_System: lymphatic system PMID: 22102703 PMID: 22556352 PMID: 23233614 PMID: 23378931 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-08ff05a2-0c9c-43c1-b58f-8e97024a29b9 Splenic Marginal Zone Lymphoma uuid-08ff05a2-0c9c-43c1-b58f-8e97024a29b9 PS:CellType B-cell PS:CellType cancer cell PS:Description Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-08ff05a2-0c9c-43c1-b58f-8e97024a29b9 PS:NodeType Pathway PS:Notes Headnote: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Splenic MZL (SMZL) is an indolent B-cell neoplasm involving spleen, bone marrow, and rarely peripheral blood. Signaling description: The pathogenesis of SMZL is not well known, however, clinical data point to an association with hepatitis C virus. The infection rate of SMZL does not exceed 15-20%. NF-kB is constitutively activated in 60% of SMZL cases due to TNFAIP3, IKBKB, TRAF3, MAP3K14, and BIRC3 mutations. Activating lesions of MYD88 and CARD11 are found in Toll-like receptor (TLR) and B-cell receptor (BCR) pathways. TP53 disruption is found in 10-15% of cases. Outcome effects: The clinical course of SMZL is heterogeneous, although the majority of cases show an indolent course with a median survival of approximately ten years. Roughly 10% of cases undergo transformation to diffuse large B-cell lymphoma. The therapeutic options for SMZL include a "watch and wait" approach, splenectomy, chemotherapy, and B-cell-depleting therapy with rituximab. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ spleen PS:Organ_System lymphatic system PS:PMID 22102703 PS:PMID 22556352 PS:PMID 23233614 PS:PMID 23378931 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09151acc-739e-4e5e-98e9-3614702deee0 NodeType: Pathway Notes: Many patients with allergic asthma have an immunological reaction that is driven predominantly by type 2 T-helper cells (Th2 cells), but not Th1 cells. Th2 cell reactions are associated with the production of immunoglobulin E (IgE) by B cells, activation of eosinophils, and the involvement of other cells and mediators that enhance the characteristic bronchial hyperresponsiveness. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-09151acc-739e-4e5e-98e9-3614702deee0 1_Th2 cell response in asthma uuid-09151acc-739e-4e5e-98e9-3614702deee0 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09151acc-739e-4e5e-98e9-3614702deee0 PS:NodeType Pathway PS:Notes Many patients with allergic asthma have an immunological reaction that is driven predominantly by type 2 T-helper cells (Th2 cells), but not Th1 cells. Th2 cell reactions are associated with the production of immunoglobulin E (IgE) by B cells, activation of eosinophils, and the involvement of other cells and mediators that enhance the characteristic bronchial hyperresponsiveness. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09267e47-08d1-4233-8326-4496c2bcc2c4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-09267e47-08d1-4233-8326-4496c2bcc2c4 Epinephrine/Gq Expression Targets uuid-09267e47-08d1-4233-8326-4496c2bcc2c4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09267e47-08d1-4233-8326-4496c2bcc2c4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-095e69fa-7337-4ea1-a69d-f0fc6bb71d72 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-095e69fa-7337-4ea1-a69d-f0fc6bb71d72 Pyrimidine Metabolism uuid-095e69fa-7337-4ea1-a69d-f0fc6bb71d72 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-095e69fa-7337-4ea1-a69d-f0fc6bb71d72 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-096265ea-7007-41d8-9f09-1cfc44bf2a05 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-096265ea-7007-41d8-9f09-1cfc44bf2a05 IL11R -> STAT3 Signaling uuid-096265ea-7007-41d8-9f09-1cfc44bf2a05 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-096265ea-7007-41d8-9f09-1cfc44bf2a05 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0989198f-5c2c-4226-8e6a-2ae1ac4ecb05 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-0989198f-5c2c-4226-8e6a-2ae1ac4ecb05 Sphingosine, Ceramide metabolism template uuid-0989198f-5c2c-4226-8e6a-2ae1ac4ecb05 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0989198f-5c2c-4226-8e6a-2ae1ac4ecb05 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-098b625d-dbbf-480a-9ebc-9e02eae3c64f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-098b625d-dbbf-480a-9ebc-9e02eae3c64f TGFBR -> ATF/GADD/MAX/TP53 Signaling uuid-098b625d-dbbf-480a-9ebc-9e02eae3c64f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-098b625d-dbbf-480a-9ebc-9e02eae3c64f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Obesity is associated with diabetes type 2, hypertension, atherogenic dyslipidemias and disorders of blood coagulation and fibrinolysis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09952114-a436-46aa-af44-b3dc36353c5e NodeType: Pathway Notes: Headnote: Obesity is closely associated with type 2 diabetes, hypertension, atherogenic dyslipidemias and disorders of blood coagulation and fibrinolysis.It is generally accepted that free fatty acids (FFA), a product of lipolysis, play a critical role in the development of obesity-related metabolic disturbances. Signaling description: The key event is an increase in plasma FFA concentration. This leads to the accumulation of fatty acyl-CoA and diacylglycerol in vascular endothelial cells, and activation of PKC. Activation of PKC interrupts insulin signaling by serine phosphorylation of IRS 1/2. PKC also has been shown to activate NAD(P)H oxidase, which produces reactive oxygen species and destroys NO, contributing to vasoconstriction. Elevation of plasma FFA levels also leads to the production of inflammatory and proatherogenic proteins through activation of NFkB signaling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: cardiovascular system PMID: 18775356 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-09952114-a436-46aa-af44-b3dc36353c5e Fatty Acids in Hypertension and Atherosclerosis Development uuid-09952114-a436-46aa-af44-b3dc36353c5e PS:CellType endothelial cell PS:Description Obesity is associated with diabetes type 2, hypertension, atherogenic dyslipidemias and disorders of blood coagulation and fibrinolysis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09952114-a436-46aa-af44-b3dc36353c5e PS:NodeType Pathway PS:Notes Headnote: Obesity is closely associated with type 2 diabetes, hypertension, atherogenic dyslipidemias and disorders of blood coagulation and fibrinolysis.It is generally accepted that free fatty acids (FFA), a product of lipolysis, play a critical role in the development of obesity-related metabolic disturbances. Signaling description: The key event is an increase in plasma FFA concentration. This leads to the accumulation of fatty acyl-CoA and diacylglycerol in vascular endothelial cells, and activation of PKC. Activation of PKC interrupts insulin signaling by serine phosphorylation of IRS 1/2. PKC also has been shown to activate NAD(P)H oxidase, which produces reactive oxygen species and destroys NO, contributing to vasoconstriction. Elevation of plasma FFA levels also leads to the production of inflammatory and proatherogenic proteins through activation of NFkB signaling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System cardiovascular system PS:PMID 18775356 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09ad1d78-d1f1-493d-8940-16616e1ff5c1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-09ad1d78-d1f1-493d-8940-16616e1ff5c1 FA-Glycerolipid cycle -+>IR uuid-09ad1d78-d1f1-493d-8940-16616e1ff5c1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09ad1d78-d1f1-493d-8940-16616e1ff5c1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09adf465-2bf5-46be-aa0d-271ac445e218 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-09adf465-2bf5-46be-aa0d-271ac445e218 Proteins with Altered Expression in Vitiligo uuid-09adf465-2bf5-46be-aa0d-271ac445e218 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09adf465-2bf5-46be-aa0d-271ac445e218 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09d12d85-68e6-41ae-8321-08508269672a NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The SNF-2-related CREB-binding protein activator protein (SRCAP) chromatin remodeling complex belongs to the SNF-2 family of ATPases and is involved in a variety of processes including the regulation of transcription and remodeling of chromatin. Signaling description: Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. SRCAP interacts with histone acetyltransferase CREBBP and serves as a co-activator for a number of transcription factors known to interact with CREBBP including CREB, androgen receptor (AR), and glucocorticoid receptor (NR3C1). Outcome effects: The SRCAP complex has the ability to catalyze the exchange of H2AFZ into nucleosomes. In mammals, SRCAP shares subunits with TIP60 and INO80 protein complexes. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-09d12d85-68e6-41ae-8321-08508269672a SRCAP in Chromatin Remodeling uuid-09d12d85-68e6-41ae-8321-08508269672a PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09d12d85-68e6-41ae-8321-08508269672a PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The SNF-2-related CREB-binding protein activator protein (SRCAP) chromatin remodeling complex belongs to the SNF-2 family of ATPases and is involved in a variety of processes including the regulation of transcription and remodeling of chromatin. Signaling description: Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. SRCAP interacts with histone acetyltransferase CREBBP and serves as a co-activator for a number of transcription factors known to interact with CREBBP including CREB, androgen receptor (AR), and glucocorticoid receptor (NR3C1). Outcome effects: The SRCAP complex has the ability to catalyze the exchange of H2AFZ into nucleosomes. In mammals, SRCAP shares subunits with TIP60 and INO80 protein complexes. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09fbae71-935b-432c-8782-b435c2e63e6a NodeType: Pathway Notes: Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by avessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: When ECs undergo inflammatory activation via proinflammatory cytokines, the increased expression of selectins (SEL), VCAM1, and ICAM1 promotes the adherence of monocytes. Adhesion molecule expression is induced by IL1B, TNF, CD40/CD40LG interactions, CCL2, and CRP, which is produced by the liver in response to IL6. The inflammatory process and action of cytokines shifts the phenotype of epithelia cells from an anticoagulant, anti-inflammatory, and vasodilatatory phenotype to a proinflammatory and procoagulant state. Anti-inflammatory cytokines lead to the reduced expression of components with anticoagulant and profibrinolytic properties such as THBD, PROCR, and PGI2. SP1 and YBX1 most likely play an important role in this process. In contrast, cytokines lead to the increased expression of cell adhesion molecules. IL1, a cytokine secreted by activated platelets, has been shown to promote endothelial activation by inducing the expression of ICAM1, CCL2, and IL6. In addition, the binding of platelet CD40LG to its receptor, CD40 on the endothelium has been shown to induce the expression of adhesion molecules such as SELE, ICAM1, and VCAM1 in addition to cytokines including IL8, CCL2 and also tissue factor on the endothelium. Adhesion molecules are important in mediating the interaction of neutrophils and platelets with endothelium, thus also promoting the inflammatory and hemostatic responses. Adhesion molecules are synthesized by ECs and are subsequently stored in the Weibel-Palade bodies of ECs. Outcome effects: The release of the Weibel-Palade body contents and relocation of adhesion molecules to the surface of ECs occurs due to increased intracellular calcium (Ca2+). Tissue damage, free radicals, and various mediators including anti-inflammatory cytokines may lead to the increase in Ca2 levels. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-09fbae71-935b-432c-8782-b435c2e63e6a Vascular Endothelial Cell Activation by Cytokines uuid-09fbae71-935b-432c-8782-b435c2e63e6a PS:CellType endothelial cell PS:Description Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09fbae71-935b-432c-8782-b435c2e63e6a PS:NodeType Pathway PS:Notes Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by avessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: When ECs undergo inflammatory activation via proinflammatory cytokines, the increased expression of selectins (SEL), VCAM1, and ICAM1 promotes the adherence of monocytes. Adhesion molecule expression is induced by IL1B, TNF, CD40/CD40LG interactions, CCL2, and CRP, which is produced by the liver in response to IL6. The inflammatory process and action of cytokines shifts the phenotype of epithelia cells from an anticoagulant, anti-inflammatory, and vasodilatatory phenotype to a proinflammatory and procoagulant state. Anti-inflammatory cytokines lead to the reduced expression of components with anticoagulant and profibrinolytic properties such as THBD, PROCR, and PGI2. SP1 and YBX1 most likely play an important role in this process. In contrast, cytokines lead to the increased expression of cell adhesion molecules. IL1, a cytokine secreted by activated platelets, has been shown to promote endothelial activation by inducing the expression of ICAM1, CCL2, and IL6. In addition, the binding of platelet CD40LG to its receptor, CD40 on the endothelium has been shown to induce the expression of adhesion molecules such as SELE, ICAM1, and VCAM1 in addition to cytokines including IL8, CCL2 and also tissue factor on the endothelium. Adhesion molecules are important in mediating the interaction of neutrophils and platelets with endothelium, thus also promoting the inflammatory and hemostatic responses. Adhesion molecules are synthesized by ECs and are subsequently stored in the Weibel-Palade bodies of ECs. Outcome effects: The release of the Weibel-Palade body contents and relocation of adhesion molecules to the surface of ECs occurs due to increased intracellular calcium (Ca2+). Tissue damage, free radicals, and various mediators including anti-inflammatory cytokines may lead to the increase in Ca2 levels. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09fc7786-5430-4344-bb08-ca9402861160 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-09fc7786-5430-4344-bb08-ca9402861160 Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling uuid-09fc7786-5430-4344-bb08-ca9402861160 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-09fc7786-5430-4344-bb08-ca9402861160 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: muscle cell Description: Facioscapulohumeral muscular dystrophy (FSHD) is the most common myopathy found in adults. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a156b93-ca58-4016-8fe8-b8a8002320ca NodeType: Pathway Notes: Facioscapulohumeral muscular dystrophy (FSHD) is the most common myopathy in adults. This is the sole case in which the activation of the normally inactive gene (DUX4) leads to the development of the pathology. Organ_System: musculoskeletal system PMID: 21734574 PMID: 23206257 PMID: 24321734 PMID: 24589735 PMID: 24882751 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-0a156b93-ca58-4016-8fe8-b8a8002320ca Muscular Dystrophy, Facioscapulohumeral uuid-0a156b93-ca58-4016-8fe8-b8a8002320ca PS:CellType muscle cell PS:Description Facioscapulohumeral muscular dystrophy (FSHD) is the most common myopathy found in adults. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a156b93-ca58-4016-8fe8-b8a8002320ca PS:NodeType Pathway PS:Notes Facioscapulohumeral muscular dystrophy (FSHD) is the most common myopathy in adults. This is the sole case in which the activation of the normally inactive gene (DUX4) leads to the development of the pathology. PS:Organ_System musculoskeletal system PS:PMID 21734574 PS:PMID 23206257 PS:PMID 24321734 PS:PMID 24589735 PS:PMID 24882751 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a17b93c-3e27-4234-8320-8e5275c85c3d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0a17b93c-3e27-4234-8320-8e5275c85c3d CCL3 Expression Targets uuid-0a17b93c-3e27-4234-8320-8e5275c85c3d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a17b93c-3e27-4234-8320-8e5275c85c3d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Reed Sternberg cell CellType: cancer cell Description: The role of microenvironment is extremely important in Hodgkin lymphoma (HL) development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a252c17-a6ee-4be1-b56c-a0550964f63e NodeType: Pathway Notes: Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). The role of microenvironment is extremely important in Hodgkin lymphoma (HL) development. Signaling description: NF-kB and JUN/FOS are major expression regulators involved in the formation of HL lesions. The majority of cells in HL lesions are a mixed infiltrate of various types of cells of the immune system (CD4 T-cells, neutrophils, eosinophils, mast cells, and others). Outcome effects: Hodgkin and Reed-Sternberg (HRS) cells produce several molecules to attract various types of immune cells. They also produce specific molecules to inhibit CD8 cytotoxic T-cell activity. Prominent lymph node fibrosis is a typical feature of most types of HL and originates from HRS cell-mediated fibroblast activation. Organ: lymph node Organ_System: lymphatic system PMID: 19078975 PMID: 23023715 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0a252c17-a6ee-4be1-b56c-a0550964f63e Hodgkin and Reed-Sternberg Cells in Hodgkin Lymphoma uuid-0a252c17-a6ee-4be1-b56c-a0550964f63e PS:CellType Reed Sternberg cell PS:CellType cancer cell PS:Description The role of microenvironment is extremely important in Hodgkin lymphoma (HL) development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a252c17-a6ee-4be1-b56c-a0550964f63e PS:NodeType Pathway PS:Notes Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). The role of microenvironment is extremely important in Hodgkin lymphoma (HL) development. Signaling description: NF-kB and JUN/FOS are major expression regulators involved in the formation of HL lesions. The majority of cells in HL lesions are a mixed infiltrate of various types of cells of the immune system (CD4 T-cells, neutrophils, eosinophils, mast cells, and others). Outcome effects: Hodgkin and Reed-Sternberg (HRS) cells produce several molecules to attract various types of immune cells. They also produce specific molecules to inhibit CD8 cytotoxic T-cell activity. Prominent lymph node fibrosis is a typical feature of most types of HL and originates from HRS cell-mediated fibroblast activation. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 19078975 PS:PMID 23023715 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a495735-80ed-426a-a796-0b2b25eb4d57 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0a495735-80ed-426a-a796-0b2b25eb4d57 CD40LG -> STAT Expression Targets uuid-0a495735-80ed-426a-a796-0b2b25eb4d57 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a495735-80ed-426a-a796-0b2b25eb4d57 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a780e9c-1629-437f-bb48-02b556c89653 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-0a780e9c-1629-437f-bb48-02b556c89653 Genes with Mutations Associated with Familial and Sporadic Hemiplegic Migraine uuid-0a780e9c-1629-437f-bb48-02b556c89653 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a780e9c-1629-437f-bb48-02b556c89653 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a87556d-7445-40b4-bb16-23f8081bfa38 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-0a87556d-7445-40b4-bb16-23f8081bfa38 Linoleic acid metabolism template uuid-0a87556d-7445-40b4-bb16-23f8081bfa38 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a87556d-7445-40b4-bb16-23f8081bfa38 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8823c7-f7bb-4810-acb6-e1777dd5cd82 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-0a8823c7-f7bb-4810-acb6-e1777dd5cd82 Xyloglucan biosythesis template uuid-0a8823c7-f7bb-4810-acb6-e1777dd5cd82 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8823c7-f7bb-4810-acb6-e1777dd5cd82 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8aa8ba-6c9c-46d0-9ced-9efd5cfa9e05 NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0a8aa8ba-6c9c-46d0-9ced-9efd5cfa9e05 Panic Disorder: Drugs Effects uuid-0a8aa8ba-6c9c-46d0-9ced-9efd5cfa9e05 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8aa8ba-6c9c-46d0-9ced-9efd5cfa9e05 PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8dc7c2-6461-4c8e-94eb-c5d5dc706aa1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0a8dc7c2-6461-4c8e-94eb-c5d5dc706aa1 CSF2 -> STAT Expression Targets uuid-0a8dc7c2-6461-4c8e-94eb-c5d5dc706aa1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8dc7c2-6461-4c8e-94eb-c5d5dc706aa1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8ee427-edf9-4b42-9670-0952915f6a4f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0a8ee427-edf9-4b42-9670-0952915f6a4f FGF9 -> STAT Expression Targets uuid-0a8ee427-edf9-4b42-9670-0952915f6a4f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a8ee427-edf9-4b42-9670-0952915f6a4f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: sebocyte Description: One of the main pathologic mechanisms underlying acne vulgaris is increased sebocyte proliferation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a9dd587-3c67-4d86-b993-47603884c1a5 NodeType: Pathway Notes: Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. One of the major pathologic processes underlying acne vulgaris is the enlargement of sebaceous gland related to the increased proliferation of sebocytes. Signaling description: Various factors provoke the increased sebocyte proliferation leading to the enlargement of sebaceous gland. For instance, milk consumption and growth hormone (GH1) stimulate IGF1 expression. Milk consumption also stimulates the INS expression. IGF1 and INS bind to their receptors and activate the MAPK signaling. The downstream signal of the activated MAPK pathway initiates cyclin D1 (CCND1) transcription via the functional interaction with JUN/FOS transcription factors including CCND1, a key regulator of cell proliferation. FGF7, FGF10, and POMC affect the same signaling through PKC and PKA, respectively. Also, in patients with acne reduced amounts of linoleic acid (which is an inhibitor of ROS formation), cause an increased production of ROS in the damaged follicular wall. G6PD and CAT are normally involved in the reduction of ROS formation; however, these enzymes are downregulated in acne vulgaris. Further, ROS interact with membrane lipids and cause the formation of cytotoxic lipid peroxides; at the same time, ROS can oxidize squalene. This leads to the upregulation of lipoxygenase (ALOX5) activity is through the exposure of peroxidated squalene products to the cell. ALOX5, along with LTA4H, converts arachidonic acid into LTB4. Lipid peroxides and LTB4 promote cell proliferation via PPARA and PPARG activation. These transcription factors are also upregulated by free fatty acids which enter the cell along with LDLR and SLC27A4. Free fatty acids are formed in the by the lipoprotein lipase of the gram-positive anaerobic bacterium Propionibacterium acnes. This is the third pathologic mechanism leading to excessive sebocyte proliferation in acne vulgaris. Outcome effects: Increased sebocyte proliferation is a key process leading to the formation of acne lesions. Sebocyte proliferation may be induced by milk consumption and GH1 via the stimulation of IGF1 expression. At the same time, ROS formation may contribute to cell proliferation through the induction of PPARG . In addition, Propionibacterium acnes, a gram-positive anaerobic bacterium known to play a role in acne formation produce fatty acids which interact with PRARA and PRARG similarly leading to sebocyte proliferation. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: skin Organ_System: integumentary system PMID: 15556719 PMID: 19555434 PMID: 20082943 PMID: 21143923 PMID: 24062871 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-0a9dd587-3c67-4d86-b993-47603884c1a5 Sebocyte Proliferation in Acne Vulgaris uuid-0a9dd587-3c67-4d86-b993-47603884c1a5 PS:CellType sebocyte PS:Description One of the main pathologic mechanisms underlying acne vulgaris is increased sebocyte proliferation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0a9dd587-3c67-4d86-b993-47603884c1a5 PS:NodeType Pathway PS:Notes Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. One of the major pathologic processes underlying acne vulgaris is the enlargement of sebaceous gland related to the increased proliferation of sebocytes. Signaling description: Various factors provoke the increased sebocyte proliferation leading to the enlargement of sebaceous gland. For instance, milk consumption and growth hormone (GH1) stimulate IGF1 expression. Milk consumption also stimulates the INS expression. IGF1 and INS bind to their receptors and activate the MAPK signaling. The downstream signal of the activated MAPK pathway initiates cyclin D1 (CCND1) transcription via the functional interaction with JUN/FOS transcription factors including CCND1, a key regulator of cell proliferation. FGF7, FGF10, and POMC affect the same signaling through PKC and PKA, respectively. Also, in patients with acne reduced amounts of linoleic acid (which is an inhibitor of ROS formation), cause an increased production of ROS in the damaged follicular wall. G6PD and CAT are normally involved in the reduction of ROS formation; however, these enzymes are downregulated in acne vulgaris. Further, ROS interact with membrane lipids and cause the formation of cytotoxic lipid peroxides; at the same time, ROS can oxidize squalene. This leads to the upregulation of lipoxygenase (ALOX5) activity is through the exposure of peroxidated squalene products to the cell. ALOX5, along with LTA4H, converts arachidonic acid into LTB4. Lipid peroxides and LTB4 promote cell proliferation via PPARA and PPARG activation. These transcription factors are also upregulated by free fatty acids which enter the cell along with LDLR and SLC27A4. Free fatty acids are formed in the by the lipoprotein lipase of the gram-positive anaerobic bacterium Propionibacterium acnes. This is the third pathologic mechanism leading to excessive sebocyte proliferation in acne vulgaris. Outcome effects: Increased sebocyte proliferation is a key process leading to the formation of acne lesions. Sebocyte proliferation may be induced by milk consumption and GH1 via the stimulation of IGF1 expression. At the same time, ROS formation may contribute to cell proliferation through the induction of PPARG . In addition, Propionibacterium acnes, a gram-positive anaerobic bacterium known to play a role in acne formation produce fatty acids which interact with PRARA and PRARG similarly leading to sebocyte proliferation. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15556719 PS:PMID 19555434 PS:PMID 20082943 PS:PMID 21143923 PS:PMID 24062871 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: The cause of familial hemiplegic migraine type 3 (FHM3) consists in mutations in SCN1A gene. The SCN1A gene encodes the pore forming alpha-1-subunit of the voltage-dependent sodium channel (Nav1.1). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ab764ef-70e3-4fdf-a8bc-bf3157ab59c5 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM3 is caused by mutations in the SCN1A gene which encodes the pore forming alpha-1-subunit of the voltage-dependent sodium (Na+) channel. This type of ion channel is localized mainly to the body and proximal dendrites of inhibitory neurons. Signaling description: The specific location of the SCN1A channel plays a key role in the development of the hyperexcitability of dendrites which is an essential component of synaptic transmission. To date, five mutations have been identified in this gene in five families. Gln1489Lys mutation leads to a faster recovery after a quick blockade of SCN1A channels which causes an increase in neuronal excitability. The rise in intracellular Na+ increases the release of glutamate into the synaptic cleft. The increase of glutamate in the synaptic cleft leads to the activation of NMDA receptors on the postsynaptic neurons and metabotropic glutamate receptors (mGluR) on the surface of astrocytes. Outcome effects: NMDA receptor activation leads to the release of K+ from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic calcium-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid. Arachidonic acid can block the K+ large conductance calcium-activated channel (KCNMA1). The main function of KCNMA1 is the removal of K+ from the extracellular space to decrease membrane depolarization. The excess of glutamate is removed from the synaptic cleft by astrocytes, which convert glutamate into glutamine. Glutamine is then transmitted to neurons where it is converted back to glutamate. Thus, Na+ channel mutations lead to the continuous release of glutamate into the synaptic cleft causing the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 16054936 PMID: 17691981 PMID: 19185185 PMID: 19499287 PMID: 20816411 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0ab764ef-70e3-4fdf-a8bc-bf3157ab59c5 Glutamate Overdose and Aura Effect in Familial Hemiplegic Migraine Type 3 uuid-0ab764ef-70e3-4fdf-a8bc-bf3157ab59c5 PS:CellType astrocyte PS:CellType neuron PS:Description The cause of familial hemiplegic migraine type 3 (FHM3) consists in mutations in SCN1A gene. The SCN1A gene encodes the pore forming alpha-1-subunit of the voltage-dependent sodium channel (Nav1.1). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ab764ef-70e3-4fdf-a8bc-bf3157ab59c5 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM3 is caused by mutations in the SCN1A gene which encodes the pore forming alpha-1-subunit of the voltage-dependent sodium (Na+) channel. This type of ion channel is localized mainly to the body and proximal dendrites of inhibitory neurons. Signaling description: The specific location of the SCN1A channel plays a key role in the development of the hyperexcitability of dendrites which is an essential component of synaptic transmission. To date, five mutations have been identified in this gene in five families. Gln1489Lys mutation leads to a faster recovery after a quick blockade of SCN1A channels which causes an increase in neuronal excitability. The rise in intracellular Na+ increases the release of glutamate into the synaptic cleft. The increase of glutamate in the synaptic cleft leads to the activation of NMDA receptors on the postsynaptic neurons and metabotropic glutamate receptors (mGluR) on the surface of astrocytes. Outcome effects: NMDA receptor activation leads to the release of K+ from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic calcium-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid. Arachidonic acid can block the K+ large conductance calcium-activated channel (KCNMA1). The main function of KCNMA1 is the removal of K+ from the extracellular space to decrease membrane depolarization. The excess of glutamate is removed from the synaptic cleft by astrocytes, which convert glutamate into glutamine. Glutamine is then transmitted to neurons where it is converted back to glutamate. Thus, Na+ channel mutations lead to the continuous release of glutamate into the synaptic cleft causing the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 16054936 PS:PMID 17691981 PS:PMID 19185185 PS:PMID 19499287 PS:PMID 20816411 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ab943ea-ee91-434a-a999-3bda894c14d1 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-0ab943ea-ee91-434a-a999-3bda894c14d1 Proteins Involved in Polycystic Kidney Disease uuid-0ab943ea-ee91-434a-a999-3bda894c14d1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ab943ea-ee91-434a-a999-3bda894c14d1 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0af11a48-405e-4e45-a4ac-a627a83dbef6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0af11a48-405e-4e45-a4ac-a627a83dbef6 FGF9 -> RUNX Expression Targets uuid-0af11a48-405e-4e45-a4ac-a627a83dbef6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0af11a48-405e-4e45-a4ac-a627a83dbef6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b163f5a-86ee-4416-880f-4005d53c4a41 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-0b163f5a-86ee-4416-880f-4005d53c4a41 TGFBR -> AP-1 Signaling uuid-0b163f5a-86ee-4416-880f-4005d53c4a41 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b163f5a-86ee-4416-880f-4005d53c4a41 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b20a254-688a-4e8c-825d-a7aa186a2731 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: stomach Organ_System: digestive system PMID: 14755326 PMID: 16954210 PMID: 20938460 PMID: 22044679 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0b20a254-688a-4e8c-825d-a7aa186a2731 CagA Phosphorylation Dependent Signaling uuid-0b20a254-688a-4e8c-825d-a7aa186a2731 PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b20a254-688a-4e8c-825d-a7aa186a2731 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ stomach PS:Organ_System digestive system PS:PMID 14755326 PS:PMID 16954210 PS:PMID 20938460 PS:PMID 22044679 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b2a6004-cedd-4684-9cca-a9ef6c5787e8 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-0b2a6004-cedd-4684-9cca-a9ef6c5787e8 Genes with Mutations in Cancer-Associated Histone Deacetylation uuid-0b2a6004-cedd-4684-9cca-a9ef6c5787e8 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b2a6004-cedd-4684-9cca-a9ef6c5787e8 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b30b749-e4ae-4de5-8d16-43007c5b4ba5 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0b30b749-e4ae-4de5-8d16-43007c5b4ba5 Phenylketonuria Anatomy and Molecular Biomarkers uuid-0b30b749-e4ae-4de5-8d16-43007c5b4ba5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b30b749-e4ae-4de5-8d16-43007c5b4ba5 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: The level of acetylcholine in lung tissue is increased in chronic obstructive pulmonary disease due to its release from nerve terminals and activation of non-neuronal cholinergic system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b4a8a3c-1a5a-4a54-9019-2636a3ea31a3 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: The level of acetylcholine in lung tissue is increased in COPD due to its release from nerve terminals and activation of non-neuronal cholinergic system. Acetylcholine is biosynthesized from choline and acetyl-CoA by choline acetyltransferase (CHAT) by several cell types in the respiratory tract. Airway neurons, airway epithelial cells, macrophages, mast cells, and fibroblasts express CHAT. Mediators of inflammation, including TAC1, prostaglandins, and TXA2, enhance the release of acetylcholine from nerve endings. Muscarinic receptor agonists induce the contraction of airway smooth muscle via Ca2+-dependent and Ca2+-independent pathways. Through GNAI1 and GNAQ, the muscarinic M2 and M3 receptors (CHRM2 and CHRM3) activate PLC, which releases IP3 and diacylglycerol following hydrolytic conversion of PIP2. IP3 induces the release of Ca2+ from internal sarcoplasmic reticulum stores. The binding of CHRM3 to CD38, through unidentified mechanisms, contributes to the production of cADPR and the release of Ca2+ through RYR3 in the sarcoplasmic reticulum. Ca2+ release increases free cytosolic Ca2+ and promotes calmodulin-dependent activation of MYLK. In addition, PLC-derived diacylglycerol activates and consequently enhances Ca2+ sensitivity. Diacylglycerol activates PKC and results in PPP1R14A phosphorylation and downstream MLCP inhibition. ROCK1, which is activated by RHOA, both phosphorylates PPP1R14A and inhibits MLCP directly. Outcome effects: MYLK-mediated phosphorylation of MYL9 in the contractile apparatus is necessary to induce smooth muscle contraction. The level of myosin light chain phosphorylation is also controlled by pathways that inhibit MLCP. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16684353 PMID: 22291719 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0b4a8a3c-1a5a-4a54-9019-2636a3ea31a3 Muscarinic Receptor-Mediated Airway Smooth Muscle Contraction uuid-0b4a8a3c-1a5a-4a54-9019-2636a3ea31a3 PS:CellType vascular smooth muscle cell PS:Description The level of acetylcholine in lung tissue is increased in chronic obstructive pulmonary disease due to its release from nerve terminals and activation of non-neuronal cholinergic system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b4a8a3c-1a5a-4a54-9019-2636a3ea31a3 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: The level of acetylcholine in lung tissue is increased in COPD due to its release from nerve terminals and activation of non-neuronal cholinergic system. Acetylcholine is biosynthesized from choline and acetyl-CoA by choline acetyltransferase (CHAT) by several cell types in the respiratory tract. Airway neurons, airway epithelial cells, macrophages, mast cells, and fibroblasts express CHAT. Mediators of inflammation, including TAC1, prostaglandins, and TXA2, enhance the release of acetylcholine from nerve endings. Muscarinic receptor agonists induce the contraction of airway smooth muscle via Ca2+-dependent and Ca2+-independent pathways. Through GNAI1 and GNAQ, the muscarinic M2 and M3 receptors (CHRM2 and CHRM3) activate PLC, which releases IP3 and diacylglycerol following hydrolytic conversion of PIP2. IP3 induces the release of Ca2+ from internal sarcoplasmic reticulum stores. The binding of CHRM3 to CD38, through unidentified mechanisms, contributes to the production of cADPR and the release of Ca2+ through RYR3 in the sarcoplasmic reticulum. Ca2+ release increases free cytosolic Ca2+ and promotes calmodulin-dependent activation of MYLK. In addition, PLC-derived diacylglycerol activates and consequently enhances Ca2+ sensitivity. Diacylglycerol activates PKC and results in PPP1R14A phosphorylation and downstream MLCP inhibition. ROCK1, which is activated by RHOA, both phosphorylates PPP1R14A and inhibits MLCP directly. Outcome effects: MYLK-mediated phosphorylation of MYL9 in the contractile apparatus is necessary to induce smooth muscle contraction. The level of myosin light chain phosphorylation is also controlled by pathways that inhibit MLCP. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16684353 PS:PMID 22291719 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b63cab0-2579-45eb-b42d-da23a83fa728 NodeType: Pathway Organ: generic Organ_System: generic PMID: 10712923 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-0b63cab0-2579-45eb-b42d-da23a83fa728 Ras Signaling uuid-0b63cab0-2579-45eb-b42d-da23a83fa728 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b63cab0-2579-45eb-b42d-da23a83fa728 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 10712923 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b78212c-238c-439f-a4fe-7e693ed6bc74 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-0b78212c-238c-439f-a4fe-7e693ed6bc74 CNR1/2 -> IL1B/2/4/6/10 Production uuid-0b78212c-238c-439f-a4fe-7e693ed6bc74 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b78212c-238c-439f-a4fe-7e693ed6bc74 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b8bd091-617f-4568-adff-a04f3135c9ad NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-0b8bd091-617f-4568-adff-a04f3135c9ad FibronectinR -> NF-kB Signaling uuid-0b8bd091-617f-4568-adff-a04f3135c9ad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b8bd091-617f-4568-adff-a04f3135c9ad PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b934d14-d191-475a-ac77-9340dd06a920 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone tissue urn:agi-pathway:uuid-0b934d14-d191-475a-ac77-9340dd06a920 Elevated Receptors -> Expression Targets in Bone uuid-0b934d14-d191-475a-ac77-9340dd06a920 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0b934d14-d191-475a-ac77-9340dd06a920 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bb9ed94-2cb4-499c-8be6-09f52f42353b NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0bb9ed94-2cb4-499c-8be6-09f52f42353b Proteins with Altered Expression in Endometrial Cancer uuid-0bb9ed94-2cb4-499c-8be6-09f52f42353b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bb9ed94-2cb4-499c-8be6-09f52f42353b PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bba1d3d-b2c1-475d-bce9-0eb1775155b6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-0bba1d3d-b2c1-475d-bce9-0eb1775155b6 EphrinR -> Actin Signaling uuid-0bba1d3d-b2c1-475d-bce9-0eb1775155b6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bba1d3d-b2c1-475d-bce9-0eb1775155b6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bd2b403-e7a9-4b87-8902-1cde69250ddc NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-0bd2b403-e7a9-4b87-8902-1cde69250ddc NSP16 inhibitors uuid-0bd2b403-e7a9-4b87-8902-1cde69250ddc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bd2b403-e7a9-4b87-8902-1cde69250ddc PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bd368d2-e45b-4ad7-9875-c3ba497b080f NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-0bd368d2-e45b-4ad7-9875-c3ba497b080f CD86 -> STAT Expression Targets uuid-0bd368d2-e45b-4ad7-9875-c3ba497b080f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bd368d2-e45b-4ad7-9875-c3ba497b080f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bf84a94-d6af-431e-a50a-22ee2d064c35 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0bf84a94-d6af-431e-a50a-22ee2d064c35 EREG -> STAT Expression Targets uuid-0bf84a94-d6af-431e-a50a-22ee2d064c35 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0bf84a94-d6af-431e-a50a-22ee2d064c35 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: After menopause the level of estradiol production is decreased leading to increased lipid accumulation and decreased lipid utilization making impact to obesity development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0c165272-d3b6-4ac4-9d1a-85d19bfeb602 NodeType: Pathway Notes: Headnote: In healthy premenopausal women estradiol maintains energy homeostasis via estrogen-alpha (ESR1) and estrogen-beta receptors (ESR2) by suppressing energy intake and lipogenesis, enhancing energy expenditure and ameliorating insulin sensitivity. Signaling description: ESRs suppress expression of SREBF1 and PPARG and thereby control expression of lipogenic enzymes FASN, SCD, ACACA. They also inhibit lipoprotein lipase (LPL) expression, taking part in lipoprotein import into the adipocyte. ESRs control glucose transporter SLC2A4 expression. ESR1 is a positive regulator of SLC2A4, whereas ESR2 has a negative one. Outcome effects: Following menopause onset, the level of estradiol production is decreased leading to an increased lipid accumulation and decreased lipid utilization contributing to obesity development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: endocrine system PMID: 20599505 PMID: 21109497 PMID: 21907136 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-0c165272-d3b6-4ac4-9d1a-85d19bfeb602 Estrogen Deficiency in Female Obesity uuid-0c165272-d3b6-4ac4-9d1a-85d19bfeb602 PS:CellType adipocyte PS:Description After menopause the level of estradiol production is decreased leading to increased lipid accumulation and decreased lipid utilization making impact to obesity development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0c165272-d3b6-4ac4-9d1a-85d19bfeb602 PS:NodeType Pathway PS:Notes Headnote: In healthy premenopausal women estradiol maintains energy homeostasis via estrogen-alpha (ESR1) and estrogen-beta receptors (ESR2) by suppressing energy intake and lipogenesis, enhancing energy expenditure and ameliorating insulin sensitivity. Signaling description: ESRs suppress expression of SREBF1 and PPARG and thereby control expression of lipogenic enzymes FASN, SCD, ACACA. They also inhibit lipoprotein lipase (LPL) expression, taking part in lipoprotein import into the adipocyte. ESRs control glucose transporter SLC2A4 expression. ESR1 is a positive regulator of SLC2A4, whereas ESR2 has a negative one. Outcome effects: Following menopause onset, the level of estradiol production is decreased leading to an increased lipid accumulation and decreased lipid utilization contributing to obesity development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System endocrine system PS:PMID 20599505 PS:PMID 21109497 PS:PMID 21907136 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: lactotroph Description: Chronic alcohol consumption has been shown to elevate blood levels of prolactin (PRL) resulting in hyperprolactinemia and various reproductive dysfunctions in both humans and animals. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0c22242c-34f6-435f-bb76-500c43a0cc37 NodeType: Pathway Notes: Headnote: Chronic alcohol drinking has been shown to elevate blood levels of prolactin (PRL) resulting in hyperprolactinemia and various reproductive dysfunctions in both humans and animals. Signaling description: Ethanol action on lactotropes involves suppression of DRD2 receptor, inhibition of G proteins and intracellular cyclic adenosine monophosphate (cAMP) signaling.An inhibitory action of GNAI3 on GNAS that is under the control of the DRD2 receptor is removed by ethanol. Ethanol, like estradiol, reduces pituitary levels of TGFB1 but increases levels of growth-stimulatory TGFB3 and FGF2. These factors have opposite effects on lactotroph cell growth. TGFB1 inhibits, TGFB3 and FGF2 stimulate the proliferation of lactotroph cells. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 18034699 PMID: 20616493 PMID: 23029123 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0c22242c-34f6-435f-bb76-500c43a0cc37 Ethanol Induced Efects in Hyperprolactinemia uuid-0c22242c-34f6-435f-bb76-500c43a0cc37 PS:CellType lactotroph PS:Description Chronic alcohol consumption has been shown to elevate blood levels of prolactin (PRL) resulting in hyperprolactinemia and various reproductive dysfunctions in both humans and animals. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0c22242c-34f6-435f-bb76-500c43a0cc37 PS:NodeType Pathway PS:Notes Headnote: Chronic alcohol drinking has been shown to elevate blood levels of prolactin (PRL) resulting in hyperprolactinemia and various reproductive dysfunctions in both humans and animals. Signaling description: Ethanol action on lactotropes involves suppression of DRD2 receptor, inhibition of G proteins and intracellular cyclic adenosine monophosphate (cAMP) signaling.An inhibitory action of GNAI3 on GNAS that is under the control of the DRD2 receptor is removed by ethanol. Ethanol, like estradiol, reduces pituitary levels of TGFB1 but increases levels of growth-stimulatory TGFB3 and FGF2. These factors have opposite effects on lactotroph cell growth. TGFB1 inhibits, TGFB3 and FGF2 stimulate the proliferation of lactotroph cells. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 18034699 PS:PMID 20616493 PS:PMID 23029123 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: cancer cell Description: T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15? of childhood and 25? of adult ALL cases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ca5e9dc-0a4b-4bb7-9240-b28e74e69729 NodeType: Pathway Notes: Headnote: T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15% of childhood and 25% of adult ALL cases. T-ALL patients frequently present high peripheral blast counts, central nervous system dissemination, and larger mediastinal masses at diagnosis. Signaling description: Several recurrent genetic alterations have been identified in T-ALL. Chromosomal translocations occur in about 20% of cases and result in either fusions between the coding regions of two genes which leads to chimeric protein expression, or fusions between proto-oncogenes and T-cell receptor (TCR) loci which triggers oncogene overexpression (e.g., TAL1, TAL2, TLX1, TLX3, HOXA, LMO1, LMO2, MYB, and others). Aberrations involving TCR gene regions can be detected in 35% of patients. One of the most frequent types of alterations in T-ALL (more than 50% of cases) is NOTCH1 mutations which initiate the activation of NOTCH1-dependent transcriptional programs. In addition, deletion or inactivating mutations in CDKN2A and CDKN2B genes occur in about 70% of cases. Furthermore, JAK1 is mutated in 18% of adult patients with T-ALL; clinically, these patients may represent an unfavorable prognostic subgroup. The activation of several signaling pathways including PI3K/Akt, MAPK, JAK-STAT, and NF-kB has also been reported in T-ALL. Additionally, IL7 production by microenvironment and CXCL12/CXCR4 interaction between stromal cells and T-cells were found to be important for T-ALL development. Outcome effects: All of the described events lead to block of apoptosis, block of differentiation, and uncontrolled proliferation that promote development and progression of T-ALL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PMID: 16826225 PMID: 17329966 PMID: 18379008 PMID: 18488097 PMID: 18596915 PMID: 18691165 PMID: 19181788 PMID: 20800819 PMID: 20861166 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-0ca5e9dc-0a4b-4bb7-9240-b28e74e69729 T-Cell Acute Lymphoblastic Leukemia uuid-0ca5e9dc-0a4b-4bb7-9240-b28e74e69729 PS:CellType T-cell PS:CellType cancer cell PS:Description T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15? of childhood and 25? of adult ALL cases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ca5e9dc-0a4b-4bb7-9240-b28e74e69729 PS:NodeType Pathway PS:Notes Headnote: T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15% of childhood and 25% of adult ALL cases. T-ALL patients frequently present high peripheral blast counts, central nervous system dissemination, and larger mediastinal masses at diagnosis. Signaling description: Several recurrent genetic alterations have been identified in T-ALL. Chromosomal translocations occur in about 20% of cases and result in either fusions between the coding regions of two genes which leads to chimeric protein expression, or fusions between proto-oncogenes and T-cell receptor (TCR) loci which triggers oncogene overexpression (e.g., TAL1, TAL2, TLX1, TLX3, HOXA, LMO1, LMO2, MYB, and others). Aberrations involving TCR gene regions can be detected in 35% of patients. One of the most frequent types of alterations in T-ALL (more than 50% of cases) is NOTCH1 mutations which initiate the activation of NOTCH1-dependent transcriptional programs. In addition, deletion or inactivating mutations in CDKN2A and CDKN2B genes occur in about 70% of cases. Furthermore, JAK1 is mutated in 18% of adult patients with T-ALL; clinically, these patients may represent an unfavorable prognostic subgroup. The activation of several signaling pathways including PI3K/Akt, MAPK, JAK-STAT, and NF-kB has also been reported in T-ALL. Additionally, IL7 production by microenvironment and CXCL12/CXCR4 interaction between stromal cells and T-cells were found to be important for T-ALL development. Outcome effects: All of the described events lead to block of apoptosis, block of differentiation, and uncontrolled proliferation that promote development and progression of T-ALL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:PMID 16826225 PS:PMID 17329966 PS:PMID 18379008 PS:PMID 18488097 PS:PMID 18596915 PS:PMID 18691165 PS:PMID 19181788 PS:PMID 20800819 PS:PMID 20861166 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cca2637-4a93-4230-958d-7d8ed25d66b6 NodeType: Pathway Notes: Mutations in genes that encode sarcomeric and nonsarcomeric proteins lead to impaired sarcomere assembly and impaired cardiomyocyte contractility. Angiotensin II (AGT), endothelin-1 (EDN1), and IL-6 are released in response to reduced contractility and mediate contractile adaptation through the release of increased levels of Ca2+ from the SR. The final morphological events resulting from these molecular mechanisms are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis, which together lead to diastolic dysfunction and heart failure. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: heart Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: myocardium urn:agi-pathway:uuid-0cca2637-4a93-4230-958d-7d8ed25d66b6 2_Cardiomyocyte hypertrophy uuid-0cca2637-4a93-4230-958d-7d8ed25d66b6 PS:CellType cardiac myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cca2637-4a93-4230-958d-7d8ed25d66b6 PS:NodeType Pathway PS:Notes Mutations in genes that encode sarcomeric and nonsarcomeric proteins lead to impaired sarcomere assembly and impaired cardiomyocyte contractility. Angiotensin II (AGT), endothelin-1 (EDN1), and IL-6 are released in response to reduced contractility and mediate contractile adaptation through the release of increased levels of Ca2+ from the SR. The final morphological events resulting from these molecular mechanisms are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis, which together lead to diastolic dysfunction and heart failure. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue myocardium PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID CellType: epithelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ce04268-5fa5-41ad-a406-6093904c4cd5 NodeType: Pathway Organ: lung PMID: 25981515 urn:agi-pathway:uuid-0ce04268-5fa5-41ad-a406-6093904c4cd5 Periostin (POSTN) in trabecular meshwork uuid-0ce04268-5fa5-41ad-a406-6093904c4cd5 PS:CellType epithelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ce04268-5fa5-41ad-a406-6093904c4cd5 PS:NodeType Pathway PS:Organ lung PS:PMID 25981515 PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ce55098-ad64-4bb9-855d-a2f8daa42dac NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0ce55098-ad64-4bb9-855d-a2f8daa42dac Proteins Involved in Symptoms of Panic Disorder uuid-0ce55098-ad64-4bb9-855d-a2f8daa42dac PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ce55098-ad64-4bb9-855d-a2f8daa42dac PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cf5d723-04ae-43d4-8788-48015dbae333 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-0cf5d723-04ae-43d4-8788-48015dbae333 ECM induces Epithelial-Mesenchymal transition uuid-0cf5d723-04ae-43d4-8788-48015dbae333 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cf5d723-04ae-43d4-8788-48015dbae333 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cfe73c5-9f33-4ce4-8c6a-8f0aadf8e952 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-0cfe73c5-9f33-4ce4-8c6a-8f0aadf8e952 NOTCH -> Expression Targets in Skin uuid-0cfe73c5-9f33-4ce4-8c6a-8f0aadf8e952 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0cfe73c5-9f33-4ce4-8c6a-8f0aadf8e952 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Toll-like receptors (TLRs) are expressed by pancreatic beta cells to detect danger from microbial products and can trigger type 1 diabetes, such as during a localized viral infection in the pancreas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d01a445-d052-4a19-b7ca-53adcf1ce944 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Toll-like receptors (TLRs) are expressed by pancreatic beta-cells, and their function is to detect danger from microbial products. It has been shown that these TLRs may trigger type 1 diabetes, specifically during a localized viral infection in the pancreas. Outcome effects: Cytokines such as IL1B, IL12B, IFNG, and TNF are secreted by immune cells including macrophages, dendritic cells (DCs), CD4 and CD8 T-cells, and natural killer (NK) cells and may cause direct damage (e.g. apoptosis) of beta-cells. Chemokines such as CXCL10, CCL2, and CCL20 are secreted by beta-cells and can recruit macrophages and other inflammatory cells to the islet area. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: endocrine system PMID: 20577267 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0d01a445-d052-4a19-b7ca-53adcf1ce944 Toll-like Receptors in beta-Cell uuid-0d01a445-d052-4a19-b7ca-53adcf1ce944 PS:CellType insulin-secreting cell PS:Description Toll-like receptors (TLRs) are expressed by pancreatic beta cells to detect danger from microbial products and can trigger type 1 diabetes, such as during a localized viral infection in the pancreas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d01a445-d052-4a19-b7ca-53adcf1ce944 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Toll-like receptors (TLRs) are expressed by pancreatic beta-cells, and their function is to detect danger from microbial products. It has been shown that these TLRs may trigger type 1 diabetes, specifically during a localized viral infection in the pancreas. Outcome effects: Cytokines such as IL1B, IL12B, IFNG, and TNF are secreted by immune cells including macrophages, dendritic cells (DCs), CD4 and CD8 T-cells, and natural killer (NK) cells and may cause direct damage (e.g. apoptosis) of beta-cells. Chemokines such as CXCL10, CCL2, and CCL20 are secreted by beta-cells and can recruit macrophages and other inflammatory cells to the islet area. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 20577267 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: FLT3 is a receptor tyrosine kinase that plays an important role in hematopoietic stem and progenitor cell survival and proliferation. FLT3 mutations occur in approximately 30-40? of all AML cases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d2874bc-d887-4bd2-a9c1-4668b78c5c74 NodeType: Pathway Notes: Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. A block of differentiation may happen at any stage of myeloblast development in different subtypes of AML. Signaling description: FLT3 is a receptor tyrosine kinase (RTK) that plays an important role in hematopoietic stem and progenitor cell survival and proliferation. FLT3 mutations occur in approximately 30-40% of all AML cases. These mutations lead to the constitutive activation of the FLT3 signaling pathway and downstream targets which enhances proliferation and survival. RAS oncogenes are key molecules in signal transduction pathways through RTKs. Activating mutations of RAS are found in approximately 25% of AML cases and occur more frequently in NRAS than in KRAS or HRAS. The hematopoietic factors, CEBPA, SPI1, and RUNX1 may be inactivated due to mutations in AML. The inactivation of CEBPA leads to block of differentiation of blasts in M1, 2, and 4 variants of AML. The inactivation of SPI1 plays the same role in AML M0, 4, 5, and 6 while the inactivation of RUNX1 occurs in AML M0 and 2. Chromosomal translocation products, AML-ETO1, AML1-MTG16, and AML1-MDS1-EVI1 act as activated oncogenes in AML M2. The chromosomal translocation product, CBFB-MYH11 acts as an oncogene in AML M4. Outcome effects: The above mentioned genetic changes enhance cell survival and proliferation and inhibit myeloid differentiation. Mutated genes: Mutated genes are shown in white-out style. References: 1). Delwel R (2012) Molecular biology of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.6:23-32. 2). Petrie K., Zelent A. (2007) AML1/ETO, a promiscuous fusion oncoprotein. Blood.100(10): 4109-10. 3). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.5:27-35. 4). Van Wijnen A., Stein G. (2007) The CBFB-MYH11 butterfly effect in hematopoiesis. Blood. 100(8) 3131-32. Organ_System: hematological system PMID: 15167927 PMID: 17658267 PMID: 19540337 PMID: 21148331 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-0d2874bc-d887-4bd2-a9c1-4668b78c5c74 Myeloid Cell Differentiation Block in Leukemia uuid-0d2874bc-d887-4bd2-a9c1-4668b78c5c74 PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description FLT3 is a receptor tyrosine kinase that plays an important role in hematopoietic stem and progenitor cell survival and proliferation. FLT3 mutations occur in approximately 30-40? of all AML cases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d2874bc-d887-4bd2-a9c1-4668b78c5c74 PS:NodeType Pathway PS:Notes Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. A block of differentiation may happen at any stage of myeloblast development in different subtypes of AML. Signaling description: FLT3 is a receptor tyrosine kinase (RTK) that plays an important role in hematopoietic stem and progenitor cell survival and proliferation. FLT3 mutations occur in approximately 30-40% of all AML cases. These mutations lead to the constitutive activation of the FLT3 signaling pathway and downstream targets which enhances proliferation and survival. RAS oncogenes are key molecules in signal transduction pathways through RTKs. Activating mutations of RAS are found in approximately 25% of AML cases and occur more frequently in NRAS than in KRAS or HRAS. The hematopoietic factors, CEBPA, SPI1, and RUNX1 may be inactivated due to mutations in AML. The inactivation of CEBPA leads to block of differentiation of blasts in M1, 2, and 4 variants of AML. The inactivation of SPI1 plays the same role in AML M0, 4, 5, and 6 while the inactivation of RUNX1 occurs in AML M0 and 2. Chromosomal translocation products, AML-ETO1, AML1-MTG16, and AML1-MDS1-EVI1 act as activated oncogenes in AML M2. The chromosomal translocation product, CBFB-MYH11 acts as an oncogene in AML M4. Outcome effects: The above mentioned genetic changes enhance cell survival and proliferation and inhibit myeloid differentiation. Mutated genes: Mutated genes are shown in white-out style. References: 1). Delwel R (2012) Molecular biology of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.6:23-32. 2). Petrie K., Zelent A. (2007) AML1/ETO, a promiscuous fusion oncoprotein. Blood.100(10): 4109-10. 3). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.5:27-35. 4). Van Wijnen A., Stein G. (2007) The CBFB-MYH11 butterfly effect in hematopoiesis. Blood. 100(8) 3131-32. PS:Organ_System hematological system PS:PMID 15167927 PS:PMID 17658267 PS:PMID 19540337 PS:PMID 21148331 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d504606-5a3c-4553-9c35-fc2d723a8cc7 NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0d504606-5a3c-4553-9c35-fc2d723a8cc7 Panic Disorder: Neurotransmission Activation via CCK-4 uuid-0d504606-5a3c-4553-9c35-fc2d723a8cc7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d504606-5a3c-4553-9c35-fc2d723a8cc7 PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d6a98c0-7541-4afc-ae7c-3b9734712ce6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0d6a98c0-7541-4afc-ae7c-3b9734712ce6 IL1A Expression Targets uuid-0d6a98c0-7541-4afc-ae7c-3b9734712ce6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d6a98c0-7541-4afc-ae7c-3b9734712ce6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d6f4afe-3254-4932-bd36-3f4ad7769ba7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0d6f4afe-3254-4932-bd36-3f4ad7769ba7 IGF1 -> CEBPA/FOXO1A Expression Targets uuid-0d6f4afe-3254-4932-bd36-3f4ad7769ba7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d6f4afe-3254-4932-bd36-3f4ad7769ba7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using iPTMnet database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d710578-77ea-4a39-82ce-e2429bb62c9d NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-0d710578-77ea-4a39-82ce-e2429bb62c9d Proteins Involved in BAD Sites Modification uuid-0d710578-77ea-4a39-82ce-e2429bb62c9d PS:Description Pathway is build using iPTMnet database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d710578-77ea-4a39-82ce-e2429bb62c9d PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d7e367a-4f54-465c-902a-2d5b1b825d10 NodeType: Pathway Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0d7e367a-4f54-465c-902a-2d5b1b825d10 Proteins with Altered Expression in Pregnancy Related Coagulation Disorders uuid-0d7e367a-4f54-465c-902a-2d5b1b825d10 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0d7e367a-4f54-465c-902a-2d5b1b825d10 PS:NodeType Pathway PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: neuron CellType: smooth muscle myocyte Description: Penile erection is a complex neurovascular response that involves integration of central nervous system activity and the release of vasodilator factors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0deaee46-e223-427d-aabe-3c84bfb698af NodeType: Pathway Notes: Headnote: Erectile dysfunction (ED) is defined as the persistent inability to maintain or achieve a penile erection sufficient for satisfactory sexual performance. Its etiology is multifactorial and risk factors include age, diabetes mellitus, neurologic diseases, smoking and cardiovascular diseases. Penile erection is a complex neurovascular response that involves integration of central nervous system activity and the release of vasodilator factors from nerves innervating the penis and the endothelium of the penile arteries. Signaling description: Nitric oxide (NO) is the principle mediator of penile erection. NO is produced in endothelial cells by eNOS (NOS3) in response to binding of acetylcholine from cholinergic nerves to muscarinic receptor CHRM3 on the corporal endothelium. NO is also produced by the nonadrenergic noncholinergic (NANC) nerves in response to central or peripheral nerve stimulation and subsequent influx of calcium through N-type calcium channels. The increase in intracellular calcium (Ca2+) results in the formation of calcium-calmodulin complexes, which activate nNOS (NOS1). NO released from NANC nerve terminals or endothelial cells diffuses into corporal smooth muscle and binds to its intracellular receptor, which is sGC. Binding of NO to sGC results in an increase in the conversion of GTP to cGMP leading to activation of protein kinase G (PKG). Activation of downstream targets of PKG results in an overall decrease in intracellular calcium by increasing uptake of intracellular calcium into sarcoplasmic reticulum and inactivating membrane calcium influx channels. Activation of a membrane-bound G-protein-coupled receptor PTGIR by prostaglandin E1 can also induce smooth muscle cell relaxation via activation of adenylate cyclase and the increased conversion of ATP to cAMP. The increase in intracellular cAMP activates PKA, which interacts with downstream targets to inhibit membrane calcium channels and increase uptake of calcium by the sarcoplasmic reticulum. This leads to an overall decrease in intracellular calcium concentration and corporal smooth muscle relaxation. Outcome effects: In ED the production and release on NO is augmented, the level of intracellular cAMP and cGMP in smooth muscle cells is low, and the level of intracellular Ca2+ is high leading to muscle contraction and lack of erection (detumescence). The activity of PKG can be prolonged via inhibiting the breakdown of cGMP by type 5 phosphodiesterase 5A (PDE5A) by agents like Viagra (Sildenafil), Levitra (Vardenafil) and Cialis (Tadalafil). Nowadays, the PDE5A inhibitors are the first-line treatment for ED.Compound with elevated level is highlighted in red and compound with reduced level is highlighted in blue. Organ: penis Organ_System: reproductive system PMID: 16411892 PMID: 23817801 PMID: 24468580 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0deaee46-e223-427d-aabe-3c84bfb698af Penile Erection Impairment uuid-0deaee46-e223-427d-aabe-3c84bfb698af PS:CellType endothelial cell PS:CellType neuron PS:CellType smooth muscle myocyte PS:Description Penile erection is a complex neurovascular response that involves integration of central nervous system activity and the release of vasodilator factors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0deaee46-e223-427d-aabe-3c84bfb698af PS:NodeType Pathway PS:Notes Headnote: Erectile dysfunction (ED) is defined as the persistent inability to maintain or achieve a penile erection sufficient for satisfactory sexual performance. Its etiology is multifactorial and risk factors include age, diabetes mellitus, neurologic diseases, smoking and cardiovascular diseases. Penile erection is a complex neurovascular response that involves integration of central nervous system activity and the release of vasodilator factors from nerves innervating the penis and the endothelium of the penile arteries. Signaling description: Nitric oxide (NO) is the principle mediator of penile erection. NO is produced in endothelial cells by eNOS (NOS3) in response to binding of acetylcholine from cholinergic nerves to muscarinic receptor CHRM3 on the corporal endothelium. NO is also produced by the nonadrenergic noncholinergic (NANC) nerves in response to central or peripheral nerve stimulation and subsequent influx of calcium through N-type calcium channels. The increase in intracellular calcium (Ca2+) results in the formation of calcium-calmodulin complexes, which activate nNOS (NOS1). NO released from NANC nerve terminals or endothelial cells diffuses into corporal smooth muscle and binds to its intracellular receptor, which is sGC. Binding of NO to sGC results in an increase in the conversion of GTP to cGMP leading to activation of protein kinase G (PKG). Activation of downstream targets of PKG results in an overall decrease in intracellular calcium by increasing uptake of intracellular calcium into sarcoplasmic reticulum and inactivating membrane calcium influx channels. Activation of a membrane-bound G-protein-coupled receptor PTGIR by prostaglandin E1 can also induce smooth muscle cell relaxation via activation of adenylate cyclase and the increased conversion of ATP to cAMP. The increase in intracellular cAMP activates PKA, which interacts with downstream targets to inhibit membrane calcium channels and increase uptake of calcium by the sarcoplasmic reticulum. This leads to an overall decrease in intracellular calcium concentration and corporal smooth muscle relaxation. Outcome effects: In ED the production and release on NO is augmented, the level of intracellular cAMP and cGMP in smooth muscle cells is low, and the level of intracellular Ca2+ is high leading to muscle contraction and lack of erection (detumescence). The activity of PKG can be prolonged via inhibiting the breakdown of cGMP by type 5 phosphodiesterase 5A (PDE5A) by agents like Viagra (Sildenafil), Levitra (Vardenafil) and Cialis (Tadalafil). Nowadays, the PDE5A inhibitors are the first-line treatment for ED.Compound with elevated level is highlighted in red and compound with reduced level is highlighted in blue. PS:Organ penis PS:Organ_System reproductive system PS:PMID 16411892 PS:PMID 23817801 PS:PMID 24468580 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e0581dd-c5ac-4f62-a235-2b6f642ed5f9 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: testis Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-0e0581dd-c5ac-4f62-a235-2b6f642ed5f9 Elevated Receptors -> Expression Targets in Testis uuid-0e0581dd-c5ac-4f62-a235-2b6f642ed5f9 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e0581dd-c5ac-4f62-a235-2b6f642ed5f9 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ testis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e078599-06ca-4ea8-ae2f-67b3b106a3de NodeType: Pathway Organ: pancreas Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0e078599-06ca-4ea8-ae2f-67b3b106a3de Proteins Involved in Neonatal Diabetes Mellitus uuid-0e078599-06ca-4ea8-ae2f-67b3b106a3de PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e078599-06ca-4ea8-ae2f-67b3b106a3de PS:NodeType Pathway PS:Organ pancreas PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: T-cell CellType: thyroid cell Description: Hashimoto's thyroiditis (HT) is one of the most common causes of hypothyroidism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e132367-1591-475f-824d-8229cf9bd4a5 NodeType: Pathway Notes: Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. In the final stages, fibrous tissue replaces normal thyroid parenchyma with some people developing hypothyroidism. Signaling description: The central phase of HT is characterized by an apparent uncontrolled production of auto-reactive CD4 T-cells, CD8 cytotoxic T-cells, and immunoglobulin G autoantibodies. In HT, INF-gamma induced IL18 production activates local immune response. Genetic predisposition of HT requires additional studies.Candidate mutated genes in HT can be classified into two groups: (1) immune regulatory genes (MHC, CTLA-4, PTPN-22, and cytokines) and (2) thyroid-specific genes (TG and TPO). Outcome effects: HT is considered to be a Th1-mediated disease resulting in the aberrant infiltration of lymphoid cells and destruction of thyroid follicles. IL18 up-regulation by INF-gamma is an immunological feature of HT patients with an important role in promoting the local immune response. Additionally, after IFN-gamma stimulation, thyrocytes secrete CXCR3-binding chemokines which in turn recruit Th1 lymphocytes causing a chronic autoimmune reaction. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Organ: thyroid gland Organ_System: endocrine system PMID: 10874534 PMID: 15762980 PMID: 17143095 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0e132367-1591-475f-824d-8229cf9bd4a5 Hashimoto's Thyroiditis uuid-0e132367-1591-475f-824d-8229cf9bd4a5 PS:CellType B-cell PS:CellType T-cell PS:CellType thyroid cell PS:Description Hashimoto's thyroiditis (HT) is one of the most common causes of hypothyroidism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e132367-1591-475f-824d-8229cf9bd4a5 PS:NodeType Pathway PS:Notes Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. In the final stages, fibrous tissue replaces normal thyroid parenchyma with some people developing hypothyroidism. Signaling description: The central phase of HT is characterized by an apparent uncontrolled production of auto-reactive CD4 T-cells, CD8 cytotoxic T-cells, and immunoglobulin G autoantibodies. In HT, INF-gamma induced IL18 production activates local immune response. Genetic predisposition of HT requires additional studies.Candidate mutated genes in HT can be classified into two groups: (1) immune regulatory genes (MHC, CTLA-4, PTPN-22, and cytokines) and (2) thyroid-specific genes (TG and TPO). Outcome effects: HT is considered to be a Th1-mediated disease resulting in the aberrant infiltration of lymphoid cells and destruction of thyroid follicles. IL18 up-regulation by INF-gamma is an immunological feature of HT patients with an important role in promoting the local immune response. Additionally, after IFN-gamma stimulation, thyrocytes secrete CXCR3-binding chemokines which in turn recruit Th1 lymphocytes causing a chronic autoimmune reaction. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 10874534 PS:PMID 15762980 PS:PMID 17143095 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Rapamycin is a central immunosuppressant in islet transplantation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e37d792-d684-43eb-a900-a318fe68b3d4 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. The drug rapamycin which is used as an immunosuppressant in islet transplantation suppresses beta-cell function. Signaling description: Rapamycin action is based on its binding to FKBP1A and inhibition of MTOR. The inhibition of MTOR leads to the arrest of the cell cycle at G1 to S phase in activated T-cells, as well as in other cell types. Outcome effects: Rapamycin is able to reduce the rate of beta-cell proliferation in transplanted rat islets as well as in host murine islets. In vitro, rapamycin treatment induces autophagy in the islets. Currently, MAP1LC3A is the sole marker for autophagosomes. In mice, rapamycin treatment of islets leads to islet dysfunction through upregulation of autophagy and downregulation of insulin production and apoptosis of beta-cells. Rapamycin suppresses high glucose-induced insulin secretion from rat pancreatic islets by reducing mitochondrial ATP production through the suppression of carbohydrate metabolism in the Krebs cycle, together with reduced OGDH activity. Animal data: rodent model. Organ: pancreas Organ_System: endocrine system PMID: 19249550 PMID: 19812126 PMID: 21297554 PMID: 22299600 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0e37d792-d684-43eb-a900-a318fe68b3d4 beta-Cell Function Inhibition by Rapamycin (Rodent Model) uuid-0e37d792-d684-43eb-a900-a318fe68b3d4 PS:CellType insulin-secreting cell PS:Description Rapamycin is a central immunosuppressant in islet transplantation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e37d792-d684-43eb-a900-a318fe68b3d4 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. The drug rapamycin which is used as an immunosuppressant in islet transplantation suppresses beta-cell function. Signaling description: Rapamycin action is based on its binding to FKBP1A and inhibition of MTOR. The inhibition of MTOR leads to the arrest of the cell cycle at G1 to S phase in activated T-cells, as well as in other cell types. Outcome effects: Rapamycin is able to reduce the rate of beta-cell proliferation in transplanted rat islets as well as in host murine islets. In vitro, rapamycin treatment induces autophagy in the islets. Currently, MAP1LC3A is the sole marker for autophagosomes. In mice, rapamycin treatment of islets leads to islet dysfunction through upregulation of autophagy and downregulation of insulin production and apoptosis of beta-cells. Rapamycin suppresses high glucose-induced insulin secretion from rat pancreatic islets by reducing mitochondrial ATP production through the suppression of carbohydrate metabolism in the Krebs cycle, together with reduced OGDH activity. Animal data: rodent model. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19249550 PS:PMID 19812126 PS:PMID 21297554 PS:PMID 22299600 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e3aaac3-95ec-442a-a505-69509701117f NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0e3aaac3-95ec-442a-a505-69509701117f Proteins Involved in Tangier Disease uuid-0e3aaac3-95ec-442a-a505-69509701117f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e3aaac3-95ec-442a-a505-69509701117f PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e3c36c0-1143-4281-a171-42d7ebfe410e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-0e3c36c0-1143-4281-a171-42d7ebfe410e FGF18 -> AP-1/CREB Expression Targets uuid-0e3c36c0-1143-4281-a171-42d7ebfe410e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e3c36c0-1143-4281-a171-42d7ebfe410e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: endothelial cell CellType: monocyte CellType: neutrophil Description: The continuous migration and infiltration of activated macrophages and T cells into atherosclerotic lesions are prominent features in human atherosclerotic disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e408382-8068-42ff-b0a9-842ea26b8268 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The continuous migration and infiltration of activated macrophages and T-cells into atherosclerotic lesions are prominent features in human atherosclerotic disease. The recruitment of these cells to lesions is guided by endothelial leukocyte adhesion molecules and chemoattractants. Chemokines, a family of small chemotactic cytokines, can be detected within atherosclerotic lesions, where they function as messengers to direct leukocytes to sites of inflammation, but may also control homeostasis and other activities of migrated cells. Outcome effects: Monocytes employ chemokine receptors such as CCR2, CCR5, and CX3CR1 to invade plaques, where they differentiate into macrophages. Neutrophils use CCL5 receptors including CCR1 and CCR5 for entering in atherosclerotic plaques in contrast to the restricted use of CCR2 and CXCR2 for peripheral venous recruitment. T-cells use CXCR3-CXCL10, CXCR6-CXCL16, and CCR5 for entering the atherosclerotic plaques. Mutated proteins: Mutated genes are shown in white-out style. Organ: blood vessel Organ_System: cardiovascular system PMID: 22064431 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-0e408382-8068-42ff-b0a9-842ea26b8268 Chemokines Signaling in Atherosclerosis uuid-0e408382-8068-42ff-b0a9-842ea26b8268 PS:CellType T-cell PS:CellType endothelial cell PS:CellType monocyte PS:CellType neutrophil PS:Description The continuous migration and infiltration of activated macrophages and T cells into atherosclerotic lesions are prominent features in human atherosclerotic disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e408382-8068-42ff-b0a9-842ea26b8268 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The continuous migration and infiltration of activated macrophages and T-cells into atherosclerotic lesions are prominent features in human atherosclerotic disease. The recruitment of these cells to lesions is guided by endothelial leukocyte adhesion molecules and chemoattractants. Chemokines, a family of small chemotactic cytokines, can be detected within atherosclerotic lesions, where they function as messengers to direct leukocytes to sites of inflammation, but may also control homeostasis and other activities of migrated cells. Outcome effects: Monocytes employ chemokine receptors such as CCR2, CCR5, and CX3CR1 to invade plaques, where they differentiate into macrophages. Neutrophils use CCL5 receptors including CCR1 and CCR5 for entering in atherosclerotic plaques in contrast to the restricted use of CCR2 and CXCR2 for peripheral venous recruitment. T-cells use CXCR3-CXCL10, CXCR6-CXCL16, and CCR5 for entering the atherosclerotic plaques. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 22064431 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e45c494-42a6-4336-bf9f-09802af562a1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-0e45c494-42a6-4336-bf9f-09802af562a1 Mieap-induced vacuole and accumulation of lysosome-like organelles within mitochondria uuid-0e45c494-42a6-4336-bf9f-09802af562a1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e45c494-42a6-4336-bf9f-09802af562a1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e506239-aa28-4755-97c9-13e32d0f1d9a NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-0e506239-aa28-4755-97c9-13e32d0f1d9a ADORA2A/B -> Vasodilation uuid-0e506239-aa28-4755-97c9-13e32d0f1d9a PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e506239-aa28-4755-97c9-13e32d0f1d9a PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of Hedgehog signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e5ddc1a-260d-406a-ab0c-cfa4861f79cc NodeType: Pathway Notes: Headnote: The Hedgehog (Hh) signaling pathway regulates cell proliferation, differentiation and tissue development in embryogenesis and is mostly inhibited in adulthood. However, the Hh cascade can be reactivated in cancer. Signaling description: In the absence of Hh ligand (SHH), Patched (PTCH) inhibits the activity of Smoothened (SMO), whose localization at the cell surface is essential to its function. Full-length GLI proteins are proteolytically cleaved to produce GLIR, derived mostly from GLI3, which represses Hh target genes. Binding of Hh to PTCH leads to its internalization and destabilization, so it no longer can carry the endogenous SMO agonist molecules outwards. The release of SMO inhibition leads to the production of GLIA, derived mostly from GLI2 ensuing the expression of the Hh target gene. Activating mutations in the SMO gene and overexpression of SHH and GLI1/2 lead to permanent Hh signaling stimulation in cancer cells. Outcome effects: In cancer, constant activation of Hh leads to uncontrolled cell proliferation and inhibition of apoptosis. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 19081070 PMID: 20696410 PMID: 21192841 PMID: 21789137 PMID: 45505772 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-0e5ddc1a-260d-406a-ab0c-cfa4861f79cc Hedgehog Signaling Activation in Cancer uuid-0e5ddc1a-260d-406a-ab0c-cfa4861f79cc PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of Hedgehog signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e5ddc1a-260d-406a-ab0c-cfa4861f79cc PS:NodeType Pathway PS:Notes Headnote: The Hedgehog (Hh) signaling pathway regulates cell proliferation, differentiation and tissue development in embryogenesis and is mostly inhibited in adulthood. However, the Hh cascade can be reactivated in cancer. Signaling description: In the absence of Hh ligand (SHH), Patched (PTCH) inhibits the activity of Smoothened (SMO), whose localization at the cell surface is essential to its function. Full-length GLI proteins are proteolytically cleaved to produce GLIR, derived mostly from GLI3, which represses Hh target genes. Binding of Hh to PTCH leads to its internalization and destabilization, so it no longer can carry the endogenous SMO agonist molecules outwards. The release of SMO inhibition leads to the production of GLIA, derived mostly from GLI2 ensuing the expression of the Hh target gene. Activating mutations in the SMO gene and overexpression of SHH and GLI1/2 lead to permanent Hh signaling stimulation in cancer cells. Outcome effects: In cancer, constant activation of Hh leads to uncontrolled cell proliferation and inhibition of apoptosis. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 19081070 PS:PMID 20696410 PS:PMID 21192841 PS:PMID 21789137 PS:PMID 45505772 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Tissue injury leading to the release of danger signals such as S100 proteins, HMGB1, heat shock proteins, phosphatidylserine containing microparticles. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e5faea1-6ad1-455a-8f88-491e009b3a84 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: Tissue injury leading to the release of danger signals such as S100 proteins, HMGB1, heat shock proteins, phosphatidylserine containing microparticles, and alteration of tissue homestasis with the oxidation of LDL and other proteins are able to activate pattern-recognition receptors to initiate a potent inflammatory response. An increasing number of endogenous ligands are being reported as candidate stimulators of pattern recognition receptors such as Toll-like receptors (TLRs) and advanced glycosylation end product-specific receptor (AGER). AGER and TLRs play important roles in mediating acute and chronic inflammation relevant for the initiation and progression of atherosclerosis. AGER activates several signal transduction cascades including the family of MAPKs and PI3K. In addition, transcription factors such as NF-kB and JUN/FOS are targets of AGER signaling. Furthermore, S100A8, S100A9, and S100A12 are endogenously expressed at various levels in cells that are closely linked to vascular disease such as neutrophils, macrophages, dendritic cells, and monocytes. Outcome effects: The released S100A8 and S100A9 exert extracellular functions, which are mediated by TLR4, AGER, and other receptors. These proteins are released from damaged/dying cells or activated cells and are included in the group of proteins termed damage-associated molecular pattern (DAMP) molecules. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PMID: 22200033 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-0e5faea1-6ad1-455a-8f88-491e009b3a84 RAGE/AGER and S100 Proteins in Cardiovascular Injury uuid-0e5faea1-6ad1-455a-8f88-491e009b3a84 PS:CellType epithelial cell PS:Description Tissue injury leading to the release of danger signals such as S100 proteins, HMGB1, heat shock proteins, phosphatidylserine containing microparticles. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e5faea1-6ad1-455a-8f88-491e009b3a84 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: Tissue injury leading to the release of danger signals such as S100 proteins, HMGB1, heat shock proteins, phosphatidylserine containing microparticles, and alteration of tissue homestasis with the oxidation of LDL and other proteins are able to activate pattern-recognition receptors to initiate a potent inflammatory response. An increasing number of endogenous ligands are being reported as candidate stimulators of pattern recognition receptors such as Toll-like receptors (TLRs) and advanced glycosylation end product-specific receptor (AGER). AGER and TLRs play important roles in mediating acute and chronic inflammation relevant for the initiation and progression of atherosclerosis. AGER activates several signal transduction cascades including the family of MAPKs and PI3K. In addition, transcription factors such as NF-kB and JUN/FOS are targets of AGER signaling. Furthermore, S100A8, S100A9, and S100A12 are endogenously expressed at various levels in cells that are closely linked to vascular disease such as neutrophils, macrophages, dendritic cells, and monocytes. Outcome effects: The released S100A8 and S100A9 exert extracellular functions, which are mediated by TLR4, AGER, and other receptors. These proteins are released from damaged/dying cells or activated cells and are included in the group of proteins termed damage-associated molecular pattern (DAMP) molecules. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 22200033 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: mast cell Description: Mast cells localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e6406a0-bb00-472c-b58e-e1133a6ca117 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Mast cells localize within the bronchial smooth muscle bundles in patients with asthma, but not in normal subjects or those with eosinophilic bronchitis. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis. Outcome effects: Chemokine receptors most commonly expressed by human lung mast cells are CCR3, CXCR1, CXCR3 and CXCR4. ASM (airway smooth muscle) derived factors (such as SCF, CXCL10) are chemotactic for mast cells and are essential for their differentiation, maturation, proliferation and survival. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16750987 PMID: 24648846 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0e6406a0-bb00-472c-b58e-e1133a6ca117 Mast-Cell Related Chemokines Signaling in Asthma uuid-0e6406a0-bb00-472c-b58e-e1133a6ca117 PS:CellType mast cell PS:Description Mast cells localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e6406a0-bb00-472c-b58e-e1133a6ca117 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Mast cells localize within the bronchial smooth muscle bundles in patients with asthma, but not in normal subjects or those with eosinophilic bronchitis. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis. Outcome effects: Chemokine receptors most commonly expressed by human lung mast cells are CCR3, CXCR1, CXCR3 and CXCR4. ASM (airway smooth muscle) derived factors (such as SCF, CXCL10) are chemotactic for mast cells and are essential for their differentiation, maturation, proliferation and survival. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16750987 PS:PMID 24648846 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: Resistance to progesterone action is one of hallmarks of endometriosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e7c0420-8112-4a82-a19a-69f8af96589b NodeType: Pathway Notes: Headnote: Resistance to progesterone action is one of hallmarks of endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PGR). Signaling description: In endometriotic cells, pathologically high ERB suppress PGR expression. Progesterone induces HSD17B2 expression which normally metabolizes the biologically potent estradiol (E2). The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. Progesterone receptor (PGR) is necessary for CRABP2 expression in endometrial cells. CRABP2 directs retinoic acid toward RARA, which results in growth arrest and apoptosis. Outcome effects: Thereby low PGR expression inhibits apoptosis and stimulates cell proliferation. Low PGR expression leads to inability to induce FOXO1 expression, activation of proliferation and impairment of apoptosis and decidualization. Organ: uterus Organ_System: reproductive system PMID: 20104427 PMID: 20108182 PMID: 22271293 PMID: 24927773 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0e7c0420-8112-4a82-a19a-69f8af96589b Progesterone Resistance in Endometriosis uuid-0e7c0420-8112-4a82-a19a-69f8af96589b PS:CellType endometrium cell PS:Description Resistance to progesterone action is one of hallmarks of endometriosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0e7c0420-8112-4a82-a19a-69f8af96589b PS:NodeType Pathway PS:Notes Headnote: Resistance to progesterone action is one of hallmarks of endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PGR). Signaling description: In endometriotic cells, pathologically high ERB suppress PGR expression. Progesterone induces HSD17B2 expression which normally metabolizes the biologically potent estradiol (E2). The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. Progesterone receptor (PGR) is necessary for CRABP2 expression in endometrial cells. CRABP2 directs retinoic acid toward RARA, which results in growth arrest and apoptosis. Outcome effects: Thereby low PGR expression inhibits apoptosis and stimulates cell proliferation. Low PGR expression leads to inability to induce FOXO1 expression, activation of proliferation and impairment of apoptosis and decidualization. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 20104427 PS:PMID 20108182 PS:PMID 22271293 PS:PMID 24927773 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ea6c991-9cda-472d-a796-71b501194267 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-0ea6c991-9cda-472d-a796-71b501194267 Z-disc/Z-line uuid-0ea6c991-9cda-472d-a796-71b501194267 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ea6c991-9cda-472d-a796-71b501194267 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top most studied anatomy biomarkers assotiated with disease Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0eaf13c0-d501-4886-8792-00012f98523b NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0eaf13c0-d501-4886-8792-00012f98523b Usher Syndrome Anatomy Biomarkers uuid-0eaf13c0-d501-4886-8792-00012f98523b PS:Description Top most studied anatomy biomarkers assotiated with disease PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0eaf13c0-d501-4886-8792-00012f98523b PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: Expression of E6 and E7 (early viral proteins) is required for cell transformation and the production of HPV particles. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ec78b55-d037-478a-a0a0-d0d7d054c764 NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). HPV16-E6 and HPV16-E7 are early viral proteins. The expression of E6 and E7 is required for cell transformation and the production of viral particles. The main target of the viral protein E6 is TP53. E6 protein interacts with and activates UBE3A. In turn, UBE3A deactivates TP53 and NFX1 by ubiquitination. At the same time, the main target of the viral protein E7 is RB1. Dysregulation of RB1 is achieved owing to the activation of CUL2, which is part of the ubiquitination complex. Thus, E7 destabilizes RB1 levels through CUL2-mediated proteasomal degradation. Outcome effects: NFX1 interacts with SAP30 and SAP25, which leads to repression of transcription of TERT in keratinocytes. TERT regulates many cell processes. When TERT is not repressed by NFX1, activation of the transition of cell cycle from G1 to S phase occurs. The telomerase activity of TERT leads to chromatin remodeling, cell survival, and viral reproduction. The activation of TERT also leads to block of apoptosis. Downregulated TP53 fails to activate CDKN1A and CDKN1B. This leads to the activation of CDK2. CDK2 plays an essential role in regulating the G1-S transition. In addition, the suppression of TP53 does not activate transcription of BAX, which is essential for apoptosis in normal cells. In addition, E7 viral protein negatively interacts with CDKN1A and CDKN1B, which leads to the activation of CDK2 and promotes cell division. Also, in the absence of RB1, DEK oncogene is activated, which blocks apoptosis and activates cell proliferation and chromatin remodeling. Further, due to the absence of interaction between RB1 with E2F4/RBL2, the MYBL2 transcription is not actiavted. MYBL2 is a transcription factor implicated in regulating the cell cycle, apoptosis, and cancer. In conclusion, all these events lead to block of apoptosis, activation G1/S transition, dysregulation of chromatin remodeling as well as the activation of cell survival and viral reproduction in the infected cell. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin PMID: 16597322 PMID: 19081593 PMID: 19861444 PMID: 23263171 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-0ec78b55-d037-478a-a0a0-d0d7d054c764 HPV E6 and E7 Induced Block of Apoptosis in Keratinocytes uuid-0ec78b55-d037-478a-a0a0-d0d7d054c764 PS:CellType cancer cell PS:CellType keratinocyte PS:Description Expression of E6 and E7 (early viral proteins) is required for cell transformation and the production of HPV particles. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ec78b55-d037-478a-a0a0-d0d7d054c764 PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). HPV16-E6 and HPV16-E7 are early viral proteins. The expression of E6 and E7 is required for cell transformation and the production of viral particles. The main target of the viral protein E6 is TP53. E6 protein interacts with and activates UBE3A. In turn, UBE3A deactivates TP53 and NFX1 by ubiquitination. At the same time, the main target of the viral protein E7 is RB1. Dysregulation of RB1 is achieved owing to the activation of CUL2, which is part of the ubiquitination complex. Thus, E7 destabilizes RB1 levels through CUL2-mediated proteasomal degradation. Outcome effects: NFX1 interacts with SAP30 and SAP25, which leads to repression of transcription of TERT in keratinocytes. TERT regulates many cell processes. When TERT is not repressed by NFX1, activation of the transition of cell cycle from G1 to S phase occurs. The telomerase activity of TERT leads to chromatin remodeling, cell survival, and viral reproduction. The activation of TERT also leads to block of apoptosis. Downregulated TP53 fails to activate CDKN1A and CDKN1B. This leads to the activation of CDK2. CDK2 plays an essential role in regulating the G1-S transition. In addition, the suppression of TP53 does not activate transcription of BAX, which is essential for apoptosis in normal cells. In addition, E7 viral protein negatively interacts with CDKN1A and CDKN1B, which leads to the activation of CDK2 and promotes cell division. Also, in the absence of RB1, DEK oncogene is activated, which blocks apoptosis and activates cell proliferation and chromatin remodeling. Further, due to the absence of interaction between RB1 with E2F4/RBL2, the MYBL2 transcription is not actiavted. MYBL2 is a transcription factor implicated in regulating the cell cycle, apoptosis, and cancer. In conclusion, all these events lead to block of apoptosis, activation G1/S transition, dysregulation of chromatin remodeling as well as the activation of cell survival and viral reproduction in the infected cell. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:PMID 16597322 PS:PMID 19081593 PS:PMID 19861444 PS:PMID 23263171 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell CellType: endothelial cell CellType: fibroblast CellType: macrophage Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ee89715-f32c-4011-a9c1-aa53abac17b1 NodeType: Pathway PMID: 15928045 PMID: 18490190 PMID: 19176383 PMID: 23888049 PMID: 25081536 PMID: 25268615 PMID: 26604323 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-0ee89715-f32c-4011-a9c1-aa53abac17b1 BSG (CD147) in Cancer Cells Motility, Invasion and Survival uuid-0ee89715-f32c-4011-a9c1-aa53abac17b1 PS:CellType cancer stem cell PS:CellType endothelial cell PS:CellType fibroblast PS:CellType macrophage PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0ee89715-f32c-4011-a9c1-aa53abac17b1 PS:NodeType Pathway PS:PMID 15928045 PS:PMID 18490190 PS:PMID 19176383 PS:PMID 23888049 PS:PMID 25081536 PS:PMID 25268615 PS:PMID 26604323 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f041d8e-b527-4f36-82af-98dd8564c4c3 NodeType: Pathway Notes: Headnote: Thrombophilias are inherited or acquired conditions which predispose an individual to thromboembolism. Pregnancy complications such as recurrent miscarriage, severe preeclampsia, intrauterine growth retardation, abruptio placentae and stillbirth have been shown to be associated with thrombophilia. Thromboembolism in pregnancy as in the non-pregnant state is linked to thrombophilia. Signaling description: The most common types of hereditary thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects. The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin (F2) G20210A mutation. F5 mutation is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. F2 mutation occurs at rates of 1-4% in the general population, 5-10% of people with thrombosis. Like F5, this abnormality is uncommon in Africans and Asians. The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. The main ones are antithrombin III (SERPINC1) deficiency, protein C (PROC) deficiency and protein S (PROS1) deficiency.SERPINC1 deficiency is present in 0.2% of the general population and 0.5-7.5% of people with venous thrombosis. PROC deficiency, too, is present in 0.2% of the population, and can be found in 2.5-6% of people with thrombosis. Milder rare congenital thrombophilias are factor XIII (F13A1) mutation and familial dysfibrinogenemia (an abnormal fibrinogen).Mutated genes are shown in white-out style. Organ_System: reproductive system PMID: 16968541 PMID: 17635737 PMID: 21116184 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood urn:agi-pathway:uuid-0f041d8e-b527-4f36-82af-98dd8564c4c3 Hereditary Thrombophilia and Pregnancy Complications uuid-0f041d8e-b527-4f36-82af-98dd8564c4c3 PS:CellType blood platelet PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f041d8e-b527-4f36-82af-98dd8564c4c3 PS:NodeType Pathway PS:Notes Headnote: Thrombophilias are inherited or acquired conditions which predispose an individual to thromboembolism. Pregnancy complications such as recurrent miscarriage, severe preeclampsia, intrauterine growth retardation, abruptio placentae and stillbirth have been shown to be associated with thrombophilia. Thromboembolism in pregnancy as in the non-pregnant state is linked to thrombophilia. Signaling description: The most common types of hereditary thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects. The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin (F2) G20210A mutation. F5 mutation is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. F2 mutation occurs at rates of 1-4% in the general population, 5-10% of people with thrombosis. Like F5, this abnormality is uncommon in Africans and Asians. The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. The main ones are antithrombin III (SERPINC1) deficiency, protein C (PROC) deficiency and protein S (PROS1) deficiency.SERPINC1 deficiency is present in 0.2% of the general population and 0.5-7.5% of people with venous thrombosis. PROC deficiency, too, is present in 0.2% of the population, and can be found in 2.5-6% of people with thrombosis. Milder rare congenital thrombophilias are factor XIII (F13A1) mutation and familial dysfibrinogenemia (an abnormal fibrinogen).Mutated genes are shown in white-out style. PS:Organ_System reproductive system PS:PMID 16968541 PS:PMID 17635737 PS:PMID 21116184 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f11b039-3d40-44f9-bf9a-b8336b074e01 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-0f11b039-3d40-44f9-bf9a-b8336b074e01 AGT+>myofibroblasts uuid-0f11b039-3d40-44f9-bf9a-b8336b074e01 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f11b039-3d40-44f9-bf9a-b8336b074e01 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f44aed5-283e-4540-9d6d-a1457311e043 NodeType: Pathway Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0f44aed5-283e-4540-9d6d-a1457311e043 Proteins Involved in Hypertrophic Cardiomyopathy uuid-0f44aed5-283e-4540-9d6d-a1457311e043 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f44aed5-283e-4540-9d6d-a1457311e043 PS:NodeType Pathway PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Bone formation is controlled by two major signaling pathways that are induced by TGFB and WNT ligands. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f658d13-3eee-452f-8a3d-3a28c02e380b NodeType: Pathway Notes: Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: Bone formation is controlled by two major signaling pathways that are induced by TGFB and WNT ligands. WNT signaling pathway results in the upregulation of RUNX2 transcription factor, which in turn upregulates the expression of TNF ligand (TNFSF11) and receptor (TNFRSF11B) and prevents the interaction of TNFSF11 with other surface receptors. TGFB signaling pathway leads to the activation of SP7 transcription factor and the expression of another TNF surface receptor (TNFRSF11A), which mediates bone resorption. Normally, both TGFB and WNT signaling pathways are active in osteoblasts and the balance of these pathways is important for an osteoblast to keep its identity. Outcome effects: The stimulation of glucocorticoid receptor NR3C1 by dexamethasone leads to the upregulation of DKK1 and SOST, which are antagonists of WNT signaling pathway. Therefore, long-term dexamethasone treatment results in chronic WNT signaling pathway insufficiency and osteoporosis due to increased bone resorption. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-0f658d13-3eee-452f-8a3d-3a28c02e380b Dexamethasone Induced Osteoporosis uuid-0f658d13-3eee-452f-8a3d-3a28c02e380b PS:Description Bone formation is controlled by two major signaling pathways that are induced by TGFB and WNT ligands. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f658d13-3eee-452f-8a3d-3a28c02e380b PS:NodeType Pathway PS:Notes Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: Bone formation is controlled by two major signaling pathways that are induced by TGFB and WNT ligands. WNT signaling pathway results in the upregulation of RUNX2 transcription factor, which in turn upregulates the expression of TNF ligand (TNFSF11) and receptor (TNFRSF11B) and prevents the interaction of TNFSF11 with other surface receptors. TGFB signaling pathway leads to the activation of SP7 transcription factor and the expression of another TNF surface receptor (TNFRSF11A), which mediates bone resorption. Normally, both TGFB and WNT signaling pathways are active in osteoblasts and the balance of these pathways is important for an osteoblast to keep its identity. Outcome effects: The stimulation of glucocorticoid receptor NR3C1 by dexamethasone leads to the upregulation of DKK1 and SOST, which are antagonists of WNT signaling pathway. Therefore, long-term dexamethasone treatment results in chronic WNT signaling pathway insufficiency and osteoporosis due to increased bone resorption. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: regulatory T-cell Description: FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations including a-Tregs, r-Tregs, and non-Tregs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f65d6ab-f416-4325-b0f0-86f9719d00ed NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations namely a-Tregs, r-Tregs, and non-Tregs. Among them, a-Tregs play the most important role as suppressors of immune reactions. The mechanism of suppressive function by a-Tregs has not been fully elucidated, but the increase in the level of soluble CTLA4 may be the result of a compensatory mechanism for the functional defects of a-Tregs in type 1A diabetes. a-Tregs express intracellular CTLA4 and CCR4 to the highest degree among the three subpopulations of Tregs. Outcome effects: a-Tregs are anergic and suppress the proliferation of responder cells and other FOXP3 Tregs (r-Tregs and non-Tregs). The IL2 signaling pathway in a-Tregs is also important in understanding the impaired function in a-Tregs. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PMID: 20559327 PMID: 23607886 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0f65d6ab-f416-4325-b0f0-86f9719d00ed Treg-Cell Activation in Diabetes Mellitus uuid-0f65d6ab-f416-4325-b0f0-86f9719d00ed PS:CellType T-cell PS:CellType regulatory T-cell PS:Description FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations including a-Tregs, r-Tregs, and non-Tregs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f65d6ab-f416-4325-b0f0-86f9719d00ed PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations namely a-Tregs, r-Tregs, and non-Tregs. Among them, a-Tregs play the most important role as suppressors of immune reactions. The mechanism of suppressive function by a-Tregs has not been fully elucidated, but the increase in the level of soluble CTLA4 may be the result of a compensatory mechanism for the functional defects of a-Tregs in type 1A diabetes. a-Tregs express intracellular CTLA4 and CCR4 to the highest degree among the three subpopulations of Tregs. Outcome effects: a-Tregs are anergic and suppress the proliferation of responder cells and other FOXP3 Tregs (r-Tregs and non-Tregs). The IL2 signaling pathway in a-Tregs is also important in understanding the impaired function in a-Tregs. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:PMID 20559327 PS:PMID 23607886 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f6a2d4e-e263-42a1-8da1-da53d43db7af NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-0f6a2d4e-e263-42a1-8da1-da53d43db7af Ataxias: Glutamate and Calcium Signaling uuid-0f6a2d4e-e263-42a1-8da1-da53d43db7af PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f6a2d4e-e263-42a1-8da1-da53d43db7af PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f6f3df5-c20a-4dee-be29-551b1e08b54e NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-0f6f3df5-c20a-4dee-be29-551b1e08b54e Congenital Hypothyroidism Mutated Genes uuid-0f6f3df5-c20a-4dee-be29-551b1e08b54e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f6f3df5-c20a-4dee-be29-551b1e08b54e PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f827112-8c09-438b-9240-10af2c5cd2fb NodeType: Pathway Notes: Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol interacts with a nuclear vitamin D receptor (VDRn). Activated VDRn forms a heterodimeric complex with Retinoid-X-Receptor (RXR) and regulate in different ways the expression of genes which have vitamin D3 response element in their promoters. Organ: generic Organ_System: generic PMID: 26950144 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-0f827112-8c09-438b-9240-10af2c5cd2fb Vitamin D Activates Transcription uuid-0f827112-8c09-438b-9240-10af2c5cd2fb PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0f827112-8c09-438b-9240-10af2c5cd2fb PS:NodeType Pathway PS:Notes Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol interacts with a nuclear vitamin D receptor (VDRn). Activated VDRn forms a heterodimeric complex with Retinoid-X-Receptor (RXR) and regulate in different ways the expression of genes which have vitamin D3 response element in their promoters. PS:Organ generic PS:Organ_System generic PS:PMID 26950144 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: fibroblast Description: UV irradiation induces the down-regulation of transforming growth factor-beta (TGF-beta). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0fc85a2d-0c4e-4e97-94a3-8889d3dc5b44 NodeType: Pathway Notes: Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: UV irradiation induces the down-regulation of transforming growth factor-beta (TGF-beta) and connective tissue growth factor in the TGF-beta/Smad/CTGF/procollagen axis and leads to the decreased synthesis of type I collagen. Type I collagen is the major structural protein in human skin, providing skin with strength and resiliency, and is synthesized as a precursor form, type I procollagen, by fibroblasts that reside in skin connective tissue. TGF-beta regulates procollagen production both directly and indirectly, via the TGF-beta regulated connective tissue growth factor (CTGF). UV irradiation impairs the TGF-beta/Smad pathway, and this impairment is associated with reduced CTGF expression and reduced type I procollagen synthesis in human skin in vivo and human skin fibroblasts in vitro. Inhibition of the TGF-beta/Smad pathway by UV radiation occurs primarily as a consequence of down-regulation of the TGF-beta receptor type II. Outcome effects: TGF-beta plays a dominant role in regulating collagen homeostasis. As a consequence of the passage of time and/or chronic exposure to ultraviolet radiation, type I procollagen synthesis is down-regulated via the TGF-beta dependent signaling. This loss of type I procollagen is a major contributing factor to thinning and increased fragility of naturally aged skin, and the wrinkled appearance of photoaged skin. Highlighted proteins: TGFBR2, CTGF, COL1A2 and collagen type I are highlighted in blue in order to illustrate the disruption of the protective skin barrier. Organ_System: integumentary system PMID: 11874477 PMID: 15331399 PMID: 21826153 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-0fc85a2d-0c4e-4e97-94a3-8889d3dc5b44 TGF-beta Signaling in Skin Aging uuid-0fc85a2d-0c4e-4e97-94a3-8889d3dc5b44 PS:CellType fibroblast PS:Description UV irradiation induces the down-regulation of transforming growth factor-beta (TGF-beta). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0fc85a2d-0c4e-4e97-94a3-8889d3dc5b44 PS:NodeType Pathway PS:Notes Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: UV irradiation induces the down-regulation of transforming growth factor-beta (TGF-beta) and connective tissue growth factor in the TGF-beta/Smad/CTGF/procollagen axis and leads to the decreased synthesis of type I collagen. Type I collagen is the major structural protein in human skin, providing skin with strength and resiliency, and is synthesized as a precursor form, type I procollagen, by fibroblasts that reside in skin connective tissue. TGF-beta regulates procollagen production both directly and indirectly, via the TGF-beta regulated connective tissue growth factor (CTGF). UV irradiation impairs the TGF-beta/Smad pathway, and this impairment is associated with reduced CTGF expression and reduced type I procollagen synthesis in human skin in vivo and human skin fibroblasts in vitro. Inhibition of the TGF-beta/Smad pathway by UV radiation occurs primarily as a consequence of down-regulation of the TGF-beta receptor type II. Outcome effects: TGF-beta plays a dominant role in regulating collagen homeostasis. As a consequence of the passage of time and/or chronic exposure to ultraviolet radiation, type I procollagen synthesis is down-regulated via the TGF-beta dependent signaling. This loss of type I procollagen is a major contributing factor to thinning and increased fragility of naturally aged skin, and the wrinkled appearance of photoaged skin. Highlighted proteins: TGFBR2, CTGF, COL1A2 and collagen type I are highlighted in blue in order to illustrate the disruption of the protective skin barrier. PS:Organ_System integumentary system PS:PMID 11874477 PS:PMID 15331399 PS:PMID 21826153 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0fe1dcc3-b2ba-409c-922e-ac31e0dd3baf NodeType: Pathway Notes: Headnote: The WAS protein plays an active role in the formation of the cytoskeleton of blood cells (mainly lymphocyte and thrombocyte). Mutations in the WAS gene mainly lead to the development of Wiskott-Aldrich syndrome. At the moment, more than 300 mutations have been described, leading to various forms of severity of the disease. Since the gene is located in the Xp11.23 region, there is an X-linked recessive disease (only boys are sick). Signaling description: The WAS protein is activated by one of the proteins of the Rho GTPase family, CDC42 (cell division cycle 42). CDC42 in blood cells is activated by a currently unknown pathway from various G-protein coupled receptors. Also, WAS is activated by a complex consisting of one of the profilin proteins and PIP2 (phosphatidylinositol 4,5-bisphosphate). The main target of WAS is the actin related protein 2/3 complex. Activation of this complex by the WAS protein and its partner, the VASP (vasodilator stimulated phosphoprotein) protein, leads to the activation of the interaction between the actin related protein 2/3 complex and F-actin. This, in turn, leads to the activation of cellular processes of cytoskeleton organization and biogenesis, as well as lamellipodium formation and platelet structure reorganization. Outcome effects: Mutations in the WAS gene lead to a complete disruption of the activation of the cytoskeleton organization and biogenesis of blood cells. This leads to the development of immunodeficiency and thrombocytopenia, as well as other severe symptoms: chronic diarrhea, chronic obstructive pulmonary disease and fever, as the main ones. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-0fe1dcc3-b2ba-409c-922e-ac31e0dd3baf Wiskott-Aldrich Syndrome Overview uuid-0fe1dcc3-b2ba-409c-922e-ac31e0dd3baf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0fe1dcc3-b2ba-409c-922e-ac31e0dd3baf PS:NodeType Pathway PS:Notes Headnote: The WAS protein plays an active role in the formation of the cytoskeleton of blood cells (mainly lymphocyte and thrombocyte). Mutations in the WAS gene mainly lead to the development of Wiskott-Aldrich syndrome. At the moment, more than 300 mutations have been described, leading to various forms of severity of the disease. Since the gene is located in the Xp11.23 region, there is an X-linked recessive disease (only boys are sick). Signaling description: The WAS protein is activated by one of the proteins of the Rho GTPase family, CDC42 (cell division cycle 42). CDC42 in blood cells is activated by a currently unknown pathway from various G-protein coupled receptors. Also, WAS is activated by a complex consisting of one of the profilin proteins and PIP2 (phosphatidylinositol 4,5-bisphosphate). The main target of WAS is the actin related protein 2/3 complex. Activation of this complex by the WAS protein and its partner, the VASP (vasodilator stimulated phosphoprotein) protein, leads to the activation of the interaction between the actin related protein 2/3 complex and F-actin. This, in turn, leads to the activation of cellular processes of cytoskeleton organization and biogenesis, as well as lamellipodium formation and platelet structure reorganization. Outcome effects: Mutations in the WAS gene lead to a complete disruption of the activation of the cytoskeleton organization and biogenesis of blood cells. This leads to the development of immunodeficiency and thrombocytopenia, as well as other severe symptoms: chronic diarrhea, chronic obstructive pulmonary disease and fever, as the main ones. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0feb2a9c-545d-4ac7-bf5c-31c559f32461 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-0feb2a9c-545d-4ac7-bf5c-31c559f32461 IL4R -> ELK/SRF/HMGY Signaling uuid-0feb2a9c-545d-4ac7-bf5c-31c559f32461 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-0feb2a9c-545d-4ac7-bf5c-31c559f32461 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10213ce8-a7ff-4c11-a990-e05cf04d195a NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-10213ce8-a7ff-4c11-a990-e05cf04d195a Genes with Mutations Associated with Age-Related Macular Degeneration uuid-10213ce8-a7ff-4c11-a990-e05cf04d195a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10213ce8-a7ff-4c11-a990-e05cf04d195a PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-102aa430-4b45-475a-bd99-08db2b50d853 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-102aa430-4b45-475a-bd99-08db2b50d853 Galactosyl glycerol biosynthesis template uuid-102aa430-4b45-475a-bd99-08db2b50d853 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-102aa430-4b45-475a-bd99-08db2b50d853 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1038c17a-8044-4838-ad5a-ab75c988c3b5 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-1038c17a-8044-4838-ad5a-ab75c988c3b5 Folate Cycle and Homocysteine Overproduction uuid-1038c17a-8044-4838-ad5a-ab75c988c3b5 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1038c17a-8044-4838-ad5a-ab75c988c3b5 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-105acfb0-1621-43ed-aff0-515b8b88f56b NodeType: Pathway Organ: eye Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-105acfb0-1621-43ed-aff0-515b8b88f56b Proteins Involved in Acute Myeloid Leukemia uuid-105acfb0-1621-43ed-aff0-515b8b88f56b PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-105acfb0-1621-43ed-aff0-515b8b88f56b PS:NodeType Pathway PS:Organ eye PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neural crest cell Description: Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1063e6d8-60b3-4f90-a45e-e30f1117b729 NodeType: Pathway Notes: Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: SOX10 is one of the key regulators of enteric nervous system development. ASCL1 and PHOX2B, which are both required for a neural progenitor cell to differentiate into an autonomic neuron, are not expressed in the absence of SOX10. SOX10, PHOX2B, PAX3, and TLX2 regulate the expression of RET, ERBB3, and L1CAM. SIM2 and ARNT2 also regulate the expression of RET and are regarded as RET modifier genes. Outcome effects: Mutations of SOX10, PHOX2B, PAX3, and ZEB2 impair migration, proliferation, or differentiation of enteric neural crest progenitor cells leading to HSCR development. The expression of neurogenic transcription factors is largely controlled by BMP signaling. Mutated genes: Mutated genes are shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15905074 PMID: 19215589 PMID: 22174542 PMID: 23043324 PMID: 23528997 PMID: 23639815 PMID: 23644063 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1063e6d8-60b3-4f90-a45e-e30f1117b729 Neurogenic Transcription Factors Role in Hirschsprung Disease uuid-1063e6d8-60b3-4f90-a45e-e30f1117b729 PS:CellType neural crest cell PS:Description Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1063e6d8-60b3-4f90-a45e-e30f1117b729 PS:NodeType Pathway PS:Notes Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: SOX10 is one of the key regulators of enteric nervous system development. ASCL1 and PHOX2B, which are both required for a neural progenitor cell to differentiate into an autonomic neuron, are not expressed in the absence of SOX10. SOX10, PHOX2B, PAX3, and TLX2 regulate the expression of RET, ERBB3, and L1CAM. SIM2 and ARNT2 also regulate the expression of RET and are regarded as RET modifier genes. Outcome effects: Mutations of SOX10, PHOX2B, PAX3, and ZEB2 impair migration, proliferation, or differentiation of enteric neural crest progenitor cells leading to HSCR development. The expression of neurogenic transcription factors is largely controlled by BMP signaling. Mutated genes: Mutated genes are shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15905074 PS:PMID 19215589 PS:PMID 22174542 PS:PMID 23043324 PS:PMID 23528997 PS:PMID 23639815 PS:PMID 23644063 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-108ff681-624e-4336-94f7-314abe786c61 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: CRH induces selective VEGFA release in mast cells without activation of degranulation. This may possibly explain how mast cells participate in inflammatory processes in the absence of allergic stimulation or degranulation. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-108ff681-624e-4336-94f7-314abe786c61 Mast-Cell Activation without Degranulation through CRHR1 Signaling uuid-108ff681-624e-4336-94f7-314abe786c61 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-108ff681-624e-4336-94f7-314abe786c61 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: CRH induces selective VEGFA release in mast cells without activation of degranulation. This may possibly explain how mast cells participate in inflammatory processes in the absence of allergic stimulation or degranulation. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-109b2d71-8c87-41c0-b494-82ca60f12223 NodeType: Pathway Organ_System: lymphatic system PMID: 24325346 PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-109b2d71-8c87-41c0-b494-82ca60f12223 Genes with Mutations in Cancer Immune Escape uuid-109b2d71-8c87-41c0-b494-82ca60f12223 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-109b2d71-8c87-41c0-b494-82ca60f12223 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PMID 24325346 PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10a498cf-9d79-4c70-95b7-cfcf477ab30d NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-10a498cf-9d79-4c70-95b7-cfcf477ab30d Proteins Involved in Angelman Syndrome uuid-10a498cf-9d79-4c70-95b7-cfcf477ab30d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10a498cf-9d79-4c70-95b7-cfcf477ab30d PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Hypoparathyroidism is a metabolic disorder characterized by deficient or absent secretion of PTH. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10c31179-983a-4cd5-8f64-63c04ca9ffe2 NodeType: Pathway Notes: Headnote: Hypoparathyroidism is an endocrine disorder characterized by deficient or absent secretion of parathyroid hormone (PTH). Loss-of-function mutations in TBX1, HOXA3, EYA1, PAX1, GCM2 protein genes lead to disruption of parathyroid glands development and may cause hypoparathyroidism. Animal data: mouse model. Mutated genes: Mutated genes are shown in white-out style. Organ: Parathyroid gland Organ_System: endocrine system PMID: 11476574 PMID: 12533514 PMID: 17382312 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-10c31179-983a-4cd5-8f64-63c04ca9ffe2 Parathyroid Glands Development (Mouse Model) uuid-10c31179-983a-4cd5-8f64-63c04ca9ffe2 PS:CellType parathyroid cell PS:Description Hypoparathyroidism is a metabolic disorder characterized by deficient or absent secretion of PTH. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10c31179-983a-4cd5-8f64-63c04ca9ffe2 PS:NodeType Pathway PS:Notes Headnote: Hypoparathyroidism is an endocrine disorder characterized by deficient or absent secretion of parathyroid hormone (PTH). Loss-of-function mutations in TBX1, HOXA3, EYA1, PAX1, GCM2 protein genes lead to disruption of parathyroid glands development and may cause hypoparathyroidism. Animal data: mouse model. Mutated genes: Mutated genes are shown in white-out style. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 11476574 PS:PMID 12533514 PS:PMID 17382312 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10d29f43-b7a5-4ff7-ae2e-8d3eac1e50df NodeType: Pathway Notes: Headnote: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway essential for normal vascular development and crucial for the angiogenic switch in tumors. ANGPT1/TEK has been shown to regulate both vascular quiescence and angiogenesis. The pathology of angiogenic switch in tumors is characterized by exit from quiescence state by endothelial cells (ECs), cell proliferation and migration with the formation of new blood vessels. Tumor ECs express elevated ANGPT2 levels, and an increased ANGPT2/ANGPT1 ratio correlates with tumor angiogenesis and poor prognosis in many cancers, making ANGPT2 an attractive therapeutic target. Signaling description: ANGPT1 is a TIE2 agonist, and ANGPT2 functions as an antagonist or a partial agonist of TIE2 in various settings. ANGPT2 attenuates ANGPT1-TEK activation in the presence of ANGPT1 but activates TEK signaling when ANGPT1 is absent, which suggests that ANGPT2 is a partial agonist. Both ANGPT1 and ANGPT2 have been shown to promote or inhibit tumorigenesis in many cases. The precise mechanism of the molecular signaling shown on this pathway is poorly understood and requires further investigations. One of hypotheses is described on the pathway. In the presence of pro-angiogenic stimuli, ECs escape their quiescent state, loose cell-cell contacts, proliferate and migrate. In the absence of cell-cell adhesions, TEK is anchored to the cell-extracellular matrix (ECM) interface through ANGPT1 binding to the ECM. In cells lacking cell-cell adhesions, ANGPTs induces integrin-dependent focal complex formation, leading to activation of PTK2. ANGPTs activate RAS-MAPK through TEK and integrins leading to cell proliferation and signalling involved in ECs migration. ANGPT2 may also stimulates tip cell migration by activating integrins independently of TEK. Outcome effects: JUN-FOS is activated leading to increased ECs cell proliferation. F-actin is activated and promotes ECs migration. Animal data: The majority of the data on ANGPT/TEK and their role in angiogenesis were revealed from animal model (mice) experiments. Organ: blood vessel Organ_System: cardiovascular system PMID: 17634421 PMID: 20054809 PMID: 20651738 PMID: 22585576 PMID: 22951441 PMID: 23908119 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-10d29f43-b7a5-4ff7-ae2e-8d3eac1e50df ANGPT/TEK Stimulates Endothelial Cell Migration in Cancer uuid-10d29f43-b7a5-4ff7-ae2e-8d3eac1e50df PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development and is crucial for the angiogenic switch in tumors. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-10d29f43-b7a5-4ff7-ae2e-8d3eac1e50df PS:NodeType Pathway PS:Notes Headnote: ANGPT/TEK signaling system is a vascular-specific receptor tyrosine kinase pathway essential for normal vascular development and crucial for the angiogenic switch in tumors. ANGPT1/TEK has been shown to regulate both vascular quiescence and angiogenesis. The pathology of angiogenic switch in tumors is characterized by exit from quiescence state by endothelial cells (ECs), cell proliferation and migration with the formation of new blood vessels. Tumor ECs express elevated ANGPT2 levels, and an increased ANGPT2/ANGPT1 ratio correlates with tumor angiogenesis and poor prognosis in many cancers, making ANGPT2 an attractive therapeutic target. Signaling description: ANGPT1 is a TIE2 agonist, and ANGPT2 functions as an antagonist or a partial agonist of TIE2 in various settings. ANGPT2 attenuates ANGPT1-TEK activation in the presence of ANGPT1 but activates TEK signaling when ANGPT1 is absent, which suggests that ANGPT2 is a partial agonist. Both ANGPT1 and ANGPT2 have been shown to promote or inhibit tumorigenesis in many cases. The precise mechanism of the molecular signaling shown on this pathway is poorly understood and requires further investigations. One of hypotheses is described on the pathway. In the presence of pro-angiogenic stimuli, ECs escape their quiescent state, loose cell-cell contacts, proliferate and migrate. In the absence of cell-cell adhesions, TEK is anchored to the cell-extracellular matrix (ECM) interface through ANGPT1 binding to the ECM. In cells lacking cell-cell adhesions, ANGPTs induces integrin-dependent focal complex formation, leading to activation of PTK2. ANGPTs activate RAS-MAPK through TEK and integrins leading to cell proliferation and signalling involved in ECs migration. ANGPT2 may also stimulates tip cell migration by activating integrins independently of TEK. Outcome effects: JUN-FOS is activated leading to increased ECs cell proliferation. F-actin is activated and promotes ECs migration. Animal data: The majority of the data on ANGPT/TEK and their role in angiogenesis were revealed from animal model (mice) experiments. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 17634421 PS:PMID 20054809 PS:PMID 20651738 PS:PMID 22585576 PS:PMID 22951441 PS:PMID 23908119 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11248553-792c-469d-8804-7cc62ff56a5a NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-11248553-792c-469d-8804-7cc62ff56a5a Proteins Involved in Adhesion, Migration and Invasion of Endometriotic Cell uuid-11248553-792c-469d-8804-7cc62ff56a5a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11248553-792c-469d-8804-7cc62ff56a5a PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11249b0b-78dc-4ec7-b96d-e070ccb6c295 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-11249b0b-78dc-4ec7-b96d-e070ccb6c295 Ser/Gly/Thr/Cys Metabolism uuid-11249b0b-78dc-4ec7-b96d-e070ccb6c295 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11249b0b-78dc-4ec7-b96d-e070ccb6c295 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1146f763-5fb0-4acc-b620-5b11ccdbc716 NodeType: Pathway Organ_System: hematological system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1146f763-5fb0-4acc-b620-5b11ccdbc716 Proteins Involved in Antiphospholipid Syndrome uuid-1146f763-5fb0-4acc-b620-5b11ccdbc716 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1146f763-5fb0-4acc-b620-5b11ccdbc716 PS:NodeType Pathway PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-118fe5e3-bf33-46a1-a27b-37cfff67799b NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-118fe5e3-bf33-46a1-a27b-37cfff67799b ADRB1 -> Prostaglandin Generation uuid-118fe5e3-bf33-46a1-a27b-37cfff67799b PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-118fe5e3-bf33-46a1-a27b-37cfff67799b PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1197d575-0a37-4c9e-8fb1-23bf530091f4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-1197d575-0a37-4c9e-8fb1-23bf530091f4 TLR4 -> IRF Signaling uuid-1197d575-0a37-4c9e-8fb1-23bf530091f4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1197d575-0a37-4c9e-8fb1-23bf530091f4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte CellType: striated muscle cell Description: Excessive alcohol intake is reported in a wide range (3-40 percent) of patients with dilated cardiomyopathy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1199b9c6-e5f4-45d2-9986-e3293d7b590c NodeType: Pathway Notes: Excessive alcohol intake is reported in a wide range (3-40 percent) of patients with dilated cardiomyopathy, furthermore, chronic excessive alcohol consumption may lead to progressive and chronic cardiac dysfunction. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 24884436 PMID: 25458176 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-1199b9c6-e5f4-45d2-9986-e3293d7b590c Alcoholic Dilated Cardiomyopathy (Mouse Model) uuid-1199b9c6-e5f4-45d2-9986-e3293d7b590c PS:CellType cardiac myocyte PS:CellType striated muscle cell PS:Description Excessive alcohol intake is reported in a wide range (3-40 percent) of patients with dilated cardiomyopathy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1199b9c6-e5f4-45d2-9986-e3293d7b590c PS:NodeType Pathway PS:Notes Excessive alcohol intake is reported in a wide range (3-40 percent) of patients with dilated cardiomyopathy, furthermore, chronic excessive alcohol consumption may lead to progressive and chronic cardiac dysfunction. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 24884436 PS:PMID 25458176 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-119c88ca-a39d-47e7-99f5-cff85933f387 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-119c88ca-a39d-47e7-99f5-cff85933f387 Catechol metabolism template uuid-119c88ca-a39d-47e7-99f5-cff85933f387 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-119c88ca-a39d-47e7-99f5-cff85933f387 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11be14bd-bccc-4237-840e-5ea0677eb092 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-11be14bd-bccc-4237-840e-5ea0677eb092 trans-Zeatin biosynthesis (plastids) template uuid-11be14bd-bccc-4237-840e-5ea0677eb092 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11be14bd-bccc-4237-840e-5ea0677eb092 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Dendritic cells (DCs) are constituents of innate system that activate T-cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11d0278a-d99c-48c1-8e4e-61447966d5fc NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. The altered function of proteins involved in pathogen pattern recognition in dendritic cells of patients with Crohn's disease is suggested to be the essential cause of inflammation development. Signaling description: NOD2 is an intracellular protein expressed in a variety of immune and non-immune cells where it is involved in recognition and defense against pathogens. NOD2 signaling initiates the activation of NF-kB through RIPK2 - MAP3K7 participation. In contrast, NOD2 may be a negative regulator of TLR4-dependent NF-kB activation. RIPK2 - independent NOD2 signaling is initiated by viral ssRNA. This process involves the binding of ssRNA to NOD2 followed by an interaction with MAVS, an adaptor protein associated with mitochondria. This leads to the activation of IRF3 and induction of beta interferon (IFNB1). Outcome effects: The interaction of NOD2 with CARD9 may determine which downstream components are activated. The strong expression of TNFSF11 in patients with Crohn's disease facilitates antigen-presenting cells migrating to Peyer's patches (intestinal mesenteric lymph nodes) to present antigens and stimulate T-cell proliferation and differentiation. The T-cells of patients with Crohn's disease react more intensely. The activation of TLR4 signaling through NF-kB also stimulates Th1 and Th17 cell differentiation and their pro-inflammatory response. Finally, strong transcriptional activity of NF-kB increases the expression of cytokines and other proteins which in turn activate the immune system. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 16461743 PMID: 18777590 PMID: 19079230 PMID: 19572373 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-11d0278a-d99c-48c1-8e4e-61447966d5fc Dendritic Cell Dysfunction in Crohn's disease uuid-11d0278a-d99c-48c1-8e4e-61447966d5fc PS:CellType dendritic cell PS:Description Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Dendritic cells (DCs) are constituents of innate system that activate T-cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11d0278a-d99c-48c1-8e4e-61447966d5fc PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. The altered function of proteins involved in pathogen pattern recognition in dendritic cells of patients with Crohn's disease is suggested to be the essential cause of inflammation development. Signaling description: NOD2 is an intracellular protein expressed in a variety of immune and non-immune cells where it is involved in recognition and defense against pathogens. NOD2 signaling initiates the activation of NF-kB through RIPK2 - MAP3K7 participation. In contrast, NOD2 may be a negative regulator of TLR4-dependent NF-kB activation. RIPK2 - independent NOD2 signaling is initiated by viral ssRNA. This process involves the binding of ssRNA to NOD2 followed by an interaction with MAVS, an adaptor protein associated with mitochondria. This leads to the activation of IRF3 and induction of beta interferon (IFNB1). Outcome effects: The interaction of NOD2 with CARD9 may determine which downstream components are activated. The strong expression of TNFSF11 in patients with Crohn's disease facilitates antigen-presenting cells migrating to Peyer's patches (intestinal mesenteric lymph nodes) to present antigens and stimulate T-cell proliferation and differentiation. The T-cells of patients with Crohn's disease react more intensely. The activation of TLR4 signaling through NF-kB also stimulates Th1 and Th17 cell differentiation and their pro-inflammatory response. Finally, strong transcriptional activity of NF-kB increases the expression of cytokines and other proteins which in turn activate the immune system. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 16461743 PS:PMID 18777590 PS:PMID 19079230 PS:PMID 19572373 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e28dd4-4b0a-4e03-8f79-6cceef24285d NodeType: Pathway Notes: Headnote: The activation of mast cells can lead to synthesis of large amounts of mediators without degranulation. Signaling description: In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: CXCL12 selectively produces IL8 from human mast cells through its receptor, CXCR4. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-11e28dd4-4b0a-4e03-8f79-6cceef24285d Mast-Cell Activation without Degranulation through CXCR4 Signaling uuid-11e28dd4-4b0a-4e03-8f79-6cceef24285d PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e28dd4-4b0a-4e03-8f79-6cceef24285d PS:NodeType Pathway PS:Notes Headnote: The activation of mast cells can lead to synthesis of large amounts of mediators without degranulation. Signaling description: In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: CXCL12 selectively produces IL8 from human mast cells through its receptor, CXCR4. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e30b30-3f8a-46e6-8d38-18acc60c0caf NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-11e30b30-3f8a-46e6-8d38-18acc60c0caf DRD3 -> Dopamine Uptake uuid-11e30b30-3f8a-46e6-8d38-18acc60c0caf PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e30b30-3f8a-46e6-8d38-18acc60c0caf PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e41e76-9cf3-4bbd-88cc-b31f9d0ea5c7 NodeType: Pathway Notes: CpG islands in the viral DNA genome are ligands for endosomal receptors like the toll-like receptor TLR9. Viral reproduction leads to the activation of TLRs and the tumor necrosis factor (TNF) pathways, which usually cause apoptosis of infected cells through receptor interacting protein (RIPK) and Fas-associated via death domain (FADD) signaling. While the uncontrolled expression of HPV16-E6 and HPV16-E7 proteins may block apoptosis and activate cell survival pathways through parallel parts of TLRs and TNF cascades. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-11e41e76-9cf3-4bbd-88cc-b31f9d0ea5c7 5_Human papilloma virus E6 and E7 proteins promote epithelial cell proliferation uuid-11e41e76-9cf3-4bbd-88cc-b31f9d0ea5c7 PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11e41e76-9cf3-4bbd-88cc-b31f9d0ea5c7 PS:NodeType Pathway PS:Notes CpG islands in the viral DNA genome are ligands for endosomal receptors like the toll-like receptor TLR9. Viral reproduction leads to the activation of TLRs and the tumor necrosis factor (TNF) pathways, which usually cause apoptosis of infected cells through receptor interacting protein (RIPK) and Fas-associated via death domain (FADD) signaling. While the uncontrolled expression of HPV16-E6 and HPV16-E7 proteins may block apoptosis and activate cell survival pathways through parallel parts of TLRs and TNF cascades. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11fadd25-efa8-408e-9e15-0375fa1632e2 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-11fadd25-efa8-408e-9e15-0375fa1632e2 NOTCH -> TCF3 Signaling uuid-11fadd25-efa8-408e-9e15-0375fa1632e2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-11fadd25-efa8-408e-9e15-0375fa1632e2 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-120e417f-1c49-4924-aec2-865b2e279a56 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-120e417f-1c49-4924-aec2-865b2e279a56 CD80 -> NF-kB Expression Targets uuid-120e417f-1c49-4924-aec2-865b2e279a56 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-120e417f-1c49-4924-aec2-865b2e279a56 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1210f9da-50f9-428d-a64d-97adf278b556 NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. The impairment of CD8 T-cell action is an important step in HIV infection. Signaling description: During HIV infection, CXCR4 in macrophages is activated by the HIV envelope glycoprotein Gp120 (env), and in turn activates PI3K through LYN, PTK2, and PTK2B. PI3K generates PIP3, which interacts with PDPK1 leading to AKT1 activation. PTK2B forms a complex with SRC, BCAR1, CRK, and PXN. Outcome effects: Activated AKT1 promotes the survival of macrophages, and PXN interacts with ELMO1-DOCK1 complex which results in actin reorganization and cell mobility through RAC1/PAK1. Highlighted proteins: Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 20380698 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-1210f9da-50f9-428d-a64d-97adf278b556 Macrophage Survival through CCR5 and CXCR4 Mediated Signaling uuid-1210f9da-50f9-428d-a64d-97adf278b556 PS:CellType macrophage PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1210f9da-50f9-428d-a64d-97adf278b556 PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. The impairment of CD8 T-cell action is an important step in HIV infection. Signaling description: During HIV infection, CXCR4 in macrophages is activated by the HIV envelope glycoprotein Gp120 (env), and in turn activates PI3K through LYN, PTK2, and PTK2B. PI3K generates PIP3, which interacts with PDPK1 leading to AKT1 activation. PTK2B forms a complex with SRC, BCAR1, CRK, and PXN. Outcome effects: Activated AKT1 promotes the survival of macrophages, and PXN interacts with ELMO1-DOCK1 complex which results in actin reorganization and cell mobility through RAC1/PAK1. Highlighted proteins: Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 20380698 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuroglia CellType: neuron Description: Normally, motor neurons express CX3CL1 and CD200 which prevent microglia from becoming neurotoxic. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12206320-e61d-4961-be4f-be61cb92f0dc NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Normally, motor neurons are characterized by a high level of CX3CL1 and CD200 expression, which prevents microglia from becoming neurotoxic. CX3CL1 can be either membrane bound or soluble (the latter results from the cleavage of membrane-bound CX3CL1 by ADAM10/17). CX3CL1 interacts with CX3CR1 on the surface of microglia cells resulting in microglia inhibition. The precise mechanism of this effect is unclear; most likely CX3CL1/CX3CR1 interaction modulates the release of proinflammatory cytokines from microglia. CD200/CD200R1 interactions lead to the activation of DOK1 and DOK2 proteins, binding of Ras-GAP and INPP5D, and subsequent downstream inhibition of Ras/MAPK and PI3K/AKT1 pathways. Outcome effects: Inhibition of Ras/MAPK and PI3K/AKT1 pathways results in a decreased expression of proinflammatory cytokines and NOS2. In amyotrophic lateral sclerosis, CX3CL1 and CD200 are downregulated in motor neurons resulting in the reversal of microglia inhibition and activation of neuroinflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. References: 1).Gorczynski RM (2012) CD200:CD200R-Mediated Regulation of Immunity. ISRN Immunology.Available from: http://dx.doi.org/10.5402/2012/682168 2). Holmannova D, et al.(2012) CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function. Acta Medica (Hradec Kralove).55(1):12-7. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16801915 PMID: 17950926 PMID: 22666587 PMID: 22696929 PMID: 22919540 PMID: 23507975 PMID: 23630462 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-12206320-e61d-4961-be4f-be61cb92f0dc Microglia and Motor Neuron Interaction Dysregulation uuid-12206320-e61d-4961-be4f-be61cb92f0dc PS:CellType neuroglia PS:CellType neuron PS:Description Normally, motor neurons express CX3CL1 and CD200 which prevent microglia from becoming neurotoxic. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12206320-e61d-4961-be4f-be61cb92f0dc PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Normally, motor neurons are characterized by a high level of CX3CL1 and CD200 expression, which prevents microglia from becoming neurotoxic. CX3CL1 can be either membrane bound or soluble (the latter results from the cleavage of membrane-bound CX3CL1 by ADAM10/17). CX3CL1 interacts with CX3CR1 on the surface of microglia cells resulting in microglia inhibition. The precise mechanism of this effect is unclear; most likely CX3CL1/CX3CR1 interaction modulates the release of proinflammatory cytokines from microglia. CD200/CD200R1 interactions lead to the activation of DOK1 and DOK2 proteins, binding of Ras-GAP and INPP5D, and subsequent downstream inhibition of Ras/MAPK and PI3K/AKT1 pathways. Outcome effects: Inhibition of Ras/MAPK and PI3K/AKT1 pathways results in a decreased expression of proinflammatory cytokines and NOS2. In amyotrophic lateral sclerosis, CX3CL1 and CD200 are downregulated in motor neurons resulting in the reversal of microglia inhibition and activation of neuroinflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. References: 1).Gorczynski RM (2012) CD200:CD200R-Mediated Regulation of Immunity. ISRN Immunology.Available from: http://dx.doi.org/10.5402/2012/682168 2). Holmannova D, et al.(2012) CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function. Acta Medica (Hradec Kralove).55(1):12-7. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16801915 PS:PMID 17950926 PS:PMID 22666587 PS:PMID 22696929 PS:PMID 22919540 PS:PMID 23507975 PS:PMID 23630462 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: CD8+ T-cell CellType: antigen-presenting cell CellType: cancer cell CellType: cancer stem cell CellType: natural killer cell Description: The loss of MHC class I antigens or impairment of antigen presentation due to mutations or decreased expression of proteasome subunits are frequent ways to evade immune recognition. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-122d0c3c-a254-4b98-b2f7-3ab5dffffa3a NodeType: Pathway Notes: Headnote: Loss of MHC class I antigens or an impairment of antigen presentation due to mutations/decreased expression of proteasome subunits allow tumor cells to evade immune recognition. Signaling description: Major histocompatibility complex (MHC) I is a cell surface molecule responsible for the transmission of intracellular antigens. The process of MHC1-mediated antigen presentation is initiated when cells take over antigens and degrade them into peptides by the proteasome. The peptides are then transported into the endoplasmic reticulum (ER) by TAP1 and TAP2. The chaperones, calnexin (CANX) and calreticulin (CALR) bind to MHCI and the peptide complex assembly. Other chaperones maintain MHC I as it binds to the TAP complex via tapasin (TAPBP). Subsequently, MHC I and the peptide complex migrate through Golgi vesicles to the outer cell membrane. Cell surface MHC I and the peptide complex, when connected with CD8 and NK cells, activate their differentiation and functions. The loss of MHC I antigens is one of the ways to evade immune recognition. Total loss of MHC I may be a result of structural changes in the beta2-microglobulin (B2M) gene resulting from mutations, deletion or loss of heterozygosity. MHC I inactivation may also result from HLA-A and HLA-B mutation or methylation. Impaired antigen presentation can also be caused by mutations/decreased expression of proteasome subunits PSMB9 and PSMB8, peptide transporters TAP1, and TAP2 as well as TAPBP chaperone. NLRC5, regulating the expression of B2M, TAP1 and PSMB9, may be mutated in cancers. HLA-G is a "nonclassical" major histocompatibility complex class Ib gene. The HLA-G presents immunomodulatory functions essential in pregnancy for the tolerance of the semi-allogenic fetus, but an abnormal expression of HLA-G has been observed in numerous pathological conditions, including tumors. HLA-G may be overexpressed in cancers and inhibits the activation of NK cells via interaction with inhibitory receptors LILRB1, LILRB2, and KIR2DL4. Outcome effects: Due to lack of HLA I, tumor antigens are not presented to NK cells and cytotoxic T-cells, and these cells are unbale to eliminate tumor cells. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 19796244 PMID: 24325346 PMID: 25318079 PMID: 26284197 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-122d0c3c-a254-4b98-b2f7-3ab5dffffa3a MHC1 Causes Antigen Presentation Failure in Cancer Immune Escape uuid-122d0c3c-a254-4b98-b2f7-3ab5dffffa3a PS:CellType CD8+ T-cell PS:CellType antigen-presenting cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType natural killer cell PS:Description The loss of MHC class I antigens or impairment of antigen presentation due to mutations or decreased expression of proteasome subunits are frequent ways to evade immune recognition. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-122d0c3c-a254-4b98-b2f7-3ab5dffffa3a PS:NodeType Pathway PS:Notes Headnote: Loss of MHC class I antigens or an impairment of antigen presentation due to mutations/decreased expression of proteasome subunits allow tumor cells to evade immune recognition. Signaling description: Major histocompatibility complex (MHC) I is a cell surface molecule responsible for the transmission of intracellular antigens. The process of MHC1-mediated antigen presentation is initiated when cells take over antigens and degrade them into peptides by the proteasome. The peptides are then transported into the endoplasmic reticulum (ER) by TAP1 and TAP2. The chaperones, calnexin (CANX) and calreticulin (CALR) bind to MHCI and the peptide complex assembly. Other chaperones maintain MHC I as it binds to the TAP complex via tapasin (TAPBP). Subsequently, MHC I and the peptide complex migrate through Golgi vesicles to the outer cell membrane. Cell surface MHC I and the peptide complex, when connected with CD8 and NK cells, activate their differentiation and functions. The loss of MHC I antigens is one of the ways to evade immune recognition. Total loss of MHC I may be a result of structural changes in the beta2-microglobulin (B2M) gene resulting from mutations, deletion or loss of heterozygosity. MHC I inactivation may also result from HLA-A and HLA-B mutation or methylation. Impaired antigen presentation can also be caused by mutations/decreased expression of proteasome subunits PSMB9 and PSMB8, peptide transporters TAP1, and TAP2 as well as TAPBP chaperone. NLRC5, regulating the expression of B2M, TAP1 and PSMB9, may be mutated in cancers. HLA-G is a "nonclassical" major histocompatibility complex class Ib gene. The HLA-G presents immunomodulatory functions essential in pregnancy for the tolerance of the semi-allogenic fetus, but an abnormal expression of HLA-G has been observed in numerous pathological conditions, including tumors. HLA-G may be overexpressed in cancers and inhibits the activation of NK cells via interaction with inhibitory receptors LILRB1, LILRB2, and KIR2DL4. Outcome effects: Due to lack of HLA I, tumor antigens are not presented to NK cells and cytotoxic T-cells, and these cells are unbale to eliminate tumor cells. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 19796244 PS:PMID 24325346 PS:PMID 25318079 PS:PMID 26284197 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-124b7812-554a-4c82-abf8-cf1d4ecc26d3 NodeType: Pathway Notes: Since cataract is a heterogeneous disease, several different mechanisms have an impact on the development of the clinical features of the disease. Calcium (Ca2+)-mediated toxicity in the lens cells is one of the major pathological mechanisms leading to different forms of cataract. Further, reactive oxygen species (ROS)–mediated and glucose-mediated toxicity are considered underlying factors in the formation of age-related cataract. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-124b7812-554a-4c82-abf8-cf1d4ecc26d3 1_Age-related cataract uuid-124b7812-554a-4c82-abf8-cf1d4ecc26d3 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-124b7812-554a-4c82-abf8-cf1d4ecc26d3 PS:NodeType Pathway PS:Notes Since cataract is a heterogeneous disease, several different mechanisms have an impact on the development of the clinical features of the disease. Calcium (Ca2+)-mediated toxicity in the lens cells is one of the major pathological mechanisms leading to different forms of cataract. Further, reactive oxygen species (ROS)–mediated and glucose-mediated toxicity are considered underlying factors in the formation of age-related cataract. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-124ff746-af21-44af-9db1-e19c1e022a60 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-124ff746-af21-44af-9db1-e19c1e022a60 Genes with Mutations in Cancer Metastasis uuid-124ff746-af21-44af-9db1-e19c1e022a60 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-124ff746-af21-44af-9db1-e19c1e022a60 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Frontotemporal dementia (FTD) is a clinical presentation of frontotemporal lobar degeneration, is characterized by behavioral and personality disorder, and language disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-127bc516-ea4f-4ad2-95d3-07d00130c47b NodeType: Pathway Notes: Frontotemporal dementia (FTD) is a clinical presentation of frontotemporal lobar degeneration, is characterized by behavioral and personality disorder, and language disorder. FTD is related with impaired protein degradation. Organ: brain Organ_System: nervous system PMID: 24549040 PMID: 24600223 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-127bc516-ea4f-4ad2-95d3-07d00130c47b Protein Degradation Dysregulation in Dementia (Hypothesis) uuid-127bc516-ea4f-4ad2-95d3-07d00130c47b PS:CellType neuron PS:Description Frontotemporal dementia (FTD) is a clinical presentation of frontotemporal lobar degeneration, is characterized by behavioral and personality disorder, and language disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-127bc516-ea4f-4ad2-95d3-07d00130c47b PS:NodeType Pathway PS:Notes Frontotemporal dementia (FTD) is a clinical presentation of frontotemporal lobar degeneration, is characterized by behavioral and personality disorder, and language disorder. FTD is related with impaired protein degradation. PS:Organ brain PS:Organ_System nervous system PS:PMID 24549040 PS:PMID 24600223 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1280cc56-9954-474a-b0f1-e45216d7fafd NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-1280cc56-9954-474a-b0f1-e45216d7fafd USP16-Mediated Epigenetic and Non-Epigenetic Effects uuid-1280cc56-9954-474a-b0f1-e45216d7fafd PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1280cc56-9954-474a-b0f1-e45216d7fafd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-128acb0b-1912-484e-b31b-4b6d19d35140 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-128acb0b-1912-484e-b31b-4b6d19d35140 Lymphotoxin B signaling uuid-128acb0b-1912-484e-b31b-4b6d19d35140 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-128acb0b-1912-484e-b31b-4b6d19d35140 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12b64cbb-4182-44a1-89cf-25fa615ad6e1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-12b64cbb-4182-44a1-89cf-25fa615ad6e1 FGF1 -> AP-1/CREB/ELK/SRF/MYC Expression Targets uuid-12b64cbb-4182-44a1-89cf-25fa615ad6e1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12b64cbb-4182-44a1-89cf-25fa615ad6e1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12f3a773-4b87-42bb-a38e-abe2ba732e1e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-12f3a773-4b87-42bb-a38e-abe2ba732e1e Hemangiogenesis uuid-12f3a773-4b87-42bb-a38e-abe2ba732e1e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-12f3a773-4b87-42bb-a38e-abe2ba732e1e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1321a6e2-9a4a-48dc-a671-4c6110242225 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-1321a6e2-9a4a-48dc-a671-4c6110242225 TGFBR -> SMAD1/5/9 Signaling uuid-1321a6e2-9a4a-48dc-a671-4c6110242225 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1321a6e2-9a4a-48dc-a671-4c6110242225 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-133e9920-7bee-4d9d-b1f1-27d74e1f8c5c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-133e9920-7bee-4d9d-b1f1-27d74e1f8c5c TLR4 -> NF-kB/IRF Expression Targets uuid-133e9920-7bee-4d9d-b1f1-27d74e1f8c5c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-133e9920-7bee-4d9d-b1f1-27d74e1f8c5c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-134f7028-ff99-4899-bf0e-71317e961114 NodeType: Pathway Organ: generic Organ_System: generic PMID: 23328704 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-134f7028-ff99-4899-bf0e-71317e961114 WNT Planar Cell Polarity (PCP) non-Canonical Signaling uuid-134f7028-ff99-4899-bf0e-71317e961114 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-134f7028-ff99-4899-bf0e-71317e961114 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 23328704 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte Description: The heart is a major target organ for thyroid hormone action and noticeable changes occur in cardiac function in patients with hypo- and hyperthyroidism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-135048b8-44d1-408d-b1c1-5071209b7df3 NodeType: Pathway Notes: Headnote: Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. The heart is a major target organ for thyroid hormone action, and noticeable changes occur in cardiac function in patients with hypo- and hyperthyroidism. Signaling description: Genomic triiodothyronine (T3) effects are mediated by binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. TR alpha (THRA) is the predominant isoform of thyroid hormone receptor in the heart. It regulates the transcription of several specific proteins critical for cardiac function including MYH genes. Extranuclear non-genomic T3 affects signaling through vitronectin receptor (integrin), which increases protein synthesis in the heart. The adrenergic-receptor complex in plasma membranes has also been shown to be upregulated by thyroid hormones. Beta 1-receptors (ADRB1 and ADRB2) are the predominant beta-adrenoceptors in cells of myocyte origin and may be responsive to T3 regulation through G protein signaling activation. Outcome effects: T3 treatment decreases MYH6 gene expression leading to enhanced cardiac contractility. The cardiac cycle is divided into systolic contraction and diastolic relaxation. The rate of diastolic relaxation of the heart is related to intracellular calcium (Ca2 ) concentration and SERCA Ca2 -ATPase (ATP2A2) activity. T3 markedly increases the expression of the sarcoplasmic reticulum ATP2A2 gene. T3 activation through integrin and beta-adrenoceptors may stimulate Ca2 -ATPase activity as well as Ca2 movement across the membrane via changes in Ca2 channels. This also contributes to heart relaxation. Finally, T3 significantly shortens diastolic relaxation, and the hyperthyroid heart relaxes at a higher speed (lusitropic activity), while diastole is prolonged in hypothyroid states. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: heart Organ_System: cardiovascular system PMID: 15632316 PMID: 19125327 PMID: 20005976 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-135048b8-44d1-408d-b1c1-5071209b7df3 Cardiovascular Effects in Hyperthyroidism uuid-135048b8-44d1-408d-b1c1-5071209b7df3 PS:CellType cardiac myocyte PS:Description The heart is a major target organ for thyroid hormone action and noticeable changes occur in cardiac function in patients with hypo- and hyperthyroidism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-135048b8-44d1-408d-b1c1-5071209b7df3 PS:NodeType Pathway PS:Notes Headnote: Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. The heart is a major target organ for thyroid hormone action, and noticeable changes occur in cardiac function in patients with hypo- and hyperthyroidism. Signaling description: Genomic triiodothyronine (T3) effects are mediated by binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. TR alpha (THRA) is the predominant isoform of thyroid hormone receptor in the heart. It regulates the transcription of several specific proteins critical for cardiac function including MYH genes. Extranuclear non-genomic T3 affects signaling through vitronectin receptor (integrin), which increases protein synthesis in the heart. The adrenergic-receptor complex in plasma membranes has also been shown to be upregulated by thyroid hormones. Beta 1-receptors (ADRB1 and ADRB2) are the predominant beta-adrenoceptors in cells of myocyte origin and may be responsive to T3 regulation through G protein signaling activation. Outcome effects: T3 treatment decreases MYH6 gene expression leading to enhanced cardiac contractility. The cardiac cycle is divided into systolic contraction and diastolic relaxation. The rate of diastolic relaxation of the heart is related to intracellular calcium (Ca2 ) concentration and SERCA Ca2 -ATPase (ATP2A2) activity. T3 markedly increases the expression of the sarcoplasmic reticulum ATP2A2 gene. T3 activation through integrin and beta-adrenoceptors may stimulate Ca2 -ATPase activity as well as Ca2 movement across the membrane via changes in Ca2 channels. This also contributes to heart relaxation. Finally, T3 significantly shortens diastolic relaxation, and the hyperthyroid heart relaxes at a higher speed (lusitropic activity), while diastole is prolonged in hypothyroid states. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 15632316 PS:PMID 19125327 PS:PMID 20005976 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-136196ef-ea63-4fd9-88f8-aa69633bece1 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-136196ef-ea63-4fd9-88f8-aa69633bece1 Leptin -> NO Production/Vasodilation uuid-136196ef-ea63-4fd9-88f8-aa69633bece1 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-136196ef-ea63-4fd9-88f8-aa69633bece1 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13675f6f-51b4-4849-a29e-59b8cdb0e286 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-13675f6f-51b4-4849-a29e-59b8cdb0e286 IAA storage via aminoacid conjugation template uuid-13675f6f-51b4-4849-a29e-59b8cdb0e286 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13675f6f-51b4-4849-a29e-59b8cdb0e286 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1377c088-e1b6-446d-9b84-1ea0faa5b378 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-1377c088-e1b6-446d-9b84-1ea0faa5b378 NGFR -> AP-1/CEBPB/CREB/ELK/SRF/TP53 Signaling uuid-1377c088-e1b6-446d-9b84-1ea0faa5b378 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1377c088-e1b6-446d-9b84-1ea0faa5b378 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast CellType: osteoclast Description: Thyroid hormones play a crucial role in skeletal growth, peak bone mass acquisition, and maintenance of bone mass. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1388cea0-40db-48dc-98e5-aca9795a23f1 NodeType: Pathway Notes: Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, sleeping difficulties, heat intolerance, diarrhea, elevated heart rate and muscle weakness. Signaling description: Thyroid hormones play a crucial role in skeletal growth, peak bone mass acquisition, and maintenance of bone mass. The thyroid hormone triiodothyronine (T3) has long been considered to play a primordial role in skeletal homeostasis. Bone architecture and strength are maintained by a balanced process of remodeling, which involves the recruitment of osteoclasts and osteoblasts. T3 can induce differentiation and inhibit proliferation of osteoblastic cells and mediate osteoclastic bone resorption through the activation of osteoblasts. However, the detailed mechanism of action of T3 in the bone is not well known. Outcome effects: T3 is a critical regulator of the IHH-bone morphogenetic protein (BMP2)-PTHLH feedback loop. In hyperthyroidism, the reduced expression of PTHLH associated with the augmentation of BMP2 enhances hypertrophic chondrocyte differentiation through SMADs signaling. The activation of DKK1 and SOST by BMP signaling can lead to the inhibition of osteoblastic cell proliferation. Conversely, thyroid hormones may regulate the differentiation of chondrocytes through the activation of WNT4 and modulating WNT signaling pathways. The expression of THRA and THRB has been described in growth plate chondrocytes, osteoblasts, and stromal cells of bone marrow and may mediate their development through common genomic and non-genomic actions. In addition, mature osteoblasts release TNFSF11, a ligand for TNFRSF11B, which is a cytokine that regulates osteoclastic differentiation and functions as a key factor for osteoclast differentiation and activation by inhibiting osteoclast apoptosis. Furthermore, T3 has been shown to promote the production of IGF1 and its binding proteins, IGFBP2-4 in bone marrow stromal cells and osteoblasts. T3 increases the expression of several bone-related genes through the IGF1R signaling (including osteocalcin (BGLAP), collagen type I, gelatinase B, and collagenase 3 (MMP13)). Finally, an excess of T3 can cause accelerated growth and bone formation in children. In adults, thyrotoxicosis leads to increased bone remodeling and an imbalance between bone resorption and formation which results in net bone loss and osteoporosis. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity is highlighted in blue. Organ: bone Organ_System: skeletal system PMID: 18585995 PMID: 22634735 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1388cea0-40db-48dc-98e5-aca9795a23f1 Bone Remodeling in Hyperthyroidism uuid-1388cea0-40db-48dc-98e5-aca9795a23f1 PS:CellType osteoblast PS:CellType osteoclast PS:Description Thyroid hormones play a crucial role in skeletal growth, peak bone mass acquisition, and maintenance of bone mass. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1388cea0-40db-48dc-98e5-aca9795a23f1 PS:NodeType Pathway PS:Notes Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, sleeping difficulties, heat intolerance, diarrhea, elevated heart rate and muscle weakness. Signaling description: Thyroid hormones play a crucial role in skeletal growth, peak bone mass acquisition, and maintenance of bone mass. The thyroid hormone triiodothyronine (T3) has long been considered to play a primordial role in skeletal homeostasis. Bone architecture and strength are maintained by a balanced process of remodeling, which involves the recruitment of osteoclasts and osteoblasts. T3 can induce differentiation and inhibit proliferation of osteoblastic cells and mediate osteoclastic bone resorption through the activation of osteoblasts. However, the detailed mechanism of action of T3 in the bone is not well known. Outcome effects: T3 is a critical regulator of the IHH-bone morphogenetic protein (BMP2)-PTHLH feedback loop. In hyperthyroidism, the reduced expression of PTHLH associated with the augmentation of BMP2 enhances hypertrophic chondrocyte differentiation through SMADs signaling. The activation of DKK1 and SOST by BMP signaling can lead to the inhibition of osteoblastic cell proliferation. Conversely, thyroid hormones may regulate the differentiation of chondrocytes through the activation of WNT4 and modulating WNT signaling pathways. The expression of THRA and THRB has been described in growth plate chondrocytes, osteoblasts, and stromal cells of bone marrow and may mediate their development through common genomic and non-genomic actions. In addition, mature osteoblasts release TNFSF11, a ligand for TNFRSF11B, which is a cytokine that regulates osteoclastic differentiation and functions as a key factor for osteoclast differentiation and activation by inhibiting osteoclast apoptosis. Furthermore, T3 has been shown to promote the production of IGF1 and its binding proteins, IGFBP2-4 in bone marrow stromal cells and osteoblasts. T3 increases the expression of several bone-related genes through the IGF1R signaling (including osteocalcin (BGLAP), collagen type I, gelatinase B, and collagenase 3 (MMP13)). Finally, an excess of T3 can cause accelerated growth and bone formation in children. In adults, thyrotoxicosis leads to increased bone remodeling and an imbalance between bone resorption and formation which results in net bone loss and osteoporosis. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity is highlighted in blue. PS:Organ bone PS:Organ_System skeletal system PS:PMID 18585995 PS:PMID 22634735 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Nephrolithiasis is a process of forming stones in kidneys. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13c447cb-2d0d-4aad-a661-e40d11224383 NodeType: Pathway Notes: Nephrolithiasis is a process of forming stones in kidneys. Acid-base homeostasis is critical for normal kidney physiology. Alkaline urine reduces solubility of calcium and phosphate products and promotes formation of kidney stones. Organ: kidney Organ_System: urinary tract PMID: 21170875 PMID: 26597304 PathwayType: signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-13c447cb-2d0d-4aad-a661-e40d11224383 Ascites uuid-13c447cb-2d0d-4aad-a661-e40d11224383 PS:CellType epithelial cell PS:Description Nephrolithiasis is a process of forming stones in kidneys. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13c447cb-2d0d-4aad-a661-e40d11224383 PS:NodeType Pathway PS:Notes Nephrolithiasis is a process of forming stones in kidneys. Acid-base homeostasis is critical for normal kidney physiology. Alkaline urine reduces solubility of calcium and phosphate products and promotes formation of kidney stones. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 21170875 PS:PMID 26597304 PS:PathwayType signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13d533cd-1973-4fc3-90e4-4215469ed662 NodeType: Pathway Notes: Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Signaling description: During phagocytosis, macrophages engulf microbes into specialized compartments known as phagosomes. Macrophages, similarly to neutrophils, can eat labeled cells by opsonins in Fc receptor-mediated and CR3-mediated processes. In addition, macrophages can swallow cells and debris without opsonin-related mechanisms. Macrophage M1 lineage, activated by classic activation signals such as IFNG, express opsonic receptors including Fcgamma R III/FCGR3A, whereas M2 macrophages are characterized by abundant levels of non-opsonic receptors. MC1R, which is expressed primarily by macrophages, recognizes mannose and fucose on the surface of pathogens and mediates phagocytosis. During MC1R-mediated phagocytosis, the actin cytoskeleton is mobilized around the nascent phagosomes. In addition to the phagocytic signals mediating particle internalization, proinflammatory signals are generated upon MC1R activation. Transcriptional activation most likely occurs via PTPRC-related signaling pathway, which is associated with MC1R receptor; however the specific mechanisms of this are unknown. A possible signaling cascade involving MC1R-dependent phagocytosis produces IL1, IL6, CSF2, TNF, and IL12. Therefore, similar to phagocytosis mediated by Fc receptor, MC1R-mediated phagocytosis is a proinflammatory process due to the production of proinflammatory cytokines. In addition, M2 macrophages play a role in the resolution of inflammation through the phagocytosis of apoptotic neutrophils. The receptors known to participate in the phagocytosis of apoptotic cells by macrophages include MSR1 and CD36 scavenger receptors, which act in conjunction with vitronectin receptor (integrin) and CD14. Outcome effects: The ligands on the apoptotic cell that are recognized by these receptors include sugars, phosphatidylserine, and surface-bound thrombospondin. CD36 has been identified as one of the receptors for collagen type I, oxidized LDL, and phosphatidylserine. Thrombospondin has been suggested to bridge apoptotic cells, CD36, and the vitronectin receptor (integrin), which results in a phagocytically active ternary complex. Vitronectin receptor (integrin) may stimulate the polymerization of actin which results in CD36-dependent internalization of apoptotic cells. CD14 has also been implicated in the recognition and internalization of apoptotic cells. It may be possible that TLR2 is the transmembrane protein that associates with LPS/LBP/CD14 ternary complex to mediate the proinflammatory response in macrophages. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-13d533cd-1973-4fc3-90e4-4215469ed662 Macrophage M2-Related Phagocytosis uuid-13d533cd-1973-4fc3-90e4-4215469ed662 PS:CellType macrophage PS:Description Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13d533cd-1973-4fc3-90e4-4215469ed662 PS:NodeType Pathway PS:Notes Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Signaling description: During phagocytosis, macrophages engulf microbes into specialized compartments known as phagosomes. Macrophages, similarly to neutrophils, can eat labeled cells by opsonins in Fc receptor-mediated and CR3-mediated processes. In addition, macrophages can swallow cells and debris without opsonin-related mechanisms. Macrophage M1 lineage, activated by classic activation signals such as IFNG, express opsonic receptors including Fcgamma R III/FCGR3A, whereas M2 macrophages are characterized by abundant levels of non-opsonic receptors. MC1R, which is expressed primarily by macrophages, recognizes mannose and fucose on the surface of pathogens and mediates phagocytosis. During MC1R-mediated phagocytosis, the actin cytoskeleton is mobilized around the nascent phagosomes. In addition to the phagocytic signals mediating particle internalization, proinflammatory signals are generated upon MC1R activation. Transcriptional activation most likely occurs via PTPRC-related signaling pathway, which is associated with MC1R receptor; however the specific mechanisms of this are unknown. A possible signaling cascade involving MC1R-dependent phagocytosis produces IL1, IL6, CSF2, TNF, and IL12. Therefore, similar to phagocytosis mediated by Fc receptor, MC1R-mediated phagocytosis is a proinflammatory process due to the production of proinflammatory cytokines. In addition, M2 macrophages play a role in the resolution of inflammation through the phagocytosis of apoptotic neutrophils. The receptors known to participate in the phagocytosis of apoptotic cells by macrophages include MSR1 and CD36 scavenger receptors, which act in conjunction with vitronectin receptor (integrin) and CD14. Outcome effects: The ligands on the apoptotic cell that are recognized by these receptors include sugars, phosphatidylserine, and surface-bound thrombospondin. CD36 has been identified as one of the receptors for collagen type I, oxidized LDL, and phosphatidylserine. Thrombospondin has been suggested to bridge apoptotic cells, CD36, and the vitronectin receptor (integrin), which results in a phagocytically active ternary complex. Vitronectin receptor (integrin) may stimulate the polymerization of actin which results in CD36-dependent internalization of apoptotic cells. CD14 has also been implicated in the recognition and internalization of apoptotic cells. It may be possible that TLR2 is the transmembrane protein that associates with LPS/LBP/CD14 ternary complex to mediate the proinflammatory response in macrophages. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13e3cf0b-1c29-4423-a39a-4157e2c58d8a NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Source: Diseases urn:agi-pathway:uuid-13e3cf0b-1c29-4423-a39a-4157e2c58d8a Proteins Involved in Polycystic Ovary Syndrome uuid-13e3cf0b-1c29-4423-a39a-4157e2c58d8a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13e3cf0b-1c29-4423-a39a-4157e2c58d8a PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: corneocyte Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13e7c925-c5fe-43db-96ac-916c9e5d82d4 NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated with impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together and provide tensile strength for the SC to resist shearing forces. Also, filaggrin (FLG) is an epithelial cell protein which is extensively deaminated through the actions of the peptidyl deiminase (PADI1) enzyme. It is subsequently degraded into small peptides and then into free amino acids. The free amino acids are then catabolized into the components of natural moisturizing factor (NMF) including lactic acid, sodium pyrrolidone carboxylic acid, urocanate, and urea. The NMF is essential for the retention of water within the corneocytes and results in their optimal hydration and swelling. Outcome effects: Defects in FLG function lead to the skin barrier disruption and decreased protection against pathogens and environmental allergens. Loss-of-function FLG mutations are an important risk factor for the development of AD. Highlighted proteins: Proteins with decreased expression or activity is highlighted in blue. Mutated genes: Mutated FLG is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 19494827 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-13e7c925-c5fe-43db-96ac-916c9e5d82d4 Epidermal Barrier Dysfunction in Atopic Dermatitis uuid-13e7c925-c5fe-43db-96ac-916c9e5d82d4 PS:CellType corneocyte PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-13e7c925-c5fe-43db-96ac-916c9e5d82d4 PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated with impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together and provide tensile strength for the SC to resist shearing forces. Also, filaggrin (FLG) is an epithelial cell protein which is extensively deaminated through the actions of the peptidyl deiminase (PADI1) enzyme. It is subsequently degraded into small peptides and then into free amino acids. The free amino acids are then catabolized into the components of natural moisturizing factor (NMF) including lactic acid, sodium pyrrolidone carboxylic acid, urocanate, and urea. The NMF is essential for the retention of water within the corneocytes and results in their optimal hydration and swelling. Outcome effects: Defects in FLG function lead to the skin barrier disruption and decreased protection against pathogens and environmental allergens. Loss-of-function FLG mutations are an important risk factor for the development of AD. Highlighted proteins: Proteins with decreased expression or activity is highlighted in blue. Mutated genes: Mutated FLG is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 19494827 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1409033a-3afb-4937-9610-60e86cc9a1d5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-1409033a-3afb-4937-9610-60e86cc9a1d5 ORF10 improves cell survival uuid-1409033a-3afb-4937-9610-60e86cc9a1d5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1409033a-3afb-4937-9610-60e86cc9a1d5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-140a68d2-be65-492f-bcc2-9dcafa80933e NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-140a68d2-be65-492f-bcc2-9dcafa80933e Genes with Mutations in Cancer Metabolic Reprogramming (Respiratory Chain) uuid-140a68d2-be65-492f-bcc2-9dcafa80933e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-140a68d2-be65-492f-bcc2-9dcafa80933e PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme which is expressed in the intestine and brain. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1414fbd1-e801-49fc-adc4-503993da7665 NodeType: Pathway Notes: Headnote: Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme expressed in the intestine and brain. The hypothalamus integrates neurohormonal signaling from the periphery, namely the gut and adipose tissue, to regulate food intake and energy homeostasis. GUCY2C represents one end of a gut-brain endocrine axis, anchored by expression in the hypothalamus. Signaling description: GUCA2B is produced in the intestine and released postprandially into the systemic circulation to travel to and activate GUCY2C in the hypothalamus to signal energy levels. In the brain, GUCY2C activation by GUCA2B leads to cGMP-dependent CNGA1 activation and calcium (Ca2 ) influx. Furthermore, GUCY2C activation and the resulting increase in intracellular cGMP may induce activation and nuclear translocation of PRKG1 and intracellular Ca2 release. The elevation of intracellular Ca2 levels regulates neurotransmitter release and potentiates synaptic transmission. Outcome effects: The possible downstream effects may include the depolarization of neurons expressing the anorexigenic neuropeptides, POMC and CARTPT, which increase the firing of anorexigenic neurons and the hyperpolarization of neurons expressing NPY and AGRP, which decrease the firing of orexigenic neurons. Thus, GUCY2C may represent a new target for anti-obesity pharmacotherapy. Organ: brain Organ_System: nervous system PMID: 21865649 PMID: 22819815 PMID: 22877138 PMID: 23375388 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-1414fbd1-e801-49fc-adc4-503993da7665 GUCY2C Signaling in Apetite Regulation uuid-1414fbd1-e801-49fc-adc4-503993da7665 PS:CellType neuron PS:Description Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme which is expressed in the intestine and brain. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1414fbd1-e801-49fc-adc4-503993da7665 PS:NodeType Pathway PS:Notes Headnote: Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme expressed in the intestine and brain. The hypothalamus integrates neurohormonal signaling from the periphery, namely the gut and adipose tissue, to regulate food intake and energy homeostasis. GUCY2C represents one end of a gut-brain endocrine axis, anchored by expression in the hypothalamus. Signaling description: GUCA2B is produced in the intestine and released postprandially into the systemic circulation to travel to and activate GUCY2C in the hypothalamus to signal energy levels. In the brain, GUCY2C activation by GUCA2B leads to cGMP-dependent CNGA1 activation and calcium (Ca2 ) influx. Furthermore, GUCY2C activation and the resulting increase in intracellular cGMP may induce activation and nuclear translocation of PRKG1 and intracellular Ca2 release. The elevation of intracellular Ca2 levels regulates neurotransmitter release and potentiates synaptic transmission. Outcome effects: The possible downstream effects may include the depolarization of neurons expressing the anorexigenic neuropeptides, POMC and CARTPT, which increase the firing of anorexigenic neurons and the hyperpolarization of neurons expressing NPY and AGRP, which decrease the firing of orexigenic neurons. Thus, GUCY2C may represent a new target for anti-obesity pharmacotherapy. PS:Organ brain PS:Organ_System nervous system PS:PMID 21865649 PS:PMID 22819815 PS:PMID 22877138 PS:PMID 23375388 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Leukotrienes LTC4, LTD4, and LTE4 are potent inflammatory mediators that act through G-protein-coupled receptors, CYSLTR1 and CYSLTR2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-142d04a3-5ece-4586-a154-5b6d29dd5eb2 NodeType: Pathway Notes: Headnote: Leukotrienes LTC4, LTD4, and LTE4 are potent inflammatory mediators that act through G-protein-coupled receptors, CYSLTR1 and CYSLTR2. Leukotrienes have been shown to induce vascular leakage and modulate endothelial function in inflammatory-related disorders. Signaling description: Endothelial dysfunction includes enhanced endothelial cell proliferation, disruption of the endothelial cell barrier in blood vessels, and increased vascular permeability and attachment of immune cells. CYSLTRs are critical mediators of vascular leakage; however the precise molecular mechanisms are unknown. CYSLTR1 appears to be the preferred receptor for Ca+ influx in epithelial and inflammatory cells. CYSLTR2 is predominantly expressed in human umbilical vein endothelial cells (HUVECs) and has been shown to be responsible for Ca2+-dependent contraction and increased endothelial permeability. CYSLTR-modulated vascular permeability seems to be mediated through trans-endothelial vesicle transport regulated by Ca2+ signaling. CYSLTR2 activation results in endothelial cell contraction and barrier disruption through ROCK1 pathway and potentiating TNF-induced attachment of leukocytes to the endothelial monolayer through the upregulation of VCAM1. The pathway displays a hypothetical scheme of forcing endothelial permeability under the action of leukotrienes. Outcome effects: Occludins (OCLN), connexins (GJA1), and cadherins (CDH1) are required for the formation of junctional stability and cell-cell contacts through their connections with the actin cytoskeleton and extracellular matrix. Proteins of the endothelial cell junction are dysregulated through RHOA-related signaling. In addition, HUVECs predominantly express CYSLTR2 and stimulation with LTD4 induces early inflammatory gene expression including EGR1, NR4A1, IL8, RCAN1, SELE, and ADAMTS1. CYSLTR1 activation in endothelial cells mediates their proliferation possibly through the activation of MAPK pathway. Organ: generic Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-142d04a3-5ece-4586-a154-5b6d29dd5eb2 Leukotriene Effect on Vascular Endothelial Cell Response uuid-142d04a3-5ece-4586-a154-5b6d29dd5eb2 PS:CellType endothelial cell PS:Description Leukotrienes LTC4, LTD4, and LTE4 are potent inflammatory mediators that act through G-protein-coupled receptors, CYSLTR1 and CYSLTR2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-142d04a3-5ece-4586-a154-5b6d29dd5eb2 PS:NodeType Pathway PS:Notes Headnote: Leukotrienes LTC4, LTD4, and LTE4 are potent inflammatory mediators that act through G-protein-coupled receptors, CYSLTR1 and CYSLTR2. Leukotrienes have been shown to induce vascular leakage and modulate endothelial function in inflammatory-related disorders. Signaling description: Endothelial dysfunction includes enhanced endothelial cell proliferation, disruption of the endothelial cell barrier in blood vessels, and increased vascular permeability and attachment of immune cells. CYSLTRs are critical mediators of vascular leakage; however the precise molecular mechanisms are unknown. CYSLTR1 appears to be the preferred receptor for Ca+ influx in epithelial and inflammatory cells. CYSLTR2 is predominantly expressed in human umbilical vein endothelial cells (HUVECs) and has been shown to be responsible for Ca2+-dependent contraction and increased endothelial permeability. CYSLTR-modulated vascular permeability seems to be mediated through trans-endothelial vesicle transport regulated by Ca2+ signaling. CYSLTR2 activation results in endothelial cell contraction and barrier disruption through ROCK1 pathway and potentiating TNF-induced attachment of leukocytes to the endothelial monolayer through the upregulation of VCAM1. The pathway displays a hypothetical scheme of forcing endothelial permeability under the action of leukotrienes. Outcome effects: Occludins (OCLN), connexins (GJA1), and cadherins (CDH1) are required for the formation of junctional stability and cell-cell contacts through their connections with the actin cytoskeleton and extracellular matrix. Proteins of the endothelial cell junction are dysregulated through RHOA-related signaling. In addition, HUVECs predominantly express CYSLTR2 and stimulation with LTD4 induces early inflammatory gene expression including EGR1, NR4A1, IL8, RCAN1, SELE, and ADAMTS1. CYSLTR1 activation in endothelial cells mediates their proliferation possibly through the activation of MAPK pathway. PS:Organ generic PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: APC/C-FZR1 complex regulates G1 cell cycle phase, M/G1 and G1/S phase transition. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-142d6ae9-e262-4acf-b39c-fe49588486e5 NodeType: Pathway Notes: Headnote: The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. Many proteins of the APC/C still have unknown functions. APC/C is largely organized into three structural domains, called the 'platform', the 'catalytic' and the 'TPR-arm, lobe or arc lamp'. The platform subcomplex (ANAPC1, ANAPC4, ANAPC5, and ANAPC15) forms a base to join the other subunits of the APC/C. The catalytic core subcomplex (ANAPC2, ANAPC11, and ANAPC10) with an E2 enzyme can provide ubiquitylation activity to the APC/C. The TPR-arm consists of several structurally related proteins with multiple tetratricopeptide (TPR) repeats (ANAPC7, ANAPC13, ANAPC16, CDC16, CDC23, CDC26, CDC27) and is required to coordinate assembly of the APC/C and mediate important interactions with regulator proteins which modulate APC/C activity. Signaling description: The core of APC/C-FZR1 (APC/C-CDH1) complex related signaling leads to M/G1 transition through a specific subset of substrate proteins. The precise mechanism of the molecular signaling on this pathway is partially known and is associated with activation of FZR1 (CDH1). Outcome effects: In the beginning of the cell cycle FZR1 (CDH1) is phosphorylated and inhibited by CDK1, preventing it from attaching to APC/C. APC/C is then free to attach CDC20 and usher the transition from metaphase to anaphase. As CDK1 gets degraded later in mitosis, CDC20 gets released and FZR1 (CDH1) can bind to APC/C, keeping it activated through the M/G1 transition. APC/C-CDH1 then continues is working in G1 phase and degrading CDC20, AURKA/B, CDC25A, GMNN and SKP2. CCNB1 is accumulated throughout this phase and activates CDK1 leads to inhibition of FZR1 (CDH1) and inactivation of APC/C-CDH1. Animal data: Role of APC/C-CDH1 in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 21261459 PMID: 25043029 PMID: 25604195 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-142d6ae9-e262-4acf-b39c-fe49588486e5 APC/C-FZR1 Complex uuid-142d6ae9-e262-4acf-b39c-fe49588486e5 PS:CellType generic PS:Description APC/C-FZR1 complex regulates G1 cell cycle phase, M/G1 and G1/S phase transition. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-142d6ae9-e262-4acf-b39c-fe49588486e5 PS:NodeType Pathway PS:Notes Headnote: The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. Many proteins of the APC/C still have unknown functions. APC/C is largely organized into three structural domains, called the 'platform', the 'catalytic' and the 'TPR-arm, lobe or arc lamp'. The platform subcomplex (ANAPC1, ANAPC4, ANAPC5, and ANAPC15) forms a base to join the other subunits of the APC/C. The catalytic core subcomplex (ANAPC2, ANAPC11, and ANAPC10) with an E2 enzyme can provide ubiquitylation activity to the APC/C. The TPR-arm consists of several structurally related proteins with multiple tetratricopeptide (TPR) repeats (ANAPC7, ANAPC13, ANAPC16, CDC16, CDC23, CDC26, CDC27) and is required to coordinate assembly of the APC/C and mediate important interactions with regulator proteins which modulate APC/C activity. Signaling description: The core of APC/C-FZR1 (APC/C-CDH1) complex related signaling leads to M/G1 transition through a specific subset of substrate proteins. The precise mechanism of the molecular signaling on this pathway is partially known and is associated with activation of FZR1 (CDH1). Outcome effects: In the beginning of the cell cycle FZR1 (CDH1) is phosphorylated and inhibited by CDK1, preventing it from attaching to APC/C. APC/C is then free to attach CDC20 and usher the transition from metaphase to anaphase. As CDK1 gets degraded later in mitosis, CDC20 gets released and FZR1 (CDH1) can bind to APC/C, keeping it activated through the M/G1 transition. APC/C-CDH1 then continues is working in G1 phase and degrading CDC20, AURKA/B, CDC25A, GMNN and SKP2. CCNB1 is accumulated throughout this phase and activates CDK1 leads to inhibition of FZR1 (CDH1) and inactivation of APC/C-CDH1. Animal data: Role of APC/C-CDH1 in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 21261459 PS:PMID 25043029 PS:PMID 25604195 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14548047-57a6-4e66-800d-8a6b383e0239 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-14548047-57a6-4e66-800d-8a6b383e0239 T-Cell Receptor -> CREBBP Signaling uuid-14548047-57a6-4e66-800d-8a6b383e0239 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14548047-57a6-4e66-800d-8a6b383e0239 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14712329-99e4-49cb-afd2-ab94fc30d588 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-14712329-99e4-49cb-afd2-ab94fc30d588 HCN synthesis template uuid-14712329-99e4-49cb-afd2-ab94fc30d588 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14712329-99e4-49cb-afd2-ab94fc30d588 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-147d63b9-38a3-4498-9568-4c28b530fba0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-147d63b9-38a3-4498-9568-4c28b530fba0 EGF -> AP-1/ATF Expression Targets uuid-147d63b9-38a3-4498-9568-4c28b530fba0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-147d63b9-38a3-4498-9568-4c28b530fba0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-148e3143-7f17-4b6d-9c3f-21329a00f1f8 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-148e3143-7f17-4b6d-9c3f-21329a00f1f8 HGFR -> STAT Signaling uuid-148e3143-7f17-4b6d-9c3f-21329a00f1f8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-148e3143-7f17-4b6d-9c3f-21329a00f1f8 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1498d506-0623-452c-8ded-77ce89cdacee NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: bone Organ: joint Organ_System: skeletal system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-1498d506-0623-452c-8ded-77ce89cdacee Elevated Receptors -> Expression Targets in Bone and Joint uuid-1498d506-0623-452c-8ded-77ce89cdacee PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1498d506-0623-452c-8ded-77ce89cdacee PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ bone PS:Organ joint PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue Cartilage PS:Tissue bone tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-149fc19e-7b0a-45dd-8228-9dcee871df17 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-149fc19e-7b0a-45dd-8228-9dcee871df17 UrokinaseR -> ELK/SRF Signaling uuid-149fc19e-7b0a-45dd-8228-9dcee871df17 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-149fc19e-7b0a-45dd-8228-9dcee871df17 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14a1fe0f-6e18-49a6-abce-c4be5d92a5d2 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-14a1fe0f-6e18-49a6-abce-c4be5d92a5d2 T-Cell Receptor -> ATF/CREB Signaling uuid-14a1fe0f-6e18-49a6-abce-c4be5d92a5d2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14a1fe0f-6e18-49a6-abce-c4be5d92a5d2 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14a90fa2-d984-4522-bdaf-fe320d3e2b98 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-14a90fa2-d984-4522-bdaf-fe320d3e2b98 IL1R -> STAT3 Signaling uuid-14a90fa2-d984-4522-bdaf-fe320d3e2b98 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14a90fa2-d984-4522-bdaf-fe320d3e2b98 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14acdc06-0b83-4119-942a-d3d38454fdd9 NodeType: Pathway Organ: Parathyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-14acdc06-0b83-4119-942a-d3d38454fdd9 Proteins Involved in Hypoparathyroidism uuid-14acdc06-0b83-4119-942a-d3d38454fdd9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14acdc06-0b83-4119-942a-d3d38454fdd9 PS:NodeType Pathway PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: generic Description: TP53 tumor suppressor gene mediates metabolic changes in cells under physiological and pathological conditions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14d44cab-630f-479c-b2b6-0520be4040bf NodeType: Pathway Notes: Headnote: TP53 regulates cell metabolism by restricting glucose import and glycolysis, and activating lipid transport, fatty acid oxidation and gluconeogenesis. Signaling description: TP53 is activated by metabolic stress (starvation exposure) through the AMPK/RPTOR/MTOR axis. MTOR/TP53 can also be activated by the amino acids glutamine and isoleucine and the fatty acid product phosphatidic acid. TP53 restricts glucose import by inhibiting the SLC2A1, SLC2A3, SLC2A4 transporters. TP53 restricts glycolysis by inhibiting enzymes PGAM1, HK2 and activating TIGAR (the last one hydrolyses fructose 2,6-bisphosphate, the activator of PFKM). TP53 activates gluconeogenesis through activation of G6PC and PCK1 via SIRT6/FOXO1. TP53 activates lipid transport and fatty acid oxidation via CPT1C, MLYCD, LPIN1 and PANK1 activation. TP53 can inhibit fatty acid synthesis through down-regulation of FASN. TP53 can also activate SCO2 and thereby regulate the respiratory chain. Outcome effects: The result of TP53 regulation is cell-, tissue- and context-dependent. This pathway represents multiple metabolic effects of TP53 in various tissues and circumstances. Organ: generic Organ: oncogenic Organ_System: generic Organ_System: oncogenic PMID: 20729871 PMID: 26122615 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: generic Tissue: oncogenic urn:agi-pathway:uuid-14d44cab-630f-479c-b2b6-0520be4040bf MTOR/TP53 Regulates Cell Metabolism uuid-14d44cab-630f-479c-b2b6-0520be4040bf PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType generic PS:Description TP53 tumor suppressor gene mediates metabolic changes in cells under physiological and pathological conditions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14d44cab-630f-479c-b2b6-0520be4040bf PS:NodeType Pathway PS:Notes Headnote: TP53 regulates cell metabolism by restricting glucose import and glycolysis, and activating lipid transport, fatty acid oxidation and gluconeogenesis. Signaling description: TP53 is activated by metabolic stress (starvation exposure) through the AMPK/RPTOR/MTOR axis. MTOR/TP53 can also be activated by the amino acids glutamine and isoleucine and the fatty acid product phosphatidic acid. TP53 restricts glucose import by inhibiting the SLC2A1, SLC2A3, SLC2A4 transporters. TP53 restricts glycolysis by inhibiting enzymes PGAM1, HK2 and activating TIGAR (the last one hydrolyses fructose 2,6-bisphosphate, the activator of PFKM). TP53 activates gluconeogenesis through activation of G6PC and PCK1 via SIRT6/FOXO1. TP53 activates lipid transport and fatty acid oxidation via CPT1C, MLYCD, LPIN1 and PANK1 activation. TP53 can inhibit fatty acid synthesis through down-regulation of FASN. TP53 can also activate SCO2 and thereby regulate the respiratory chain. Outcome effects: The result of TP53 regulation is cell-, tissue- and context-dependent. This pathway represents multiple metabolic effects of TP53 in various tissues and circumstances. PS:Organ generic PS:Organ oncogenic PS:Organ_System generic PS:Organ_System oncogenic PS:PMID 20729871 PS:PMID 26122615 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue generic PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14d9ca72-5576-4da3-9f2f-e47b2e268efa NodeType: Pathway Notes: Headnote: Misfolded huntingtin (HTT) induces endoplasmic reticulum (ER) stress contributing to pathogenesis of Huntington Disease. ER stress is alleviated by the activation of an adaptive reaction known as the unfolded protein response (UPR), whereas chronic ER stress triggers apoptosis by the same pathway. Signaling description: UPR signaling is initiated by the activation of at least three distinct stress sensors located at the ER membrane known as ERN1 (IRE1a), EIF2AK3 (PERK) and ATF6. ERN1 is as a regulator of mutant HTT clearance. ERN1 cleaves and activates XBP1 triggering autophagy via FOXO1 and its target genes. ERN1 also activates TRAF2/MAPK8 and my induce apoptosis. MAPK8 activation also increased expression of ATG5 and Beclin-1 responsible for autophagy.Upon activation EIF2AK3 phosphorylates eIF2alpha (EIF2S1) leading to activation of ATF4. ATF4 induces the expression of ATG12, ATG5 and BECN1, providing a direct link between UPR signaling and the control of autophagy. ATF6 activates XBP-1 with consequent events. CHOP (DDIT3) gene promoter contains binding sites for all of the major inducers of the unfolded protein response (UPR), including ATF4, ATF6, and XBP-1, and these transcription induce DDIT3 gene transcription. DDIT3 induces apoptosis, through a Bcl-2-inhibitable mechanism. Outcome effects: Mutant HTT binds to and activates type 1 inositol 1,4,5-trisphosphate receptor (ITPR1), mediating calcium release from the endoplasmic reticulum and cytoplasmic calcium overload.Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 16200199 PMID: 21189122 PMID: 22617512 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-14d9ca72-5576-4da3-9f2f-e47b2e268efa ER Stress in Huntington Disease uuid-14d9ca72-5576-4da3-9f2f-e47b2e268efa PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14d9ca72-5576-4da3-9f2f-e47b2e268efa PS:NodeType Pathway PS:Notes Headnote: Misfolded huntingtin (HTT) induces endoplasmic reticulum (ER) stress contributing to pathogenesis of Huntington Disease. ER stress is alleviated by the activation of an adaptive reaction known as the unfolded protein response (UPR), whereas chronic ER stress triggers apoptosis by the same pathway. Signaling description: UPR signaling is initiated by the activation of at least three distinct stress sensors located at the ER membrane known as ERN1 (IRE1a), EIF2AK3 (PERK) and ATF6. ERN1 is as a regulator of mutant HTT clearance. ERN1 cleaves and activates XBP1 triggering autophagy via FOXO1 and its target genes. ERN1 also activates TRAF2/MAPK8 and my induce apoptosis. MAPK8 activation also increased expression of ATG5 and Beclin-1 responsible for autophagy.Upon activation EIF2AK3 phosphorylates eIF2alpha (EIF2S1) leading to activation of ATF4. ATF4 induces the expression of ATG12, ATG5 and BECN1, providing a direct link between UPR signaling and the control of autophagy. ATF6 activates XBP-1 with consequent events. CHOP (DDIT3) gene promoter contains binding sites for all of the major inducers of the unfolded protein response (UPR), including ATF4, ATF6, and XBP-1, and these transcription induce DDIT3 gene transcription. DDIT3 induces apoptosis, through a Bcl-2-inhibitable mechanism. Outcome effects: Mutant HTT binds to and activates type 1 inositol 1,4,5-trisphosphate receptor (ITPR1), mediating calcium release from the endoplasmic reticulum and cytoplasmic calcium overload.Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 16200199 PS:PMID 21189122 PS:PMID 22617512 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: The core of TAM receptor signaling through PI3K - PDPK1 - AKT1 leads to alpha2beta3 integrin complex activation and platelet platelets adhesion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14eb30af-d0a3-4bce-ae94-bd34a1da2c4e NodeType: Pathway Notes: Headnote: The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. Signaling description: GAS6 and PROS1 are well known ligands for TAM receptors. Platelets express all three TAM receptors, AXL, MERTK and TYRO3. Single mice knockouts of AXL, MERTK and TYRO3 have shown that all three receptors are required for normal platelet aggregation. Outcome effects: The core of TAM receptor signaling through PI3K - PDPK1 - AKT1 leads to alpha2beta3 integrin complex activation and platelet platelet adhesion. Animal data: Role of TAM receptors for the platelet function was revealed from animal model experiments. Organ: generic Organ_System: hematological system PMID: 18620092 PMID: 24596417 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-14eb30af-d0a3-4bce-ae94-bd34a1da2c4e TAM Receptors in Platelet Aggregation uuid-14eb30af-d0a3-4bce-ae94-bd34a1da2c4e PS:CellType blood platelet PS:Description The core of TAM receptor signaling through PI3K - PDPK1 - AKT1 leads to alpha2beta3 integrin complex activation and platelet platelets adhesion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-14eb30af-d0a3-4bce-ae94-bd34a1da2c4e PS:NodeType Pathway PS:Notes Headnote: The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. Signaling description: GAS6 and PROS1 are well known ligands for TAM receptors. Platelets express all three TAM receptors, AXL, MERTK and TYRO3. Single mice knockouts of AXL, MERTK and TYRO3 have shown that all three receptors are required for normal platelet aggregation. Outcome effects: The core of TAM receptor signaling through PI3K - PDPK1 - AKT1 leads to alpha2beta3 integrin complex activation and platelet platelet adhesion. Animal data: Role of TAM receptors for the platelet function was revealed from animal model experiments. PS:Organ generic PS:Organ_System hematological system PS:PMID 18620092 PS:PMID 24596417 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1531f4de-323f-45e5-88c5-54b13fc77d97 NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1531f4de-323f-45e5-88c5-54b13fc77d97 Proteins Involved in Chronic Obstructive Pulmonary Disease uuid-1531f4de-323f-45e5-88c5-54b13fc77d97 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1531f4de-323f-45e5-88c5-54b13fc77d97 PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15822e3b-7336-4638-abf6-b89aa8b697b0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-15822e3b-7336-4638-abf6-b89aa8b697b0 PLAU -> STAT1 Expression Targets uuid-15822e3b-7336-4638-abf6-b89aa8b697b0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15822e3b-7336-4638-abf6-b89aa8b697b0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-158e7af9-ff05-4363-9481-4d470024d4e2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-158e7af9-ff05-4363-9481-4d470024d4e2 IL15 Expression Targets uuid-158e7af9-ff05-4363-9481-4d470024d4e2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-158e7af9-ff05-4363-9481-4d470024d4e2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Nephrolithiasis is a process of forming stones in the kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-158e8bc5-b17b-4485-8272-b8f5af56f178 NodeType: Pathway Notes: Nephrolithiasis refers to the process of forming a kidney stone. The pathology of nephrolithiasis is related to increased excretion of Ca2+. Mutations in TRPV5/6, VDR, CALB1 genes and a high level of parathyroid hormone (PTH) may lead to impaired Ca2+ reabsorption in the renal tubule. Organ: kidney Organ_System: urinary tract PMID: 19198886 PMID: 24376311 PMID: 25504362 PMID: 25905296 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-158e8bc5-b17b-4485-8272-b8f5af56f178 Ca2+ Reabsorption Dysregulation in Urolithiasis uuid-158e8bc5-b17b-4485-8272-b8f5af56f178 PS:CellType epithelial cell PS:Description Nephrolithiasis is a process of forming stones in the kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-158e8bc5-b17b-4485-8272-b8f5af56f178 PS:NodeType Pathway PS:Notes Nephrolithiasis refers to the process of forming a kidney stone. The pathology of nephrolithiasis is related to increased excretion of Ca2+. Mutations in TRPV5/6, VDR, CALB1 genes and a high level of parathyroid hormone (PTH) may lead to impaired Ca2+ reabsorption in the renal tubule. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 19198886 PS:PMID 24376311 PS:PMID 25504362 PS:PMID 25905296 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-159a2564-9722-46cd-9160-78caecfc79e0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-159a2564-9722-46cd-9160-78caecfc79e0 GCG Expression Targets uuid-159a2564-9722-46cd-9160-78caecfc79e0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-159a2564-9722-46cd-9160-78caecfc79e0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a2c2db-c2f6-4530-9c58-81684387811f NodeType: Pathway Organ: generic Organ_System: generic PMID: 10433517 PMID: 21599535 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-15a2c2db-c2f6-4530-9c58-81684387811f Insulin Signaling uuid-15a2c2db-c2f6-4530-9c58-81684387811f PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a2c2db-c2f6-4530-9c58-81684387811f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 10433517 PS:PMID 21599535 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a2c7fe-b65c-4bc3-ba75-48a20fb25b0d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-15a2c7fe-b65c-4bc3-ba75-48a20fb25b0d SARS endoRNAse (NSP15) inhibitors uuid-15a2c7fe-b65c-4bc3-ba75-48a20fb25b0d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a2c7fe-b65c-4bc3-ba75-48a20fb25b0d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The function of rRNA is to provide a mechanism for decoding mRNA into amino acids at the center of a small ribosomal subunit and to interact with tRNAs during translation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a3ccf6-c96c-4ff0-a849-1e28bb0fad2c NodeType: Pathway Notes: Headnote: The function of rRNA is to provide a mechanism for coding mRNA into amino acids at the center of a small ribosomal subunit and to interact with tRNAs during translation. Signaling description: Three rRNA genes including 18S, 5.8S, and 28S rRNA are transcribed by RNA polymerase I while 5S rRNA is transcribed by RNA polymerase III. 18S, 5.8S, and 28S rRNAs are synthesized as part of a single large precursor that undergoes a series of enzymatic cleavage steps to produce mature rRNA molecules. The promoter of rRNA precursor gene consists of two regions, a core promoter element (CPE) and an upstream control element (UCE). UBTF recognizes UCE, whereas SL1 complex (TBP, TAF1A, TAF1B, and TAF1C) recognizes CPE. SL1 complex is activated by phosphorylation in mitosis, while UBTF is phosphorylated and activated in the G1 phase. RNA polymerase I and additional factors bind UBTF and SL1 complex, thus forming the initiation complex. TTF1 protein binds to eukaryotic transcription units for ribosomal genes which contain the SalI restriction site (Sal BOX) and causes the termination of transcription and disassembly of the RNA polymerase I complex. Outcome effects: Following transcriptional termination, 80S ribonucleoprotein (RNP) precursor is formed, which contains a 5' leader sequence and 18S, 5.8S and 28S rRNAs separated by spacer RNAs. The position of cleavage sites in ribosomal RNA precursor (pre-rRNA) and the specific sites of 2-O-methylation and pseudouridine formation are determined by approximately 150 different small nucleolar RNAs (snoRNAs or RNA modification guide). Like small nuclear RNAs (snRNAs), snoRNAs associate with proteins and form snoRNPs. One large class of snoRNAs, called ribonuclease MRP, catalyzes one of the cleavages by which transcribed spacer sequences are removed from pre-rRNA. The cleavage of rRNA precursor leads to 20S (containing 18S rRNA) and 60S ribosomal subunits (containing 5.8S, 28S and 5S rRNAs). Unlike all other rRNAs, 5S rRNA transcription is performed by RNA polymerase III. The process is similar to tRNA transcription, starting with the binding of GTF3A to the intragenic (lying within the transcribed DNA sequence) 5S rRNA control sequence box C. GTF3A binding is required for subsequent TFIIIC positioning. In turn, TFIIIC causes the correct positioning of TFIIIB (TBP, BRF, and BDP1), which then recruits RNA polymerase III. Transcription begins immediately following the assembly of the initiation complex and continues until RNA polymerase III reaches a termination signal. Without further processing, 5S rRNA diffuses to the nucleolus where it assembles with the 28S and 5.8S rRNAs and proteins into large ribosomal subunits. The rRNAs are associated with ribosomal proteins in a self-organizing mode, forming both large and small ribosomal subunits which are then separately transported to the cytoplasm to take part in protein synthesis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-15a3ccf6-c96c-4ff0-a849-1e28bb0fad2c rRNA Transcription and Processing uuid-15a3ccf6-c96c-4ff0-a849-1e28bb0fad2c PS:CellType generic PS:Description The function of rRNA is to provide a mechanism for decoding mRNA into amino acids at the center of a small ribosomal subunit and to interact with tRNAs during translation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15a3ccf6-c96c-4ff0-a849-1e28bb0fad2c PS:NodeType Pathway PS:Notes Headnote: The function of rRNA is to provide a mechanism for coding mRNA into amino acids at the center of a small ribosomal subunit and to interact with tRNAs during translation. Signaling description: Three rRNA genes including 18S, 5.8S, and 28S rRNA are transcribed by RNA polymerase I while 5S rRNA is transcribed by RNA polymerase III. 18S, 5.8S, and 28S rRNAs are synthesized as part of a single large precursor that undergoes a series of enzymatic cleavage steps to produce mature rRNA molecules. The promoter of rRNA precursor gene consists of two regions, a core promoter element (CPE) and an upstream control element (UCE). UBTF recognizes UCE, whereas SL1 complex (TBP, TAF1A, TAF1B, and TAF1C) recognizes CPE. SL1 complex is activated by phosphorylation in mitosis, while UBTF is phosphorylated and activated in the G1 phase. RNA polymerase I and additional factors bind UBTF and SL1 complex, thus forming the initiation complex. TTF1 protein binds to eukaryotic transcription units for ribosomal genes which contain the SalI restriction site (Sal BOX) and causes the termination of transcription and disassembly of the RNA polymerase I complex. Outcome effects: Following transcriptional termination, 80S ribonucleoprotein (RNP) precursor is formed, which contains a 5' leader sequence and 18S, 5.8S and 28S rRNAs separated by spacer RNAs. The position of cleavage sites in ribosomal RNA precursor (pre-rRNA) and the specific sites of 2-O-methylation and pseudouridine formation are determined by approximately 150 different small nucleolar RNAs (snoRNAs or RNA modification guide). Like small nuclear RNAs (snRNAs), snoRNAs associate with proteins and form snoRNPs. One large class of snoRNAs, called ribonuclease MRP, catalyzes one of the cleavages by which transcribed spacer sequences are removed from pre-rRNA. The cleavage of rRNA precursor leads to 20S (containing 18S rRNA) and 60S ribosomal subunits (containing 5.8S, 28S and 5S rRNAs). Unlike all other rRNAs, 5S rRNA transcription is performed by RNA polymerase III. The process is similar to tRNA transcription, starting with the binding of GTF3A to the intragenic (lying within the transcribed DNA sequence) 5S rRNA control sequence box C. GTF3A binding is required for subsequent TFIIIC positioning. In turn, TFIIIC causes the correct positioning of TFIIIB (TBP, BRF, and BDP1), which then recruits RNA polymerase III. Transcription begins immediately following the assembly of the initiation complex and continues until RNA polymerase III reaches a termination signal. Without further processing, 5S rRNA diffuses to the nucleolus where it assembles with the 28S and 5.8S rRNAs and proteins into large ribosomal subunits. The rRNAs are associated with ribosomal proteins in a self-organizing mode, forming both large and small ribosomal subunits which are then separately transported to the cytoplasm to take part in protein synthesis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Not all self-antigens are expressed at the primary site of lymphocyte development, the thymus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15c60aca-3d81-4760-926e-4806883e5b18 NodeType: Pathway Notes: Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Peripheral tolerance occurs in the peripheral lymphoid organs (lymph node and spleen) following T-cell maturation. Signaling description: It is crucial to control the tolerance of lymphocytes that first encounter their cognate self-antigens outside of the thymus such as in the case of food antigens, developmental antigens, and antigens displayed during chronic infection. Both anergy and deletion of self-reactive T-cells can occur in the periphery. There are several key mechanisms of T- and B-cell tolerance. Inhibitory receptor engagement and strong activation lead to T-cell tolerance. PDCD1, BTLA, and CTLA4 receptors block T-cell proliferation through the dephosphorylation of ZAP70 and AKT1. The lack of co-stimulation occurs when the expression of ligands for co-stimulating T-cell receptor (TCR) complex receptors, CD40 and CD28 is downregulated. Outcome effects: T-cells, without a positive signal from the TCR complex, undergo apoptosis. In addition, high amounts of ligands for death receptors such as FAS, TNFRSF25, and TNFRSF10A lead to the activation of death receptor-mediated apoptosis. Lastly, regulatory T-lymphocytes (Treg) function to prevent, downregulate, or limit autoaggressive immune responses in the immune system. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-15c60aca-3d81-4760-926e-4806883e5b18 Peripheral T-Cell Tolerance uuid-15c60aca-3d81-4760-926e-4806883e5b18 PS:CellType T-cell PS:Description Not all self-antigens are expressed at the primary site of lymphocyte development, the thymus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15c60aca-3d81-4760-926e-4806883e5b18 PS:NodeType Pathway PS:Notes Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Peripheral tolerance occurs in the peripheral lymphoid organs (lymph node and spleen) following T-cell maturation. Signaling description: It is crucial to control the tolerance of lymphocytes that first encounter their cognate self-antigens outside of the thymus such as in the case of food antigens, developmental antigens, and antigens displayed during chronic infection. Both anergy and deletion of self-reactive T-cells can occur in the periphery. There are several key mechanisms of T- and B-cell tolerance. Inhibitory receptor engagement and strong activation lead to T-cell tolerance. PDCD1, BTLA, and CTLA4 receptors block T-cell proliferation through the dephosphorylation of ZAP70 and AKT1. The lack of co-stimulation occurs when the expression of ligands for co-stimulating T-cell receptor (TCR) complex receptors, CD40 and CD28 is downregulated. Outcome effects: T-cells, without a positive signal from the TCR complex, undergo apoptosis. In addition, high amounts of ligands for death receptors such as FAS, TNFRSF25, and TNFRSF10A lead to the activation of death receptor-mediated apoptosis. Lastly, regulatory T-lymphocytes (Treg) function to prevent, downregulate, or limit autoaggressive immune responses in the immune system. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15c9e48c-ffe6-414c-98dd-7a264e41d976 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-15c9e48c-ffe6-414c-98dd-7a264e41d976 Mitophagy uuid-15c9e48c-ffe6-414c-98dd-7a264e41d976 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15c9e48c-ffe6-414c-98dd-7a264e41d976 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15cc8fb6-e629-4c81-83f4-0b8711a757bf NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-15cc8fb6-e629-4c81-83f4-0b8711a757bf Chlorophyll biosynthesis template uuid-15cc8fb6-e629-4c81-83f4-0b8711a757bf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15cc8fb6-e629-4c81-83f4-0b8711a757bf PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15dd507e-9029-4877-b673-99ef3048fcd9 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-15dd507e-9029-4877-b673-99ef3048fcd9 T-Cell Receptor -> NF-kB Signaling uuid-15dd507e-9029-4877-b673-99ef3048fcd9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15dd507e-9029-4877-b673-99ef3048fcd9 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15f479a4-8483-46a6-a5fb-3720bdb873d9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-15f479a4-8483-46a6-a5fb-3720bdb873d9 FGF1 -> NCOR2 Expression Target uuid-15f479a4-8483-46a6-a5fb-3720bdb873d9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15f479a4-8483-46a6-a5fb-3720bdb873d9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA mutations are common in primary human cancers. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15fc3f79-e831-4c88-bede-cdc66dd7a410 NodeType: Pathway Notes: Headnote: Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mutations in mitochondrial DNA are common in primary human cancers. Signaling description: Mutations in respiratory chain proteins may affect the components of complex I (NADH dehydrogenase (ubiquinone)) including ND1/2/3/4/4L/5/6, complex III (ubiquinol-cytochrome c reductase) including CYTB, complex IV (cytochrome c oxidase) including COX1/2/3, TRNL1 and complex V (H+-transporting two-sector ATPase) including ATP6/8. Complex I may also be inhibited by hypoxia/HIF1A-dependent NDUFA4L2. Subunits of complex IV (COX6C/7A1/7C) may be inhibited by SNAI1 that is activated during epithelial to mesenchymal transition in cancer cells. Complex IV may also be down-regulated in TP53-mutated cancers due to the impairment of TP53/ SCO2 interaction. Outcome effects: The outcome is mitochondrial dysfunction and impairment of oxidative phosphorylation, decrease in ATP production and increase of ADP amount. Importantly, ADP and AMP can activate AMPK and impair MTOR signaling. Complex I and III produce ROS and thereby modulate diverse cellular functions including apoptosis and HIF activation. It is still unclear whether mitochondrial DNA mutations exert a pro- or anti-tumorigenic effect (both effects are observed in different cases). The effect is cancer-type dependent and mutation-dependent. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming (Respiratory Chain)" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15248896 PMID: 16892080 PMID: 21543342 PMID: 24163135 PMID: 25057353 PMID: 26041263 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-15fc3f79-e831-4c88-bede-cdc66dd7a410 Respiratory Chain Impairment in Cancer uuid-15fc3f79-e831-4c88-bede-cdc66dd7a410 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA mutations are common in primary human cancers. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15fc3f79-e831-4c88-bede-cdc66dd7a410 PS:NodeType Pathway PS:Notes Headnote: Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mutations in mitochondrial DNA are common in primary human cancers. Signaling description: Mutations in respiratory chain proteins may affect the components of complex I (NADH dehydrogenase (ubiquinone)) including ND1/2/3/4/4L/5/6, complex III (ubiquinol-cytochrome c reductase) including CYTB, complex IV (cytochrome c oxidase) including COX1/2/3, TRNL1 and complex V (H+-transporting two-sector ATPase) including ATP6/8. Complex I may also be inhibited by hypoxia/HIF1A-dependent NDUFA4L2. Subunits of complex IV (COX6C/7A1/7C) may be inhibited by SNAI1 that is activated during epithelial to mesenchymal transition in cancer cells. Complex IV may also be down-regulated in TP53-mutated cancers due to the impairment of TP53/ SCO2 interaction. Outcome effects: The outcome is mitochondrial dysfunction and impairment of oxidative phosphorylation, decrease in ATP production and increase of ADP amount. Importantly, ADP and AMP can activate AMPK and impair MTOR signaling. Complex I and III produce ROS and thereby modulate diverse cellular functions including apoptosis and HIF activation. It is still unclear whether mitochondrial DNA mutations exert a pro- or anti-tumorigenic effect (both effects are observed in different cases). The effect is cancer-type dependent and mutation-dependent. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming (Respiratory Chain)" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15248896 PS:PMID 16892080 PS:PMID 21543342 PS:PMID 24163135 PS:PMID 25057353 PS:PMID 26041263 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell Description: The response of dendritic cells (DCs) to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15fe003b-79dd-42d1-b221-7f83aeca5686 NodeType: Pathway Notes: Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. Signaling description: The response of dendritic cells (DCs) to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). However in psoriasis, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with cathelicidin antimicrobial peptide (CAMP). CAMP can bind self-RNA released by dying cells, protect them from extracellular degradation, and transport them into endosomal compartments of DCs. In pDCs, self-RNA-CAMP complexes activate TLR7 and, similar to the self-DNA-CAMP complexes, trigger the secretion of IFNA1 without inducing maturation or the production of IL6 and TNF. In contrast to self-DNA-CAMP complexes, self-RNA-CAMP complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF and IL6 as well as the differentiation of mDCs into mature DCs. Further, S100 proteins belong to a multi-gene family of low molecular weight calcium binding proteins encoded within a well-known psoriasis susceptibility locus (PSOR4) on chromosome 1q21. Outcome effects: TLR7, 8 and 9 were all shown to contribute to autoimmune diseases. S100A7 and S100A8/A9 which are prominent members of this protein family are upregulated in skin inflammation and psoriasis. S100A8/A9 plays a role in myeloid differentiation, inflammation, and exerts antimicrobial activity. S100A7 is produced by keratinocytes surrounding the wound and is released into the wound exudate. S100A8/A9 interacts with AGER and has been shown to interact with TLR4 via the interaction with S100A8. The receptors, AGER and TLR4 are found on the surface of immune system cells and endothelial cells. Although the signaling pathways for both receptor groups are different, they both ultimately activate NF-kB transcription factor which, in turn, activates genes encoding adhesion proteins, proinflammatory cytokines, and proangiogenic factors. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 18611439 PMID: 19292913 PMID: 22969767 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-15fe003b-79dd-42d1-b221-7f83aeca5686 Dendritic Cells Function in Psoriasis uuid-15fe003b-79dd-42d1-b221-7f83aeca5686 PS:CellType dendritic cell PS:Description The response of dendritic cells (DCs) to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-15fe003b-79dd-42d1-b221-7f83aeca5686 PS:NodeType Pathway PS:Notes Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. Signaling description: The response of dendritic cells (DCs) to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). However in psoriasis, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with cathelicidin antimicrobial peptide (CAMP). CAMP can bind self-RNA released by dying cells, protect them from extracellular degradation, and transport them into endosomal compartments of DCs. In pDCs, self-RNA-CAMP complexes activate TLR7 and, similar to the self-DNA-CAMP complexes, trigger the secretion of IFNA1 without inducing maturation or the production of IL6 and TNF. In contrast to self-DNA-CAMP complexes, self-RNA-CAMP complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF and IL6 as well as the differentiation of mDCs into mature DCs. Further, S100 proteins belong to a multi-gene family of low molecular weight calcium binding proteins encoded within a well-known psoriasis susceptibility locus (PSOR4) on chromosome 1q21. Outcome effects: TLR7, 8 and 9 were all shown to contribute to autoimmune diseases. S100A7 and S100A8/A9 which are prominent members of this protein family are upregulated in skin inflammation and psoriasis. S100A8/A9 plays a role in myeloid differentiation, inflammation, and exerts antimicrobial activity. S100A7 is produced by keratinocytes surrounding the wound and is released into the wound exudate. S100A8/A9 interacts with AGER and has been shown to interact with TLR4 via the interaction with S100A8. The receptors, AGER and TLR4 are found on the surface of immune system cells and endothelial cells. Although the signaling pathways for both receptor groups are different, they both ultimately activate NF-kB transcription factor which, in turn, activates genes encoding adhesion proteins, proinflammatory cytokines, and proangiogenic factors. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18611439 PS:PMID 19292913 PS:PMID 22969767 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16241f1d-e66a-497f-b0a1-0e5ff21b5674 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-16241f1d-e66a-497f-b0a1-0e5ff21b5674 Cholestasis model uuid-16241f1d-e66a-497f-b0a1-0e5ff21b5674 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16241f1d-e66a-497f-b0a1-0e5ff21b5674 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16378ade-5fd5-4a82-9cc2-0ba8a8dc00ce NodeType: Pathway Notes: During the prediabetes phase, impaired peripheral self-tolerance (apoptosis of T cells) in the pancreatic lymph node switches on the cell-mediated immune response against pancreatic cells and provokes B cells to express antibeta-cell autoantibodies. Mutations in the HLA genes and mutations (epigenetic changes, or posttranslational modifications) in several proteins secreted by beta cells allow the binding of MHC with self-antigens and activate T-cell expansion. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-16378ade-5fd5-4a82-9cc2-0ba8a8dc00ce 2_Defective tolerance of autoreactive T-cell in T1D uuid-16378ade-5fd5-4a82-9cc2-0ba8a8dc00ce PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16378ade-5fd5-4a82-9cc2-0ba8a8dc00ce PS:NodeType Pathway PS:Notes During the prediabetes phase, impaired peripheral self-tolerance (apoptosis of T cells) in the pancreatic lymph node switches on the cell-mediated immune response against pancreatic cells and provokes B cells to express antibeta-cell autoantibodies. Mutations in the HLA genes and mutations (epigenetic changes, or posttranslational modifications) in several proteins secreted by beta cells allow the binding of MHC with self-antigens and activate T-cell expansion. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-163d74b4-455b-4440-9e0d-4ef92fbc7b91 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-163d74b4-455b-4440-9e0d-4ef92fbc7b91 IL3 Expression Targets uuid-163d74b4-455b-4440-9e0d-4ef92fbc7b91 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-163d74b4-455b-4440-9e0d-4ef92fbc7b91 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16505365-2e33-4b9a-a84f-3558df6a1e00 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-16505365-2e33-4b9a-a84f-3558df6a1e00 ADRB1 -> Ion Channels uuid-16505365-2e33-4b9a-a84f-3558df6a1e00 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16505365-2e33-4b9a-a84f-3558df6a1e00 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Impairment of death receptor signaling blocks extrinsic pathway of apoptosis in cancers. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1660b145-506a-4263-9912-48fa54ca60b7 NodeType: Pathway Notes: Headnote: Death receptors and their ligands are key participants in the extrinsic apoptotic pathway. Death receptors include TNFRSF1A, FAS, TNFRSF25, TNFRSF10A/B, TNFRSF21, NGFR. FAS and TNFRSF10A/B act through FADD and activate CASP8/10. TNFRSF1A/21/25 and NGFR use TRADD to activate CASP2 and NFKB. Signaling description: Death receptor signaling can be impaired in cancers due to multiple mechanisms. For example, FAS, TNFRSF10A/B, TRADD can inactivated by mutations, or NGFR and FADD can be down-regulated. One of the mechanisms of FADD down-regulation is inhibition by HPV16-E6. Overexpressed CFLAR may inhibit CASP8/10. In addition, NFKB signaling may be impaired. Outcome effects: Caspases are not activated and apoptosis is blocked. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Description of viral proteins: HPV16-E6 shown in grey is viral protein. Organ: oncogenic Organ_System: oncogenic PMID: 21943236 PMID: 23637280 PMID: 25840763 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-1660b145-506a-4263-9912-48fa54ca60b7 Apoptosis Block by Death Receptor Signaling in Cancer uuid-1660b145-506a-4263-9912-48fa54ca60b7 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Impairment of death receptor signaling blocks extrinsic pathway of apoptosis in cancers. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1660b145-506a-4263-9912-48fa54ca60b7 PS:NodeType Pathway PS:Notes Headnote: Death receptors and their ligands are key participants in the extrinsic apoptotic pathway. Death receptors include TNFRSF1A, FAS, TNFRSF25, TNFRSF10A/B, TNFRSF21, NGFR. FAS and TNFRSF10A/B act through FADD and activate CASP8/10. TNFRSF1A/21/25 and NGFR use TRADD to activate CASP2 and NFKB. Signaling description: Death receptor signaling can be impaired in cancers due to multiple mechanisms. For example, FAS, TNFRSF10A/B, TRADD can inactivated by mutations, or NGFR and FADD can be down-regulated. One of the mechanisms of FADD down-regulation is inhibition by HPV16-E6. Overexpressed CFLAR may inhibit CASP8/10. In addition, NFKB signaling may be impaired. Outcome effects: Caspases are not activated and apoptosis is blocked. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Description of viral proteins: HPV16-E6 shown in grey is viral protein. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21943236 PS:PMID 23637280 PS:PMID 25840763 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1663d48c-d60e-47c5-ad9b-1562b58fbbed NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-1663d48c-d60e-47c5-ad9b-1562b58fbbed Myeloid Progenitor Cell -> GEMM - CFU Surface Expression Markers uuid-1663d48c-d60e-47c5-ad9b-1562b58fbbed PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1663d48c-d60e-47c5-ad9b-1562b58fbbed PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Lung disease is the major cause of mortality of cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1685527c-677e-459e-a38b-3728cf15474b NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. There are more than a thousand known mutations in the CFTR gene divided into 5 different classes. Class I CFTR mutations affect its biosynthesis; class II mutations affect protein maturation, and aberrantly folded CFTR protein is degraded in the endoplasmic reticulum by endoplasmic reticulum (ER)-associated degradation (ERAD) and the ubiquitin-proteasome system (UPS); class III mutations affect Cl- channel regulation and gating, and in this case CFTR protein is trafficked to the cell membrane, but then fails to respond to cAMP stimulation. The first three classes usually lead to the classic CF phenotype with pancreatic insufficiency. Further, class IV mutations affect Cl- conductance, and class V mutations interfere with normal transcription and thereby reduce the amount of otherwise normal CFTR. The latter two classes are mostly associated with a milder expression of the disease. The diversity of mutations explains the penetrance of the disease. There are several theories of how defects in the CFTR and cellular function cause the clinical effects. One theory is that the lack of Cl-, iodide, and thiocyanate exiting through the CFTR protein channel leads to the accumulation of a more viscous, nutrient-rich mucus in the lungs that allows bacteria, mostly Staphylococcus aureus or Pseudomonas aeruginosa, to hide from the body's immune system. Another theory is that CFTR protein failure leads to an increase in Na+ and Cl- uptake, which results in increased water reabsorption and creates thick, dehydrated mucus. According to this (Hypothesis), mucus on the epithelium forms plaques with hypoxic niches that can harbor bacteria, particularly Pseudomonas aeruginosa. The prevailing (Hypothesis) for pathophysiology in the CF lung has been linked to the disruption of CFTR-mediated negative regulation of ENaC, leading to Na+ hyperabsorption and dehydration of the airway. The oxidative stress theory states that the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Outcome effects: The constitutive activation of NF-kB signaling results in increased amounts of reactive oxygen species (ROS) being generated by neutrophils accumulated in the airway. Oxidative stress additionally stimulates the synthesis of IL8 and antioxidants such as glutathione and thiocyanate in epithelial cells, and mutant CFTR in epithelial cells is unable to channel these antioxidants into the airways. Bacterial killing in the airway is diminished as well, since thiocyanate also has antimicrobial properties. Pathogens activate the NF-kB pathway resulting in chronic infection, neutrophilic inflammation, and progressive airway destruction. The elevated level of IL8 is a marker of CF. Even in the absence of pathogens, there is an increased expression of IL8 in the lungs of CF patients allowing inflammation to progress. This is possibly due to the ability of functional CFTR protein to inhibit NF-kB through TNFRSF1A or TLR4 pathways. In CF, the expression of TLR4 is reduced on the surface of epithelial cells, resulting in a decreased activation of MYD88 signaling. Further, epithelial cells produce decreased amounts of type I interferon (IFNB1) in response to Pseudomonas aeruginosa infection most likely from the action of PIAS1. IFNB1 response is central to the clearan Organ: lung Organ_System: respiratory system PMID: 12940920 PMID: 22481418 PMID: 23630497 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1685527c-677e-459e-a38b-3728cf15474b Airway Epithelial Cell Dysfunction uuid-1685527c-677e-459e-a38b-3728cf15474b PS:CellType epithelial cell PS:Description Lung disease is the major cause of mortality of cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1685527c-677e-459e-a38b-3728cf15474b PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. There are more than a thousand known mutations in the CFTR gene divided into 5 different classes. Class I CFTR mutations affect its biosynthesis; class II mutations affect protein maturation, and aberrantly folded CFTR protein is degraded in the endoplasmic reticulum by endoplasmic reticulum (ER)-associated degradation (ERAD) and the ubiquitin-proteasome system (UPS); class III mutations affect Cl- channel regulation and gating, and in this case CFTR protein is trafficked to the cell membrane, but then fails to respond to cAMP stimulation. The first three classes usually lead to the classic CF phenotype with pancreatic insufficiency. Further, class IV mutations affect Cl- conductance, and class V mutations interfere with normal transcription and thereby reduce the amount of otherwise normal CFTR. The latter two classes are mostly associated with a milder expression of the disease. The diversity of mutations explains the penetrance of the disease. There are several theories of how defects in the CFTR and cellular function cause the clinical effects. One theory is that the lack of Cl-, iodide, and thiocyanate exiting through the CFTR protein channel leads to the accumulation of a more viscous, nutrient-rich mucus in the lungs that allows bacteria, mostly Staphylococcus aureus or Pseudomonas aeruginosa, to hide from the body's immune system. Another theory is that CFTR protein failure leads to an increase in Na+ and Cl- uptake, which results in increased water reabsorption and creates thick, dehydrated mucus. According to this (Hypothesis), mucus on the epithelium forms plaques with hypoxic niches that can harbor bacteria, particularly Pseudomonas aeruginosa. The prevailing (Hypothesis) for pathophysiology in the CF lung has been linked to the disruption of CFTR-mediated negative regulation of ENaC, leading to Na+ hyperabsorption and dehydration of the airway. The oxidative stress theory states that the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Outcome effects: The constitutive activation of NF-kB signaling results in increased amounts of reactive oxygen species (ROS) being generated by neutrophils accumulated in the airway. Oxidative stress additionally stimulates the synthesis of IL8 and antioxidants such as glutathione and thiocyanate in epithelial cells, and mutant CFTR in epithelial cells is unable to channel these antioxidants into the airways. Bacterial killing in the airway is diminished as well, since thiocyanate also has antimicrobial properties. Pathogens activate the NF-kB pathway resulting in chronic infection, neutrophilic inflammation, and progressive airway destruction. The elevated level of IL8 is a marker of CF. Even in the absence of pathogens, there is an increased expression of IL8 in the lungs of CF patients allowing inflammation to progress. This is possibly due to the ability of functional CFTR protein to inhibit NF-kB through TNFRSF1A or TLR4 pathways. In CF, the expression of TLR4 is reduced on the surface of epithelial cells, resulting in a decreased activation of MYD88 signaling. Further, epithelial cells produce decreased amounts of type I interferon (IFNB1) in response to Pseudomonas aeruginosa infection most likely from the action of PIAS1. IFNB1 response is central to the clearan PS:Organ lung PS:Organ_System respiratory system PS:PMID 12940920 PS:PMID 22481418 PS:PMID 23630497 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: General of hypothetical mechanisms that lead to activation of nNOS and iNOS in postsynaptic neurons by glutamate in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16924384-7ba5-48bc-ac4f-d4729e160b5b NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. In FHM1, FHM2, and FHM3, the proposed increased amounts of glutamate in the synaptic cleft are caused by mutations in CACNA1A, ATP1A2, and SCN1A genes, respectively. Signaling description: At the postsynaptic membrane, glutamate interacts with ionotropic glutamate receptors, AMPA (GRIA) and NMDA. The activation of these receptors leads to intracellular calcium (Ca2+) flux and activation of calmodulin. Calmodulin triggers the NF-kB-dependent pathway that activates the transcription of inducible nitric oxide (NO) synthase (NOS2 or iNOS) through phosphatidylinositol 3-kinase (PI3K). In addition, calmodulin directly binds to and phosphorylates neuronal NO synthase (NOS1 or nNOS) bringing it to an activated state. Outcome effects: Increased NO synthesis leads to the dilation of vessels in dura mater causing headache. Thus, mutations in FHM1, FHM2, and FHM3 result in the continuous release of glutamate into the synaptic cleft and the activation of NO synthesis in neurons. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 12964492 PMID: 17691981 PMID: 19499287 PMID: 19767882 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-16924384-7ba5-48bc-ac4f-d4729e160b5b nNOS (NOS1) and iNOS (NOS2) Activation via Glutamate uuid-16924384-7ba5-48bc-ac4f-d4729e160b5b PS:CellType neuron PS:Description General of hypothetical mechanisms that lead to activation of nNOS and iNOS in postsynaptic neurons by glutamate in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16924384-7ba5-48bc-ac4f-d4729e160b5b PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. In FHM1, FHM2, and FHM3, the proposed increased amounts of glutamate in the synaptic cleft are caused by mutations in CACNA1A, ATP1A2, and SCN1A genes, respectively. Signaling description: At the postsynaptic membrane, glutamate interacts with ionotropic glutamate receptors, AMPA (GRIA) and NMDA. The activation of these receptors leads to intracellular calcium (Ca2+) flux and activation of calmodulin. Calmodulin triggers the NF-kB-dependent pathway that activates the transcription of inducible nitric oxide (NO) synthase (NOS2 or iNOS) through phosphatidylinositol 3-kinase (PI3K). In addition, calmodulin directly binds to and phosphorylates neuronal NO synthase (NOS1 or nNOS) bringing it to an activated state. Outcome effects: Increased NO synthesis leads to the dilation of vessels in dura mater causing headache. Thus, mutations in FHM1, FHM2, and FHM3 result in the continuous release of glutamate into the synaptic cleft and the activation of NO synthesis in neurons. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 12964492 PS:PMID 17691981 PS:PMID 19499287 PS:PMID 19767882 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16adcbb6-f5f3-40ec-8857-6669e2d009c2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-16adcbb6-f5f3-40ec-8857-6669e2d009c2 pleural mesothelial cells->myofibroblats uuid-16adcbb6-f5f3-40ec-8857-6669e2d009c2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16adcbb6-f5f3-40ec-8857-6669e2d009c2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16ae2851-01d2-4763-8b85-48e8d84d8afd NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-16ae2851-01d2-4763-8b85-48e8d84d8afd H2AK119 Epigenetic Modifications - Overview uuid-16ae2851-01d2-4763-8b85-48e8d84d8afd PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16ae2851-01d2-4763-8b85-48e8d84d8afd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16c607ac-5463-4e10-baa2-f008df8403d8 NodeType: Pathway urn:agi-pathway:uuid-16c607ac-5463-4e10-baa2-f008df8403d8 mTOR signaling uuid-16c607ac-5463-4e10-baa2-f008df8403d8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16c607ac-5463-4e10-baa2-f008df8403d8 PS:NodeType Pathway PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16efbcd5-d9e5-4a68-bc15-e936bf35b081 NodeType: Pathway PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-16efbcd5-d9e5-4a68-bc15-e936bf35b081 Dendritic Cell Activation in COVID19 uuid-16efbcd5-d9e5-4a68-bc15-e936bf35b081 PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-16efbcd5-d9e5-4a68-bc15-e936bf35b081 PS:NodeType Pathway PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17114d58-c52b-4d08-8026-43a0a5561694 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: Tooth Organ_System: skeletal system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: dental enamel urn:agi-pathway:uuid-17114d58-c52b-4d08-8026-43a0a5561694 Elevated Receptors -> Expression Targets in Tooth uuid-17114d58-c52b-4d08-8026-43a0a5561694 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17114d58-c52b-4d08-8026-43a0a5561694 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ Tooth PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue dental enamel PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The role of mutations in the CACNA1C gene in the development of autism symptoms of Timothy Syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1725f15a-6b86-4756-ac2e-b203ae11459c NodeType: Pathway Notes: CACNA1C gene mutations are associated with the development of autism symptoms in patients with Timothy Syndrome. Organ_System: nervous system PMID: 21664226 PMID: 22999068 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-1725f15a-6b86-4756-ac2e-b203ae11459c Timothy Syndrome uuid-1725f15a-6b86-4756-ac2e-b203ae11459c PS:Description The role of mutations in the CACNA1C gene in the development of autism symptoms of Timothy Syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1725f15a-6b86-4756-ac2e-b203ae11459c PS:NodeType Pathway PS:Notes CACNA1C gene mutations are associated with the development of autism symptoms in patients with Timothy Syndrome. PS:Organ_System nervous system PS:PMID 21664226 PS:PMID 22999068 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1726ddb6-2baa-4e55-9ebe-47e542903f8e NodeType: Pathway Notes: Headnote: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. Signaling description: Although the majority of ARVC-causing mutations are in genes encoding desmosomal proteins, a few ARVC mutations have been detected in genes unrelated to intercellular junction complexes, such as RYR2 (ryanodine receptor 2), TGFB3 (transforming growth factor beta 3), TMEM43 (transmembrane protein 43), DES (desmin), TTN (titin), LMNA (lamin A/C), and SCN5A (sodium channel, voltage gated, type V alpha subunit). Outcome effects: Mutations in the RYR2 gene have been shown to account for an atypical form of ARVC associated with polymorphic ventricular arrhythmias and for catecholaminergic polymorphic ventricular tachycardia, a peculiar malignant arrhythmic disease. Mutations in RYR2 are thought to result in an uncontrolled calcium leak in the cardiac myocyte, leading to arrhythmia. TGFB3 regulates cytokine-stimulating fibrosis and modulates cell adhesion. It is currently unknown, how a mutation of TGFB3 causes ARVC. TMEM43 codes for a novel transmembrane protein, which may be a target of PPAR-?. The pathogenic effect of the abnormal gene product is unknown. Mutated proteins: Mutated genes are shown in white-out style. Organ: heart Organ_System: cardiovascular system PMID: 23468208 PMID: 25516623 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-1726ddb6-2baa-4e55-9ebe-47e542903f8e Cardiomyocyte Dysfunction uuid-1726ddb6-2baa-4e55-9ebe-47e542903f8e PS:CellType cardiac myocyte PS:Description Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1726ddb6-2baa-4e55-9ebe-47e542903f8e PS:NodeType Pathway PS:Notes Headnote: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. Signaling description: Although the majority of ARVC-causing mutations are in genes encoding desmosomal proteins, a few ARVC mutations have been detected in genes unrelated to intercellular junction complexes, such as RYR2 (ryanodine receptor 2), TGFB3 (transforming growth factor beta 3), TMEM43 (transmembrane protein 43), DES (desmin), TTN (titin), LMNA (lamin A/C), and SCN5A (sodium channel, voltage gated, type V alpha subunit). Outcome effects: Mutations in the RYR2 gene have been shown to account for an atypical form of ARVC associated with polymorphic ventricular arrhythmias and for catecholaminergic polymorphic ventricular tachycardia, a peculiar malignant arrhythmic disease. Mutations in RYR2 are thought to result in an uncontrolled calcium leak in the cardiac myocyte, leading to arrhythmia. TGFB3 regulates cytokine-stimulating fibrosis and modulates cell adhesion. It is currently unknown, how a mutation of TGFB3 causes ARVC. TMEM43 codes for a novel transmembrane protein, which may be a target of PPAR-?. The pathogenic effect of the abnormal gene product is unknown. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 23468208 PS:PMID 25516623 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17325f3b-4b21-4335-8494-cb22fc29e278 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-17325f3b-4b21-4335-8494-cb22fc29e278 LDLR -> Expression Targets in Lymphoid System and Blood uuid-17325f3b-4b21-4335-8494-cb22fc29e278 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17325f3b-4b21-4335-8494-cb22fc29e278 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Activated B-cell-like (ABC) diffuse large B-cell lymphoma is a subtype of DLBCL identified by gene-expression profile. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1744e525-5454-48c8-a998-0fa1076b7725 NodeType: Pathway Notes: Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization. Activated B-cell-like DLBCL (ABC DLBCL) is a subtype of DLBCL identified by gene-expression profile. Signaling description: The pathogenetic hallmark of ABC DLBCL is the constitutive activation of the NF-kB signaling pathway that promotes cell survival, proliferation, and inhibition of apoptosis. Approximately 30% of ABC DLBCLs harbor mutations/deletions of TNFAIP3 (A20) which acts as a negative regulator of NF-kB signaling. NFKBIZ amplification is also detected in 9% of ABC DLBCL cases which activates targets in the NF-kB signaling pathway. About 30% of ABC DLBCL tumors have activating mutations in MYD88, leading to the constitutive activation of NF-kB signaling and JAK/STAT3 pathway. About 10% of ABC DLBCL patients harbor activating mutations in CARD11 and 20% of ABC lymphomas have mutations in CD79A or CD79B leading to chronic active B-cell receptor signaling. In conclusion, ABC DLBCL has an unfavorable prognosis and remains the least curable form of this malignancy despite many recent advances in therapy. Outcome effects: ABC DLBCLs are characterized by amplifications and consecutive overexpression of the antiapoptotic BCL2 gene as well as deletions affecting CDKN2A and CDKN2B. BCL6 dependency occurs in ABC cell lines, with or without a BCL6 translocation. BCL2 and NFATC1 are consistently upregulated by the gain/amplification of 18q while the gain/amplification of 19q leads to the overexpression of SPIB. IL6 and IL10 are overexpressed in an autocrine manner and play an important role in pathogenesis. ABC DLBCLs characteristically express several genes that are normally expressed in plasma cells. However, full differentiation into plasma cells seems to be blocked by genetic abnormalities involving the function of PRDM1 (Blimp-1), the master regulator of plasmacytic differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 19577170 PMID: 20393178 PMID: 22224767 PMID: 22409819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1744e525-5454-48c8-a998-0fa1076b7725 Diffuse Large-B-Cell Lymphoma ABC Subtype uuid-1744e525-5454-48c8-a998-0fa1076b7725 PS:CellType B-cell PS:CellType cancer cell PS:Description Activated B-cell-like (ABC) diffuse large B-cell lymphoma is a subtype of DLBCL identified by gene-expression profile. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1744e525-5454-48c8-a998-0fa1076b7725 PS:NodeType Pathway PS:Notes Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization. Activated B-cell-like DLBCL (ABC DLBCL) is a subtype of DLBCL identified by gene-expression profile. Signaling description: The pathogenetic hallmark of ABC DLBCL is the constitutive activation of the NF-kB signaling pathway that promotes cell survival, proliferation, and inhibition of apoptosis. Approximately 30% of ABC DLBCLs harbor mutations/deletions of TNFAIP3 (A20) which acts as a negative regulator of NF-kB signaling. NFKBIZ amplification is also detected in 9% of ABC DLBCL cases which activates targets in the NF-kB signaling pathway. About 30% of ABC DLBCL tumors have activating mutations in MYD88, leading to the constitutive activation of NF-kB signaling and JAK/STAT3 pathway. About 10% of ABC DLBCL patients harbor activating mutations in CARD11 and 20% of ABC lymphomas have mutations in CD79A or CD79B leading to chronic active B-cell receptor signaling. In conclusion, ABC DLBCL has an unfavorable prognosis and remains the least curable form of this malignancy despite many recent advances in therapy. Outcome effects: ABC DLBCLs are characterized by amplifications and consecutive overexpression of the antiapoptotic BCL2 gene as well as deletions affecting CDKN2A and CDKN2B. BCL6 dependency occurs in ABC cell lines, with or without a BCL6 translocation. BCL2 and NFATC1 are consistently upregulated by the gain/amplification of 18q while the gain/amplification of 19q leads to the overexpression of SPIB. IL6 and IL10 are overexpressed in an autocrine manner and play an important role in pathogenesis. ABC DLBCLs characteristically express several genes that are normally expressed in plasma cells. However, full differentiation into plasma cells seems to be blocked by genetic abnormalities involving the function of PRDM1 (Blimp-1), the master regulator of plasmacytic differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 19577170 PS:PMID 20393178 PS:PMID 22224767 PS:PMID 22409819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-174cf7c2-7833-46b1-86b5-969a224a8337 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-174cf7c2-7833-46b1-86b5-969a224a8337 UrokinaseR signaling uuid-174cf7c2-7833-46b1-86b5-969a224a8337 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-174cf7c2-7833-46b1-86b5-969a224a8337 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-175c087f-20df-4335-8db0-48efd6809096 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-175c087f-20df-4335-8db0-48efd6809096 Proteins Involved in High-Grade Serous Ovarian Carcinoma uuid-175c087f-20df-4335-8db0-48efd6809096 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-175c087f-20df-4335-8db0-48efd6809096 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17623a02-a16e-470c-b55f-9d28ef6b6f87 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. IL17F is expressed in activated CD4 T cells, basophils, and mast cells, the three major cell types involved in allergic airway inflammation. Bronchial epithelial cells are a novel cell source of IL17F in response to IL33, which they produce in response to IL33. Outcome effects: IL33 induces IL17F via the ST2-ERK1/2-MSK1 signaling pathway in bronchial epithelial cells. Further, IL17F induces IL11, IGFI and CCL20 expression in bronchial epithelial cells. IL17F receptor is a heterodimer of I17RA and IL17RC, which recruits TRAF6, leading to the activation of MAP3K7. The Raf1-MEK1/2-ERK1/2-p90RSK/MSK1-CREB is the central signaling pathway activated by I17RA and IL17RC. On the other hand, IL17F also activates transcriptional factors such as NF-?B. In addition, in humans, the expression of IGFI is significantly increased within the airways of subjects with severe asthma. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 20565710 PMID: 22540331 PMID: 24829928 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-17623a02-a16e-470c-b55f-9d28ef6b6f87 IL17F Signaling in Bronchial Epithelial Cell in Asthma uuid-17623a02-a16e-470c-b55f-9d28ef6b6f87 PS:CellType epithelial cell PS:Description The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17623a02-a16e-470c-b55f-9d28ef6b6f87 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. IL17F is expressed in activated CD4 T cells, basophils, and mast cells, the three major cell types involved in allergic airway inflammation. Bronchial epithelial cells are a novel cell source of IL17F in response to IL33, which they produce in response to IL33. Outcome effects: IL33 induces IL17F via the ST2-ERK1/2-MSK1 signaling pathway in bronchial epithelial cells. Further, IL17F induces IL11, IGFI and CCL20 expression in bronchial epithelial cells. IL17F receptor is a heterodimer of I17RA and IL17RC, which recruits TRAF6, leading to the activation of MAP3K7. The Raf1-MEK1/2-ERK1/2-p90RSK/MSK1-CREB is the central signaling pathway activated by I17RA and IL17RC. On the other hand, IL17F also activates transcriptional factors such as NF-?B. In addition, in humans, the expression of IGFI is significantly increased within the airways of subjects with severe asthma. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 20565710 PS:PMID 22540331 PS:PMID 24829928 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17687b37-0321-4482-9439-32afc01dce67 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-17687b37-0321-4482-9439-32afc01dce67 Slit2-ROBO1->EMT uuid-17687b37-0321-4482-9439-32afc01dce67 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17687b37-0321-4482-9439-32afc01dce67 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1781bc2d-9abf-4576-a12c-3dfe47914674 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1781bc2d-9abf-4576-a12c-3dfe47914674 Proteins Involved in Diffuse Large-B-Cell Lymphoma uuid-1781bc2d-9abf-4576-a12c-3dfe47914674 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1781bc2d-9abf-4576-a12c-3dfe47914674 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-178a0acb-800a-4326-8978-b79ff9acc85b NodeType: Pathway Notes: CD4+ gluten-specific T-helper (Th) cells in celiac disease recognize deamidated gluten-derived peptides presented by either HLA-DQ2 or HLA-DQ8 as antigens, and they respond to those peptides by expressing high levels of inflammatory cytokines. These cytokines in turn affect the epithelial cells and activate intraepithelial lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-178a0acb-800a-4326-8978-b79ff9acc85b 1_CD4+ T cell and epithelial cell response in celiac disease uuid-178a0acb-800a-4326-8978-b79ff9acc85b PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-178a0acb-800a-4326-8978-b79ff9acc85b PS:NodeType Pathway PS:Notes CD4+ gluten-specific T-helper (Th) cells in celiac disease recognize deamidated gluten-derived peptides presented by either HLA-DQ2 or HLA-DQ8 as antigens, and they respond to those peptides by expressing high levels of inflammatory cytokines. These cytokines in turn affect the epithelial cells and activate intraepithelial lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17cd4f83-2ec2-43a8-a979-d9816a2300a1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-17cd4f83-2ec2-43a8-a979-d9816a2300a1 OGF+>migration uuid-17cd4f83-2ec2-43a8-a979-d9816a2300a1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17cd4f83-2ec2-43a8-a979-d9816a2300a1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17d26a47-f753-4716-8631-2e9846699a86 NodeType: Pathway Notes: The diversity of CFTR mutations in cystic fibrosis determines the penetrance of the disease. Six different classes of mutations in the CFTR gene have been linked to cystic fibrosis. Class I mutations affect the biosynthesis of CFTR and include the most severe CF phenotypes in which no protein is synthesized. Class II mutations result in folding defects of the CFTR protein. The class II mutation delta F508 (Phe508del mutation) is the most common genetic alteration in cystic fibrosis and leads to the deletion of phenylalanine at position 508. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-17d26a47-f753-4716-8631-2e9846699a86 1_CFTR expression and degradation in epithelial cells in cystic fibrosis (class I-II mutations) uuid-17d26a47-f753-4716-8631-2e9846699a86 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17d26a47-f753-4716-8631-2e9846699a86 PS:NodeType Pathway PS:Notes The diversity of CFTR mutations in cystic fibrosis determines the penetrance of the disease. Six different classes of mutations in the CFTR gene have been linked to cystic fibrosis. Class I mutations affect the biosynthesis of CFTR and include the most severe CF phenotypes in which no protein is synthesized. Class II mutations result in folding defects of the CFTR protein. The class II mutation delta F508 (Phe508del mutation) is the most common genetic alteration in cystic fibrosis and leads to the deletion of phenylalanine at position 508. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: The cause of familial hemiplegic migraine type 2 (FHM2) consists in mutations in ATP1A2 gene that encodes an alpha-2 subunit of neuronal and glial K /Na -ATPase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17d5a2eb-73e1-4852-919e-b2d70b44be62 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM2 is caused by mutations in the ATP1A2 that encodes an alpha-2 subunit of the neuronal and glial Na+/K+-ATPase. This ATPase is a transmembrane ion-pump and contributes to the accumulation of membrane potential by pumping potassium (K+) into the cell and sodium (Na+) out of the cell. Up to now, over 50 mutations in ATP1A2 have been identified. These are mostly deletions and reading frame shifts. The reduced activity of Na+/K+-ATPase leads to the disruption of ion balance and glutamate reuptake from the synaptic cleft by glial cells. This results in a slow recovery of neuronal activity after stimulation. The most severe clinical phenotype observed with Leu764Pro, Trp887Arg, and Gly615Arg mutations is characterized by the full loss of Na+/K+-ATPase activity. The Thr345Ala mutation causes a partial reduction of the Na+/K+-ATPase activity, a decrease in affinity to intracellular K+, slower current of K+ from the intercellular space, and a slower recovery after neuronal excitation. The reduction or loss of Na /K -ATPase activity leads to the accumulation of K+ in the extracellular space and Na+ within the cell. Met731Thr and Arg689Gln mutations reduce catalytic turnover, which also leads to the accumulation of K+ in the extracellular space Outcome effects: The accumulation of K+ in the extracellular space and Na+ within the cell disrupts the glutamate transporters and increases the glutamate concentration in the synaptic cleft which leads to the permanent activation of NMDA receptors on the postsynaptic neurons and metabotropic glutamate receptors (mGluR) on the surface of astrocytes. NMDA receptor activation leads to the release of K+ from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic calcium-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid, whichcan block the K large conductance calcium-activated channel (KCNMA1). The main function of KCNMA1 is the removal of K+ from the extracellular space to decrease membrane depolarization. The excess of glutamate is removed from the synaptic cleft by astrocytes, which convert glutamate into glutamine. Glutamine is then transmitted to neurons where it is converted back to glutamate. Thus, the effects of Na+/K+-ATPase mutations result from the continuous release of glutamate into the synaptic cleft where one consequence is the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12539047 PMID: 15308625 PMID: 17691981 PMID: 19185185 PMID: 19499287 PMID: 20816411 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-17d5a2eb-73e1-4852-919e-b2d70b44be62 Glutamate Overdose and Aura Effect in Migraine Type 2 uuid-17d5a2eb-73e1-4852-919e-b2d70b44be62 PS:CellType astrocyte PS:CellType neuron PS:Description The cause of familial hemiplegic migraine type 2 (FHM2) consists in mutations in ATP1A2 gene that encodes an alpha-2 subunit of neuronal and glial K /Na -ATPase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17d5a2eb-73e1-4852-919e-b2d70b44be62 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM2 is caused by mutations in the ATP1A2 that encodes an alpha-2 subunit of the neuronal and glial Na+/K+-ATPase. This ATPase is a transmembrane ion-pump and contributes to the accumulation of membrane potential by pumping potassium (K+) into the cell and sodium (Na+) out of the cell. Up to now, over 50 mutations in ATP1A2 have been identified. These are mostly deletions and reading frame shifts. The reduced activity of Na+/K+-ATPase leads to the disruption of ion balance and glutamate reuptake from the synaptic cleft by glial cells. This results in a slow recovery of neuronal activity after stimulation. The most severe clinical phenotype observed with Leu764Pro, Trp887Arg, and Gly615Arg mutations is characterized by the full loss of Na+/K+-ATPase activity. The Thr345Ala mutation causes a partial reduction of the Na+/K+-ATPase activity, a decrease in affinity to intracellular K+, slower current of K+ from the intercellular space, and a slower recovery after neuronal excitation. The reduction or loss of Na /K -ATPase activity leads to the accumulation of K+ in the extracellular space and Na+ within the cell. Met731Thr and Arg689Gln mutations reduce catalytic turnover, which also leads to the accumulation of K+ in the extracellular space Outcome effects: The accumulation of K+ in the extracellular space and Na+ within the cell disrupts the glutamate transporters and increases the glutamate concentration in the synaptic cleft which leads to the permanent activation of NMDA receptors on the postsynaptic neurons and metabotropic glutamate receptors (mGluR) on the surface of astrocytes. NMDA receptor activation leads to the release of K+ from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic calcium-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid, whichcan block the K large conductance calcium-activated channel (KCNMA1). The main function of KCNMA1 is the removal of K+ from the extracellular space to decrease membrane depolarization. The excess of glutamate is removed from the synaptic cleft by astrocytes, which convert glutamate into glutamine. Glutamine is then transmitted to neurons where it is converted back to glutamate. Thus, the effects of Na+/K+-ATPase mutations result from the continuous release of glutamate into the synaptic cleft where one consequence is the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12539047 PS:PMID 15308625 PS:PMID 17691981 PS:PMID 19185185 PS:PMID 19499287 PS:PMID 20816411 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17e22d93-003d-4d23-a793-7d1f57fad6c8 NodeType: Pathway Notes: Headnote: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs), small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. TLRs can cause autoimmune disease, when they become receptors for fragments of native DNA/RNA and molecules released by apoptotic cells. In humans, ten functional receptors (TLR1-10) have been identified. TLR1, TLR2, and TLR6 are highly similar and specifically recognize components from gram-positive bacteria including LPA, macrophage-activating lipopeptide from Mycoplasma fermentans (MALP2), and diacylated lipopeptides. The specific signaling cascade activated by TLRs depends on the type of cytoplasmic adaptor molecules. TLR1, TLR2, and TLR6 recruit the adaptors, MYD88 and TIRAP. The MYD88-TIRAP-dependent pathway triggers NF-kB, MAPK1, MAPK8, p38 MAPK (MAPK14) activation. All of these transcription factors are responsible for the expression of inflammatory and immune system response genes such as IL12, TNF, IFNs, and CCL5. In addition, TRAF6 directly activates IRF5, which is a transcription factor that is important for the expression of IFNs. Outcome effects: Finally, TLR1-, TLR2-, and TLR6-mediated pathways lead to immune system activation and result in cellular and humoral defense against viruses and bacteria. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-17e22d93-003d-4d23-a793-7d1f57fad6c8 Toll-like Receptors Act through MYD88-TIRAP Signaling uuid-17e22d93-003d-4d23-a793-7d1f57fad6c8 PS:CellType endothelial cell PS:Description Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17e22d93-003d-4d23-a793-7d1f57fad6c8 PS:NodeType Pathway PS:Notes Headnote: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs), small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. TLRs can cause autoimmune disease, when they become receptors for fragments of native DNA/RNA and molecules released by apoptotic cells. In humans, ten functional receptors (TLR1-10) have been identified. TLR1, TLR2, and TLR6 are highly similar and specifically recognize components from gram-positive bacteria including LPA, macrophage-activating lipopeptide from Mycoplasma fermentans (MALP2), and diacylated lipopeptides. The specific signaling cascade activated by TLRs depends on the type of cytoplasmic adaptor molecules. TLR1, TLR2, and TLR6 recruit the adaptors, MYD88 and TIRAP. The MYD88-TIRAP-dependent pathway triggers NF-kB, MAPK1, MAPK8, p38 MAPK (MAPK14) activation. All of these transcription factors are responsible for the expression of inflammatory and immune system response genes such as IL12, TNF, IFNs, and CCL5. In addition, TRAF6 directly activates IRF5, which is a transcription factor that is important for the expression of IFNs. Outcome effects: Finally, TLR1-, TLR2-, and TLR6-mediated pathways lead to immune system activation and result in cellular and humoral defense against viruses and bacteria. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17ea85eb-a6e9-42d1-b7e0-06672ccded4a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-17ea85eb-a6e9-42d1-b7e0-06672ccded4a SARS inhibits apoptosis (hypothesis) uuid-17ea85eb-a6e9-42d1-b7e0-06672ccded4a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17ea85eb-a6e9-42d1-b7e0-06672ccded4a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17fa7c41-3f15-47e8-9cac-133659bea6e9 NodeType: Pathway Notes: The mammalian target of rapamycin (mTOR) signaling pathway merges different input signals in the cell to play central role in regulation of cell metabolism, growth, proliferation and survival. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PMID: 20965424 PMID: 21123733 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-17fa7c41-3f15-47e8-9cac-133659bea6e9 Hypoxia Inhibits mTOR Signaling uuid-17fa7c41-3f15-47e8-9cac-133659bea6e9 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-17fa7c41-3f15-47e8-9cac-133659bea6e9 PS:NodeType Pathway PS:Notes The mammalian target of rapamycin (mTOR) signaling pathway merges different input signals in the cell to play central role in regulation of cell metabolism, growth, proliferation and survival. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 20965424 PS:PMID 21123733 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top substances from published studies for disease treatment Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-180a56dd-c34e-4f8d-88fe-89424ee384c4 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-180a56dd-c34e-4f8d-88fe-89424ee384c4 Ovarian Cancer Clinical Trials uuid-180a56dd-c34e-4f8d-88fe-89424ee384c4 PS:Description Top substances from published studies for disease treatment PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-180a56dd-c34e-4f8d-88fe-89424ee384c4 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-181d93bc-14a4-450a-9f7b-a6b08731cf95 NodeType: Pathway Notes: Headnote: Haploid gametes are produced by reductive nuclear division of a diploid germ cell in a specialized process known as meiosis. Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males. Retinoic acid (RA) induces expression of the critical pre-meiosis gene STRA8 in germ cells of the fetal ovary. Signaling description: The mesonephros attached to the ovary expresses RA synthesizing enzymes RALDH2/3 (ALDH1A2/3) and ovarian granulosa / interstitial cell expresses RALDH1 (ALDH1A1), resulting in the production of high levels of RA. RA binds RAR/RXRs on both identified RAREs of the STRA8 promoter to induce transcription. Meiosis then progresses in ovarian germ cells. Organ: ovary Organ: testis Organ_System: reproductive system PMID: 17715177 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-181d93bc-14a4-450a-9f7b-a6b08731cf95 Retinoic Acid in Meiosis Regulation uuid-181d93bc-14a4-450a-9f7b-a6b08731cf95 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-181d93bc-14a4-450a-9f7b-a6b08731cf95 PS:NodeType Pathway PS:Notes Headnote: Haploid gametes are produced by reductive nuclear division of a diploid germ cell in a specialized process known as meiosis. Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males. Retinoic acid (RA) induces expression of the critical pre-meiosis gene STRA8 in germ cells of the fetal ovary. Signaling description: The mesonephros attached to the ovary expresses RA synthesizing enzymes RALDH2/3 (ALDH1A2/3) and ovarian granulosa / interstitial cell expresses RALDH1 (ALDH1A1), resulting in the production of high levels of RA. RA binds RAR/RXRs on both identified RAREs of the STRA8 promoter to induce transcription. Meiosis then progresses in ovarian germ cells. PS:Organ ovary PS:Organ testis PS:Organ_System reproductive system PS:PMID 17715177 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1830fe13-734f-402f-9577-e38bc6cd11e0 NodeType: Pathway Notes: Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Over 50 genes have been associated with RP to date, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. Many proteins mutated in RP normally take part in either phototransduction or in retinol metabolism (visual cycle). Disease causative proteins implicated in phototransduction include rhodopsin (RHO), phosphodiesterases 6A/B/G (PDE6A, PDE6B, and PDE6G), guanylate cyclases 2D and 2F (GUCY2D and GUCY2F), guanylate cyclase activators 1A/B (GUCA1A and GUCA1B), cyclic nucleotide gated channels alpha 1 and beta 1 (CNGA1 and CNGB1), and arrestin 1 (SAG). Outcome effects: The apoptosis of photoreceptors is a common event in retinal degeneration independently of implicated mutated genes, although the triggering signals leading to retinal cell apoptosis remain largely unknown. Mutated proteins: Mutated gene is shown in white-out style. Organ: Retina Organ: eye Organ_System: sensory system PMID: 22074925 PMID: 22131869 PMID: 24702842 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1830fe13-734f-402f-9577-e38bc6cd11e0 Rod Photoreceptor Signaling Impairment in Retinitis Pigmentosa uuid-1830fe13-734f-402f-9577-e38bc6cd11e0 PS:CellType retina cell PS:Description Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1830fe13-734f-402f-9577-e38bc6cd11e0 PS:NodeType Pathway PS:Notes Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Over 50 genes have been associated with RP to date, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. Many proteins mutated in RP normally take part in either phototransduction or in retinol metabolism (visual cycle). Disease causative proteins implicated in phototransduction include rhodopsin (RHO), phosphodiesterases 6A/B/G (PDE6A, PDE6B, and PDE6G), guanylate cyclases 2D and 2F (GUCY2D and GUCY2F), guanylate cyclase activators 1A/B (GUCA1A and GUCA1B), cyclic nucleotide gated channels alpha 1 and beta 1 (CNGA1 and CNGB1), and arrestin 1 (SAG). Outcome effects: The apoptosis of photoreceptors is a common event in retinal degeneration independently of implicated mutated genes, although the triggering signals leading to retinal cell apoptosis remain largely unknown. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 22074925 PS:PMID 22131869 PS:PMID 24702842 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1847c4d9-c333-4214-8bd5-13125d57aba4 NodeType: Pathway Notes: Headnote: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Signaling description: Ritonavir is capable of directly binding HSP90AA1 in the endoplasmic reticulum and inhibiting its chaperone activity, thus promoting unfolded protein response (UPR). HSP90AA1 normally participates in the folding of PDPK1 kinase, a key player in PIP3/AKT1 signaling pathway, which is essential for signal transduction from INSR to glucose transporter (SLC2A4). Outcome effects: Thus, the PIP3/AKT1 pathway becomes repressed with the administration of ritonavir causing cells to become insensitive to insulin. Organ: pancreas Organ_System: endocrine system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-1847c4d9-c333-4214-8bd5-13125d57aba4 Ritonavir Induced Diabetes uuid-1847c4d9-c333-4214-8bd5-13125d57aba4 PS:CellType insulin-secreting cell PS:Description Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1847c4d9-c333-4214-8bd5-13125d57aba4 PS:NodeType Pathway PS:Notes Headnote: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Signaling description: Ritonavir is capable of directly binding HSP90AA1 in the endoplasmic reticulum and inhibiting its chaperone activity, thus promoting unfolded protein response (UPR). HSP90AA1 normally participates in the folding of PDPK1 kinase, a key player in PIP3/AKT1 signaling pathway, which is essential for signal transduction from INSR to glucose transporter (SLC2A4). Outcome effects: Thus, the PIP3/AKT1 pathway becomes repressed with the administration of ritonavir causing cells to become insensitive to insulin. PS:Organ pancreas PS:Organ_System endocrine system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The primary function of pancreatic beta cells is to produce and release insulin in response to glucose. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-186f5e14-9306-4401-b4c2-d9d873b1d3c4 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: The primary function of pancreatic beta-cells is to produce and release insulin in response to glucose. GIP and GCG potentiate as much as 70% of the meal-induced insulin secretion in beta-cells. Various other hormones and neurotransmitters including VIP, CCK and ADCYAP1 potentiate insulin secretion by generating cAMP via the GNAQ stimulation in pancreatic beta-cells. Similarly to hormone stimulation, glucose, acetylcholine, serotonin, and fatty acids induce oscillations of cAMP and Ca2 levels generating pulsatile insulin release. Outcome effects: G-protein related activation of PIK3CG regulates beta-cell Ca2 -dependent exocytosis by controlling the membrane-associated pool of secretory granules and modulation of cortical F-actin density. PKC activates the rat ion channel TRPM4 following the GNAQ /PLCB1/diacylglycerol pathway stimulation, and this activation leads to membrane depolarization which causes Ca2 influx and insulin release. Osmotic, thermal, or pharmacological activation of another ion channel, TRPV4 enhances glucose-stimulated insulin secretion. Organ: pancreas Organ_System: endocrine system PMID: 22701540 PMID: 23694765 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-186f5e14-9306-4401-b4c2-d9d873b1d3c4 G-Proteins Signaling in Insulin Secretion in beta-Cell uuid-186f5e14-9306-4401-b4c2-d9d873b1d3c4 PS:CellType insulin-secreting cell PS:Description The primary function of pancreatic beta cells is to produce and release insulin in response to glucose. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-186f5e14-9306-4401-b4c2-d9d873b1d3c4 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: The primary function of pancreatic beta-cells is to produce and release insulin in response to glucose. GIP and GCG potentiate as much as 70% of the meal-induced insulin secretion in beta-cells. Various other hormones and neurotransmitters including VIP, CCK and ADCYAP1 potentiate insulin secretion by generating cAMP via the GNAQ stimulation in pancreatic beta-cells. Similarly to hormone stimulation, glucose, acetylcholine, serotonin, and fatty acids induce oscillations of cAMP and Ca2 levels generating pulsatile insulin release. Outcome effects: G-protein related activation of PIK3CG regulates beta-cell Ca2 -dependent exocytosis by controlling the membrane-associated pool of secretory granules and modulation of cortical F-actin density. PKC activates the rat ion channel TRPM4 following the GNAQ /PLCB1/diacylglycerol pathway stimulation, and this activation leads to membrane depolarization which causes Ca2 influx and insulin release. Osmotic, thermal, or pharmacological activation of another ion channel, TRPV4 enhances glucose-stimulated insulin secretion. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22701540 PS:PMID 23694765 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-188b6975-64a3-4f6c-a24c-e2856ebe1fbc NodeType: Pathway Notes: Headnote: Obstetric complications are the hallmark of antiphospholipid syndrome (APS). Recurrent miscarriage, early delivery, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/eclampsia, HELLP syndrome, arterial or venous thrombosis and placental insufficiency are the most severe APS-related complication for pregnant women. Signaling description: Antiphospholipid antibodies (aPL) promote activation of endothelial cells, monocytes and platelets.aPL antibodies bind to beta-2GPI (APOH) that in turn binds to endothelial cell membrane receptors (TLR4 and ANXA2) and induces phosphorylation of p38 MAPK (MAPK14) and NFkB activation leading to a proinflammatory and prothrombotic effect (expression of VCAM1, ICAM1, SELE, F3, IL-1A, IL-6 and IL-8). Organ: blood vessel Organ_System: reproductive system PMID: 17894016 PMID: 20822807 PMID: 21556027 PMID: 22439075 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-188b6975-64a3-4f6c-a24c-e2856ebe1fbc Antiphospholipid Antibodies and Endothelial Cell Interaction uuid-188b6975-64a3-4f6c-a24c-e2856ebe1fbc PS:CellType endothelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-188b6975-64a3-4f6c-a24c-e2856ebe1fbc PS:NodeType Pathway PS:Notes Headnote: Obstetric complications are the hallmark of antiphospholipid syndrome (APS). Recurrent miscarriage, early delivery, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/eclampsia, HELLP syndrome, arterial or venous thrombosis and placental insufficiency are the most severe APS-related complication for pregnant women. Signaling description: Antiphospholipid antibodies (aPL) promote activation of endothelial cells, monocytes and platelets.aPL antibodies bind to beta-2GPI (APOH) that in turn binds to endothelial cell membrane receptors (TLR4 and ANXA2) and induces phosphorylation of p38 MAPK (MAPK14) and NFkB activation leading to a proinflammatory and prothrombotic effect (expression of VCAM1, ICAM1, SELE, F3, IL-1A, IL-6 and IL-8). PS:Organ blood vessel PS:Organ_System reproductive system PS:PMID 17894016 PS:PMID 20822807 PS:PMID 21556027 PS:PMID 22439075 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: CD4+ memory T-cell CellType: T-cell Description: CD4+ gluten-specific T helper (Th) cells express high levels of interleukin 21 and interferon gamma which affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18b97994-df9e-452c-be37-aa852f0d8765 NodeType: Pathway Notes: Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine which affects genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Tissue transglutaminase is a calcium dependent enzyme which mediates ordered and specific deamidation of gliadins, creating an epitope that binds efficiently to DQ2 and is recognized by gut-derived T-cells. Throughout gluten consumption, these tissue transglutaminase autoantibodies are produced by the mucosa of the small intestine, and detected in patients' serum.CD4+ gluten-specific T helper (Th) cells recognize the deamidated gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 and respond by expressing high levels of interleukin 21 and interferon gamma. Outcome effects: These cytokines affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. This response leads directly to tissue remodelling and flattening of the intestinal mucosa.Description of Highlighted proteins: IL21, IL2, IL4, IL6, IFN-gamma and gliadin are highlighted in red in order to emphasize their increased expression and role in violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease.Description of Mutated genes: CTLA4, HLA DQ2, HLA DQ8, ICOS and CD28 genes with white out style have genetic variants which increase susceptibility to Celiac disease. Organ: colon Organ: small intestine Organ_System: digestive system Organ_System: lymphatic system PMID: 20947431 PMID: 23917697 PMID: 26972670 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-18b97994-df9e-452c-be37-aa852f0d8765 CD4+T-Cell Response in Celiac Disease uuid-18b97994-df9e-452c-be37-aa852f0d8765 PS:CellType CD4+ memory T-cell PS:CellType T-cell PS:Description CD4+ gluten-specific T helper (Th) cells express high levels of interleukin 21 and interferon gamma which affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18b97994-df9e-452c-be37-aa852f0d8765 PS:NodeType Pathway PS:Notes Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine which affects genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Tissue transglutaminase is a calcium dependent enzyme which mediates ordered and specific deamidation of gliadins, creating an epitope that binds efficiently to DQ2 and is recognized by gut-derived T-cells. Throughout gluten consumption, these tissue transglutaminase autoantibodies are produced by the mucosa of the small intestine, and detected in patients' serum.CD4+ gluten-specific T helper (Th) cells recognize the deamidated gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 and respond by expressing high levels of interleukin 21 and interferon gamma. Outcome effects: These cytokines affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. This response leads directly to tissue remodelling and flattening of the intestinal mucosa.Description of Highlighted proteins: IL21, IL2, IL4, IL6, IFN-gamma and gliadin are highlighted in red in order to emphasize their increased expression and role in violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease.Description of Mutated genes: CTLA4, HLA DQ2, HLA DQ8, ICOS and CD28 genes with white out style have genetic variants which increase susceptibility to Celiac disease. PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:Organ_System lymphatic system PS:PMID 20947431 PS:PMID 23917697 PS:PMID 26972670 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18c22b23-4d74-45b0-ba16-0765f63d74cd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-18c22b23-4d74-45b0-ba16-0765f63d74cd NRG1 -> HIF1A Expression Target uuid-18c22b23-4d74-45b0-ba16-0765f63d74cd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18c22b23-4d74-45b0-ba16-0765f63d74cd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: Retinoic acid (RA) plays an important role in normal function of the human endometrium. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18c57d87-1166-48aa-8089-b15d16356832 NodeType: Pathway Notes: Headnote: Retinoic acid (RA) plays an important role in normal function of the human endometrium. RA may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2) and cell survival-promoting fatty acid binding protein 5 (FABP5). Endometriotic tissues and cells from women with endometriosis are characterized by altered expression of genes involved in the regulation of synthesis and action of RA. Signaling description: CRABP2 directs RA toward RARA, which results in growth arrest and apoptosis, whereas FABP5 directs RA to bind PPARD, which promotes expression of pro-survival genes. In endometriosis, there is a decrease of the expression of CRABP2 but not FABP5. Endometriosis is also associated with a greatly reduced expression of a gene regulating the cellular uptake of retinol (STRA6) and therefore decreased the availability of the substrate for RA synthesis. Progesterone receptor (PGR) is necessary for high STRA6 and CRABP2 expression in endometrial stromal cells. PGR is down-regulated by ESR2. The retinoic acid catabolic enzyme CYP26A1, is a progesterone responsive gene that is upregulated in women with endometriosis. CYP26A1 inactivates retinoic acid and contributes to establishment of endometriotic lesions.HSD17B2 catalyzes the conversion of estradiol (E2) to estrone (E1) and is downregulated in endometriosis due to low expression of PGR. The result is deficient metabolism of E2 in endometriotic tissues giving rise to high local concentrations of E2. Outcome effects: The consequent decrease of the ratio of CRABP2 to FABP5 may be important in directing actions of RA toward increasing growth and reducing apoptosis of endometriotic tissues. Organ: uterus Organ_System: reproductive system PMID: 20108182 PMID: 20702525 PMID: 21659316 PMID: 22464761 PMID: 23337719 PMID: 24927773 PMID: 25143356 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-18c57d87-1166-48aa-8089-b15d16356832 Retinoic Acid Role in Endometriosis uuid-18c57d87-1166-48aa-8089-b15d16356832 PS:CellType endometrium cell PS:Description Retinoic acid (RA) plays an important role in normal function of the human endometrium. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18c57d87-1166-48aa-8089-b15d16356832 PS:NodeType Pathway PS:Notes Headnote: Retinoic acid (RA) plays an important role in normal function of the human endometrium. RA may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2) and cell survival-promoting fatty acid binding protein 5 (FABP5). Endometriotic tissues and cells from women with endometriosis are characterized by altered expression of genes involved in the regulation of synthesis and action of RA. Signaling description: CRABP2 directs RA toward RARA, which results in growth arrest and apoptosis, whereas FABP5 directs RA to bind PPARD, which promotes expression of pro-survival genes. In endometriosis, there is a decrease of the expression of CRABP2 but not FABP5. Endometriosis is also associated with a greatly reduced expression of a gene regulating the cellular uptake of retinol (STRA6) and therefore decreased the availability of the substrate for RA synthesis. Progesterone receptor (PGR) is necessary for high STRA6 and CRABP2 expression in endometrial stromal cells. PGR is down-regulated by ESR2. The retinoic acid catabolic enzyme CYP26A1, is a progesterone responsive gene that is upregulated in women with endometriosis. CYP26A1 inactivates retinoic acid and contributes to establishment of endometriotic lesions.HSD17B2 catalyzes the conversion of estradiol (E2) to estrone (E1) and is downregulated in endometriosis due to low expression of PGR. The result is deficient metabolism of E2 in endometriotic tissues giving rise to high local concentrations of E2. Outcome effects: The consequent decrease of the ratio of CRABP2 to FABP5 may be important in directing actions of RA toward increasing growth and reducing apoptosis of endometriotic tissues. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 20108182 PS:PMID 20702525 PS:PMID 21659316 PS:PMID 22464761 PS:PMID 23337719 PS:PMID 24927773 PS:PMID 25143356 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18ee52f0-cd1e-4c08-b577-484dd3b7bdc6 NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T-cells. Signaling description: Antigen-specific CD8+cells play a central role in the pathophysiology of vitiligo. The presence cytotoxic CD8+ T cells in the perilesional skin, coincides with the destruction of melanocytes. Outcome effects: Sensitized CD8+ T-cells are attracted to melanocytic autoantigens and are responsible for melanocyte destruction as the primary event in vitiligo. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 20958268 PMID: 23668538 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-18ee52f0-cd1e-4c08-b577-484dd3b7bdc6 Acute Cytotoxic CD8+T-Cell Response against Melanocytes uuid-18ee52f0-cd1e-4c08-b577-484dd3b7bdc6 PS:CellType T-cell PS:Description Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18ee52f0-cd1e-4c08-b577-484dd3b7bdc6 PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T-cells. Signaling description: Antigen-specific CD8+cells play a central role in the pathophysiology of vitiligo. The presence cytotoxic CD8+ T cells in the perilesional skin, coincides with the destruction of melanocytes. Outcome effects: Sensitized CD8+ T-cells are attracted to melanocytic autoantigens and are responsible for melanocyte destruction as the primary event in vitiligo. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 20958268 PS:PMID 23668538 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18f7392c-38bd-4d6c-8171-604e11fc7723 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-18f7392c-38bd-4d6c-8171-604e11fc7723 CHRM1/2/3 -> Vascular Motility uuid-18f7392c-38bd-4d6c-8171-604e11fc7723 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-18f7392c-38bd-4d6c-8171-604e11fc7723 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The prolactin's (PRL) main function in women is to stimulate and maintain the breastfeeding directly acting on lactotrophs cells of the mammary glands. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19299757-0a4b-4ec9-a33a-8a45d59a4be2 NodeType: Pathway Notes: Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk.Signaling descripton: PRL's main function in women is to stimulate and maintain the breastfeeding directly acting on lactotrophs cells of the mammary glands. PRL is the hormone primarily responsible for the synthesis of milk proteins, lactose, and lipids, all major components of milk. Outcome effects: Functional development of mammary epithelium during pregnancy depends mostly on PRL signaling. Proliferation and differentiation of secretory mammary epithelium is dependent on PRL and JAK2-STAT5 pathway. Organ: breast Organ_System: integumentary system PMID: 25589271 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-19299757-0a4b-4ec9-a33a-8a45d59a4be2 PRL and CSH Action in Mammary Gland uuid-19299757-0a4b-4ec9-a33a-8a45d59a4be2 PS:Description The prolactin's (PRL) main function in women is to stimulate and maintain the breastfeeding directly acting on lactotrophs cells of the mammary glands. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19299757-0a4b-4ec9-a33a-8a45d59a4be2 PS:NodeType Pathway PS:Notes Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk.Signaling descripton: PRL's main function in women is to stimulate and maintain the breastfeeding directly acting on lactotrophs cells of the mammary glands. PRL is the hormone primarily responsible for the synthesis of milk proteins, lactose, and lipids, all major components of milk. Outcome effects: Functional development of mammary epithelium during pregnancy depends mostly on PRL signaling. Proliferation and differentiation of secretory mammary epithelium is dependent on PRL and JAK2-STAT5 pathway. PS:Organ breast PS:Organ_System integumentary system PS:PMID 25589271 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-195746ab-8c3e-43e0-8527-85dd3b3ff002 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-195746ab-8c3e-43e0-8527-85dd3b3ff002 CNR1-> Expression Targets in Nerve Tissue uuid-195746ab-8c3e-43e0-8527-85dd3b3ff002 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-195746ab-8c3e-43e0-8527-85dd3b3ff002 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19611f81-6c72-4ecb-89f4-bd486466df65 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-19611f81-6c72-4ecb-89f4-bd486466df65 TCR -> NFAT Expression Targets uuid-19611f81-6c72-4ecb-89f4-bd486466df65 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19611f81-6c72-4ecb-89f4-bd486466df65 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19679caa-3b5d-441a-9a37-38145749996d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-19679caa-3b5d-441a-9a37-38145749996d S100P Expression Target uuid-19679caa-3b5d-441a-9a37-38145749996d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19679caa-3b5d-441a-9a37-38145749996d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Actin filaments associated with myosin are required for many types of cell movements. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19e2dd26-d586-4995-9ce4-a9b2ee8e6635 NodeType: Pathway Notes: Headnote: The actin filaments associated with myosin are required for many types of cell movements. Signaling description: Myosins are motor proteins that travel toward the plus end of the actin filaments in an ATP-dependent fashion. Myosin II, a conventional two-headed myosin, has an important role in muscle contractions. The sarcomere or unit of contraction is composed of parallel arrays of actin filaments (thin filaments) and bundles of myosin II (thick filaments). A cross-bridge between the thick and thin filaments is formed by the head group of myosin binding to actin. In contrast to myosin II, other types of myosin do not form filaments and therefore are not involved in contraction. Myosin I can attach to an organelle or to the plasma membrane and move it along the actin filament. In addition to myosin I and II, at least 12 other classes of unconventional myosins (III through XIV) have been identified but their functions have yet to be determined. Outcome effects: Troponin complex is essential for muscle contraction for skeletal and cardiac muscles. When calcium (Ca2+) binds to troponin, the positions of troponin and tropomyosin are altered on the thin filament and myosin then has access to its binding site on actin. However, in nonmuscle and smooth muscle cells, contraction is regulated primarily by Ca2+-mediated activation of myosin light-chain kinases. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-19e2dd26-d586-4995-9ce4-a9b2ee8e6635 Actomyosin-Based Movement uuid-19e2dd26-d586-4995-9ce4-a9b2ee8e6635 PS:CellType generic PS:Description Actin filaments associated with myosin are required for many types of cell movements. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19e2dd26-d586-4995-9ce4-a9b2ee8e6635 PS:NodeType Pathway PS:Notes Headnote: The actin filaments associated with myosin are required for many types of cell movements. Signaling description: Myosins are motor proteins that travel toward the plus end of the actin filaments in an ATP-dependent fashion. Myosin II, a conventional two-headed myosin, has an important role in muscle contractions. The sarcomere or unit of contraction is composed of parallel arrays of actin filaments (thin filaments) and bundles of myosin II (thick filaments). A cross-bridge between the thick and thin filaments is formed by the head group of myosin binding to actin. In contrast to myosin II, other types of myosin do not form filaments and therefore are not involved in contraction. Myosin I can attach to an organelle or to the plasma membrane and move it along the actin filament. In addition to myosin I and II, at least 12 other classes of unconventional myosins (III through XIV) have been identified but their functions have yet to be determined. Outcome effects: Troponin complex is essential for muscle contraction for skeletal and cardiac muscles. When calcium (Ca2+) binds to troponin, the positions of troponin and tropomyosin are altered on the thin filament and myosin then has access to its binding site on actin. However, in nonmuscle and smooth muscle cells, contraction is regulated primarily by Ca2+-mediated activation of myosin light-chain kinases. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19ef0687-4335-42ba-93a7-0a4f182dc0fa NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-19ef0687-4335-42ba-93a7-0a4f182dc0fa TTR Expression Targets uuid-19ef0687-4335-42ba-93a7-0a4f182dc0fa PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19ef0687-4335-42ba-93a7-0a4f182dc0fa PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f54278-2367-4e9a-8222-37dc4f9292de NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-19f54278-2367-4e9a-8222-37dc4f9292de HGFR -> FOXO3A Signaling uuid-19f54278-2367-4e9a-8222-37dc4f9292de PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f54278-2367-4e9a-8222-37dc4f9292de PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: antigen-presenting cell CellType: cancer cell CellType: cancer stem cell CellType: dendritic cell CellType: effector T-cell Description: IDO1 is enzyme, taking part in catalyzing tryptophan to kynurenine. Depletion of tryptophan and excess of kynurenine leads to immunosuppression. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f83d3b-99ec-47fd-95a1-fc8f973ac7cd NodeType: Pathway Notes: Headnote: IDO1 is an enzyme involved in catalyzing tryptophan to kynurenine. Tryptophan depletion and an excess of kynurenine lead to immunosuppression (inhibition of CD4+ T-cells, CD8+ T-cells, NK cells and activation of Treg cells and myeloid-derived suppressor cells). IDO is strongly up-regulated in tumor cells, tumor stromal cells and immune cells, particularly in dendritic cells (DC). Signaling description: IFNG, IL6, IL1B, TNF and DAMP (ex., HMGB1) activate IDO1 transcription mainly through NFKB and JAK/STAT pathways. In regulatory DC, IDO1 is up-regulated by the reverse signaling from Treg co-regulatory receptors, such as CTLA4 and TNFRSF18 (GITR). CD80/CD86 activates the PI3K/AKT pathway and canonical NF-kappaB pathway. The CD80/CD86-induced PI3K signaling is also affected by a cross-talk with the NOTCH1 signaling. This cross-talk is facilitated by a NOTCH-mediated up-regulation of the expression PIN1, which in turn increases the enzyme activity of casein kinase II. "Back-signaling" from CTLA-4 to CD80/CD86 can also be mediated via FOXO3. CD200 and CD40LG also participate in IDO1 activation through NFKB signaling. It is not known yet whether it is the reverse or direct signaling. IDO1 hyperactivity leads to local tryptophan depletion, inhibition of MTOR and activation of EIF2AK4. Kynurenine is produced as a result of IDO-mediated tryptophan catabolism and interacts with AHR. Another tryptophan catabolizing enzyme, TDO2, is also important in driving cancer growth. Outcome effects: In CD8+ T cells, the IDO1-induced activation of EIF2AK4 leads to cell-cycle arrest and functional anergy. In CD4+ T cells, the activation of EIF2AK4 blocks TH17 differentiation and promotes de novo Treg differentiation and activation of functional suppressor activity in mature Tregs. Overall, EIF2AK4 appears to enhance Treg activity, and inhibit T-effector cells. The depletion of tryptophan and kynurenine excess also induce the inhibition of NK cells and activation of myeloid-derived suppressor cell. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 17767193 PMID: 18364004 PMID: 21517753 PMID: 23103127 PMID: 24325346 PMID: 24415757 PMID: 24711084 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-19f83d3b-99ec-47fd-95a1-fc8f973ac7cd IDO1 in Cancer Immune Escape uuid-19f83d3b-99ec-47fd-95a1-fc8f973ac7cd PS:CellType antigen-presenting cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType dendritic cell PS:CellType effector T-cell PS:Description IDO1 is enzyme, taking part in catalyzing tryptophan to kynurenine. Depletion of tryptophan and excess of kynurenine leads to immunosuppression. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f83d3b-99ec-47fd-95a1-fc8f973ac7cd PS:NodeType Pathway PS:Notes Headnote: IDO1 is an enzyme involved in catalyzing tryptophan to kynurenine. Tryptophan depletion and an excess of kynurenine lead to immunosuppression (inhibition of CD4+ T-cells, CD8+ T-cells, NK cells and activation of Treg cells and myeloid-derived suppressor cells). IDO is strongly up-regulated in tumor cells, tumor stromal cells and immune cells, particularly in dendritic cells (DC). Signaling description: IFNG, IL6, IL1B, TNF and DAMP (ex., HMGB1) activate IDO1 transcription mainly through NFKB and JAK/STAT pathways. In regulatory DC, IDO1 is up-regulated by the reverse signaling from Treg co-regulatory receptors, such as CTLA4 and TNFRSF18 (GITR). CD80/CD86 activates the PI3K/AKT pathway and canonical NF-kappaB pathway. The CD80/CD86-induced PI3K signaling is also affected by a cross-talk with the NOTCH1 signaling. This cross-talk is facilitated by a NOTCH-mediated up-regulation of the expression PIN1, which in turn increases the enzyme activity of casein kinase II. "Back-signaling" from CTLA-4 to CD80/CD86 can also be mediated via FOXO3. CD200 and CD40LG also participate in IDO1 activation through NFKB signaling. It is not known yet whether it is the reverse or direct signaling. IDO1 hyperactivity leads to local tryptophan depletion, inhibition of MTOR and activation of EIF2AK4. Kynurenine is produced as a result of IDO-mediated tryptophan catabolism and interacts with AHR. Another tryptophan catabolizing enzyme, TDO2, is also important in driving cancer growth. Outcome effects: In CD8+ T cells, the IDO1-induced activation of EIF2AK4 leads to cell-cycle arrest and functional anergy. In CD4+ T cells, the activation of EIF2AK4 blocks TH17 differentiation and promotes de novo Treg differentiation and activation of functional suppressor activity in mature Tregs. Overall, EIF2AK4 appears to enhance Treg activity, and inhibit T-effector cells. The depletion of tryptophan and kynurenine excess also induce the inhibition of NK cells and activation of myeloid-derived suppressor cell. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 17767193 PS:PMID 18364004 PS:PMID 21517753 PS:PMID 23103127 PS:PMID 24325346 PS:PMID 24415757 PS:PMID 24711084 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f91d47-915c-4305-a781-c75ac407f174 NodeType: Pathway Organ: penis Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-19f91d47-915c-4305-a781-c75ac407f174 Proteins with Altered Expression in Erectile Dysfunction uuid-19f91d47-915c-4305-a781-c75ac407f174 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-19f91d47-915c-4305-a781-c75ac407f174 PS:NodeType Pathway PS:Organ penis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a0d7615-731c-4e57-84f3-05d1c449e699 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-1a0d7615-731c-4e57-84f3-05d1c449e699 CD38/CD3 -> JUN/FOS/NF-kB Signaling in T-cell Proliferation uuid-1a0d7615-731c-4e57-84f3-05d1c449e699 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a0d7615-731c-4e57-84f3-05d1c449e699 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a6448fd-be91-4810-a3c0-e3eba9962c86 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-1a6448fd-be91-4810-a3c0-e3eba9962c86 NSP10 interactions uuid-1a6448fd-be91-4810-a3c0-e3eba9962c86 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a6448fd-be91-4810-a3c0-e3eba9962c86 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a6c48ca-7bf2-4c19-8e10-c51728194773 NodeType: Pathway Notes: Obstruction of aqueous humor drainage through trabecular meshwork is often a significant feature of glaucoma. The trabecular meshwork (TM) and Schlemm’s canal comprise the outflow system for aqueous humor (AH) in the eye. TM is a network of beams covered with endothelial cells. Outflow resistance is dependent on the condition of the TM extracellular matrix and on the size and volume of the endothelial cells covering the constituent beams. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-1a6c48ca-7bf2-4c19-8e10-c51728194773 1_Trabecular meshwork and Schlemm's canal endothelial cell volume and contractility uuid-1a6c48ca-7bf2-4c19-8e10-c51728194773 PS:CellType endothelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a6c48ca-7bf2-4c19-8e10-c51728194773 PS:NodeType Pathway PS:Notes Obstruction of aqueous humor drainage through trabecular meshwork is often a significant feature of glaucoma. The trabecular meshwork (TM) and Schlemm’s canal comprise the outflow system for aqueous humor (AH) in the eye. TM is a network of beams covered with endothelial cells. Outflow resistance is dependent on the condition of the TM extracellular matrix and on the size and volume of the endothelial cells covering the constituent beams. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a8a3b88-344b-4a1b-b9c4-686451fa076a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1a8a3b88-344b-4a1b-b9c4-686451fa076a EDN1 Expression Targets uuid-1a8a3b88-344b-4a1b-b9c4-686451fa076a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1a8a3b88-344b-4a1b-b9c4-686451fa076a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: skeletal muscle cell Description: Skeletal muscle wasting and body fat wasting are two main manifestations of cancer cachexia. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1aa99ac2-ffb2-4f69-b39f-c8395da4d7a9 NodeType: Pathway Notes: Headnote: Cancer cachexia is a devastating syndrome that affects around 50-80% of cancer patients leading to substantial weight loss, primarily from loss of skeletal muscle and body fat. Signaling description: Major signaling pathways activated in cancer cachexia are TNF/NFKB, Activin/MSTN/ACVR/SMAD/FOXO3, IL6/JAK/STAT3/CEBPD. IGF1 and it's signaling are down-regulated in cancer cachexia resulting in down-regulation of MTOR and protein synthesis as well as activation of proteolysis through FOXO1/3. CAST can be inhibited in cancer leading to CALP1/2 activation and apoptosis induction. Outcome effects: FOXO1/2, NFKB and CEBPD upregulate TRIM63 and FBXO32, the main proteins, responsible for protein degradation in cachexia. FOXO3 also regulates MAP1LC3B and BNIP3 thereby inducing autophagy. CALP1/2 activate CASP3 and induce apoptosis. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Cachexia-specific decrease of IGF1 is shown on the pathway on an exceptional basis. Organ_System: musculoskeletal system PMID: 23770121 PMID: 25291291 PMID: 26112046 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-1aa99ac2-ffb2-4f69-b39f-c8395da4d7a9 Skeletal Muscle Wasting in Cancer Cachexia uuid-1aa99ac2-ffb2-4f69-b39f-c8395da4d7a9 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType skeletal muscle cell PS:Description Skeletal muscle wasting and body fat wasting are two main manifestations of cancer cachexia. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1aa99ac2-ffb2-4f69-b39f-c8395da4d7a9 PS:NodeType Pathway PS:Notes Headnote: Cancer cachexia is a devastating syndrome that affects around 50-80% of cancer patients leading to substantial weight loss, primarily from loss of skeletal muscle and body fat. Signaling description: Major signaling pathways activated in cancer cachexia are TNF/NFKB, Activin/MSTN/ACVR/SMAD/FOXO3, IL6/JAK/STAT3/CEBPD. IGF1 and it's signaling are down-regulated in cancer cachexia resulting in down-regulation of MTOR and protein synthesis as well as activation of proteolysis through FOXO1/3. CAST can be inhibited in cancer leading to CALP1/2 activation and apoptosis induction. Outcome effects: FOXO1/2, NFKB and CEBPD upregulate TRIM63 and FBXO32, the main proteins, responsible for protein degradation in cachexia. FOXO3 also regulates MAP1LC3B and BNIP3 thereby inducing autophagy. CALP1/2 activate CASP3 and induce apoptosis. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Cachexia-specific decrease of IGF1 is shown on the pathway on an exceptional basis. PS:Organ_System musculoskeletal system PS:PMID 23770121 PS:PMID 25291291 PS:PMID 26112046 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ab80c80-d45c-44c9-be20-54e16ba06488 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-1ab80c80-d45c-44c9-be20-54e16ba06488 SARS N protein inhibitors uuid-1ab80c80-d45c-44c9-be20-54e16ba06488 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ab80c80-d45c-44c9-be20-54e16ba06488 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ad13ede-46ad-42fc-97aa-2d190015dc1a NodeType: Pathway Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1ad13ede-46ad-42fc-97aa-2d190015dc1a Proteins Involved in Presbycusis uuid-1ad13ede-46ad-42fc-97aa-2d190015dc1a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ad13ede-46ad-42fc-97aa-2d190015dc1a PS:NodeType Pathway PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ad1ea99-c221-4058-a595-6fd64e8e3d28 NodeType: Pathway Notes: Microangiopathy itself does not reveal the full complexity of DN pathogenic mechanisms. The signaling pathways directly triggered by hyperglycemia and hypoxia are similar in different cell types although they demonstrate some cellular specificity. In neurons, hyperglycemia induces apoptosis and ER stress, and it alters autophagy. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-1ad1ea99-c221-4058-a595-6fd64e8e3d28 2_Neuron and Schwann cell death uuid-1ad1ea99-c221-4058-a595-6fd64e8e3d28 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ad1ea99-c221-4058-a595-6fd64e8e3d28 PS:NodeType Pathway PS:Notes Microangiopathy itself does not reveal the full complexity of DN pathogenic mechanisms. The signaling pathways directly triggered by hyperglycemia and hypoxia are similar in different cell types although they demonstrate some cellular specificity. In neurons, hyperglycemia induces apoptosis and ER stress, and it alters autophagy. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ae048fd-e674-49f6-bcc5-53a229b901d8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-1ae048fd-e674-49f6-bcc5-53a229b901d8 Mixed acid fermentation template uuid-1ae048fd-e674-49f6-bcc5-53a229b901d8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ae048fd-e674-49f6-bcc5-53a229b901d8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PMID Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1af52132-485d-466b-b362-41684d230f76 NodeType: Pathway PMID: 18313409 urn:agi-pathway:uuid-1af52132-485d-466b-b362-41684d230f76 TGFb+>Translation uuid-1af52132-485d-466b-b362-41684d230f76 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1af52132-485d-466b-b362-41684d230f76 PS:NodeType Pathway PS:PMID 18313409 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: Arterial Hypertension (AH) is the most common chronic disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1af92396-2bbd-4a81-b16f-f4bcb0801fb5 NodeType: Pathway Notes: Arterial Hypertension (AH) is the most common chronic disease. Intracellular Ca2 homeostasis is essential for vascular function and blood pressure regulation. TRPM4/6/7/8 play an important role in cellular Ca2 homeostasis. Organ: blood vessel Organ_System: cardiovascular system PMID: 21150127 PMID: 21290322 PMID: 22750058 PMID: 23443854 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-1af92396-2bbd-4a81-b16f-f4bcb0801fb5 TRPM4/6/7/8 Signaling in Arterial Hypertension (Hypothesis) uuid-1af92396-2bbd-4a81-b16f-f4bcb0801fb5 PS:CellType vascular smooth muscle cell PS:Description Arterial Hypertension (AH) is the most common chronic disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1af92396-2bbd-4a81-b16f-f4bcb0801fb5 PS:NodeType Pathway PS:Notes Arterial Hypertension (AH) is the most common chronic disease. Intracellular Ca2 homeostasis is essential for vascular function and blood pressure regulation. TRPM4/6/7/8 play an important role in cellular Ca2 homeostasis. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 21150127 PS:PMID 21290322 PS:PMID 22750058 PS:PMID 23443854 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: thymocyte Description: Myasthenia gravis (MG) is a B-cell mediated autoimmune disease in which antibodies are directed against proteins concentrated at the neuromuscular junction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1afd8fbb-dfc6-4888-aa3f-872be39a941c NodeType: Pathway Notes: Headnote: Myasthenia gravis (MG) is a T-cell dependent, B-cell mediated autoimmune disease in which antibodies are directed against proteins concentrated at the neuromuscular junction, primarily against nicotinic acetylcholine receptor (nAChR). MG patients with the early-onset form have thymic follicular hyperplasia with elevated serum nAChR antibody titers and nAChR-specific CD4 T-cells. Signaling description: The thymus is essential for T-cell differentiation and for the establishment of central tolerance. Normally, the number of B cells is very small in the thymus; while in the thymus of nAChR-MG patients, there is a presence of a tumor (i.e., thymoma) or germinal centers (GCs) containing a large number of B-cells (i.e., follicular hyperplasia). B-cells from MG thymus are already activated and do not require additional activation to produce anti-nAChR antibodies. Polymorphisms in CHRND, HLA A1-B8-DR3 haplotype, and the TNF-a-308 allele 2 have been shown to increase the risk of early-onset MG. Mutations in the CHRNA1 promoter are associated with early onset of autoimmune MG in two independent human populations (France and U.K.). IRF8 and AIRE are involved in regulating CHRNA1 expression as autoantigens in thymocytes. The inflammatory microenvironment is a strong predisposition factor for MG. The mutant variant of the main potent pro-inflammatory molecule, TNF correlates with overexpression of TNF in MG patients. TNF is significantly increased not only in thymus cells, but also in the sera of MG patients. Many factors trigger MG including infections, hormones, vitamin D, diet, and microbiota. Estrogens have a strong influence on the generation of naïve CD4 and CD8 T-cells in the thymus. Thymocytes from MG patients are more sensitive to the effects of estrogen and display an increased expression of ER-a due to the inflammatory environment. In MG patients, plasma vitamin D levels are significantly lower than in healthy controls. Outcome effects: The pro-inflammatory effects of TNF are primarily due to its ability to activate NF-kB, leading to the expression of inflammatory genes. Thymic epithelial cells from MG patients overproduce pro-inflammatory IL6, IL1A, and IFNB1. Their expression may be induced by several pathways including LPS/TLR/NF-kB. TLR4 is overexpressed in MG thymus. TLR4 stimulation in MG thymic epithelial cells increases CCL17 and CCL22 expression and induces the production of Th17-related cytokines. IFNB1 induces specific a-AChR, CXCL13 expression in thymic epithelial cells. TNFSF13B, which favors autoreactive B cells, is also induced by IFNB1 in thymic epithelial cell cultures. TNFSF13B and BIRC5 may be involved in promoting the survival and maturation of autoreactive B cells in the disease. TNFSF13B levels are increased in patients with MG. BIRC5-positive cells with B lymphocyte and plasma cell markers are present at significant levels in the circulation of humans with MG. BIRC5 is absent in normal adult tissue. In addition, CXCL13, CCL21, and CXCL12 are involved in the attraction of peripheral B cells to the MG thymus. CXCL13 and CCL21 are overexpressed in the thymus of MG patients. In addition, miRNAs are involved in the control of the development of inflammatory T cells, including T helper 17 (Th17) cell and Th1 cell subsets. The expression of MIR155 and MIR146A in peripheral B cells is higher in MG when compared with healthy controls. Thymic regulatory T-cell (Treg) cells are dysfunctional in MG patients and thymic conventional T (Tconv) cells are resistant to suppression by Treg cells. The resistance of Tconv cells has been explained by the inflammatory microenvironment such as TNF which may contribute to the resistance of Tconv cells to suppression. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: thymus gland Organ_System: lymphatic system PMID: 17080188 PMID: 23995274 PMID: 24294607 PMID: 24389034 PMID: 24405842 PMID: 24934596 PMID: 25050620 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1afd8fbb-dfc6-4888-aa3f-872be39a941c Thymic Follicular Hyperplasia uuid-1afd8fbb-dfc6-4888-aa3f-872be39a941c PS:CellType B-cell PS:CellType thymocyte PS:Description Myasthenia gravis (MG) is a B-cell mediated autoimmune disease in which antibodies are directed against proteins concentrated at the neuromuscular junction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1afd8fbb-dfc6-4888-aa3f-872be39a941c PS:NodeType Pathway PS:Notes Headnote: Myasthenia gravis (MG) is a T-cell dependent, B-cell mediated autoimmune disease in which antibodies are directed against proteins concentrated at the neuromuscular junction, primarily against nicotinic acetylcholine receptor (nAChR). MG patients with the early-onset form have thymic follicular hyperplasia with elevated serum nAChR antibody titers and nAChR-specific CD4 T-cells. Signaling description: The thymus is essential for T-cell differentiation and for the establishment of central tolerance. Normally, the number of B cells is very small in the thymus; while in the thymus of nAChR-MG patients, there is a presence of a tumor (i.e., thymoma) or germinal centers (GCs) containing a large number of B-cells (i.e., follicular hyperplasia). B-cells from MG thymus are already activated and do not require additional activation to produce anti-nAChR antibodies. Polymorphisms in CHRND, HLA A1-B8-DR3 haplotype, and the TNF-a-308 allele 2 have been shown to increase the risk of early-onset MG. Mutations in the CHRNA1 promoter are associated with early onset of autoimmune MG in two independent human populations (France and U.K.). IRF8 and AIRE are involved in regulating CHRNA1 expression as autoantigens in thymocytes. The inflammatory microenvironment is a strong predisposition factor for MG. The mutant variant of the main potent pro-inflammatory molecule, TNF correlates with overexpression of TNF in MG patients. TNF is significantly increased not only in thymus cells, but also in the sera of MG patients. Many factors trigger MG including infections, hormones, vitamin D, diet, and microbiota. Estrogens have a strong influence on the generation of naïve CD4 and CD8 T-cells in the thymus. Thymocytes from MG patients are more sensitive to the effects of estrogen and display an increased expression of ER-a due to the inflammatory environment. In MG patients, plasma vitamin D levels are significantly lower than in healthy controls. Outcome effects: The pro-inflammatory effects of TNF are primarily due to its ability to activate NF-kB, leading to the expression of inflammatory genes. Thymic epithelial cells from MG patients overproduce pro-inflammatory IL6, IL1A, and IFNB1. Their expression may be induced by several pathways including LPS/TLR/NF-kB. TLR4 is overexpressed in MG thymus. TLR4 stimulation in MG thymic epithelial cells increases CCL17 and CCL22 expression and induces the production of Th17-related cytokines. IFNB1 induces specific a-AChR, CXCL13 expression in thymic epithelial cells. TNFSF13B, which favors autoreactive B cells, is also induced by IFNB1 in thymic epithelial cell cultures. TNFSF13B and BIRC5 may be involved in promoting the survival and maturation of autoreactive B cells in the disease. TNFSF13B levels are increased in patients with MG. BIRC5-positive cells with B lymphocyte and plasma cell markers are present at significant levels in the circulation of humans with MG. BIRC5 is absent in normal adult tissue. In addition, CXCL13, CCL21, and CXCL12 are involved in the attraction of peripheral B cells to the MG thymus. CXCL13 and CCL21 are overexpressed in the thymus of MG patients. In addition, miRNAs are involved in the control of the development of inflammatory T cells, including T helper 17 (Th17) cell and Th1 cell subsets. The expression of MIR155 and MIR146A in peripheral B cells is higher in MG when compared with healthy controls. Thymic regulatory T-cell (Treg) cells are dysfunctional in MG patients and thymic conventional T (Tconv) cells are resistant to suppression by Treg cells. The resistance of Tconv cells has been explained by the inflammatory microenvironment such as TNF which may contribute to the resistance of Tconv cells to suppression. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ thymus gland PS:Organ_System lymphatic system PS:PMID 17080188 PS:PMID 23995274 PS:PMID 24294607 PS:PMID 24389034 PS:PMID 24405842 PS:PMID 24934596 PS:PMID 25050620 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b05429c-bb59-42f9-98ca-f80f5f3f688f NodeType: Pathway Notes: The leading causes of osteoclast dysfunction are multiple mutations in the genes involved in osteoclast function. As a result of genetic mutations, the adhesion of osteoclasts to the bone and bone acidification is impaired, leading to a physiological reduction of bone resorption. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-1b05429c-bb59-42f9-98ca-f80f5f3f688f 1_Osteoclast functional impairment in osteopetrosis uuid-1b05429c-bb59-42f9-98ca-f80f5f3f688f PS:CellType osteoclast PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b05429c-bb59-42f9-98ca-f80f5f3f688f PS:NodeType Pathway PS:Notes The leading causes of osteoclast dysfunction are multiple mutations in the genes involved in osteoclast function. As a result of genetic mutations, the adhesion of osteoclasts to the bone and bone acidification is impaired, leading to a physiological reduction of bone resorption. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b1fa325-cc86-4c17-8c46-d192c4a99840 NodeType: Pathway Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1b1fa325-cc86-4c17-8c46-d192c4a99840 Genes with Mutations Associated with Pregnancy Related Coagulation Disorders uuid-1b1fa325-cc86-4c17-8c46-d192c4a99840 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b1fa325-cc86-4c17-8c46-d192c4a99840 PS:NodeType Pathway PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b3097e5-29eb-486e-a5d0-449ce3008a19 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1b3097e5-29eb-486e-a5d0-449ce3008a19 Proteins Involved in Phenylketonuria uuid-1b3097e5-29eb-486e-a5d0-449ce3008a19 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b3097e5-29eb-486e-a5d0-449ce3008a19 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Neutrophils are released into the bloodstream where they circulate and die by apoptosis (half-life ~7 hours) or respond to signals of localized infection. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b313ce4-f30d-41c7-9f3b-24218f21e0b3 NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Neutrophils are released into the bloodstream, where they circulate and die by apoptosis (half-life ~7 hours) or respond to signals of localized infection. They migrate through vascular endothelial walls into tight tissue spaces seeking out the infectious agents for phagocytosis and destruction. Mature neutrophils in the blood differ significantly from those in the focus of inflammation in terms of their membrane receptor pattern and the state of activation of their intracellular signaling pathways. The activation extent can vary from priming up to complete activation. A high level of neutrophil activation leads to the destruction of pathogens due to degranulation and the production of large amounts of reactive oxygen and nitrogen species. Priming is defined as the enhancement or amplification of neutrophil respiratory burst in response to a given activating stimulus following exposure to the priming agent. Neutrophil degranulation and activation of NAD(P)H oxidase occurs only in neutrophils that have been primed before activation. The factors activating neutrophil priming do not cause the release of ROS and the content of granules directly, but trigger signaling cascades required for the initiation of these processes. These factors can be divided into early-phase cytokines including TNF, IL2, and TLR ligands or late-phase chemoattractants and growth factors including IL8, LTB4 and CSF3. Some priming agents, including LTB4 and platelet-activating factor, cause an immediate and rapid rise in intracellular Ca2+. Other priming agents, such as TNF, CSF3, and LPS, are associated with less rapid increases in intracellular Ca2+ and require longer incubation periods to achieve the priming effect. The mechanism of regulating priming is poorly understood. It is possible that priming is connected to the transcriptional regulation of membrane receptors and control of the synthesis of small molecules such as arachidonic acid derivatives. Outcome effects: Neutrophils in the priming state are characterized by the expression of ITGAM, SELL, FPR1, CXCR2, C5AR1, FASLG, CD14, and other receptors. The precise signaling pathways of neutrophil priming are not well known. It is possible that TNF promotes firm neutrophil adhesion through ITGAM upregulation on the neutrophil surface through the MAPK14 pathway. In addition, CSF3 enhances the expression of ITGB2. CSF3 has been shown to enhance the expression of PCNA in mature neutrophils, which in turn supports the strategy of neutrophil survival. Lastly, IL4 is an anti-inflammatory cytokine that inhibits the expression of IL8 in neutrophils. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-1b313ce4-f30d-41c7-9f3b-24218f21e0b3 Neutrophil Recruitment and Priming uuid-1b313ce4-f30d-41c7-9f3b-24218f21e0b3 PS:CellType neutrophil PS:Description Neutrophils are released into the bloodstream where they circulate and die by apoptosis (half-life ~7 hours) or respond to signals of localized infection. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b313ce4-f30d-41c7-9f3b-24218f21e0b3 PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Neutrophils are released into the bloodstream, where they circulate and die by apoptosis (half-life ~7 hours) or respond to signals of localized infection. They migrate through vascular endothelial walls into tight tissue spaces seeking out the infectious agents for phagocytosis and destruction. Mature neutrophils in the blood differ significantly from those in the focus of inflammation in terms of their membrane receptor pattern and the state of activation of their intracellular signaling pathways. The activation extent can vary from priming up to complete activation. A high level of neutrophil activation leads to the destruction of pathogens due to degranulation and the production of large amounts of reactive oxygen and nitrogen species. Priming is defined as the enhancement or amplification of neutrophil respiratory burst in response to a given activating stimulus following exposure to the priming agent. Neutrophil degranulation and activation of NAD(P)H oxidase occurs only in neutrophils that have been primed before activation. The factors activating neutrophil priming do not cause the release of ROS and the content of granules directly, but trigger signaling cascades required for the initiation of these processes. These factors can be divided into early-phase cytokines including TNF, IL2, and TLR ligands or late-phase chemoattractants and growth factors including IL8, LTB4 and CSF3. Some priming agents, including LTB4 and platelet-activating factor, cause an immediate and rapid rise in intracellular Ca2+. Other priming agents, such as TNF, CSF3, and LPS, are associated with less rapid increases in intracellular Ca2+ and require longer incubation periods to achieve the priming effect. The mechanism of regulating priming is poorly understood. It is possible that priming is connected to the transcriptional regulation of membrane receptors and control of the synthesis of small molecules such as arachidonic acid derivatives. Outcome effects: Neutrophils in the priming state are characterized by the expression of ITGAM, SELL, FPR1, CXCR2, C5AR1, FASLG, CD14, and other receptors. The precise signaling pathways of neutrophil priming are not well known. It is possible that TNF promotes firm neutrophil adhesion through ITGAM upregulation on the neutrophil surface through the MAPK14 pathway. In addition, CSF3 enhances the expression of ITGB2. CSF3 has been shown to enhance the expression of PCNA in mature neutrophils, which in turn supports the strategy of neutrophil survival. Lastly, IL4 is an anti-inflammatory cytokine that inhibits the expression of IL8 in neutrophils. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: mesenchymal stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b3fd71e-f3bb-4b5c-989a-dc3e2bba3ccc NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-1b3fd71e-f3bb-4b5c-989a-dc3e2bba3ccc Proteins with Altered Expression in Cancer Metastases uuid-1b3fd71e-f3bb-4b5c-989a-dc3e2bba3ccc PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType mesenchymal stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b3fd71e-f3bb-4b5c-989a-dc3e2bba3ccc PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b432069-1ec0-4083-a33e-ade03969154f NodeType: Pathway Notes: Studies have described more than 100 variations associated with ulcerative colitis. However, much more additional work is needed to confirm the associations and the disease-specific manifestations for many of declared variations. Sometimes, it is impossible to separate ulcerative colitis from Crohn’s disease and other manifestations of inflammatory bowel diseases in data analysis and in diagnosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-1b432069-1ec0-4083-a33e-ade03969154f 4_2_Genes with mutations currently associated with ulcerative colitis uuid-1b432069-1ec0-4083-a33e-ade03969154f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b432069-1ec0-4083-a33e-ade03969154f PS:NodeType Pathway PS:Notes Studies have described more than 100 variations associated with ulcerative colitis. However, much more additional work is needed to confirm the associations and the disease-specific manifestations for many of declared variations. Sometimes, it is impossible to separate ulcerative colitis from Crohn’s disease and other manifestations of inflammatory bowel diseases in data analysis and in diagnosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: FASN is overexpressed in many human cancers including prostate cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b83359d-2f2f-4bd0-916e-76afe4295633 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Fatty acid synthase (FASN) is a multi-functional protein. Its major function is to catalyze the synthesis of palmitate. It has been demonstrated that FASN is overexpressed in many human cancers including prostate cancer. FASN is transcriptionally regulated by nuclear orphan receptor LXR-alpha (NR1H3) and sterol regulatory element binding transcription factor 1 (SREBF1). Peroxisome proliferator-activated receptor gamma (PPARG) activates NR1H3, while runt-related transcription factors (Runt) inhibit NR1H3. MAPK1,3 activate SREBF1, whereas serine/threonine protein kinase B (AKT/PCB) inhibits SREBF1 via glycogen synthase kinase 3 beta (GSK3B). FASN participates in the normal functioning of many systems and processes. Outcome effects: The overexpression of FASN function leads to a reduction in apoptosis and an increase in cell growth, proliferation, invasion, and prostate tumor initiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: prostate Organ_System: urinary tract PMID: 19318631 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1b83359d-2f2f-4bd0-916e-76afe4295633 Fatty Acid Synthase (FASN) Signaling uuid-1b83359d-2f2f-4bd0-916e-76afe4295633 PS:CellType cancer cell PS:Description FASN is overexpressed in many human cancers including prostate cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b83359d-2f2f-4bd0-916e-76afe4295633 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Fatty acid synthase (FASN) is a multi-functional protein. Its major function is to catalyze the synthesis of palmitate. It has been demonstrated that FASN is overexpressed in many human cancers including prostate cancer. FASN is transcriptionally regulated by nuclear orphan receptor LXR-alpha (NR1H3) and sterol regulatory element binding transcription factor 1 (SREBF1). Peroxisome proliferator-activated receptor gamma (PPARG) activates NR1H3, while runt-related transcription factors (Runt) inhibit NR1H3. MAPK1,3 activate SREBF1, whereas serine/threonine protein kinase B (AKT/PCB) inhibits SREBF1 via glycogen synthase kinase 3 beta (GSK3B). FASN participates in the normal functioning of many systems and processes. Outcome effects: The overexpression of FASN function leads to a reduction in apoptosis and an increase in cell growth, proliferation, invasion, and prostate tumor initiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 19318631 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8876c8-bc60-43e2-bfa3-08e12cde37d7 NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. Signaling description: When the S phase is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. DNA replication takes place only at specific loci on the chromosomal DNA termed replication origins. Newly synthesized CDC6/CDC18 temporally associates with ORC (Origin Recognition Complexes) and is essential for the assembly of preRC (pre Replication Complex) at origins of replication, prior to the initiation of DNA synthesis. Histone production occurs during the S phase, but rates of RNA transcription and protein synthesis are very low during this phase. In the S-phase, CycA - CDK2 complex initiates DNA replication. CycE regulates the transcription of genes that encode the replication machinery, but has also been implicated in the initiation DNA replication process in mammalian cells. The synthesis and accumulation of CycB also occurs during S-phase. In G1 phase, CycB is synthesized but stays inactive due to FZR1/APC-dependent degradation. Outcome effects: During the S/G2/M state, CycA - CDK2 turns off FZR1, allowing CycB to accumulate, so that the cell will eventually be able to enter mitosis. In G2, the cell prepares for mitosis. Spoecifically, significant biosynthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-1b8876c8-bc60-43e2-bfa3-08e12cde37d7 S/G2 Phase Transition uuid-1b8876c8-bc60-43e2-bfa3-08e12cde37d7 PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8876c8-bc60-43e2-bfa3-08e12cde37d7 PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. Signaling description: When the S phase is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. DNA replication takes place only at specific loci on the chromosomal DNA termed replication origins. Newly synthesized CDC6/CDC18 temporally associates with ORC (Origin Recognition Complexes) and is essential for the assembly of preRC (pre Replication Complex) at origins of replication, prior to the initiation of DNA synthesis. Histone production occurs during the S phase, but rates of RNA transcription and protein synthesis are very low during this phase. In the S-phase, CycA - CDK2 complex initiates DNA replication. CycE regulates the transcription of genes that encode the replication machinery, but has also been implicated in the initiation DNA replication process in mammalian cells. The synthesis and accumulation of CycB also occurs during S-phase. In G1 phase, CycB is synthesized but stays inactive due to FZR1/APC-dependent degradation. Outcome effects: During the S/G2/M state, CycA - CDK2 turns off FZR1, allowing CycB to accumulate, so that the cell will eventually be able to enter mitosis. In G2, the cell prepares for mitosis. Spoecifically, significant biosynthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8ca885-3de1-4348-8994-ba546ac179d7 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-1b8ca885-3de1-4348-8994-ba546ac179d7 tocochromanol biosynthesis template uuid-1b8ca885-3de1-4348-8994-ba546ac179d7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8ca885-3de1-4348-8994-ba546ac179d7 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8f4022-5a28-4623-9adb-0f6655a524e5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-1b8f4022-5a28-4623-9adb-0f6655a524e5 MgrX2+>Lacrimation (hypothesis) uuid-1b8f4022-5a28-4623-9adb-0f6655a524e5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b8f4022-5a28-4623-9adb-0f6655a524e5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b9b9b02-8d3a-4f64-a5f1-2a52d0563a52 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1b9b9b02-8d3a-4f64-a5f1-2a52d0563a52 VEGFC -> CTNNB Expression Target uuid-1b9b9b02-8d3a-4f64-a5f1-2a52d0563a52 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1b9b9b02-8d3a-4f64-a5f1-2a52d0563a52 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: A-cell (X-like) CellType: neuron Description: Ghrelin and Nesfatin-1 (A-cells (X-like) products) regulate stomach functional state and satiety. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ba00f2b-996e-4150-9e03-6aee96efe664 NodeType: Pathway Notes: Headnote: Products released by A-cells (stomach enteroendocrine cells similar to X-cells) regulate stomach functional state and satiety. Activation of A-cells initiates expression and release of ghrelin and nesfatin-1, which activate mucosal endings of vagal afferent neurons which transmit the nerve impulse through vagal nerve to the brain. Signaling description: Activation of GHSR1 by ghrelin induces transmission of the nerve impulse through enhanced PLCb1 and PKC activation and calcium mobilization which stimulate the transmission of nerve impulse by unknown mechanisms. The nerve impulse transmitted through vagal nerve activates gastric motility and pancreatic juice secretion and weakens the feeling of the satiety. Ghrelin is released in the first wave of secretion and nesfatin-1 in the second wave (10-20 minutes after the ghrelin). Nesfatin-1 acts through unknown GPCR that activates cAMP/PKC pathway and extracellular Ca2+ influx. Intracellular calcium interacts and activates GUCA1B /cGMP synthesis and K+ channel opening. Extracellular K+ leads to membrane depolarization and transmission of the nerve impulse through vagal nerve to the brain region which reduces gastric motility, pancreatic juice secretion and satiety. Outcome effects: Ghrelin and nesfatin-1 activate signaling in mucosal endings of vagal afferent neurons. These two neuropeptides have opposite functions. Outcome effects: Ghrelin and nesfatin-1 activates signaling in mucosal endings of vagal afferent neurons. These two neuropeptides have opposite function. Organ: stomach Organ: vagus nerve Organ_System: digestive system Organ_System: nervous system PMID: 24061204 PMID: 24381790 PMID: 27754932 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium Tissue: nerve tissue urn:agi-pathway:uuid-1ba00f2b-996e-4150-9e03-6aee96efe664 Ghrelin and Nesfatin-1 Regulate Stomach Functional State and Satiety uuid-1ba00f2b-996e-4150-9e03-6aee96efe664 PS:CellType A-cell (X-like) PS:CellType neuron PS:Description Ghrelin and Nesfatin-1 (A-cells (X-like) products) regulate stomach functional state and satiety. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ba00f2b-996e-4150-9e03-6aee96efe664 PS:NodeType Pathway PS:Notes Headnote: Products released by A-cells (stomach enteroendocrine cells similar to X-cells) regulate stomach functional state and satiety. Activation of A-cells initiates expression and release of ghrelin and nesfatin-1, which activate mucosal endings of vagal afferent neurons which transmit the nerve impulse through vagal nerve to the brain. Signaling description: Activation of GHSR1 by ghrelin induces transmission of the nerve impulse through enhanced PLCb1 and PKC activation and calcium mobilization which stimulate the transmission of nerve impulse by unknown mechanisms. The nerve impulse transmitted through vagal nerve activates gastric motility and pancreatic juice secretion and weakens the feeling of the satiety. Ghrelin is released in the first wave of secretion and nesfatin-1 in the second wave (10-20 minutes after the ghrelin). Nesfatin-1 acts through unknown GPCR that activates cAMP/PKC pathway and extracellular Ca2+ influx. Intracellular calcium interacts and activates GUCA1B /cGMP synthesis and K+ channel opening. Extracellular K+ leads to membrane depolarization and transmission of the nerve impulse through vagal nerve to the brain region which reduces gastric motility, pancreatic juice secretion and satiety. Outcome effects: Ghrelin and nesfatin-1 activate signaling in mucosal endings of vagal afferent neurons. These two neuropeptides have opposite functions. Outcome effects: Ghrelin and nesfatin-1 activates signaling in mucosal endings of vagal afferent neurons. These two neuropeptides have opposite function. PS:Organ stomach PS:Organ vagus nerve PS:Organ_System digestive system PS:Organ_System nervous system PS:PMID 24061204 PS:PMID 24381790 PS:PMID 27754932 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Serotonin is one of the most important brain neurotransmitters for regulating the sleep/wake cycle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bbb1b73-d2bc-42a9-a465-e227b012bc77 NodeType: Pathway Notes: Headnote: Serotonin is one of the most important brain neurotransmitters for regulating the sleep/wake cycle. High levels of serotonin are associated with wakefulness and lower levels with sleep. Serotonin is involved in wakefulness, in triggering sleep, and in REM sleep. Signaling description: A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SLC6A4). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. SRIs are used predominantly as antidepressants, though they are also commonly used in the treatment of other psychological conditions such as anxiety disorders and eating disorders. Outcome effects: Insomnia is one of the common side effects of SRI. Organ: brain Organ_System: nervous system PMID: 18772053 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-1bbb1b73-d2bc-42a9-a465-e227b012bc77 Serotonin Reuptake Inhibition in Sleep Dysregulation uuid-1bbb1b73-d2bc-42a9-a465-e227b012bc77 PS:CellType neuron PS:Description Serotonin is one of the most important brain neurotransmitters for regulating the sleep/wake cycle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bbb1b73-d2bc-42a9-a465-e227b012bc77 PS:NodeType Pathway PS:Notes Headnote: Serotonin is one of the most important brain neurotransmitters for regulating the sleep/wake cycle. High levels of serotonin are associated with wakefulness and lower levels with sleep. Serotonin is involved in wakefulness, in triggering sleep, and in REM sleep. Signaling description: A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SLC6A4). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. SRIs are used predominantly as antidepressants, though they are also commonly used in the treatment of other psychological conditions such as anxiety disorders and eating disorders. Outcome effects: Insomnia is one of the common side effects of SRI. PS:Organ brain PS:Organ_System nervous system PS:PMID 18772053 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bbca56b-eda3-4611-91d8-9eac45b30336 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19900593 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-1bbca56b-eda3-4611-91d8-9eac45b30336 JNK/MAPK Signaling uuid-1bbca56b-eda3-4611-91d8-9eac45b30336 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bbca56b-eda3-4611-91d8-9eac45b30336 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19900593 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bc1b3e9-9dc3-4587-b2c7-32f912a0216f NodeType: Pathway Notes: Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). The disease is clinically and genetically heterogeneous with at least 15 chromosomal loci being assigned to three clinical Usher syndrome types, namely USH1A-G, USH2A-C, and USH3A. Signaling description: Proteins whose genes are mutated in Usher syndrome are located in the stereocilia of the inner ear hair cells and involved in different molecular processes such as motor activity and cell adhesion. Outcome effects: USH1 genes code for the molecular motor myosin VIIa (MYO7A, USH1B), two cell-cell adhesion cadherin proteins, cadherin 23 (CDH23, USH1D), protocadherin 15 (PCDH15, USH1F), and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). Alterations in the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. USH2 genes code for the transmembrane protein USH2A ("usherin"), the G-protein-coupled 7-transmembrane receptor GPR98 (VLGR1b, USH2C), and DFNB31 (USH2D). USH3A gene encodes clarin-1 (CLRN1). Mutated proteins: Mutated proteins are shown in white-out style. Organ: ear Organ_System: sensory system PMID: 16219682 PMID: 16545802 PMID: 16987892 PMID: 20379205 PMID: 20624897 PMID: 22311968 PMID: 24022220 PMID: 24239741 PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1bc1b3e9-9dc3-4587-b2c7-32f912a0216f Proteins Mutated in Cochlear Hair Cell Stereocilia uuid-1bc1b3e9-9dc3-4587-b2c7-32f912a0216f PS:CellType sensory hair cell PS:Description Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bc1b3e9-9dc3-4587-b2c7-32f912a0216f PS:NodeType Pathway PS:Notes Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). The disease is clinically and genetically heterogeneous with at least 15 chromosomal loci being assigned to three clinical Usher syndrome types, namely USH1A-G, USH2A-C, and USH3A. Signaling description: Proteins whose genes are mutated in Usher syndrome are located in the stereocilia of the inner ear hair cells and involved in different molecular processes such as motor activity and cell adhesion. Outcome effects: USH1 genes code for the molecular motor myosin VIIa (MYO7A, USH1B), two cell-cell adhesion cadherin proteins, cadherin 23 (CDH23, USH1D), protocadherin 15 (PCDH15, USH1F), and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). Alterations in the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. USH2 genes code for the transmembrane protein USH2A ("usherin"), the G-protein-coupled 7-transmembrane receptor GPR98 (VLGR1b, USH2C), and DFNB31 (USH2D). USH3A gene encodes clarin-1 (CLRN1). Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ ear PS:Organ_System sensory system PS:PMID 16219682 PS:PMID 16545802 PS:PMID 16987892 PS:PMID 20379205 PS:PMID 20624897 PS:PMID 22311968 PS:PMID 24022220 PS:PMID 24239741 PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: keratinocyte CellType: macrophage CellType: mast cell Description: The deficiency of IL36 receptor antagonist, IL1F5 (DITRA; OMIM 614204) is an autosomal recessive autoinflammatory disease characterized by generalized psoriasis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1be00b20-56b3-4d6e-a731-b9b91fc12529 NodeType: Pathway Notes: Headnote: The deficiency of IL36 receptor antagonist, IL1F5 (DITRA; OMIM 614204) is an autosomal recessive autoinflammatory disease characterized by generalized psoriasis. The recent identification of DITRA as an autoinflammatory disease adds a new dermatological feature, psoriasis, to the range of manifestations observed in patients with these conditions. DITRA is associated with mutations in the gene encoding IL36RN (IL1F5). Patients with DITRA, in contrast to those with DIRA, have a high-grade fever and general malaise during an attack. However, the disease mainly affects the skin and its hallmark is pustular psoriasis. Signaling description: IL36RN (IL1F5) is a protein that inhibits proinflammatory IL36 signaling. IL1F5 and the three agonists IL36A (IL1F6), IL36B (IL1F8), and IL36G (IL1F9), as well as IL1RL2, are highly expressed in epithelial tissues such as skin, trachea, and esophagus. IL36 is a member of the IL1 family and may have a role in the innate immune response to pathogens. Outcome effects: The mutation affects both the stability of IL1F5 and interaction with its receptor, IL1RL2 and lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 21848462 PMID: 24247370 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-1be00b20-56b3-4d6e-a731-b9b91fc12529 IL36 Receptor Antagonist (IL1F5) Deficiency (DITRA) uuid-1be00b20-56b3-4d6e-a731-b9b91fc12529 PS:CellType dendritic cell PS:CellType keratinocyte PS:CellType macrophage PS:CellType mast cell PS:Description The deficiency of IL36 receptor antagonist, IL1F5 (DITRA; OMIM 614204) is an autosomal recessive autoinflammatory disease characterized by generalized psoriasis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1be00b20-56b3-4d6e-a731-b9b91fc12529 PS:NodeType Pathway PS:Notes Headnote: The deficiency of IL36 receptor antagonist, IL1F5 (DITRA; OMIM 614204) is an autosomal recessive autoinflammatory disease characterized by generalized psoriasis. The recent identification of DITRA as an autoinflammatory disease adds a new dermatological feature, psoriasis, to the range of manifestations observed in patients with these conditions. DITRA is associated with mutations in the gene encoding IL36RN (IL1F5). Patients with DITRA, in contrast to those with DIRA, have a high-grade fever and general malaise during an attack. However, the disease mainly affects the skin and its hallmark is pustular psoriasis. Signaling description: IL36RN (IL1F5) is a protein that inhibits proinflammatory IL36 signaling. IL1F5 and the three agonists IL36A (IL1F6), IL36B (IL1F8), and IL36G (IL1F9), as well as IL1RL2, are highly expressed in epithelial tissues such as skin, trachea, and esophagus. IL36 is a member of the IL1 family and may have a role in the innate immune response to pathogens. Outcome effects: The mutation affects both the stability of IL1F5 and interaction with its receptor, IL1RL2 and lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 21848462 PS:PMID 24247370 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bee2484-a3bf-44a8-a488-b3375b655d29 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-1bee2484-a3bf-44a8-a488-b3375b655d29 ADRA2A -> Neurotransmitter Release uuid-1bee2484-a3bf-44a8-a488-b3375b655d29 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1bee2484-a3bf-44a8-a488-b3375b655d29 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c0b4f54-433e-4ac2-948c-7c8a276260f9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-1c0b4f54-433e-4ac2-948c-7c8a276260f9 Corneal stroma ECM remodeling uuid-1c0b4f54-433e-4ac2-948c-7c8a276260f9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c0b4f54-433e-4ac2-948c-7c8a276260f9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuroglia CellType: neuron Description: Neuroinflammation is now recognized as an important aspect of pathology in amyotrophic lateral sclerosis (ALS). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c2ae26b-3ace-4fc5-b048-ab1ec9ac7f6f NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Neuroinflammation is now recognized as an important aspect amyotrophic lateral sclerosis (ALS) pathology. In ALS, astrocytes and microglia are markedly activated and produce many pro-inflammatory molecules including TNF, IL6, IL1B, IGF1, PGE2, and others. Normally, motor neurons produce CX3CL1 and CD200, which prevent microglia from becoming neurotoxic. However, in ALS these factors are downregulated. Outcome effects: As a result, the pro-inflammatory factors can ultimately cause damage to motor neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 19833209 PMID: 22051914 PMID: 23110760 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-1c2ae26b-3ace-4fc5-b048-ab1ec9ac7f6f Neuroinflammation in Amyotrophic Lateral Sclerosis uuid-1c2ae26b-3ace-4fc5-b048-ab1ec9ac7f6f PS:CellType astrocyte PS:CellType neuroglia PS:CellType neuron PS:Description Neuroinflammation is now recognized as an important aspect of pathology in amyotrophic lateral sclerosis (ALS). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c2ae26b-3ace-4fc5-b048-ab1ec9ac7f6f PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Neuroinflammation is now recognized as an important aspect amyotrophic lateral sclerosis (ALS) pathology. In ALS, astrocytes and microglia are markedly activated and produce many pro-inflammatory molecules including TNF, IL6, IL1B, IGF1, PGE2, and others. Normally, motor neurons produce CX3CL1 and CD200, which prevent microglia from becoming neurotoxic. However, in ALS these factors are downregulated. Outcome effects: As a result, the pro-inflammatory factors can ultimately cause damage to motor neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 19833209 PS:PMID 22051914 PS:PMID 23110760 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: chondroblast CellType: fibroblast CellType: mammary epithelial cell Description: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer syndrome occuring due to a germline mutation in the TP53 gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c2f5666-fb0e-41b4-96de-9a61d39ffca8 NodeType: Pathway Notes: Headnote: Li-Fraumeni syndrome (LFS), also known as sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome, is an autosomal dominant cancer syndrome caused largely by a germline mutation in the TP53 tumor suppressor gene. LFS results in cancers most often occurring in childhood or young adulthood. Survivors also have an increased risk for developing multiple neoplasms, with particularly high occurrences of breast cancer, soft tissue sarcomas, and brain tumors. At least 70% of individuals with LFS have an identifiable germline mutation in TP53, while few families with cancers characteristic of LFS have mutations in the CHEK2 gene, also a tumor suppressor. Signaling description: The key processes involved in LFS are cell proliferation, block of apoptosis, loss of cell differentiation, and cell cycle arrest. Normally, TP53 stimulates CDKN1A which inhibits the activity of CDK2 and CDK4. CDK2 and CDK4 suppress cell cycle and initiate cell proliferation and differentiation. TP53 promotes BAX and BBC3 resulting in activation of the apoptotic caspase cascade. In addition, TP53 induces CEBPA that is involved in cell proliferation and differentiation. CHEK2 phosphorylates and activates TP53. Outcome effects: Mutations in TP53 and CHEK2 genes lead to redundant proliferation, block of apoptosis, and the disruption of cell cycle and differentiation Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ: breast Organ_System: integumentary system Organ_System: nervous system PMID: 19056046 PMID: 20522432 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: Cartilage Tissue: connective tissue Tissue: epithelium urn:agi-pathway:uuid-1c2f5666-fb0e-41b4-96de-9a61d39ffca8 Li-Fraumeni Syndrome uuid-1c2f5666-fb0e-41b4-96de-9a61d39ffca8 PS:CellType chondroblast PS:CellType fibroblast PS:CellType mammary epithelial cell PS:Description Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer syndrome occuring due to a germline mutation in the TP53 gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c2f5666-fb0e-41b4-96de-9a61d39ffca8 PS:NodeType Pathway PS:Notes Headnote: Li-Fraumeni syndrome (LFS), also known as sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome, is an autosomal dominant cancer syndrome caused largely by a germline mutation in the TP53 tumor suppressor gene. LFS results in cancers most often occurring in childhood or young adulthood. Survivors also have an increased risk for developing multiple neoplasms, with particularly high occurrences of breast cancer, soft tissue sarcomas, and brain tumors. At least 70% of individuals with LFS have an identifiable germline mutation in TP53, while few families with cancers characteristic of LFS have mutations in the CHEK2 gene, also a tumor suppressor. Signaling description: The key processes involved in LFS are cell proliferation, block of apoptosis, loss of cell differentiation, and cell cycle arrest. Normally, TP53 stimulates CDKN1A which inhibits the activity of CDK2 and CDK4. CDK2 and CDK4 suppress cell cycle and initiate cell proliferation and differentiation. TP53 promotes BAX and BBC3 resulting in activation of the apoptotic caspase cascade. In addition, TP53 induces CEBPA that is involved in cell proliferation and differentiation. CHEK2 phosphorylates and activates TP53. Outcome effects: Mutations in TP53 and CHEK2 genes lead to redundant proliferation, block of apoptosis, and the disruption of cell cycle and differentiation Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ breast PS:Organ_System integumentary system PS:Organ_System nervous system PS:PMID 19056046 PS:PMID 20522432 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue Cartilage PS:Tissue connective tissue PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c4b0cde-ce33-4d5f-bdf6-126faf892a2c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1c4b0cde-ce33-4d5f-bdf6-126faf892a2c AVP/Gq -> CREB/ELK/SRF/AP-1/EGR Expression Targets uuid-1c4b0cde-ce33-4d5f-bdf6-126faf892a2c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c4b0cde-ce33-4d5f-bdf6-126faf892a2c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: PTPN22 is a protein tyrosine phosphatase and a critical gatekeeper of T-cell receptor (TCR) signaling. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c5eed5d-050b-43e9-8c7f-16df0502972b NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: PTPN22 is a protein tyrosine phosphatase and a critical gatekeeper of T-cell receptor (TCR) signaling. In the TCR signaling pathway, PTPN22 inhibits the activity of key signaling effectors such as ZAP70 and LCK, which attenuates T-cell activation. The genetic variation of the PTPN22 gene leads to increased T-cell activation. TCR binds to MHC class II protein complex of antigen presenting cells (APCs) and transduces the signal through TCR/CD3 complex, which with PTPRC modulates the phosphorylation and activation of LCK and ZAP70. The latter is recruited to the TCR/CD3 complex where it becomes activated which promotes the recruitment and phosphorylation of LAT. The latter promotes activation of the MAPK1/3 pathway and phosphorylation of PLCG1, which results in the hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2) to produce the second messengers diacylglycerol and inositol triphosphate (IP3). Diacylglycerol activates PRKCQ which leads to transcription factor NF-kB activation. IP3 triggers the release of Ca2+ which binds to calmodulin and activates calcineurin to promote IL2, IL5, and IL4 gene transcription through the transcription factor NF-AT. Outcome effects: The produced cytokines regulate cell proliferation and differentiation, and the lack of PTPN22 results in increased cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PMID: 16184347 PMID: 16824621 PMID: 22364193 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone marrow Tissue: bone tissue urn:agi-pathway:uuid-1c5eed5d-050b-43e9-8c7f-16df0502972b PTPN22 Role in Rheumatoid Arthritis uuid-1c5eed5d-050b-43e9-8c7f-16df0502972b PS:CellType T-cell PS:Description PTPN22 is a protein tyrosine phosphatase and a critical gatekeeper of T-cell receptor (TCR) signaling. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c5eed5d-050b-43e9-8c7f-16df0502972b PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: PTPN22 is a protein tyrosine phosphatase and a critical gatekeeper of T-cell receptor (TCR) signaling. In the TCR signaling pathway, PTPN22 inhibits the activity of key signaling effectors such as ZAP70 and LCK, which attenuates T-cell activation. The genetic variation of the PTPN22 gene leads to increased T-cell activation. TCR binds to MHC class II protein complex of antigen presenting cells (APCs) and transduces the signal through TCR/CD3 complex, which with PTPRC modulates the phosphorylation and activation of LCK and ZAP70. The latter is recruited to the TCR/CD3 complex where it becomes activated which promotes the recruitment and phosphorylation of LAT. The latter promotes activation of the MAPK1/3 pathway and phosphorylation of PLCG1, which results in the hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2) to produce the second messengers diacylglycerol and inositol triphosphate (IP3). Diacylglycerol activates PRKCQ which leads to transcription factor NF-kB activation. IP3 triggers the release of Ca2+ which binds to calmodulin and activates calcineurin to promote IL2, IL5, and IL4 gene transcription through the transcription factor NF-AT. Outcome effects: The produced cytokines regulate cell proliferation and differentiation, and the lack of PTPN22 results in increased cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:PMID 16184347 PS:PMID 16824621 PS:PMID 22364193 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone marrow PS:Tissue bone tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage CellType: neutrophil Description: Both monocytes and macrophages in patients with systemic lupus erythematosus (SLE) have a defect in apoptotic cell clearance and overproduce inflammatory cytokines. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c6dd21a-3ad9-409d-b5a1-50d3d13b670a NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Defective clearance of apoptotic cells is implicated in the development of SLE. Signaling description: Macrophages of SLE patients show an increased expression of genes involved in inflammation and autophagy. Neutrophils from patient with SLE exhibit an abnormal phenotype with decreased ability for phagocytosis of dead cells, as well as the increased apoptosis and aggregation. They release NETs (Neutrophil Extracellular Traps), which contribute to the development of autoimmunity. Outcome effects: Neutrophils and macrophages show a defect in apoptotic cell clearance and overproduce inflammatory cytokines in patients with SLE. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ_System: hematological system PMID: 21060334 PMID: 23227085 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1c6dd21a-3ad9-409d-b5a1-50d3d13b670a Neutrophil and Macrophage Function in Systemic Lupus Erythematosus uuid-1c6dd21a-3ad9-409d-b5a1-50d3d13b670a PS:CellType macrophage PS:CellType neutrophil PS:Description Both monocytes and macrophages in patients with systemic lupus erythematosus (SLE) have a defect in apoptotic cell clearance and overproduce inflammatory cytokines. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c6dd21a-3ad9-409d-b5a1-50d3d13b670a PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Defective clearance of apoptotic cells is implicated in the development of SLE. Signaling description: Macrophages of SLE patients show an increased expression of genes involved in inflammation and autophagy. Neutrophils from patient with SLE exhibit an abnormal phenotype with decreased ability for phagocytosis of dead cells, as well as the increased apoptosis and aggregation. They release NETs (Neutrophil Extracellular Traps), which contribute to the development of autoimmunity. Outcome effects: Neutrophils and macrophages show a defect in apoptotic cell clearance and overproduce inflammatory cytokines in patients with SLE. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:PMID 21060334 PS:PMID 23227085 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Mutations of sarcomeric and non-sarcomeric proteins are the main causative factors of hypertrophic cardiomyopathy development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c788b73-f4c5-448a-9075-6276e9a129b5 NodeType: Pathway Notes: Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Signaling description: Mutations of sarcomeric and non-sarcomeric protein genes are the major causative factors in the development of HCM. These mutations lead to impaired sarcomere assembly and impaired cardiomyocyte contractility. Angiotensin II (AGT), endothelin-1 (EDN1), TNF, and IL6 are released in response to reduced contractility and mediate contractile adaptation through increased calcium (Ca2+) release from the sarcoplasmic reticulum. Outcome effects: The increase in intracellular Ca2+ activates calmodulin-calcineurin and CAMK- histone deacetylase pathways triggering the transcription of MEF2A, GATA4, and NFATC1, which induces hypertrophy through the expression of contractile proteins. They also induce the expression of fetal isoforms of proteins such as natriuretic peptide A (NPPA), natriuretic peptide B (NPPB), and skeletal muscle actin alpha 1 (ACTA1). AGT, EDN1, TNF, and IL6 activate NF-KB, STAT, JUN/FOS, and SMAD and thereby drive the increase of TIMP1, TIMP2, MMP2, and MMP9 transcription and remodeling of the extracellular matrix. MMPs are inhibited by TIMPs once they are activated, but the gelatinases (MMP2 and MMP9) can form complexes with TIMPs, when the enzymes are in the latent form. In addition, increased myocardial fibrosis occurs due to the increased production of TGFB1 by cardiomyocytes and increased fibroblast proliferation and function. In conclusion, the final morphological events resulting from these molecular mechanisms are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis, which all lead to diastolic dysfunction and heart failure Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 12775656 PMID: 19136482 PMID: 20438756 PMID: 21825071 PMID: 22027658 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-1c788b73-f4c5-448a-9075-6276e9a129b5 Cardiomyocyte Hypertrophy uuid-1c788b73-f4c5-448a-9075-6276e9a129b5 PS:CellType cardiac myocyte PS:Description Mutations of sarcomeric and non-sarcomeric proteins are the main causative factors of hypertrophic cardiomyopathy development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c788b73-f4c5-448a-9075-6276e9a129b5 PS:NodeType Pathway PS:Notes Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Signaling description: Mutations of sarcomeric and non-sarcomeric protein genes are the major causative factors in the development of HCM. These mutations lead to impaired sarcomere assembly and impaired cardiomyocyte contractility. Angiotensin II (AGT), endothelin-1 (EDN1), TNF, and IL6 are released in response to reduced contractility and mediate contractile adaptation through increased calcium (Ca2+) release from the sarcoplasmic reticulum. Outcome effects: The increase in intracellular Ca2+ activates calmodulin-calcineurin and CAMK- histone deacetylase pathways triggering the transcription of MEF2A, GATA4, and NFATC1, which induces hypertrophy through the expression of contractile proteins. They also induce the expression of fetal isoforms of proteins such as natriuretic peptide A (NPPA), natriuretic peptide B (NPPB), and skeletal muscle actin alpha 1 (ACTA1). AGT, EDN1, TNF, and IL6 activate NF-KB, STAT, JUN/FOS, and SMAD and thereby drive the increase of TIMP1, TIMP2, MMP2, and MMP9 transcription and remodeling of the extracellular matrix. MMPs are inhibited by TIMPs once they are activated, but the gelatinases (MMP2 and MMP9) can form complexes with TIMPs, when the enzymes are in the latent form. In addition, increased myocardial fibrosis occurs due to the increased production of TGFB1 by cardiomyocytes and increased fibroblast proliferation and function. In conclusion, the final morphological events resulting from these molecular mechanisms are prominent myocardial hypertrophy, myocardial disarray, and increased interstitial fibrosis, which all lead to diastolic dysfunction and heart failure Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 12775656 PS:PMID 19136482 PS:PMID 20438756 PS:PMID 21825071 PS:PMID 22027658 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: taste bud cell Description: Taste receptors activation in taste bud cells stimulates the transmission of nerve impulse. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c85cf9c-7a57-418d-99aa-7e97b57693e8 NodeType: Pathway Notes: Headnote: Taste receptor activation is a major part in regulation of eating behavior. These receptors are expressed on the surface of taste bud cells of tongue and connected with gustatory afferent nerve fiber. Signaling description: Taste 1 receptor heterodimers (T1R2/T1R3 and T1R1/T1R3) and taste 2 receptors (TAS2Rs) are activated by various nutrients. These receptors interact with alpha-gustducin (GNAT3). At the same time, CASR interacts with unidentified G-proteins in taste bud cells. Further, the G-proteins activate PLCB2 inositol (1,4,5)P3 synthesis and intracellular Ca2+ influx. In turn, calcium activates TRPM5 leading to membrane depolarization and action potential initiation which stimulate gustatory afferent nerve fiber and transmission of signal to the brain. Outcome effects: Activation of taste receptors on taste bud cells stimulate action potential initiation and transmission of nerve impulse. Organ: taste bud Organ_System: sensory system PMID: 17053812 PMID: 24061204 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-1c85cf9c-7a57-418d-99aa-7e97b57693e8 Taste Receptors Activation in Tongue uuid-1c85cf9c-7a57-418d-99aa-7e97b57693e8 PS:CellType taste bud cell PS:Description Taste receptors activation in taste bud cells stimulates the transmission of nerve impulse. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c85cf9c-7a57-418d-99aa-7e97b57693e8 PS:NodeType Pathway PS:Notes Headnote: Taste receptor activation is a major part in regulation of eating behavior. These receptors are expressed on the surface of taste bud cells of tongue and connected with gustatory afferent nerve fiber. Signaling description: Taste 1 receptor heterodimers (T1R2/T1R3 and T1R1/T1R3) and taste 2 receptors (TAS2Rs) are activated by various nutrients. These receptors interact with alpha-gustducin (GNAT3). At the same time, CASR interacts with unidentified G-proteins in taste bud cells. Further, the G-proteins activate PLCB2 inositol (1,4,5)P3 synthesis and intracellular Ca2+ influx. In turn, calcium activates TRPM5 leading to membrane depolarization and action potential initiation which stimulate gustatory afferent nerve fiber and transmission of signal to the brain. Outcome effects: Activation of taste receptors on taste bud cells stimulate action potential initiation and transmission of nerve impulse. PS:Organ taste bud PS:Organ_System sensory system PS:PMID 17053812 PS:PMID 24061204 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c885d3f-e67b-4822-81cd-8f402b9897e2 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-1c885d3f-e67b-4822-81cd-8f402b9897e2 PTGER1/4 -> Vascular Motility uuid-1c885d3f-e67b-4822-81cd-8f402b9897e2 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c885d3f-e67b-4822-81cd-8f402b9897e2 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: The role of macrophages in the pathogenesis of type 1 diabetes has been suggested in early studies. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c9268fd-a229-40fe-86ef-31c9d7c46da1 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: It has long been recognized that macrophages are implicated in the pathogenesis of type 1 diabetes. TNF- and IL1B-producing macrophages have been observed in pancreatic islet infiltrates from patients with recent-onset type 1 diabetes. These cells are detected in the islet infiltrates of young NOD (Non-Obese Diabetic) mice. Inhibition of the influx of these cells into the pancreas by blocking an adhesion-promoting receptor on the cell surface or their depletion, prevents the development of type 1 diabetes. Research suggests that the recruitment of macrophages to islets is mediated by the secretion of CCL1 and CCL2 by CD4 T-cells and pancreatic beta-cells, respectively. Outcome effects: Macrophages recruited to the pancreas produce IL1B, TNF, and reactive oxygen species (ROS) which may cause beta-cell death. In vivo and in vitro studies in rodents have demonstrated that macrophages may play a pathogenic role on beta-cells via the production of pro-inflammatory cytokines such as TNF and IL1B. Macrophages produce IL12 and promote efficient differentiation of diabetogenic CD8 cytotoxic T-lymphocytes (CTls) leading the onset of type 1 diabetes. Animal data: TNF- and IL1B-producing macrophages were detected in the islet infiltrates of young NOD mice. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system PMID: 20577267 PMID: 21712017 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1c9268fd-a229-40fe-86ef-31c9d7c46da1 Macrophage Function in Diabetes Mellitus Type 1 uuid-1c9268fd-a229-40fe-86ef-31c9d7c46da1 PS:CellType macrophage PS:Description The role of macrophages in the pathogenesis of type 1 diabetes has been suggested in early studies. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1c9268fd-a229-40fe-86ef-31c9d7c46da1 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: It has long been recognized that macrophages are implicated in the pathogenesis of type 1 diabetes. TNF- and IL1B-producing macrophages have been observed in pancreatic islet infiltrates from patients with recent-onset type 1 diabetes. These cells are detected in the islet infiltrates of young NOD (Non-Obese Diabetic) mice. Inhibition of the influx of these cells into the pancreas by blocking an adhesion-promoting receptor on the cell surface or their depletion, prevents the development of type 1 diabetes. Research suggests that the recruitment of macrophages to islets is mediated by the secretion of CCL1 and CCL2 by CD4 T-cells and pancreatic beta-cells, respectively. Outcome effects: Macrophages recruited to the pancreas produce IL1B, TNF, and reactive oxygen species (ROS) which may cause beta-cell death. In vivo and in vitro studies in rodents have demonstrated that macrophages may play a pathogenic role on beta-cells via the production of pro-inflammatory cytokines such as TNF and IL1B. Macrophages produce IL12 and promote efficient differentiation of diabetogenic CD8 cytotoxic T-lymphocytes (CTls) leading the onset of type 1 diabetes. Animal data: TNF- and IL1B-producing macrophages were detected in the islet infiltrates of young NOD mice. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:PMID 20577267 PS:PMID 21712017 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ca740ed-5b60-4fba-8ac5-af17be21c35f NodeType: Pathway Notes: Headnote: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. ARVC is caused by genetic defects in myocardial desmosomes, areas on the surface of heart muscle cells, which link the cells together. The desmosomes are composed of several proteins, and many of those proteins can have harmful mutations. Signaling description: Desmosomes are major cell-cell junctions, particularly abundant in epidermal cells and cardiomyocytes. The JUP gene comprises 13 exons, coding for 745 amino acids and an 81.75-kd protein. JUP cytoplasmic protein also known as gamma catenin is found in both submembranous plaques of desmosomes and intermediate junctions. The protein, a member of the catenin family, forms distinct complexes with cadherins and desmosomal cadherins. It contains a distinct repeating amino acid motif called the armadillo repeat. Mutations of JUP affect the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms. The DSP gene comprises 24 exons, encoding 2871 amino acids. The wild-type DSP gene product - desmoplakin, along with plakoglobin, anchors desmosomal cadherins, forming an ordered array of non-transmembrane proteins, which then bind to keratin intermediate filaments. The abnormalities in desmoplakin lead to desmosomal instability. Defective desmosomes cannot sustain the constant mechanical stress in contracting cardiomyocytes, resulting in cardiac dysfunction and cell death. The PKP2 gene comprises 14 exons. The wild-type PKP2 gene product is a desmosomal protein, which provides structural and functional integrity to adjacent cells. Abnormalities in plakophilin are thought to perturb intercellular connections and lead to arrhythmia. The DSG2 gene comprises 15 exons spanning 48.6 kb. The wild-type DSG2 gene product, desmoglein-2, is a member of the desmoglein family and is an essential component of the desmosome. DSG2 is expressed in myocardium. The effect of an abnormal gene product is unknown at this point. The DSC2 gene comprises 17 exons spanning 32 kb. The wild-type DSC2 gene product, desmocollin-2, is ubiquitously expressed in desmosomal tissues and is the only one of three desmocollin isoforms present in cardiac tissue. Desmocollins bind desmogleins through their extracellular domains in a Ca2+-dependent manner and their cytoplasmic domains have binding sites for plakoglobin. Desmocollin mutations that result in an isoform lacking the last 37 amino acid residues of the carboxyl-terminal domain of DSC2a are unable to bind plakoglobin. Outcome effects: The majority of disease-causing mutations detected in patients with ARVC occur in genes encoding desmosomal proteins. Highlighted proteins: Entities with increased level or activity are highlighted in red, entities with reduced level or activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. Organ: heart Organ_System: cardiovascular system PMID: 20301310 PMID: 23468208 PMID: 25516623 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-1ca740ed-5b60-4fba-8ac5-af17be21c35f Desmosome Dysfunction in Cardiomyocyte uuid-1ca740ed-5b60-4fba-8ac5-af17be21c35f PS:CellType cardiac myocyte PS:Description Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ca740ed-5b60-4fba-8ac5-af17be21c35f PS:NodeType Pathway PS:Notes Headnote: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. ARVC is caused by genetic defects in myocardial desmosomes, areas on the surface of heart muscle cells, which link the cells together. The desmosomes are composed of several proteins, and many of those proteins can have harmful mutations. Signaling description: Desmosomes are major cell-cell junctions, particularly abundant in epidermal cells and cardiomyocytes. The JUP gene comprises 13 exons, coding for 745 amino acids and an 81.75-kd protein. JUP cytoplasmic protein also known as gamma catenin is found in both submembranous plaques of desmosomes and intermediate junctions. The protein, a member of the catenin family, forms distinct complexes with cadherins and desmosomal cadherins. It contains a distinct repeating amino acid motif called the armadillo repeat. Mutations of JUP affect the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms. The DSP gene comprises 24 exons, encoding 2871 amino acids. The wild-type DSP gene product - desmoplakin, along with plakoglobin, anchors desmosomal cadherins, forming an ordered array of non-transmembrane proteins, which then bind to keratin intermediate filaments. The abnormalities in desmoplakin lead to desmosomal instability. Defective desmosomes cannot sustain the constant mechanical stress in contracting cardiomyocytes, resulting in cardiac dysfunction and cell death. The PKP2 gene comprises 14 exons. The wild-type PKP2 gene product is a desmosomal protein, which provides structural and functional integrity to adjacent cells. Abnormalities in plakophilin are thought to perturb intercellular connections and lead to arrhythmia. The DSG2 gene comprises 15 exons spanning 48.6 kb. The wild-type DSG2 gene product, desmoglein-2, is a member of the desmoglein family and is an essential component of the desmosome. DSG2 is expressed in myocardium. The effect of an abnormal gene product is unknown at this point. The DSC2 gene comprises 17 exons spanning 32 kb. The wild-type DSC2 gene product, desmocollin-2, is ubiquitously expressed in desmosomal tissues and is the only one of three desmocollin isoforms present in cardiac tissue. Desmocollins bind desmogleins through their extracellular domains in a Ca2+-dependent manner and their cytoplasmic domains have binding sites for plakoglobin. Desmocollin mutations that result in an isoform lacking the last 37 amino acid residues of the carboxyl-terminal domain of DSC2a are unable to bind plakoglobin. Outcome effects: The majority of disease-causing mutations detected in patients with ARVC occur in genes encoding desmosomal proteins. Highlighted proteins: Entities with increased level or activity are highlighted in red, entities with reduced level or activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20301310 PS:PMID 23468208 PS:PMID 25516623 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Upon entry into the thymus, precursors lack expression of CD4 and CD8 and are called double negative (DN). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1cea09fb-8fc6-4425-af6c-3c2b622bc9e9 NodeType: Pathway Notes: Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Signaling description: Upon entry into the thymus, precursors lack expression of CD4 and CD8 and are called double negative (DN). Progenitor cells enter the thymus at the cortico-medullary junction (CMJ) and move through the cortex as the cells progress through DN1 (CD44 /CD25-) and DN2 (CD44 /CD25), arriving at the subcapsular zone as they enter DN3 (CD44-/CD25). At the DN3/DN4 stage of T-cell maturation, proteins produced from effectively rearranged T-cell receptor (TCR) beta genes must be assembled into the pre-TCR complex, which consists of a TCR beta chain (TRB@), the invariant pre-TCR alpha chain, and proteins of the CD3 receptor complex. Outcome effects: The assembly of a functional pre-TCR complex leads to alpha/beta lineage commitment and involves expansion, expression of CD4 and CD8 coreceptors, and rearrangement of the TCR alpha locus. Thus, double positive (DP) thymocytes that reside in the cortex are the first population capable of expressing mature TCRs at the cell surface. Only T-cells that have a functional pre-TCR survive the transition from DN4 to DP thymocytes, in a process also known as beta-selection. If the pre-TCR complex is not assembled normally, TP53 activation causes apoptosis and negative selection of pre-T cells. In addition, IL7R signaling is important for triggering the synthesis of invariant pre-TCR alpha chain. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-1cea09fb-8fc6-4425-af6c-3c2b622bc9e9 T-Cell Maturation (Hypothesis) uuid-1cea09fb-8fc6-4425-af6c-3c2b622bc9e9 PS:CellType T-cell PS:Description Upon entry into the thymus, precursors lack expression of CD4 and CD8 and are called double negative (DN). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1cea09fb-8fc6-4425-af6c-3c2b622bc9e9 PS:NodeType Pathway PS:Notes Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Signaling description: Upon entry into the thymus, precursors lack expression of CD4 and CD8 and are called double negative (DN). Progenitor cells enter the thymus at the cortico-medullary junction (CMJ) and move through the cortex as the cells progress through DN1 (CD44 /CD25-) and DN2 (CD44 /CD25), arriving at the subcapsular zone as they enter DN3 (CD44-/CD25). At the DN3/DN4 stage of T-cell maturation, proteins produced from effectively rearranged T-cell receptor (TCR) beta genes must be assembled into the pre-TCR complex, which consists of a TCR beta chain (TRB@), the invariant pre-TCR alpha chain, and proteins of the CD3 receptor complex. Outcome effects: The assembly of a functional pre-TCR complex leads to alpha/beta lineage commitment and involves expansion, expression of CD4 and CD8 coreceptors, and rearrangement of the TCR alpha locus. Thus, double positive (DP) thymocytes that reside in the cortex are the first population capable of expressing mature TCRs at the cell surface. Only T-cells that have a functional pre-TCR survive the transition from DN4 to DP thymocytes, in a process also known as beta-selection. If the pre-TCR complex is not assembled normally, TP53 activation causes apoptosis and negative selection of pre-T cells. In addition, IL7R signaling is important for triggering the synthesis of invariant pre-TCR alpha chain. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1cf1dbc1-26d0-461e-81b2-4426c3c316f1 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-1cf1dbc1-26d0-461e-81b2-4426c3c316f1 Glycogen Metabolism uuid-1cf1dbc1-26d0-461e-81b2-4426c3c316f1 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1cf1dbc1-26d0-461e-81b2-4426c3c316f1 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d184bf9-45f1-41fd-8760-34d8cac6bb80 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-1d184bf9-45f1-41fd-8760-34d8cac6bb80 Polyamine metabolism template uuid-1d184bf9-45f1-41fd-8760-34d8cac6bb80 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d184bf9-45f1-41fd-8760-34d8cac6bb80 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1e2c88-fcb2-47f1-b173-96fca7edff72 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-1d1e2c88-fcb2-47f1-b173-96fca7edff72 IL7R -> FOXO/NF-kB Signaling uuid-1d1e2c88-fcb2-47f1-b173-96fca7edff72 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1e2c88-fcb2-47f1-b173-96fca7edff72 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1e2fbb-aaee-4299-abe1-03cf28cd43cf NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1d1e2fbb-aaee-4299-abe1-03cf28cd43cf Leptin -> STAT Expression Targets uuid-1d1e2fbb-aaee-4299-abe1-03cf28cd43cf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1e2fbb-aaee-4299-abe1-03cf28cd43cf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1eaae8-6426-4fe1-a89b-6c3438c771cb NodeType: Pathway Organ: generic Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-1d1eaae8-6426-4fe1-a89b-6c3438c771cb Proteins with Altered Expression in Aging uuid-1d1eaae8-6426-4fe1-a89b-6c3438c771cb PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1eaae8-6426-4fe1-a89b-6c3438c771cb PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Leptin and CCK-8 enhance the effects of each other in the nodose ganglia neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1f746b-e117-4b5f-bce5-dfed9cfff17c NodeType: Pathway Notes: Headnote: Leptin and CCK-8 regulate eating behavior by stimulating the sense of the satiety. Headnote: Leptin and CCK-8 regulate eating behavior by stimulating the sense of the satiety. Receptors to leptin and CCK-8 are located in nodose ganglia neuron (inferior ganglion of the vagus nerve, vagal afferent neurons). Signaling description: In nodose ganglia neuron CCK-8 interacts with cholecystokinin A receptor (CCKAR) which via GNA11 activates PLCB1. PLCB1/diacylglycerol activate PKC/SRC/HRAS signaling, and HRAS, in turn activates MAPK signaling which leads to FOS activation and EGR1 transcription and translocation to the nucleus with the help of IPO7. Leptin signaling in the nodose ganglia neuron occurs via the leptin receptor (LEPR) and JAK2/IRS2/PI3K signaling. PI3K activates STAT3 mediated EGR1 transcription. STAT3 activates K+ channel and leads to the efflux of K+ and transmission of the nerve impulse. STAT3 activates SOCS3 transcription that inhibits the LEPR signaling. The CCK-8 and leptin signaling pathways enhance each other via co-stimulation. CCKAR signaling also activates PI3K and RHOA by SRC. LEPR signaling pathway also activates PTPN11/MAP2K1 and SRC. The cross-talk of the CCK-8 and leptin signaling enhances the expression of the CART prepropeptide (CARTPT) by EGR1. CARTPT is proteolytically processed to generate multiple biologically active peptides. These peptides are involved in appetite, energy balance, maintenance of body weight, reward and addiction, and the stress response. Outcome effects: The CCK-8 and leptin signaling pathways co-stimulate each other in the nodal ganglia neurons to induce release of CART prepropeptide. Animal data: The synergistic action of leptin and CCK-8 in nodose ganglia neuron was established in animal models. Organ: brain Organ_System: nervous system PMID: 21270124 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-1d1f746b-e117-4b5f-bce5-dfed9cfff17c Leptin and CCK8 Activate Nodose Ganglia Neuron uuid-1d1f746b-e117-4b5f-bce5-dfed9cfff17c PS:CellType neuron PS:Description Leptin and CCK-8 enhance the effects of each other in the nodose ganglia neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d1f746b-e117-4b5f-bce5-dfed9cfff17c PS:NodeType Pathway PS:Notes Headnote: Leptin and CCK-8 regulate eating behavior by stimulating the sense of the satiety. Headnote: Leptin and CCK-8 regulate eating behavior by stimulating the sense of the satiety. Receptors to leptin and CCK-8 are located in nodose ganglia neuron (inferior ganglion of the vagus nerve, vagal afferent neurons). Signaling description: In nodose ganglia neuron CCK-8 interacts with cholecystokinin A receptor (CCKAR) which via GNA11 activates PLCB1. PLCB1/diacylglycerol activate PKC/SRC/HRAS signaling, and HRAS, in turn activates MAPK signaling which leads to FOS activation and EGR1 transcription and translocation to the nucleus with the help of IPO7. Leptin signaling in the nodose ganglia neuron occurs via the leptin receptor (LEPR) and JAK2/IRS2/PI3K signaling. PI3K activates STAT3 mediated EGR1 transcription. STAT3 activates K+ channel and leads to the efflux of K+ and transmission of the nerve impulse. STAT3 activates SOCS3 transcription that inhibits the LEPR signaling. The CCK-8 and leptin signaling pathways enhance each other via co-stimulation. CCKAR signaling also activates PI3K and RHOA by SRC. LEPR signaling pathway also activates PTPN11/MAP2K1 and SRC. The cross-talk of the CCK-8 and leptin signaling enhances the expression of the CART prepropeptide (CARTPT) by EGR1. CARTPT is proteolytically processed to generate multiple biologically active peptides. These peptides are involved in appetite, energy balance, maintenance of body weight, reward and addiction, and the stress response. Outcome effects: The CCK-8 and leptin signaling pathways co-stimulate each other in the nodal ganglia neurons to induce release of CART prepropeptide. Animal data: The synergistic action of leptin and CCK-8 in nodose ganglia neuron was established in animal models. PS:Organ brain PS:Organ_System nervous system PS:PMID 21270124 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d45c3d7-be17-4df2-8562-c13708cb2ede NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1d45c3d7-be17-4df2-8562-c13708cb2ede TGFB2-TGFBR1 Expression Targets uuid-1d45c3d7-be17-4df2-8562-c13708cb2ede PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d45c3d7-be17-4df2-8562-c13708cb2ede PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The production of immunosuppressing neuropeptides, such as alpha melanocyte stimulating hormone (aMSH), may play an essential role during the pathogenesis of immune and inflammatory reactions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d480ccc-748f-4056-9892-e454fc3d7b69 NodeType: Pathway Notes: Headnote: The production of immunosuppressing neuropeptides, such as alpha melanocyte stimulating hormone (aMSH), may play an essential role in the pathogenesis of immune and inflammatory reactions. In addition to the pituitary gland in the brain, aMSH is synthesized in several tissues including skin, placenta, testis, ovary, kidney, and adrenal gland. Signaling description: aMSH and ACTH neuropeptides are derived from proopiomelanocortin (POMC) proteolytic cleavage. PCSK2, PCSK1, and CPE are necessary to produce mature aMSH. aMSH modulates immune reactions through the activation of MC1R signaling. MC1R, specific for aMSH and ACTH, is expressed in the skin on keratinocytes, dendritic cells, macrophages, and endothelial cells. aMSH suppresses the proinflammatory activity of macrophages. In macrophages, aMSH inhibits LPS-stimulated NO generation and the production of TNF and IL1. Outcome effects: aMSH engagement of MC1R activates cAMP-dependent PKA, which mediates intracellular signaling leading to the suppression of p38 MAPK and NF-kB activation. aMSH most likely suppresses NF-kB through IRAK1/IRAK3 interactions in activated macrophages. It is also known that MC1R expression requires aMSH inhibition effects on the inflammatory activity of macrophages. aMSH also downregulates CD14 on the surface of macrophages, however the exact mechanism is currently unknown. In dendritic cells, aMSH downregulates the expression of co-stimulatory molecules such as CD86 and CD40, but induces the production of suppressor factor IL10 via poorly understood signaling. The activation of RAPGEF4/RAPGEF3, which translates cAMP signal to MAPK3/MAPK1 via BRAF pathway in a PKA-independent manner, is likely essential for the induction of IL10 synthesis. aMSH also inhibits NF-kB activation not only in macrophages, but also in a T-cell line and human neutrophils. Thus, aMSH suppresses systemic acute-phase response to infection. On endothelial cells, aMSH is capable of down- regulating LPS-induced expression of adhesion molecules such as VCAM1 and SELE. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-1d480ccc-748f-4056-9892-e454fc3d7b69 MC1R in anti-Inflammatory Signaling uuid-1d480ccc-748f-4056-9892-e454fc3d7b69 PS:CellType generic PS:Description The production of immunosuppressing neuropeptides, such as alpha melanocyte stimulating hormone (aMSH), may play an essential role during the pathogenesis of immune and inflammatory reactions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d480ccc-748f-4056-9892-e454fc3d7b69 PS:NodeType Pathway PS:Notes Headnote: The production of immunosuppressing neuropeptides, such as alpha melanocyte stimulating hormone (aMSH), may play an essential role in the pathogenesis of immune and inflammatory reactions. In addition to the pituitary gland in the brain, aMSH is synthesized in several tissues including skin, placenta, testis, ovary, kidney, and adrenal gland. Signaling description: aMSH and ACTH neuropeptides are derived from proopiomelanocortin (POMC) proteolytic cleavage. PCSK2, PCSK1, and CPE are necessary to produce mature aMSH. aMSH modulates immune reactions through the activation of MC1R signaling. MC1R, specific for aMSH and ACTH, is expressed in the skin on keratinocytes, dendritic cells, macrophages, and endothelial cells. aMSH suppresses the proinflammatory activity of macrophages. In macrophages, aMSH inhibits LPS-stimulated NO generation and the production of TNF and IL1. Outcome effects: aMSH engagement of MC1R activates cAMP-dependent PKA, which mediates intracellular signaling leading to the suppression of p38 MAPK and NF-kB activation. aMSH most likely suppresses NF-kB through IRAK1/IRAK3 interactions in activated macrophages. It is also known that MC1R expression requires aMSH inhibition effects on the inflammatory activity of macrophages. aMSH also downregulates CD14 on the surface of macrophages, however the exact mechanism is currently unknown. In dendritic cells, aMSH downregulates the expression of co-stimulatory molecules such as CD86 and CD40, but induces the production of suppressor factor IL10 via poorly understood signaling. The activation of RAPGEF4/RAPGEF3, which translates cAMP signal to MAPK3/MAPK1 via BRAF pathway in a PKA-independent manner, is likely essential for the induction of IL10 synthesis. aMSH also inhibits NF-kB activation not only in macrophages, but also in a T-cell line and human neutrophils. Thus, aMSH suppresses systemic acute-phase response to infection. On endothelial cells, aMSH is capable of down- regulating LPS-induced expression of adhesion molecules such as VCAM1 and SELE. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Link PS:NodeType PS:Organ PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: leukocyte Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4a4fb2-1bc8-4a9e-9c5a-edf760cfc5fe NodeType: Pathway Organ: Blood Vessels PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-1d4a4fb2-1bc8-4a9e-9c5a-edf760cfc5fe Leukocyte Adhesion to Endothelial Cell uuid-1d4a4fb2-1bc8-4a9e-9c5a-edf760cfc5fe PS:CellType endothelial cell PS:CellType leukocyte PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4a4fb2-1bc8-4a9e-9c5a-edf760cfc5fe PS:NodeType Pathway PS:Organ Blood Vessels PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4c06bd-c3be-4382-a126-b1e7a2990694 NodeType: Pathway Organ: colon Organ: intestine Organ_System: digestive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1d4c06bd-c3be-4382-a126-b1e7a2990694 Proteins Involved in Hirschsprung Disease uuid-1d4c06bd-c3be-4382-a126-b1e7a2990694 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4c06bd-c3be-4382-a126-b1e7a2990694 PS:NodeType Pathway PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4ee01c-9dd9-4feb-bb56-6241151b3369 NodeType: Pathway Notes: Crystallin alpha B (CRYAB) activity is associated with the remission of multiple sclerosis due to decrease in inflammation and neuronal death. Organ: brain Organ_System: nervous system PMID: 19444308 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-1d4ee01c-9dd9-4feb-bb56-6241151b3369 Crystallin alpha B (CRYAB) Suppresses Multiple Sclerosis uuid-1d4ee01c-9dd9-4feb-bb56-6241151b3369 PS:CellType T-cell PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d4ee01c-9dd9-4feb-bb56-6241151b3369 PS:NodeType Pathway PS:Notes Crystallin alpha B (CRYAB) activity is associated with the remission of multiple sclerosis due to decrease in inflammation and neuronal death. PS:Organ brain PS:Organ_System nervous system PS:PMID 19444308 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Type I estrogen-dependent endometrioid endometrial carcinoma (EEC) is the most common subtype of gynecological cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d52d6d3-33d3-4210-a452-38d4c4a217ac NodeType: Pathway Notes: Headnote: Endometrial carcinoma (EC) is the most common gynecological malignant tumor in the westen world. Overall, approximately 2-3% of women develop EC. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma (EEC) and type II estrogen-independent EC with serous papillary or clear cell morphology. EEC is the most common subtype of gynecological cancer. Signaling description: EEC is characterized by mutations in KRAS, PIK3CA, PTEN, ARID1A, and beta-catenin (CTNNB1) genes, as well as mutations in mismatch repair genes such as MLH1, MSH2, MSH3, and MSH6. In addition, type I EEC is characterized by a reduced expression of PGR (progesterone receptor) and overexpression of growth factor receptors and their ligands such as EGFRs (the EGFR family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4)), as well as IGF1R, FGFR2, WNT, ESR1 (estrogen receptor 1), and CTNNB1. The overexpression of these receptors causes the constitutive activation of the AKT1 cascades, mitogen-activated protein kinase (MAPK) signaling cascades, and the WNT/CTNNB1 signaling pathway. IN particular, ligand-bound membrane EGFRs, IGF1R, FGFR2, and ESR1 activate PIK3CA, which in turn activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT1-mediated signaling, and mutations in PTEN gene lead to the constitutive activation of AKT1. Outcome effects: The constitutive signaling activation in EEC leads to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of endometrial epithelial cells; whereas mutations in mismatch repair genes cause block of DNA repair. Specifically, activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and the suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. EGFRs mediate Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs and IGF1R also interact with SHC1/GRB2/SOS1 and activate BRAF, which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. In addition, ligand-bound cytoplasmic ESR1 moves into the nucleus. Then, nuclear ESR1 interacts with transcription factors, NCOA1/NCOA3/EP300 and forms the transcription complex which induces cell proliferation. The WNT/CTNNB1 signaling pathway controls various cellular functions including proliferation, differentiation, apoptosis, survival, migration, embryonic development, tumorigenesis, and polarity. In the absence of WNTs, CTNNB1 is associated with a complex which includes the adenomatous polyposis coli (APC) tumor suppressor, axin1 (AXIN1), glycogen synthase kinase-3beta (GSK3B), and casein kinase 1 (CSNK1A1). This complex formation induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B, which results in the ubiquitination and degradation of CTNNB1 protein by the proteasome. When WNT proteins bind to LRP5/6 and FZD, DVL1 is activated and inhibits GSK3B, which results in the cytosolic CTNNB1 stabilization. Also, AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic CTNNB1 protein. Activated CTNNB1 protein then translocates into the nucleus wh Organ: uterus Organ_System: reproductive system PMID: 18061438 PMID: 20396392 PMID: 21317462 PMID: 22498825 PMID: 22653804 PMID: 22888282 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endometrium Tissue: epithelium urn:agi-pathway:uuid-1d52d6d3-33d3-4210-a452-38d4c4a217ac Endometrioid Endometrial Cancer uuid-1d52d6d3-33d3-4210-a452-38d4c4a217ac PS:CellType cancer cell PS:CellType epithelial cell PS:Description Type I estrogen-dependent endometrioid endometrial carcinoma (EEC) is the most common subtype of gynecological cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d52d6d3-33d3-4210-a452-38d4c4a217ac PS:NodeType Pathway PS:Notes Headnote: Endometrial carcinoma (EC) is the most common gynecological malignant tumor in the westen world. Overall, approximately 2-3% of women develop EC. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma (EEC) and type II estrogen-independent EC with serous papillary or clear cell morphology. EEC is the most common subtype of gynecological cancer. Signaling description: EEC is characterized by mutations in KRAS, PIK3CA, PTEN, ARID1A, and beta-catenin (CTNNB1) genes, as well as mutations in mismatch repair genes such as MLH1, MSH2, MSH3, and MSH6. In addition, type I EEC is characterized by a reduced expression of PGR (progesterone receptor) and overexpression of growth factor receptors and their ligands such as EGFRs (the EGFR family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4)), as well as IGF1R, FGFR2, WNT, ESR1 (estrogen receptor 1), and CTNNB1. The overexpression of these receptors causes the constitutive activation of the AKT1 cascades, mitogen-activated protein kinase (MAPK) signaling cascades, and the WNT/CTNNB1 signaling pathway. IN particular, ligand-bound membrane EGFRs, IGF1R, FGFR2, and ESR1 activate PIK3CA, which in turn activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT1-mediated signaling, and mutations in PTEN gene lead to the constitutive activation of AKT1. Outcome effects: The constitutive signaling activation in EEC leads to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of endometrial epithelial cells; whereas mutations in mismatch repair genes cause block of DNA repair. Specifically, activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and the suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. EGFRs mediate Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs and IGF1R also interact with SHC1/GRB2/SOS1 and activate BRAF, which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. In addition, ligand-bound cytoplasmic ESR1 moves into the nucleus. Then, nuclear ESR1 interacts with transcription factors, NCOA1/NCOA3/EP300 and forms the transcription complex which induces cell proliferation. The WNT/CTNNB1 signaling pathway controls various cellular functions including proliferation, differentiation, apoptosis, survival, migration, embryonic development, tumorigenesis, and polarity. In the absence of WNTs, CTNNB1 is associated with a complex which includes the adenomatous polyposis coli (APC) tumor suppressor, axin1 (AXIN1), glycogen synthase kinase-3beta (GSK3B), and casein kinase 1 (CSNK1A1). This complex formation induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B, which results in the ubiquitination and degradation of CTNNB1 protein by the proteasome. When WNT proteins bind to LRP5/6 and FZD, DVL1 is activated and inhibits GSK3B, which results in the cytosolic CTNNB1 stabilization. Also, AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic CTNNB1 protein. Activated CTNNB1 protein then translocates into the nucleus wh PS:Organ uterus PS:Organ_System reproductive system PS:PMID 18061438 PS:PMID 20396392 PS:PMID 21317462 PS:PMID 22498825 PS:PMID 22653804 PS:PMID 22888282 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endometrium PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d6bc056-7641-4a29-8a77-9ae861e148c0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1d6bc056-7641-4a29-8a77-9ae861e148c0 HMGB1 Expression Targets uuid-1d6bc056-7641-4a29-8a77-9ae861e148c0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d6bc056-7641-4a29-8a77-9ae861e148c0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: In patients with SLE, Th2-related cytokines are increased, whereas Th1-related cytokines are decreased. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d981c7f-416f-4f4b-b9d0-b3141902506c NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. At the same time, the role of Th1 and Th2 cytokines in the pathogenesis of SLE is controversial. In patients with SLE, Th2-related cytokines are increased, while Th1 cytokines are decreased. Thus, SLE was initially considered to be a Th2 predominant disease. However, it appears that Th1 or Th2 dominance depends on the stage of the disease and involvement. One of the possible mechanisms is through the increase in calcium levels. This occurs due to the pathological activation of SYK signaling. Outcome effects: At the end of the SYK signaling cascade, the expression of IL4, IL5, IL9, IL13, and CD40LG is up-regulated. Finally, the Th2 response promotes the production of high amounts of antibodies by B lymphocytes and induces the survival of eosinophils. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: lymphatic system PMID: 19355907 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-1d981c7f-416f-4f4b-b9d0-b3141902506c Th1-Cell Function in Systemic Lupus Erythematosus uuid-1d981c7f-416f-4f4b-b9d0-b3141902506c PS:CellType T-cell PS:Description In patients with SLE, Th2-related cytokines are increased, whereas Th1-related cytokines are decreased. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1d981c7f-416f-4f4b-b9d0-b3141902506c PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. At the same time, the role of Th1 and Th2 cytokines in the pathogenesis of SLE is controversial. In patients with SLE, Th2-related cytokines are increased, while Th1 cytokines are decreased. Thus, SLE was initially considered to be a Th2 predominant disease. However, it appears that Th1 or Th2 dominance depends on the stage of the disease and involvement. One of the possible mechanisms is through the increase in calcium levels. This occurs due to the pathological activation of SYK signaling. Outcome effects: At the end of the SYK signaling cascade, the expression of IL4, IL5, IL9, IL13, and CD40LG is up-regulated. Finally, the Th2 response promotes the production of high amounts of antibodies by B lymphocytes and induces the survival of eosinophils. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 19355907 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1dbd2923-2b69-4301-b55b-7836dbfb9c2a NodeType: Pathway Notes: Patients with COPD, similarly to patients with asthma, have increased luminal mucus secretion (see Asthma). Mucin hypersecretion is strengthened especially with age and with chronic respiratory tract infections. Excessive mucus production and impaired mucociliary clearance cause airway obstruction and facilitate the spread of respiratory infections in patients with COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-1dbd2923-2b69-4301-b55b-7836dbfb9c2a 4_Mucin hyperproduction in goblet and mucous cells in COPD uuid-1dbd2923-2b69-4301-b55b-7836dbfb9c2a PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1dbd2923-2b69-4301-b55b-7836dbfb9c2a PS:NodeType Pathway PS:Notes Patients with COPD, similarly to patients with asthma, have increased luminal mucus secretion (see Asthma). Mucin hypersecretion is strengthened especially with age and with chronic respiratory tract infections. Excessive mucus production and impaired mucociliary clearance cause airway obstruction and facilitate the spread of respiratory infections in patients with COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1dca2e05-b36e-498e-ba34-f3f4399db2b0 NodeType: Pathway Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: middle ear mucosa urn:agi-pathway:uuid-1dca2e05-b36e-498e-ba34-f3f4399db2b0 Proteins Involved in Otitis Media uuid-1dca2e05-b36e-498e-ba34-f3f4399db2b0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1dca2e05-b36e-498e-ba34-f3f4399db2b0 PS:NodeType Pathway PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue middle ear mucosa PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ddcb78d-171c-492f-bb23-967b5dc8749d NodeType: Pathway Notes: Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The classical pathway of complement is initiated when an antibody, usually IgM, IgG3, or IgG1, is bound to multiple sites on a cell surface of a pathogen. Free antibodies cannot activate complement in a solution because of the structural requirements of binding to complement component C1q. Activated C1S is capable of binding, cleaving, and activating the serine proteases C4 and C2 which are the subsequent components of the classical pathway. When a C4 molecule interacts with the activated C1S proteases, it is cleaved at a smaller fragment of the alpha chain called C4A and the larger fragment C4B. C2 is also cleaved into C2B and a smaller, inactive fragment of C2A which diffuses away. The C2B fragment associates with a C4B fragment bound to the pathogen and forms C3 convertase which cleaves and activates the complement component C3. C3B binds the C3 convertase to form C5 convertase that cleaves the next component of the cascade which is C5. A single cleavage in the C5 molecule also leads to the formation of two fragments including C5A and C5B. Outcome effects: The major consequence of activation of the complement system is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments.The function of C5B is to initiate the formation of MAC, which can make holes in the membranes of bacterial pathogens and eukaryotic cells. The end form of MAC consists of the tetramolecular C5B-C8 complex (approximately 550kD) and a tubular poly-C9 (approximately 1100kD). Once inserted into the cell membranes, it creates complete transmembrane channels leading to osmotic lysis of the cell. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-1ddcb78d-171c-492f-bb23-967b5dc8749d Complement Classical Pathway uuid-1ddcb78d-171c-492f-bb23-967b5dc8749d PS:CellType generic PS:Description The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ddcb78d-171c-492f-bb23-967b5dc8749d PS:NodeType Pathway PS:Notes Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The classical pathway of complement is initiated when an antibody, usually IgM, IgG3, or IgG1, is bound to multiple sites on a cell surface of a pathogen. Free antibodies cannot activate complement in a solution because of the structural requirements of binding to complement component C1q. Activated C1S is capable of binding, cleaving, and activating the serine proteases C4 and C2 which are the subsequent components of the classical pathway. When a C4 molecule interacts with the activated C1S proteases, it is cleaved at a smaller fragment of the alpha chain called C4A and the larger fragment C4B. C2 is also cleaved into C2B and a smaller, inactive fragment of C2A which diffuses away. The C2B fragment associates with a C4B fragment bound to the pathogen and forms C3 convertase which cleaves and activates the complement component C3. C3B binds the C3 convertase to form C5 convertase that cleaves the next component of the cascade which is C5. A single cleavage in the C5 molecule also leads to the formation of two fragments including C5A and C5B. Outcome effects: The major consequence of activation of the complement system is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments.The function of C5B is to initiate the formation of MAC, which can make holes in the membranes of bacterial pathogens and eukaryotic cells. The end form of MAC consists of the tetramolecular C5B-C8 complex (approximately 550kD) and a tubular poly-C9 (approximately 1100kD). Once inserted into the cell membranes, it creates complete transmembrane channels leading to osmotic lysis of the cell. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: The size of skeletal muscle can change in response to a variety of environmental signals such as loading, nutrients, and starvation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1de7cb91-bcd7-4327-8034-9b1c1387e94d NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: The size of skeletal muscle can change in response to a variety of environmental signals such as loading, nutrients, and starvation. Insulin growth factor 1 (IGF1) regulates muscle mass via the IGF1/MAPK and IGF1/AKT1 signaling pathways. Hypertrophic signaling through IGF1 is also coupled with mechanical signals by means of the calcium-induced activation of calcineurin. Outcome effects: IGF1 signaling regulates muscle mass in three ways: 1) increasing the number of myofibers through the activation of stem cell proliferation, differentiation, and myoblast fusion into myotubes via IGF1/MAPK and IGF1/AKT1 branches; 2) increasing protein synthesis by mTOR activation through IGF1/AKT1 and; 3) repressing muscle atrophy pathways via FOXO repression through IGF1/AKT1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-1de7cb91-bcd7-4327-8034-9b1c1387e94d IGF1 Role in Muscle Hypertrophy uuid-1de7cb91-bcd7-4327-8034-9b1c1387e94d PS:CellType muscle cell PS:Description The size of skeletal muscle can change in response to a variety of environmental signals such as loading, nutrients, and starvation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1de7cb91-bcd7-4327-8034-9b1c1387e94d PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: The size of skeletal muscle can change in response to a variety of environmental signals such as loading, nutrients, and starvation. Insulin growth factor 1 (IGF1) regulates muscle mass via the IGF1/MAPK and IGF1/AKT1 signaling pathways. Hypertrophic signaling through IGF1 is also coupled with mechanical signals by means of the calcium-induced activation of calcineurin. Outcome effects: IGF1 signaling regulates muscle mass in three ways: 1) increasing the number of myofibers through the activation of stem cell proliferation, differentiation, and myoblast fusion into myotubes via IGF1/MAPK and IGF1/AKT1 branches; 2) increasing protein synthesis by mTOR activation through IGF1/AKT1 and; 3) repressing muscle atrophy pathways via FOXO repression through IGF1/AKT1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ded46ea-ff97-4294-b199-9734a3c3d637 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1ded46ea-ff97-4294-b199-9734a3c3d637 NRG1 -> CREB/CREBBP/ELK/SRF/MYC Expression Targets uuid-1ded46ea-ff97-4294-b199-9734a3c3d637 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ded46ea-ff97-4294-b199-9734a3c3d637 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Dietary carbohydrates in humans are digested prior to absorption. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e228e80-2148-4630-aa20-230c4ca5a5a4 NodeType: Pathway Notes: Headnote: Type 2 diabetes is a chronic metabolic disease characterized by abnormally high blood sugar levels and insulin resistance. Early symptoms include frequent urination, increased thirst, weight loss, increased hunger and fatigue. Long-term symptoms include heart disease, strokes, diabetic retinopathy, and kidney failure. Diabetes mellitus type 2 involves impaired insulin sensitivity (insulin resistance) and decreased insulin secretion at the final stages of disease. The origin of the pathology is complex and has various triggers such as a high-fat diet and obesity with a genetic predisposition to hypertension. Signaling description: Dietary carbohydrates in humans are digested prior to absorption. Starch is digested to dextrins by alpha-amylases (salivary and pancreatic). Both maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) digest starch, dextrins, maltose, and maltotriose. SI also converts sucrose to fructose and glucose. LCT converts lactose to galactose and glucose. Glucose and galactose are initially transported into the enterocyte by SLC5A1; while, fructose is transported by SLC2A2 or SLC2A5 located in the apical brush border membrane; and then, all of them exit the enterocyte through the basolateral membrane by either SLC2A2 or exocytosis. Transport by SLC5A1 induces rapid insertion and activation of SLC2A2 in the brush border membrane by a PRKCB-dependent mechanism. Moreover, the trafficking of apical SLC2A2 is rapidly up-regulated by glucose-mediated signaling through TAS1R2/3 activating PLCB2 and PRKCB. Outcome effects: Due to their function at the final steps of starch digestion MGAM and SI are important target enzymes for the treatment of type-2 diabetes. MGAM inhibitors such as miglitol and acarbose are used in patients with diabetes mellitus type 2 to prevent the breakdown of complex carbohydrates into glucose. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: pancreas Organ_System: endocrine system PMID: 23964564 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1e228e80-2148-4630-aa20-230c4ca5a5a4 MGAM Inhibitors uuid-1e228e80-2148-4630-aa20-230c4ca5a5a4 PS:CellType insulin-secreting cell PS:Description Dietary carbohydrates in humans are digested prior to absorption. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e228e80-2148-4630-aa20-230c4ca5a5a4 PS:NodeType Pathway PS:Notes Headnote: Type 2 diabetes is a chronic metabolic disease characterized by abnormally high blood sugar levels and insulin resistance. Early symptoms include frequent urination, increased thirst, weight loss, increased hunger and fatigue. Long-term symptoms include heart disease, strokes, diabetic retinopathy, and kidney failure. Diabetes mellitus type 2 involves impaired insulin sensitivity (insulin resistance) and decreased insulin secretion at the final stages of disease. The origin of the pathology is complex and has various triggers such as a high-fat diet and obesity with a genetic predisposition to hypertension. Signaling description: Dietary carbohydrates in humans are digested prior to absorption. Starch is digested to dextrins by alpha-amylases (salivary and pancreatic). Both maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) digest starch, dextrins, maltose, and maltotriose. SI also converts sucrose to fructose and glucose. LCT converts lactose to galactose and glucose. Glucose and galactose are initially transported into the enterocyte by SLC5A1; while, fructose is transported by SLC2A2 or SLC2A5 located in the apical brush border membrane; and then, all of them exit the enterocyte through the basolateral membrane by either SLC2A2 or exocytosis. Transport by SLC5A1 induces rapid insertion and activation of SLC2A2 in the brush border membrane by a PRKCB-dependent mechanism. Moreover, the trafficking of apical SLC2A2 is rapidly up-regulated by glucose-mediated signaling through TAS1R2/3 activating PLCB2 and PRKCB. Outcome effects: Due to their function at the final steps of starch digestion MGAM and SI are important target enzymes for the treatment of type-2 diabetes. MGAM inhibitors such as miglitol and acarbose are used in patients with diabetes mellitus type 2 to prevent the breakdown of complex carbohydrates into glucose. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 23964564 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e45d1be-1e8c-475c-b490-e8a033147e83 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-1e45d1be-1e8c-475c-b490-e8a033147e83 Proteins with Altered Expression in Tumor-Promoting Inflammation uuid-1e45d1be-1e8c-475c-b490-e8a033147e83 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e45d1be-1e8c-475c-b490-e8a033147e83 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e51d183-9114-423d-9edc-8f2b1b7547c6 NodeType: Pathway Organ: generic Organ_System: generic PMID: 24698685 PMID: 25402640 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-1e51d183-9114-423d-9edc-8f2b1b7547c6 mTOR Signaling Activation by Amino Acids uuid-1e51d183-9114-423d-9edc-8f2b1b7547c6 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e51d183-9114-423d-9edc-8f2b1b7547c6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 24698685 PS:PMID 25402640 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e58f6e7-4b70-478b-b3df-f090062464ea NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1e58f6e7-4b70-478b-b3df-f090062464ea Proteins with Altered Expression in Primary Ovarian Insufficiency uuid-1e58f6e7-4b70-478b-b3df-f090062464ea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e58f6e7-4b70-478b-b3df-f090062464ea PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e6052a0-5796-46d4-b5eb-cc735958ac47 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1e6052a0-5796-46d4-b5eb-cc735958ac47 Model of PPARG signaling in psoriasis (short version) uuid-1e6052a0-5796-46d4-b5eb-cc735958ac47 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e6052a0-5796-46d4-b5eb-cc735958ac47 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: The integrin family of cell adhesion receptors regulates a diverse array of cellular functions including motility, invasion, proliferation and survival and contributes to cancer progression. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e6660cf-bae1-4948-bdb2-40fb20c5a0b3 NodeType: Pathway Notes: Headnote: Integrins are transmembrane receptors that facilitate cell-to-matrix adhesion. Ligands for integrins include fibronectin (FN1), vitronectin (VTN), collagens, laminins, and some other proteins. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular processes such as regulation of cell cycle and organization of cytoskeleton. Integrins are obligate heterodimers, each of them having two subunits, alpha and beta. Mammalian integrins have eighteen alpha and eight beta subunit variants. Signaling description: A wide variety of integrins contribute to tumor progression including VLA-4 (integrin alpha 4 beta 1), VLA-2 (integrin alpha 2 beta 1), integrin alpha V beta 6, VLA-5 (integrin alpha V beta 1), integrin alpha 5 beta 5, vitronectin receptor (integrin alpha 5 beta 3), integrin alpha 6 beta 4, VLA-6 (integrin alpha 6 beta 1), VLA-3 (integrin alpha 3 beta 1), integrin alpha 11 beta 1, and others. Although integrins themselves lack kinase activity, they recruit and activate kinases, such as PTK2, SRC and some others through clustering. Integrins also couple the ECM to actin cytoskeleton by recruiting proteins such asTLN1, PXN, VCL, and others. In tumor cells, cooperation between integrins and members of the EGF receptor family affect many aspects of tumour progression. Interactions between EGFR / ERBB2 and integrin alpha 6 beta 4 / VLA-6 /VLA-3 were described in various types of cancer. Integrins are prime regulators of adhesion, spreading, and migration of cells. The integrin signaling activates RAC1, CDC42, RHOA through PTK1/BCAR1/DOCK1, resulting in actin polymerization. The MMP-mediated ECM degradation is necessary for cancer cell invasion. MMPs may be overexpressed due to integrin-induced MAPK/JUN-FOS activation. Vitronectin receptor - bound DMP1, IBSP and SPP1 specifically bind and activate MMP2/3/9 respectively. Integrin ligation enhances cell survival through several mechanisms, including increased expression of CFLAR, activation of the PI3K-AKT pathway with subsequent upregulation of BCL2 and downregulation of BAX, BAD, CASP3/8. Integrins promote cell cycle progression through RAC-dependent and JUN/FOS-dependent CCND1 over-expression. Outcome effects: Activation of cancer cell motility, invasion, proliferation and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18187454 PMID: 18292776 PMID: 18497750 PMID: 19339545 PMID: 20029421 PMID: 22481923 PMID: 27563880 PMID: 27929432 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-1e6660cf-bae1-4948-bdb2-40fb20c5a0b3 Integrins in Cancer Cell Motility, Invasion and Survival uuid-1e6660cf-bae1-4948-bdb2-40fb20c5a0b3 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description The integrin family of cell adhesion receptors regulates a diverse array of cellular functions including motility, invasion, proliferation and survival and contributes to cancer progression. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e6660cf-bae1-4948-bdb2-40fb20c5a0b3 PS:NodeType Pathway PS:Notes Headnote: Integrins are transmembrane receptors that facilitate cell-to-matrix adhesion. Ligands for integrins include fibronectin (FN1), vitronectin (VTN), collagens, laminins, and some other proteins. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular processes such as regulation of cell cycle and organization of cytoskeleton. Integrins are obligate heterodimers, each of them having two subunits, alpha and beta. Mammalian integrins have eighteen alpha and eight beta subunit variants. Signaling description: A wide variety of integrins contribute to tumor progression including VLA-4 (integrin alpha 4 beta 1), VLA-2 (integrin alpha 2 beta 1), integrin alpha V beta 6, VLA-5 (integrin alpha V beta 1), integrin alpha 5 beta 5, vitronectin receptor (integrin alpha 5 beta 3), integrin alpha 6 beta 4, VLA-6 (integrin alpha 6 beta 1), VLA-3 (integrin alpha 3 beta 1), integrin alpha 11 beta 1, and others. Although integrins themselves lack kinase activity, they recruit and activate kinases, such as PTK2, SRC and some others through clustering. Integrins also couple the ECM to actin cytoskeleton by recruiting proteins such asTLN1, PXN, VCL, and others. In tumor cells, cooperation between integrins and members of the EGF receptor family affect many aspects of tumour progression. Interactions between EGFR / ERBB2 and integrin alpha 6 beta 4 / VLA-6 /VLA-3 were described in various types of cancer. Integrins are prime regulators of adhesion, spreading, and migration of cells. The integrin signaling activates RAC1, CDC42, RHOA through PTK1/BCAR1/DOCK1, resulting in actin polymerization. The MMP-mediated ECM degradation is necessary for cancer cell invasion. MMPs may be overexpressed due to integrin-induced MAPK/JUN-FOS activation. Vitronectin receptor - bound DMP1, IBSP and SPP1 specifically bind and activate MMP2/3/9 respectively. Integrin ligation enhances cell survival through several mechanisms, including increased expression of CFLAR, activation of the PI3K-AKT pathway with subsequent upregulation of BCL2 and downregulation of BAX, BAD, CASP3/8. Integrins promote cell cycle progression through RAC-dependent and JUN/FOS-dependent CCND1 over-expression. Outcome effects: Activation of cancer cell motility, invasion, proliferation and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18187454 PS:PMID 18292776 PS:PMID 18497750 PS:PMID 19339545 PS:PMID 20029421 PS:PMID 22481923 PS:PMID 27563880 PS:PMID 27929432 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e7b526d-d6b1-444a-9b4c-695c80b86a71 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-1e7b526d-d6b1-444a-9b4c-695c80b86a71 MacrophageR -> CEBPB -> NF-kB Signaling uuid-1e7b526d-d6b1-444a-9b4c-695c80b86a71 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e7b526d-d6b1-444a-9b4c-695c80b86a71 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e9c3659-6306-4141-bc2b-4780c8cc2a44 NodeType: Pathway Notes: Headnote: Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss. They can be divided into retinal vascular diseases, in which there is neovascularization (NV) of retina, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Signaling description: Retinal hypoxia is a key feature of retinal NV resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGFB), placental growth factor (PGF), stromal-derived growth factor-1 (CXCL12) and their receptors as well as other hypoxia-regulated gene products such as angiopoietin-2 (ANGPT2). Hypoxia has not been demonstrated as part of choroidal NV. VEGF also diffuse to the anterior chamber leading to NV and open- or close-angle glaucoma development. Anti-VEGF treatment may be beneficial in NV disorders of the eye. Organ: eye Organ_System: sensory system PMID: 23329331 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1e9c3659-6306-4141-bc2b-4780c8cc2a44 HIF1A in Pathologic Ocular Neovascularization uuid-1e9c3659-6306-4141-bc2b-4780c8cc2a44 PS:CellType retina cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1e9c3659-6306-4141-bc2b-4780c8cc2a44 PS:NodeType Pathway PS:Notes Headnote: Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss. They can be divided into retinal vascular diseases, in which there is neovascularization (NV) of retina, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Signaling description: Retinal hypoxia is a key feature of retinal NV resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGFB), placental growth factor (PGF), stromal-derived growth factor-1 (CXCL12) and their receptors as well as other hypoxia-regulated gene products such as angiopoietin-2 (ANGPT2). Hypoxia has not been demonstrated as part of choroidal NV. VEGF also diffuse to the anterior chamber leading to NV and open- or close-angle glaucoma development. Anti-VEGF treatment may be beneficial in NV disorders of the eye. PS:Organ eye PS:Organ_System sensory system PS:PMID 23329331 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ea29793-395f-4c9d-806d-1f926ba9ee41 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-1ea29793-395f-4c9d-806d-1f926ba9ee41 CGRP -> Calcium Influx uuid-1ea29793-395f-4c9d-806d-1f926ba9ee41 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ea29793-395f-4c9d-806d-1f926ba9ee41 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1eac1a28-2246-43a7-93d5-0fde1acac220 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1eac1a28-2246-43a7-93d5-0fde1acac220 Thrombopoietin -> STAT Expression Targets uuid-1eac1a28-2246-43a7-93d5-0fde1acac220 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1eac1a28-2246-43a7-93d5-0fde1acac220 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ead068f-5d4d-4d3e-9479-3e6495cfa14d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-1ead068f-5d4d-4d3e-9479-3e6495cfa14d Pterine biosynthesis template uuid-1ead068f-5d4d-4d3e-9479-3e6495cfa14d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ead068f-5d4d-4d3e-9479-3e6495cfa14d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ec53eae-3f11-4fcc-92af-e382a8ec57c2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1ec53eae-3f11-4fcc-92af-e382a8ec57c2 VEGFA -> ATF/CREB/ELK-SRF Expression Targets uuid-1ec53eae-3f11-4fcc-92af-e382a8ec57c2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ec53eae-3f11-4fcc-92af-e382a8ec57c2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Sertoli cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1edabe30-2cbc-401d-a59f-da568732800e NodeType: Pathway Notes: Headnote: Sertoli cells are the somatic cells in the testis, which provide structural and metabolic support to the developing germ cells. Follicle-stimulating hormone (FSH) and testosterone are the two major endocrine signals that act in the testis to regulate Sertoli cells function and spermatogenesis efficiency. Testosterone is essential to maintain spermatogenesis and male fertility. Mutations in testosterone receptor androgen receptor (AR) cause androgen insensitivity syndrome (AIS) in which various phenotypes may be seen such as ambiguous genitalia, partial labialscrotal fusion, hypospadias, bifid scrotum, gynecomastia and infertility.Cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome is mutated in 60-90% of patients with congenital bilateral absence of the vas deferens (CBAVD). Signaling description: The classical mechanism of testosterone action is to activate gene transcription by causing the androgen receptor (AR) to translocate to and bind specific DNA regulatory elements. Numerous genes and proteins are upregulated in response to testosterone but few are known to be induced in Sertoli cells by androgens through AR binding to gene promoter elements. Testosterone has been found to act via two non-classical pathways in Sertoli cells: 1) testosterone-mediated calcium influx, 2) ERK/MAP kinase and CREB transcription factor activation.Testosterone stimulation can depolarize the Sertoli cell and cause calcium influx Ca2+ into Sertoli cells. Testosterone interacts with an unknown receptor in the plasma membrane that has characteristics of a Gq coupled G-protein coupled receptor (GPCR). Phospholipase C (PLC) is activated to cleave PIP2 into IP3 and DAG. Lower concentrations of PIP2 inhibit K+/ATP channels causing membrane depolarization and Ca2+ entry via L-type Ca2+ channels.Testosterone acting via AR is able to recruit and activate SRC, which causes the activation of the EGFR. EGFR then activates the MAPK cascade most probably through RAS, resulting in the subsequent activation of CREB1. CBAVD is a form of obstructive azoospermia in which there is a disconnection betweenthe epididymis and the ejaculatory duct that causes a functional block to natural fertilization. There are experimental data obtained on Sertoli cells indicating the involvement of CFTR in spermatogensis. CFTR mediated entry of HCO3activates the cAMP pathway leading to full activation of the transcription factors CREB and CREM, and subsequent up-regulation of genes involved in spermatogenesis. CREM (cAMP response element modulator) is a key transcription factor in early round spermatids and activates many genes of spermiogenesis, including TNP1/2, PRM1/2, TESK1, and LDHC.CFTR also negatively regulates the NF-kB/COX2/PGE2 pathway, defect of which can disrupt the tight junction (TJs) and thus the blood-testicular barrier (BTB).Genes that regulate cellular differentiation and chromatin remodeling (TNP1/2, PRM1/2) also may be mutated and cause male infertility. Outcome effects: In the absence of testosterone stimulation, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. Organ: testis Organ_System: reproductive system PMID: 15985628 PMID: 16825108 PMID: 18989307 PMID: 20403869 PMID: 22709980 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-1edabe30-2cbc-401d-a59f-da568732800e Sertoli Cells Dysfunction Causes Male Infertility uuid-1edabe30-2cbc-401d-a59f-da568732800e PS:CellType Sertoli cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1edabe30-2cbc-401d-a59f-da568732800e PS:NodeType Pathway PS:Notes Headnote: Sertoli cells are the somatic cells in the testis, which provide structural and metabolic support to the developing germ cells. Follicle-stimulating hormone (FSH) and testosterone are the two major endocrine signals that act in the testis to regulate Sertoli cells function and spermatogenesis efficiency. Testosterone is essential to maintain spermatogenesis and male fertility. Mutations in testosterone receptor androgen receptor (AR) cause androgen insensitivity syndrome (AIS) in which various phenotypes may be seen such as ambiguous genitalia, partial labialscrotal fusion, hypospadias, bifid scrotum, gynecomastia and infertility.Cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome is mutated in 60-90% of patients with congenital bilateral absence of the vas deferens (CBAVD). Signaling description: The classical mechanism of testosterone action is to activate gene transcription by causing the androgen receptor (AR) to translocate to and bind specific DNA regulatory elements. Numerous genes and proteins are upregulated in response to testosterone but few are known to be induced in Sertoli cells by androgens through AR binding to gene promoter elements. Testosterone has been found to act via two non-classical pathways in Sertoli cells: 1) testosterone-mediated calcium influx, 2) ERK/MAP kinase and CREB transcription factor activation.Testosterone stimulation can depolarize the Sertoli cell and cause calcium influx Ca2+ into Sertoli cells. Testosterone interacts with an unknown receptor in the plasma membrane that has characteristics of a Gq coupled G-protein coupled receptor (GPCR). Phospholipase C (PLC) is activated to cleave PIP2 into IP3 and DAG. Lower concentrations of PIP2 inhibit K+/ATP channels causing membrane depolarization and Ca2+ entry via L-type Ca2+ channels.Testosterone acting via AR is able to recruit and activate SRC, which causes the activation of the EGFR. EGFR then activates the MAPK cascade most probably through RAS, resulting in the subsequent activation of CREB1. CBAVD is a form of obstructive azoospermia in which there is a disconnection betweenthe epididymis and the ejaculatory duct that causes a functional block to natural fertilization. There are experimental data obtained on Sertoli cells indicating the involvement of CFTR in spermatogensis. CFTR mediated entry of HCO3activates the cAMP pathway leading to full activation of the transcription factors CREB and CREM, and subsequent up-regulation of genes involved in spermatogenesis. CREM (cAMP response element modulator) is a key transcription factor in early round spermatids and activates many genes of spermiogenesis, including TNP1/2, PRM1/2, TESK1, and LDHC.CFTR also negatively regulates the NF-kB/COX2/PGE2 pathway, defect of which can disrupt the tight junction (TJs) and thus the blood-testicular barrier (BTB).Genes that regulate cellular differentiation and chromatin remodeling (TNP1/2, PRM1/2) also may be mutated and cause male infertility. Outcome effects: In the absence of testosterone stimulation, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. PS:Organ testis PS:Organ_System reproductive system PS:PMID 15985628 PS:PMID 16825108 PS:PMID 18989307 PS:PMID 20403869 PS:PMID 22709980 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: epithelial cell Description: There is an increase in apoptotic alveolar epithelial cells in the lungs of chronic obstructive pulmonary disease (COPD) patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1edb4d3e-49e1-4c70-b304-a38b1806a9b0 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: There is an increase in alveolar epithelial cell apoptosis in the lungs of COPD patients, and loss of alveolar epithelial cells is one of the major factors in the development of emphysema. FAS ligand (FASLG) and tumor necrosis factor (TNF) trigger apoptosis by binding FAS and TNFRSF1A. The death receptors recruit procaspase-8 through the adaptor protein FADD. In the endoplasmic reticulum (ER) pathway, CASP12 is activated in response to stress signals such as hypoxia. In addition, cigarette smoke induces ER stress response through ATF4-mediated induction of DDIT3 which leads to apoptosis. MAP1LC3B, an autophagic protein, is involved in the regulation of cigarette smoke-induced apoptosis. Under normal conditions, MAP1LC3B forms a multimeric complex with CAV1 and the death receptor FAS in pulmonary epithelial cells. Research has shown that stimulation of epithelial cells with cigarette smoke extract results in rapid dissociation of these complexes. MAP1LC3B facilitates the dissociation of CAV1 from FAS, allowing FAS to stimulate apoptosis through the formation of the death inducing signal complex with FADD and CASP8. Signaling description: Following cleavage, mature CASP8 then activates CASP3 or cleaves BID. Truncated BID interacts with BAX. CYCS is released through a pore formed in the outer mitochondrial membrane. MMP7 cleaves and activates FASLG, thereby mediating apoptosis. Cytotoxic T-cells can release granzyme B (GZMB) and perforin (PRF1), a pore-forming protein. GZMB activates CASP3 through cleavage and can also cleave CASP8. The effector CASP3 cleaves DFFA and releases it from DFFB, which then translocates from the cytoplasm to the nucleus and acts as an active endonuclease and fragments DNA. Organ: lung Organ_System: respiratory system PMID: 16571143 PMID: 19436685 PMID: 20956295 PMID: 21200154 PMID: 21697995 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-1edb4d3e-49e1-4c70-b304-a38b1806a9b0 Alveolar Epithelial Cell Apoptosis in COPD uuid-1edb4d3e-49e1-4c70-b304-a38b1806a9b0 PS:CellType T-cell PS:CellType epithelial cell PS:Description There is an increase in apoptotic alveolar epithelial cells in the lungs of chronic obstructive pulmonary disease (COPD) patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1edb4d3e-49e1-4c70-b304-a38b1806a9b0 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: There is an increase in alveolar epithelial cell apoptosis in the lungs of COPD patients, and loss of alveolar epithelial cells is one of the major factors in the development of emphysema. FAS ligand (FASLG) and tumor necrosis factor (TNF) trigger apoptosis by binding FAS and TNFRSF1A. The death receptors recruit procaspase-8 through the adaptor protein FADD. In the endoplasmic reticulum (ER) pathway, CASP12 is activated in response to stress signals such as hypoxia. In addition, cigarette smoke induces ER stress response through ATF4-mediated induction of DDIT3 which leads to apoptosis. MAP1LC3B, an autophagic protein, is involved in the regulation of cigarette smoke-induced apoptosis. Under normal conditions, MAP1LC3B forms a multimeric complex with CAV1 and the death receptor FAS in pulmonary epithelial cells. Research has shown that stimulation of epithelial cells with cigarette smoke extract results in rapid dissociation of these complexes. MAP1LC3B facilitates the dissociation of CAV1 from FAS, allowing FAS to stimulate apoptosis through the formation of the death inducing signal complex with FADD and CASP8. Signaling description: Following cleavage, mature CASP8 then activates CASP3 or cleaves BID. Truncated BID interacts with BAX. CYCS is released through a pore formed in the outer mitochondrial membrane. MMP7 cleaves and activates FASLG, thereby mediating apoptosis. Cytotoxic T-cells can release granzyme B (GZMB) and perforin (PRF1), a pore-forming protein. GZMB activates CASP3 through cleavage and can also cleave CASP8. The effector CASP3 cleaves DFFA and releases it from DFFB, which then translocates from the cytoplasm to the nucleus and acts as an active endonuclease and fragments DNA. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16571143 PS:PMID 19436685 PS:PMID 20956295 PS:PMID 21200154 PS:PMID 21697995 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ee481a2-f7f7-4d61-a9ba-0d9d2e101262 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-1ee481a2-f7f7-4d61-a9ba-0d9d2e101262 Proteins Involved in Arterial Hypertension uuid-1ee481a2-f7f7-4d61-a9ba-0d9d2e101262 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ee481a2-f7f7-4d61-a9ba-0d9d2e101262 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1eeba21f-45a1-4844-a764-fd3eabdb62db NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1eeba21f-45a1-4844-a764-fd3eabdb62db AREG -> NFATC Expression Target uuid-1eeba21f-45a1-4844-a764-fd3eabdb62db PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1eeba21f-45a1-4844-a764-fd3eabdb62db PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Precise mechanisms by which cilia participate in normal physiology are largely undefined. One of hypotheses is described on the pathway. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f23f5a0-9b63-4771-85d7-518303b368bf NodeType: Pathway Notes: Headnote: The localization of PKD1/2, PKHD1, DCDC2, KIF3A, CEP290 and NPHP1/3/4 and INVS at the primary cilium and basal bodies is proposed to be crucial for their function as mechanosensory antennae of fluid flow in the kidney. However, precise mechanisms by which cilia participate in normal physiology and CKD pathogenesis are largely undefined. One of hypotheses is described on the pathway. Signaling description: The PKD1-PKD2 complex located at the primary cilia surface and functions as a fluid shear sensor to regulate the calcium signal. KIF3A-KIF3B-KIFAP3 complex are the essential intraflagellar transport-associated kinesin-2 motors. Outcome effects: PKHD1 stimulates PKD2 channel activity in the presence of the kinesin-2 motor. CEP290 and DCDC2 interact with KIF3A to microtubule organization. PKD1 binds with NPHP1-4 complex that localized to microtubule-based structures. INVS and KIF3A modulate cytoskeleton organization and cell polarity via interaction with CTNNB1. Organ: kidney Organ_System: urinary tract PMID: 23904226 PMID: 25575298 PMID: 27512790 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: epithelium urn:agi-pathway:uuid-1f23f5a0-9b63-4771-85d7-518303b368bf Kidney Cells Cilia Organization uuid-1f23f5a0-9b63-4771-85d7-518303b368bf PS:CellType epithelial cell PS:Description Precise mechanisms by which cilia participate in normal physiology are largely undefined. One of hypotheses is described on the pathway. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f23f5a0-9b63-4771-85d7-518303b368bf PS:NodeType Pathway PS:Notes Headnote: The localization of PKD1/2, PKHD1, DCDC2, KIF3A, CEP290 and NPHP1/3/4 and INVS at the primary cilium and basal bodies is proposed to be crucial for their function as mechanosensory antennae of fluid flow in the kidney. However, precise mechanisms by which cilia participate in normal physiology and CKD pathogenesis are largely undefined. One of hypotheses is described on the pathway. Signaling description: The PKD1-PKD2 complex located at the primary cilia surface and functions as a fluid shear sensor to regulate the calcium signal. KIF3A-KIF3B-KIFAP3 complex are the essential intraflagellar transport-associated kinesin-2 motors. Outcome effects: PKHD1 stimulates PKD2 channel activity in the presence of the kinesin-2 motor. CEP290 and DCDC2 interact with KIF3A to microtubule organization. PKD1 binds with NPHP1-4 complex that localized to microtubule-based structures. INVS and KIF3A modulate cytoskeleton organization and cell polarity via interaction with CTNNB1. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 23904226 PS:PMID 25575298 PS:PMID 27512790 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f25a0b9-3cdc-4bf7-806f-acc640b33259 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1f25a0b9-3cdc-4bf7-806f-acc640b33259 HGF -> FOXO3A Expression Targets uuid-1f25a0b9-3cdc-4bf7-806f-acc640b33259 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f25a0b9-3cdc-4bf7-806f-acc640b33259 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Hereditary Hemorrhagic Telangiectasia (HHT) (I78.0) is an autosomal dominant genetic disorder of the blood vessels. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f2a9819-d0e5-4101-9793-ffd7a8da692e NodeType: Pathway Notes: Headnote: Hereditary hemorrhagic telangiectasia (HHT) (I78.0) is an autosomal dominant genetic disorder of the blood vessels which affects approximately 1 in 5,000 people (males and females from all racial and ethnic groups). The disorder is also referred to as Osler-Weber-Rendu disease (OWRD), named after several doctors who studied HHT over 100 years ago. Currently , three general types of the disease are described including HHT1 caused by a mutation in the ENG gene, HHT2 caused by a mutation in the ACVRL1 gene, and JPHT (juvenile polyposis hemorrhagic telangiectasia) caused by a mutation in the SMAD4 gene, as well as PPH (pulmonary primary hypertension) combined with HHT caused by a mutation in the BMPR2 gene. In each case, extensive vascular growth occurs with blood vessels having an abnormal structure and more than 70% of them lacking the muscle layer. This is caused by extensive proliferation and migration of endothelial cells and the absence of vessel maturation phase. Signaling description: The receptors for TGFB1 and GDF2, such as ACVRL1, TGFBR1, and TGFBR2, as well as their co-receptors ENG and BMP2, are co-located on the surface of endothelial cells. ACVRL1 and TGFBR1 receptors trigger the opposite cellular responses: TGFB1 and ACVRL1/TGFBR2 promote migration and proliferation of endothelial cells, while TGFB1 and TGFBR1/TGFBR2 inhibit these effects and support the formation of extracellular matrix. These two opposite effects correspond to two different phases of angiogenesis: activation (proliferation and migration of endothelial cells with formation of new vessels) and dormancy state (absence of proliferation, generation of extracellular matrix, recruiting of smooth muscle cells, and stabilization of blood vessels). This antagonism is regulated on the molecular level by the SMAD family proteins. The opposite actions of ACVRL1 and TGFBR1 in endothelial cells constitute the basis for the complex mechanism of equilibrium controlled by TGFB1. Low doses of this cytokine stimulate the proliferation and migration of endothelial cells via the ACVRL1/SMAD1/SMAD5 pathway, while high doses of TGFB1 inhibit these reactions and activate the TGFBR1/SMAD2/SMAD3 pathway. A mutation in the ENG gene activates the ENG/PIP3/AKT1 signaling, which leads to SMAD3 repression. Specifically, this pathway stimulates the activation of AKT1 which blocks the SMAD3/ TGFBR1 interaction. Outcome effects: Non-phosphorylated SMAD3 does not form a complex with SMAD4, SMAD2, and ATF3, and thus cannot be moved into the nucleus. SMAD3 is also the activator of the ENG transcription, and thus, upon SMAD3 activation, the feedback loop is triggered. An increase in ENG subsequently blocks ENG/AKT1/SMAD pathway. Therefore, mutation in the ENG gene leads to the arrest of ENG/AKT1/SMAD pathway and activation of SMAD3 and SMAD4 which leads to prolonged cell proliferation. Mutations in ACVRL1 gene generally affect intracellular kinase domain which is presumably required for the ENG activation. The absence of ENG activation results in the same consequences as mutations in the ENG gene in which the ENG/PIP3/AKT1 pathway leading to SMAD3 repression becomes blocked. As a result, SMAD2/SMAD3/SMAD4 complex cannot be activated. This is supported by reduced ENG expression in patients with mutations in ACVRL1. In addition, mutations in the SMAD4 gene prevent the formation of SMAD2/SMAD3/SMAD4 complex and translocation of SMAD3 into the nucleus. SMAD2/SMAD3/SMAD4 complex is also required for recruiting ATF3, the repressor of ID1 gene transcription. The absence of ID1 transcriptional repression leads to its continuous transcriptional activation through SMAD1, SMAD5, and SMAD9. This results in further proliferation and migration of endothelial cells. Also, the activation of ENG expression and arrest of proliferation of endothelial cells fails to occur. Mutations in the BMPR2 gene have recently been discovered which possibly prevent the ENG/BMPR2 complex formation. Fu Organ: blood vessel Organ_System: cardiovascular system PMID: 16595794 PMID: 20345718 PMID: 21546842 PMID: 23972370 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-1f2a9819-d0e5-4101-9793-ffd7a8da692e Hereditary Hemorrhagic Telangiectasia uuid-1f2a9819-d0e5-4101-9793-ffd7a8da692e PS:CellType endothelial cell PS:Description Hereditary Hemorrhagic Telangiectasia (HHT) (I78.0) is an autosomal dominant genetic disorder of the blood vessels. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f2a9819-d0e5-4101-9793-ffd7a8da692e PS:NodeType Pathway PS:Notes Headnote: Hereditary hemorrhagic telangiectasia (HHT) (I78.0) is an autosomal dominant genetic disorder of the blood vessels which affects approximately 1 in 5,000 people (males and females from all racial and ethnic groups). The disorder is also referred to as Osler-Weber-Rendu disease (OWRD), named after several doctors who studied HHT over 100 years ago. Currently , three general types of the disease are described including HHT1 caused by a mutation in the ENG gene, HHT2 caused by a mutation in the ACVRL1 gene, and JPHT (juvenile polyposis hemorrhagic telangiectasia) caused by a mutation in the SMAD4 gene, as well as PPH (pulmonary primary hypertension) combined with HHT caused by a mutation in the BMPR2 gene. In each case, extensive vascular growth occurs with blood vessels having an abnormal structure and more than 70% of them lacking the muscle layer. This is caused by extensive proliferation and migration of endothelial cells and the absence of vessel maturation phase. Signaling description: The receptors for TGFB1 and GDF2, such as ACVRL1, TGFBR1, and TGFBR2, as well as their co-receptors ENG and BMP2, are co-located on the surface of endothelial cells. ACVRL1 and TGFBR1 receptors trigger the opposite cellular responses: TGFB1 and ACVRL1/TGFBR2 promote migration and proliferation of endothelial cells, while TGFB1 and TGFBR1/TGFBR2 inhibit these effects and support the formation of extracellular matrix. These two opposite effects correspond to two different phases of angiogenesis: activation (proliferation and migration of endothelial cells with formation of new vessels) and dormancy state (absence of proliferation, generation of extracellular matrix, recruiting of smooth muscle cells, and stabilization of blood vessels). This antagonism is regulated on the molecular level by the SMAD family proteins. The opposite actions of ACVRL1 and TGFBR1 in endothelial cells constitute the basis for the complex mechanism of equilibrium controlled by TGFB1. Low doses of this cytokine stimulate the proliferation and migration of endothelial cells via the ACVRL1/SMAD1/SMAD5 pathway, while high doses of TGFB1 inhibit these reactions and activate the TGFBR1/SMAD2/SMAD3 pathway. A mutation in the ENG gene activates the ENG/PIP3/AKT1 signaling, which leads to SMAD3 repression. Specifically, this pathway stimulates the activation of AKT1 which blocks the SMAD3/ TGFBR1 interaction. Outcome effects: Non-phosphorylated SMAD3 does not form a complex with SMAD4, SMAD2, and ATF3, and thus cannot be moved into the nucleus. SMAD3 is also the activator of the ENG transcription, and thus, upon SMAD3 activation, the feedback loop is triggered. An increase in ENG subsequently blocks ENG/AKT1/SMAD pathway. Therefore, mutation in the ENG gene leads to the arrest of ENG/AKT1/SMAD pathway and activation of SMAD3 and SMAD4 which leads to prolonged cell proliferation. Mutations in ACVRL1 gene generally affect intracellular kinase domain which is presumably required for the ENG activation. The absence of ENG activation results in the same consequences as mutations in the ENG gene in which the ENG/PIP3/AKT1 pathway leading to SMAD3 repression becomes blocked. As a result, SMAD2/SMAD3/SMAD4 complex cannot be activated. This is supported by reduced ENG expression in patients with mutations in ACVRL1. In addition, mutations in the SMAD4 gene prevent the formation of SMAD2/SMAD3/SMAD4 complex and translocation of SMAD3 into the nucleus. SMAD2/SMAD3/SMAD4 complex is also required for recruiting ATF3, the repressor of ID1 gene transcription. The absence of ID1 transcriptional repression leads to its continuous transcriptional activation through SMAD1, SMAD5, and SMAD9. This results in further proliferation and migration of endothelial cells. Also, the activation of ENG expression and arrest of proliferation of endothelial cells fails to occur. Mutations in the BMPR2 gene have recently been discovered which possibly prevent the ENG/BMPR2 complex formation. Fu PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 16595794 PS:PMID 20345718 PS:PMID 21546842 PS:PMID 23972370 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f40e8a6-ec80-4ad1-a2b5-8c0d51f1bc9d NodeType: Pathway Notes: Headnote: Beta-catenin signaling plays major role in female phenotype development. Signaling description: In the absence of SRY, levels of RSPO1 rise and cause increased WNT4.Beta-catenin begins to accumulate as a response to RSPO1-WNT4 signaling. In XX germ cells, beta-catenin levels could accumulate sufficiently to repress SOX9 activity. At later stages, FOXL2 increases, which might help, perhaps in concert with estrogen receptor, to maintain granulosa (follicle) cell differentiation by repressing SOX9 and FGF9 expression. It is hypothesized that in the XX individual, the expression of WNT4 leads to the expression of DAX1 (NR0B1), which in turn blocks the expression of SOX9 and thus any testicular differentiation. WNT4 antagonizes the expression of activin B (INHBB) and induces the activin B antagonist, follistatin (FST), theoretically through beta-catenin, preventing testis vasculature development. Highlighted proteins: Key players of female sex determination are highlighted in red. Key players of male sex determination (repressed) are highlighted in blue. SRY is white-out because it is located in chromosome Y and absent in females. Organ: ovary Organ_System: reproductive system PMID: 17237341 PMID: 24866114 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-1f40e8a6-ec80-4ad1-a2b5-8c0d51f1bc9d Female Sex Determination uuid-1f40e8a6-ec80-4ad1-a2b5-8c0d51f1bc9d PS:CellType oocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f40e8a6-ec80-4ad1-a2b5-8c0d51f1bc9d PS:NodeType Pathway PS:Notes Headnote: Beta-catenin signaling plays major role in female phenotype development. Signaling description: In the absence of SRY, levels of RSPO1 rise and cause increased WNT4.Beta-catenin begins to accumulate as a response to RSPO1-WNT4 signaling. In XX germ cells, beta-catenin levels could accumulate sufficiently to repress SOX9 activity. At later stages, FOXL2 increases, which might help, perhaps in concert with estrogen receptor, to maintain granulosa (follicle) cell differentiation by repressing SOX9 and FGF9 expression. It is hypothesized that in the XX individual, the expression of WNT4 leads to the expression of DAX1 (NR0B1), which in turn blocks the expression of SOX9 and thus any testicular differentiation. WNT4 antagonizes the expression of activin B (INHBB) and induces the activin B antagonist, follistatin (FST), theoretically through beta-catenin, preventing testis vasculature development. Highlighted proteins: Key players of female sex determination are highlighted in red. Key players of male sex determination (repressed) are highlighted in blue. SRY is white-out because it is located in chromosome Y and absent in females. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 17237341 PS:PMID 24866114 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f450166-e801-43b8-80db-ade691032e79 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1f450166-e801-43b8-80db-ade691032e79 NPY Expression Targets uuid-1f450166-e801-43b8-80db-ade691032e79 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f450166-e801-43b8-80db-ade691032e79 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f481583-c726-49ae-ac52-5785dd985505 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-1f481583-c726-49ae-ac52-5785dd985505 Proteins with Altered Expression in Cancer-Associated Dysregulated DNA Repair uuid-1f481583-c726-49ae-ac52-5785dd985505 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f481583-c726-49ae-ac52-5785dd985505 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell CellType: smooth muscle myocyte Description: Angiotensin II is one of the most important vasoactive agents involved in the development of hypertension, cardiovascular remodeling, and hypertrophy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f9b74c7-d722-4d2f-8582-6598b196a1c6 NodeType: Pathway Notes: Headnote: Angiotensin II, the active form of the angiotensinogen (AGT) precursor, is one of the central vasoactive agents involved in the development of hypertension, cardiovascular remodeling, and hypertrophy. Signaling description: Angiotensin II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). ROS, such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in the cardiovascular system. The major source of ROS in endothelium, cardiomyocytes, and vascular smooth muscle cells is NAD(P)H oxidase complex, which is efficiently activated by AGT, acting through G-protein-coupled receptor AT1 (AGTR1). The activation of NAD(P)H oxidase complex requires a concerted effort of protein kinase C (PKC), RAC1 and ceramides. The highly reactive and short-living superoxide radical, produced by NAD(P)H oxidase, is rapidly metabolized to H2O2 by Cu2+ /Zn2+ superoxide dismutase (SOD1). H2O2 is a stable oxidant, which can diffuse through membranes and act at long distances as a modulator of redox-sensitive cellular factors. Outcome effects: Through the upregulation of SRC-kinase, H2O2 is involved in the transactivation of EGFR followed by the activation of MAPK1 cascade. This leads to the intensification of translation, subsequent cell growth, and hypertrophy. MAPK1 is also involved in the activation of matrix metalloproteinases, which results in extracellular matrix remodeling and facilitation of cell migration. Conversely, the SRC activation mediates ACT/AKT1 activation, which enhances cell growth, contributes to cell migration, and activates cell survival through HSPB1 phosphorylation. AGT-mediated activation of cell proliferation involves the induction of redox-sensitive MAP-kinases (MAP3K5, p38, and MAPK8) and kinases of the JAK/STAT pathway (PTK2B and JAK2) by H2O2. H2O2-activated p38 kinase contributes to cardiovascular remodeling and cell survival through the upregulation of extracellular matrix components and phosphorylation of HSPB1, respectively. H2O2 stabilizes and enhances its effect on these pathways by inhibiting phosphatases, which downregulate the action of the targeted kinases. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-1f9b74c7-d722-4d2f-8582-6598b196a1c6 ROS in Angiotensin Mediated Cardiovascular Remodeling and Hypertrophy uuid-1f9b74c7-d722-4d2f-8582-6598b196a1c6 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Angiotensin II is one of the most important vasoactive agents involved in the development of hypertension, cardiovascular remodeling, and hypertrophy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1f9b74c7-d722-4d2f-8582-6598b196a1c6 PS:NodeType Pathway PS:Notes Headnote: Angiotensin II, the active form of the angiotensinogen (AGT) precursor, is one of the central vasoactive agents involved in the development of hypertension, cardiovascular remodeling, and hypertrophy. Signaling description: Angiotensin II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). ROS, such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in the cardiovascular system. The major source of ROS in endothelium, cardiomyocytes, and vascular smooth muscle cells is NAD(P)H oxidase complex, which is efficiently activated by AGT, acting through G-protein-coupled receptor AT1 (AGTR1). The activation of NAD(P)H oxidase complex requires a concerted effort of protein kinase C (PKC), RAC1 and ceramides. The highly reactive and short-living superoxide radical, produced by NAD(P)H oxidase, is rapidly metabolized to H2O2 by Cu2+ /Zn2+ superoxide dismutase (SOD1). H2O2 is a stable oxidant, which can diffuse through membranes and act at long distances as a modulator of redox-sensitive cellular factors. Outcome effects: Through the upregulation of SRC-kinase, H2O2 is involved in the transactivation of EGFR followed by the activation of MAPK1 cascade. This leads to the intensification of translation, subsequent cell growth, and hypertrophy. MAPK1 is also involved in the activation of matrix metalloproteinases, which results in extracellular matrix remodeling and facilitation of cell migration. Conversely, the SRC activation mediates ACT/AKT1 activation, which enhances cell growth, contributes to cell migration, and activates cell survival through HSPB1 phosphorylation. AGT-mediated activation of cell proliferation involves the induction of redox-sensitive MAP-kinases (MAP3K5, p38, and MAPK8) and kinases of the JAK/STAT pathway (PTK2B and JAK2) by H2O2. H2O2-activated p38 kinase contributes to cardiovascular remodeling and cell survival through the upregulation of extracellular matrix components and phosphorylation of HSPB1, respectively. H2O2 stabilizes and enhances its effect on these pathways by inhibiting phosphatases, which downregulate the action of the targeted kinases. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fa28d14-2e86-4cf7-8068-e683d87d7ebf NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1fa28d14-2e86-4cf7-8068-e683d87d7ebf IGF1 -> MEF/MYOD/MYOG Expression Targets uuid-1fa28d14-2e86-4cf7-8068-e683d87d7ebf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fa28d14-2e86-4cf7-8068-e683d87d7ebf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fac1cd3-2011-4f69-98aa-7fd9b30706f4 NodeType: Pathway Organ: colon Organ: intestine Organ_System: digestive system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-1fac1cd3-2011-4f69-98aa-7fd9b30706f4 Proteins Involved in Ulcerative Colitis uuid-1fac1cd3-2011-4f69-98aa-7fd9b30706f4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fac1cd3-2011-4f69-98aa-7fd9b30706f4 PS:NodeType Pathway PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fd1a179-da95-4669-a167-60a859e4e348 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-1fd1a179-da95-4669-a167-60a859e4e348 Urea Cycle and Arginine Metabolism uuid-1fd1a179-da95-4669-a167-60a859e4e348 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1fd1a179-da95-4669-a167-60a859e4e348 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ff10ff2-25c7-489a-8dba-0933990455d0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1ff10ff2-25c7-489a-8dba-0933990455d0 NOTCH Expression Targets uuid-1ff10ff2-25c7-489a-8dba-0933990455d0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ff10ff2-25c7-489a-8dba-0933990455d0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ff5d55e-2d21-45e0-8e5f-be48cb3b77f6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-1ff5d55e-2d21-45e0-8e5f-be48cb3b77f6 IFNW1/IFNR Expression Target uuid-1ff5d55e-2d21-45e0-8e5f-be48cb3b77f6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ff5d55e-2d21-45e0-8e5f-be48cb3b77f6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Normally, adiponectin modulates a number of metabolic processes including glucose regulation and fatty acid oxidation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ffd0596-55f0-4c93-8852-a2d4710dd68c NodeType: Pathway Notes: Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Inflammation in adipose tissue can cause insulin resistance. Signaling description: Normally, adiponectin modulates a number of metabolic processes including glucose regulation and fatty acid oxidation. Adiponectin is exclusively secreted from the adipose tissue. The levels of the hormone are inversely correlated with body fat percentage in adults. Obesity induces the secretion of proinflammatory cytokines, TNF and IL6 by macrophages and adipose tissue itself. These cytokines, through the JAK/STAT3/JUN/FOS/MYC/SIRT1/FOXO1 axis, inhibit peroxisome proliferator-activated receptor gamma protein (PPARG), which forms heterodimers with RXRA and binds to the promoter region of adiponectin (ADIPOQ) resulting in gene transcription. A high-fat diet provokes the activation of protein kinases PRKACA and PKIA by an unknown mechanism leading to the elevated expression of the activating transcription factor 3 (ATF3), which is the negative regulator of adiponectin transcription. A high-fat diet also causes endoplasmic reticulum stress in the adipose tissue. Free fatty acids mediate the generation of reactive oxygen species (ROS) which interact with proteins leading to un-/misfolded protein formation and the downregulation of adiponectin transcription factors, CEBPA and CEBPB. In addition, increased activation of the negative regulator, NFATC4 occurs in response to insulin-like growth factor 1 (IGF1) action in adipocytes. Outcome effects: Therefore, obesity/high fat diet can disrupt adiponectin synthesis via a number of signaling routes leading to impaired glucose and fatty acid metabolism. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: endocrine system PMID: 15919796 PMID: 18789331 PMID: 22450341 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: generic urn:agi-pathway:uuid-1ffd0596-55f0-4c93-8852-a2d4710dd68c Adiponectin Synthesis Declines in Insulin Resistance uuid-1ffd0596-55f0-4c93-8852-a2d4710dd68c PS:CellType generic PS:Description Normally, adiponectin modulates a number of metabolic processes including glucose regulation and fatty acid oxidation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-1ffd0596-55f0-4c93-8852-a2d4710dd68c PS:NodeType Pathway PS:Notes Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Inflammation in adipose tissue can cause insulin resistance. Signaling description: Normally, adiponectin modulates a number of metabolic processes including glucose regulation and fatty acid oxidation. Adiponectin is exclusively secreted from the adipose tissue. The levels of the hormone are inversely correlated with body fat percentage in adults. Obesity induces the secretion of proinflammatory cytokines, TNF and IL6 by macrophages and adipose tissue itself. These cytokines, through the JAK/STAT3/JUN/FOS/MYC/SIRT1/FOXO1 axis, inhibit peroxisome proliferator-activated receptor gamma protein (PPARG), which forms heterodimers with RXRA and binds to the promoter region of adiponectin (ADIPOQ) resulting in gene transcription. A high-fat diet provokes the activation of protein kinases PRKACA and PKIA by an unknown mechanism leading to the elevated expression of the activating transcription factor 3 (ATF3), which is the negative regulator of adiponectin transcription. A high-fat diet also causes endoplasmic reticulum stress in the adipose tissue. Free fatty acids mediate the generation of reactive oxygen species (ROS) which interact with proteins leading to un-/misfolded protein formation and the downregulation of adiponectin transcription factors, CEBPA and CEBPB. In addition, increased activation of the negative regulator, NFATC4 occurs in response to insulin-like growth factor 1 (IGF1) action in adipocytes. Outcome effects: Therefore, obesity/high fat diet can disrupt adiponectin synthesis via a number of signaling routes leading to impaired glucose and fatty acid metabolism. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System endocrine system PS:PMID 15919796 PS:PMID 18789331 PS:PMID 22450341 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-200f77b4-b98e-446d-b6f9-663378b736f0 NodeType: Pathway Notes: Somatostatin has antisecretory action and inhibits secretion of other hormones. Somatostatin receptors belong to the G protein coupled receptor family. Organ: generic Organ_System: generic PMID: 20149677 PMID: 23872332 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-200f77b4-b98e-446d-b6f9-663378b736f0 Somatostatin Receptors Signaling uuid-200f77b4-b98e-446d-b6f9-663378b736f0 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-200f77b4-b98e-446d-b6f9-663378b736f0 PS:NodeType Pathway PS:Notes Somatostatin has antisecretory action and inhibits secretion of other hormones. Somatostatin receptors belong to the G protein coupled receptor family. PS:Organ generic PS:Organ_System generic PS:PMID 20149677 PS:PMID 23872332 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2015c446-00ec-44b6-8f9e-693bc156d1a2 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Source: Diseases urn:agi-pathway:uuid-2015c446-00ec-44b6-8f9e-693bc156d1a2 Genes with Mutations Associated with Cataract uuid-2015c446-00ec-44b6-8f9e-693bc156d1a2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2015c446-00ec-44b6-8f9e-693bc156d1a2 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-202c3bc1-a294-422e-9955-e3bbd7631367 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-202c3bc1-a294-422e-9955-e3bbd7631367 Choline metaboilsm template uuid-202c3bc1-a294-422e-9955-e3bbd7631367 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-202c3bc1-a294-422e-9955-e3bbd7631367 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-202efaa3-1072-4b46-8bbe-18994585f4c8 NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-202efaa3-1072-4b46-8bbe-18994585f4c8 Panic Disorder: Posible Action of Lactate in Panic Attack Induction uuid-202efaa3-1072-4b46-8bbe-18994585f4c8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-202efaa3-1072-4b46-8bbe-18994585f4c8 PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-203f46b5-5966-4266-a2df-0deaeb5b93d0 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-203f46b5-5966-4266-a2df-0deaeb5b93d0 Lipid A export uuid-203f46b5-5966-4266-a2df-0deaeb5b93d0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-203f46b5-5966-4266-a2df-0deaeb5b93d0 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: The block of apoptosis of synovial fibroblasts is commonly seen in rheumatoid arthritis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20422787-ac62-4774-977e-3a8501bf34f1 NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. The block of apoptosis of synovial fibroblasts is commonly seen in rheumatoid arthritis. Signaling description: In RA, increased SUMO1 levels are observed in synovial fibroblasts. The protein interacts with FAS and TNF receptors to protect cells from apoptosis. Also, TNFRSF6B and TNFRSF11B bind and inhibit FASLG and TNFSF10, respectively which contributes to the disruption of apoptosis in pathology. Normally, TNF, FASLG, and TNFSF10 interact with their receptors TNFRSF1A/TNFRSF1B, FAS, and TNFRSF10B, respectively on the cell surface to induce apoptosis. The activation of TNFRSF1, FAS, and TNFRSF10 leads to the recruitment of CASP8 and the TRADD-FADD complex. CASP8 activates CASP3 through two pathways. In the first pathway, CASP8 cleaves BID and its active part is translocated into mitochondria where it triggers CYCS release through BAX activation. CYCS affects CASP9 which activates CASP3. In the second pathway, CASP8 activates CASP3 directly. In addition, there is another common pathway for TNF and FASLG leading to apoptosis which involves MAP3K5 activation. MAP3K5, through MAPK8 and MAPK14, inactivates the anti-apoptotic factor BCL2. TNF also activates the recruitment of other TRADD (through binding to TNFRSF1B), leading to the activation of NF-kB via TRAF2/MAP3K14. Outcome effects: Activation of CASP3 directly promotes apoptosis. NF-kB suppresses apoptosis by inducing the transcription of anti-apoptotic genes such as BIRC2, BIRC3, and BIRC5, which inhibit CASP9. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 11759230 PMID: 19199037 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-20422787-ac62-4774-977e-3a8501bf34f1 Apoptosis Block in Synovial Fibroblast uuid-20422787-ac62-4774-977e-3a8501bf34f1 PS:CellType fibroblast PS:Description The block of apoptosis of synovial fibroblasts is commonly seen in rheumatoid arthritis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20422787-ac62-4774-977e-3a8501bf34f1 PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. The block of apoptosis of synovial fibroblasts is commonly seen in rheumatoid arthritis. Signaling description: In RA, increased SUMO1 levels are observed in synovial fibroblasts. The protein interacts with FAS and TNF receptors to protect cells from apoptosis. Also, TNFRSF6B and TNFRSF11B bind and inhibit FASLG and TNFSF10, respectively which contributes to the disruption of apoptosis in pathology. Normally, TNF, FASLG, and TNFSF10 interact with their receptors TNFRSF1A/TNFRSF1B, FAS, and TNFRSF10B, respectively on the cell surface to induce apoptosis. The activation of TNFRSF1, FAS, and TNFRSF10 leads to the recruitment of CASP8 and the TRADD-FADD complex. CASP8 activates CASP3 through two pathways. In the first pathway, CASP8 cleaves BID and its active part is translocated into mitochondria where it triggers CYCS release through BAX activation. CYCS affects CASP9 which activates CASP3. In the second pathway, CASP8 activates CASP3 directly. In addition, there is another common pathway for TNF and FASLG leading to apoptosis which involves MAP3K5 activation. MAP3K5, through MAPK8 and MAPK14, inactivates the anti-apoptotic factor BCL2. TNF also activates the recruitment of other TRADD (through binding to TNFRSF1B), leading to the activation of NF-kB via TRAF2/MAP3K14. Outcome effects: Activation of CASP3 directly promotes apoptosis. NF-kB suppresses apoptosis by inducing the transcription of anti-apoptotic genes such as BIRC2, BIRC3, and BIRC5, which inhibit CASP9. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11759230 PS:PMID 19199037 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Tissue bone tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: insulin-secreting cell Description: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20539941-6419-437d-b7ce-b45eb0852205 NodeType: Pathway Notes: Headnote: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. PDAC has a very poor prognosis due to the inability to diagnose the disease at an early and localized stage. Approximately 90% of all pancreatic tumors metastasize beyond the pancreas. Epidemiological and experimental studies have suggested a link between pancreatic cancer to smoking, diabetes, and a high-fat diet. However, it is not clear how these factors influence pancreatic cancer. It is generally believed that PDAC and cancers of exocrine pancreas originate from ductal cells. Signaling description: PDAC is characterized by mutations in PTEN, KRAS, BRAF, TP53, SMAD4, ARID1, BRCA1/2, MLH1/2/6, STK11, CDKN2A, ATM, and TGFBR2 genes as well as the overexpression of growth factors and their receptors (EGFRs, VEGFRs, MET, and IGF1R), NOTCH1, WNT, and AKT1. Outcome effects: These changes cause block of apoptosis, disruption of cell cycle and differentiation, redundant proliferation and migration of epithelial pancreatic cells, block of chromatin remodeling and DNA repair, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 22806689 PMID: 23135763 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-20539941-6419-437d-b7ce-b45eb0852205 Pancreatic Ductal Carcinoma uuid-20539941-6419-437d-b7ce-b45eb0852205 PS:CellType cancer cell PS:CellType insulin-secreting cell PS:Description Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20539941-6419-437d-b7ce-b45eb0852205 PS:NodeType Pathway PS:Notes Headnote: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. PDAC has a very poor prognosis due to the inability to diagnose the disease at an early and localized stage. Approximately 90% of all pancreatic tumors metastasize beyond the pancreas. Epidemiological and experimental studies have suggested a link between pancreatic cancer to smoking, diabetes, and a high-fat diet. However, it is not clear how these factors influence pancreatic cancer. It is generally believed that PDAC and cancers of exocrine pancreas originate from ductal cells. Signaling description: PDAC is characterized by mutations in PTEN, KRAS, BRAF, TP53, SMAD4, ARID1, BRCA1/2, MLH1/2/6, STK11, CDKN2A, ATM, and TGFBR2 genes as well as the overexpression of growth factors and their receptors (EGFRs, VEGFRs, MET, and IGF1R), NOTCH1, WNT, and AKT1. Outcome effects: These changes cause block of apoptosis, disruption of cell cycle and differentiation, redundant proliferation and migration of epithelial pancreatic cells, block of chromatin remodeling and DNA repair, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 22806689 PS:PMID 23135763 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20561252-fa2b-420c-b8f5-44c826144547 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-20561252-fa2b-420c-b8f5-44c826144547 protein S-nitrosylation in Huntington uuid-20561252-fa2b-420c-b8f5-44c826144547 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20561252-fa2b-420c-b8f5-44c826144547 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-206a541d-8c21-4bc9-91d2-cfc6ba10f535 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-206a541d-8c21-4bc9-91d2-cfc6ba10f535 Dopamine degradation template uuid-206a541d-8c21-4bc9-91d2-cfc6ba10f535 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-206a541d-8c21-4bc9-91d2-cfc6ba10f535 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: The most common mutation in cystic fibrosis (CF) occurs in the CFTR gene that leads to a deletion of phenylalanine at position 508. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-206cbdaf-27fb-4a15-b8d7-d3e46d8f3d82 NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: The most common pathological mutation in the CFTR gene leads to a deletion of phenylalanine at position 508 (DeltaF508). This mutation results in a folding defect, retention of the protein in the endoplasmic reticulum (ER), and its subsequent degradation by the proteasome. CF patients exhibit a typical phenotype characterized by thick mucus secretions obstructing the airways and persistent pulmonary infections leading to pulmonary failure and death. CFTR is synthesized in the ER and then begins the process of maturation by folding and N-glycosylation, which is monitored by chaperone proteins. Correctly folded CFTR is transported to the Golgi for maturation before trafficking to the apical cell surface. CANX, COPII, GOPC, and RHOQ regulate the maturation and trafficking of normal CFTR from the ER to the Golgi. Mutant CFTR is degraded via proteasome endopeptidase complex or is transported to aggresomes near the microtubule-organizing center. Most mutant DeltaF508-CFTR are recognized as misfolded by ER-associated degradation (ERAD), shuttled out of the ER, and targeted for proteosomal degradation. Outcome effects: Two ubiquitin ligase complexes are needed for mutated CFTR degradation including ER membrane-associated ubiquitin ligase complex (DERL1, RNF5, and UBE2J2) and cytosolic ubiquitin ligase complex (STUB1 and UBE2D1). Since improperly folded CFTR undergoes ubiquitination-mediated degradation, it is hypothesized that Hsc70 (HSPA8) promotes ERAD of DeltaF508-CFTR, which involves a co-chaperone known as STUB1. HSPBP1 binds HSPA8 and this binding decreases the ubiquitin ligase activity of STUB1. Since DeltaF508-CFTR is a misfolded protein, it is believed that DeltaF508-CFTR-expressing cells activate the nuclear transcription mechanism of genes called unfolded protein response (UPR). It has been discovered that protein levels of HSPA5 and activated ATF6 are increased in DeltaF508-CFTR-containing cells. The UPR is comprised of the regulator protein, HSPA5 and a number of signal transducers including ATF6 and EIF2AK3, which lead to ERAD, apoptosis, and decreased biosynthesis. ERP29 is ubiquitously expressed and seems to play a role in CFTR trafficking in the lung. Mutated proteins: Mutated gene is shown in white-out style. Organ: lung Organ_System: sensory system PMID: 17098482 PMID: 22481418 PMID: 22822398 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-206cbdaf-27fb-4a15-b8d7-d3e46d8f3d82 CFTR Misfolding and Degradation (Class II Mutations) uuid-206cbdaf-27fb-4a15-b8d7-d3e46d8f3d82 PS:CellType epithelial cell PS:Description The most common mutation in cystic fibrosis (CF) occurs in the CFTR gene that leads to a deletion of phenylalanine at position 508. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-206cbdaf-27fb-4a15-b8d7-d3e46d8f3d82 PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: The most common pathological mutation in the CFTR gene leads to a deletion of phenylalanine at position 508 (DeltaF508). This mutation results in a folding defect, retention of the protein in the endoplasmic reticulum (ER), and its subsequent degradation by the proteasome. CF patients exhibit a typical phenotype characterized by thick mucus secretions obstructing the airways and persistent pulmonary infections leading to pulmonary failure and death. CFTR is synthesized in the ER and then begins the process of maturation by folding and N-glycosylation, which is monitored by chaperone proteins. Correctly folded CFTR is transported to the Golgi for maturation before trafficking to the apical cell surface. CANX, COPII, GOPC, and RHOQ regulate the maturation and trafficking of normal CFTR from the ER to the Golgi. Mutant CFTR is degraded via proteasome endopeptidase complex or is transported to aggresomes near the microtubule-organizing center. Most mutant DeltaF508-CFTR are recognized as misfolded by ER-associated degradation (ERAD), shuttled out of the ER, and targeted for proteosomal degradation. Outcome effects: Two ubiquitin ligase complexes are needed for mutated CFTR degradation including ER membrane-associated ubiquitin ligase complex (DERL1, RNF5, and UBE2J2) and cytosolic ubiquitin ligase complex (STUB1 and UBE2D1). Since improperly folded CFTR undergoes ubiquitination-mediated degradation, it is hypothesized that Hsc70 (HSPA8) promotes ERAD of DeltaF508-CFTR, which involves a co-chaperone known as STUB1. HSPBP1 binds HSPA8 and this binding decreases the ubiquitin ligase activity of STUB1. Since DeltaF508-CFTR is a misfolded protein, it is believed that DeltaF508-CFTR-expressing cells activate the nuclear transcription mechanism of genes called unfolded protein response (UPR). It has been discovered that protein levels of HSPA5 and activated ATF6 are increased in DeltaF508-CFTR-containing cells. The UPR is comprised of the regulator protein, HSPA5 and a number of signal transducers including ATF6 and EIF2AK3, which lead to ERAD, apoptosis, and decreased biosynthesis. ERP29 is ubiquitously expressed and seems to play a role in CFTR trafficking in the lung. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ lung PS:Organ_System sensory system PS:PMID 17098482 PS:PMID 22481418 PS:PMID 22822398 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by behavioral and personality disorder, and language disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2070915a-2584-45a8-bc44-9a523f1cf427 NodeType: Pathway Notes: Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by behavioral and personality disorder, and language disorder, which includes primary progressive aphasia and semantic dementia. Organ: brain Organ_System: nervous system PMID: 17003069 PMID: 24600223 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-2070915a-2584-45a8-bc44-9a523f1cf427 Synaptic Exocytosis in Dementia uuid-2070915a-2584-45a8-bc44-9a523f1cf427 PS:CellType neuron PS:Description Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by behavioral and personality disorder, and language disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2070915a-2584-45a8-bc44-9a523f1cf427 PS:NodeType Pathway PS:Notes Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by behavioral and personality disorder, and language disorder, which includes primary progressive aphasia and semantic dementia. PS:Organ brain PS:Organ_System nervous system PS:PMID 17003069 PS:PMID 24600223 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-207d64b3-16c6-4673-8a27-ae1f7d5831a8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-207d64b3-16c6-4673-8a27-ae1f7d5831a8 Thiamine biosynthesis template uuid-207d64b3-16c6-4673-8a27-ae1f7d5831a8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-207d64b3-16c6-4673-8a27-ae1f7d5831a8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2087d04b-bfd1-4b48-9ac1-3282342255d2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2087d04b-bfd1-4b48-9ac1-3282342255d2 Ascorbate degradation template uuid-2087d04b-bfd1-4b48-9ac1-3282342255d2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2087d04b-bfd1-4b48-9ac1-3282342255d2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-208d2de5-f5ae-4865-b9a3-c3f6ec626aaa NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-208d2de5-f5ae-4865-b9a3-c3f6ec626aaa IFNG -> ARRB1/STAT1 Signaling uuid-208d2de5-f5ae-4865-b9a3-c3f6ec626aaa PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-208d2de5-f5ae-4865-b9a3-c3f6ec626aaa PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell Description: Asthma is an IgE-mediated sensitization to inhaled allergens with a Th2 cell response and subsequent eosinophilic inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20a6e14b-dd2d-4b4d-9561-ad35092cd932 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Asthma is an IgE-mediated sensitization to inhaled allergens which involves a Th2-cell response and subsequent eosinophilic inflammation. Th2 cytokines are believed to regulate IgE synthesis, and eosinophil numbers and activity are thought to play a central role in asthma pathogenesis. Although a number of cytokines are involved in forcing B-cell to produce antibody and generate plasma cells, only IL4 and IL13 are known to promote isotype switching to IgE. B-cells in the lymphoid tissue obtain signals from T-cells acting as antigen presenting cells in B-cell maturation. Th2-cells deliver antigens in the MHC II complex to the B-cell receptor (BCR). Cytokines secreted by T-cells is the second signal provided by T-cells for B-cell proliferation and differentiation into plasma cells. Outcome effects: During B-cell maturation, genetic recombination and isotype switching of immunoglobulin genes occurs. This is necessary to start transcription of immunoglobulins. The binding of CD40 on B-cell surface to the CD40 ligand on T-cells induces isotype switching from the initial IgM response. Start of AICDA expression is the major primary point in this process of isotype switching of immunoglobulin genes. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 21738882 PMID: 24632082 PMID: 25367117 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-20a6e14b-dd2d-4b4d-9561-ad35092cd932 B-Cell Mediated IgE Production in Asthma uuid-20a6e14b-dd2d-4b4d-9561-ad35092cd932 PS:CellType B-cell PS:Description Asthma is an IgE-mediated sensitization to inhaled allergens with a Th2 cell response and subsequent eosinophilic inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20a6e14b-dd2d-4b4d-9561-ad35092cd932 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Asthma is an IgE-mediated sensitization to inhaled allergens which involves a Th2-cell response and subsequent eosinophilic inflammation. Th2 cytokines are believed to regulate IgE synthesis, and eosinophil numbers and activity are thought to play a central role in asthma pathogenesis. Although a number of cytokines are involved in forcing B-cell to produce antibody and generate plasma cells, only IL4 and IL13 are known to promote isotype switching to IgE. B-cells in the lymphoid tissue obtain signals from T-cells acting as antigen presenting cells in B-cell maturation. Th2-cells deliver antigens in the MHC II complex to the B-cell receptor (BCR). Cytokines secreted by T-cells is the second signal provided by T-cells for B-cell proliferation and differentiation into plasma cells. Outcome effects: During B-cell maturation, genetic recombination and isotype switching of immunoglobulin genes occurs. This is necessary to start transcription of immunoglobulins. The binding of CD40 on B-cell surface to the CD40 ligand on T-cells induces isotype switching from the initial IgM response. Start of AICDA expression is the major primary point in this process of isotype switching of immunoglobulin genes. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 21738882 PS:PMID 24632082 PS:PMID 25367117 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20ada741-727e-4a83-a9dd-b0e5f8d3502a NodeType: Pathway Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Cell Process urn:agi-pathway:uuid-20ada741-727e-4a83-a9dd-b0e5f8d3502a dsRNA Induces Viral Stress Response uuid-20ada741-727e-4a83-a9dd-b0e5f8d3502a PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20ada741-727e-4a83-a9dd-b0e5f8d3502a PS:NodeType Pathway PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20de55bd-ab2d-4b69-bc79-8f607dee5411 NodeType: Pathway Notes: Alveolar epithelial cells exposed to cigarette smoke often undergo apoptosis, develop impaired DNA repair, undergo autophagy or express the ER-stress response, and produce inflammatory mediators and proteases. Altogether, cigarette smoke provokes destruction of the alveolar septum and promotes the development of pulmonary emphysema. Cigarette smoke can activate epithelial cells to secrete a variety of inflammatory mediators and proteases. Inflammatory mediators are responsible for macrophage, neutrophil, and T-cell recruitment. Transforming growth factor beta 1 (TGFB1) plays a significant role in the induction of pulmonary fibrosis. Proteases are responsible for extracellular matrix degradation that contributes to alveolar septal destruction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-20de55bd-ab2d-4b69-bc79-8f607dee5411 1_Cigarette smoke causes dysfunction and production of inflammatory mediators in alveolar epithelial cells uuid-20de55bd-ab2d-4b69-bc79-8f607dee5411 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20de55bd-ab2d-4b69-bc79-8f607dee5411 PS:NodeType Pathway PS:Notes Alveolar epithelial cells exposed to cigarette smoke often undergo apoptosis, develop impaired DNA repair, undergo autophagy or express the ER-stress response, and produce inflammatory mediators and proteases. Altogether, cigarette smoke provokes destruction of the alveolar septum and promotes the development of pulmonary emphysema. Cigarette smoke can activate epithelial cells to secrete a variety of inflammatory mediators and proteases. Inflammatory mediators are responsible for macrophage, neutrophil, and T-cell recruitment. Transforming growth factor beta 1 (TGFB1) plays a significant role in the induction of pulmonary fibrosis. Proteases are responsible for extracellular matrix degradation that contributes to alveolar septal destruction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Bloodstream monocytes are a heterogeneous lineage of the cell and distinct cell subsets that can be defined by the expression of several receptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20ec8ce0-6c73-44e7-874b-ae2e5730e854 NodeType: Pathway Notes: Headnote: Bloodstream monocytes are a heterogeneous lineage of the cell and distinct cell subsets that can be defined by the expression of several receptors. Monocytes differentiate into macrophages and dendritic cells in tissues and focuses of inflammation. Monocytes, and their macrophage and dendritic cell progeny, serve three main functions in the immune system including phagocytosis, antigen presentation, and cytokine production. Signaling description: Monocytes are divided into subclasses due to the expression levels of CD14 and CD16 membrane receptors. Classical monocytes are characterized by a high expression level of CD14 cell surface receptors including CD14 CD16- monocyte. The non-classical or proinflammatory subclass of monocytes has high levels of CD16 and CD14 expression (CD16 CD14). Other surface molecules that are highly expressed on CD14 CD16 monocytes are chemokine receptors CCR5 and CX3CR1, ITGAX, PECAM1, SPN, MHC class II protein complex, and CXCR4. SPN is a sialylated glycoprotein expressed on the surface of most hematopoietic cells and has been implicated in cell adhesion and signaling. SPN activation enhances hydrogen peroxide (H2O2) production in monocytes; however the detailed mechanisms of this effect are poorly understood. CD16 proinflammatory monocytes express higher levels of CX3CR1 and CSF1R. CSF1 is a potent maturation signal for monocytes and a survival and proliferative factor for macrophages. CSF1 and low levels of CSF2 dramatically increase macrophage generation, whereas higher concentrations of CSF2 result in the inhibition of CSF1-mediated macrophage growth. Outcome effects: Most inflammatory monocytes are thought to differentiate into macrophages, which are important for the clearance of pathogens and for the resolution of inflammation. The number of proinflammatory monocytes increases in injured tissue. Proinflammatory cytokines may activate the differentiation of this subclass of monocytes. For example, TGFA has been shown to induce CD16 expression on monocytes. Proinflammatory monocytes also produce lower levels of IL10 in response to a TLR4 agonist and higher amounts of TNF and IL12B in response to TLR4 and TLR2 agonists. Monocytes kill bacteria by producing reactive nitrogen intermediates (RNIs) and reactive oxygen intermediates (ROIs) and through the differentiation of macrophages and production of proinflammatory cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-20ec8ce0-6c73-44e7-874b-ae2e5730e854 CD16/CD14 Proinflammatory Monocyte Activation uuid-20ec8ce0-6c73-44e7-874b-ae2e5730e854 PS:CellType macrophage PS:Description Bloodstream monocytes are a heterogeneous lineage of the cell and distinct cell subsets that can be defined by the expression of several receptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-20ec8ce0-6c73-44e7-874b-ae2e5730e854 PS:NodeType Pathway PS:Notes Headnote: Bloodstream monocytes are a heterogeneous lineage of the cell and distinct cell subsets that can be defined by the expression of several receptors. Monocytes differentiate into macrophages and dendritic cells in tissues and focuses of inflammation. Monocytes, and their macrophage and dendritic cell progeny, serve three main functions in the immune system including phagocytosis, antigen presentation, and cytokine production. Signaling description: Monocytes are divided into subclasses due to the expression levels of CD14 and CD16 membrane receptors. Classical monocytes are characterized by a high expression level of CD14 cell surface receptors including CD14 CD16- monocyte. The non-classical or proinflammatory subclass of monocytes has high levels of CD16 and CD14 expression (CD16 CD14). Other surface molecules that are highly expressed on CD14 CD16 monocytes are chemokine receptors CCR5 and CX3CR1, ITGAX, PECAM1, SPN, MHC class II protein complex, and CXCR4. SPN is a sialylated glycoprotein expressed on the surface of most hematopoietic cells and has been implicated in cell adhesion and signaling. SPN activation enhances hydrogen peroxide (H2O2) production in monocytes; however the detailed mechanisms of this effect are poorly understood. CD16 proinflammatory monocytes express higher levels of CX3CR1 and CSF1R. CSF1 is a potent maturation signal for monocytes and a survival and proliferative factor for macrophages. CSF1 and low levels of CSF2 dramatically increase macrophage generation, whereas higher concentrations of CSF2 result in the inhibition of CSF1-mediated macrophage growth. Outcome effects: Most inflammatory monocytes are thought to differentiate into macrophages, which are important for the clearance of pathogens and for the resolution of inflammation. The number of proinflammatory monocytes increases in injured tissue. Proinflammatory cytokines may activate the differentiation of this subclass of monocytes. For example, TGFA has been shown to induce CD16 expression on monocytes. Proinflammatory monocytes also produce lower levels of IL10 in response to a TLR4 agonist and higher amounts of TNF and IL12B in response to TLR4 and TLR2 agonists. Monocytes kill bacteria by producing reactive nitrogen intermediates (RNIs) and reactive oxygen intermediates (ROIs) and through the differentiation of macrophages and production of proinflammatory cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-210ae8bf-92cd-4ba5-a5ce-4ad72adf24d5 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-210ae8bf-92cd-4ba5-a5ce-4ad72adf24d5 TLR3 -> IRF Signaling uuid-210ae8bf-92cd-4ba5-a5ce-4ad72adf24d5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-210ae8bf-92cd-4ba5-a5ce-4ad72adf24d5 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2117ad7a-b926-4bec-ac47-ea553a6a435e NodeType: Pathway Notes: Further progression of the disease invokes the excessive release of cytokines and growth factors, which cause endothelial injury, podocyte and mesangial cell (specialized cells of the glomeruli that provide structural support and regulate filtration rate) dysfunction, and glomerular filtration damage. One of the main podocyte functions is the formation of filtration slits through which small molecules pass and protein molecules are retained. Increased levels of TGFB1 and TNF make a significant contribution to podocyte dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2117ad7a-b926-4bec-ac47-ea553a6a435e 2_Podocyte dysfunction in glomerulonephritis uuid-2117ad7a-b926-4bec-ac47-ea553a6a435e PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2117ad7a-b926-4bec-ac47-ea553a6a435e PS:NodeType Pathway PS:Notes Further progression of the disease invokes the excessive release of cytokines and growth factors, which cause endothelial injury, podocyte and mesangial cell (specialized cells of the glomeruli that provide structural support and regulate filtration rate) dysfunction, and glomerular filtration damage. One of the main podocyte functions is the formation of filtration slits through which small molecules pass and protein molecules are retained. Increased levels of TGFB1 and TNF make a significant contribution to podocyte dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-211e92dd-4678-40e4-a8d7-dfe64ba7d6d0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-211e92dd-4678-40e4-a8d7-dfe64ba7d6d0 GAS6 -> AP-1/CREB Expression Targets uuid-211e92dd-4678-40e4-a8d7-dfe64ba7d6d0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-211e92dd-4678-40e4-a8d7-dfe64ba7d6d0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: myeloid progenitor cell Description: Leukotrienes are primarily known for their role in the chemotaxis of myeloid cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21307f83-9eb2-4ea4-9314-175505bf0a7a NodeType: Pathway Notes: Headnote: Leukotrienes are primarily known for their role in the chemotaxis of myeloid cells. Signaling description: LTB4 is a powerful chemoattractant for neutrophils. Leukotrienes LTD4 and LTE4, that signal via CYSLTR1 and CYSLTR2, can increase proliferation of mast cells through the activation of GNAI1/PRKCE/RAF1/MAPK3/MAPK1, which are downstream signals important for cell-cycle progression. In addition, CYSLTRs are direct chemoattractants for eosinophils and have been shown to enhance eosinophil migration in vivo. PGD2 is a potent stimulator of eosinophil chemotaxis. PGE2 induces both pro- and anti-inflammatory effects. PGE2 acts via PTGER3, PTGER4, PTGER2, and PTGER1 receptors. Outcome effects: PTGER3 and PTGER4 receptors are widely distributed throughout the body and signal through GNAS, which leads to increased cAMP levels and inhibition of myeloid cell function. Therefore, PGE2 decreases T-cell proliferation and lymphocyte migration via PTGER3 and PTGER4 signaling. Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-21307f83-9eb2-4ea4-9314-175505bf0a7a Eicosanoids in Myeloid Cell Activation uuid-21307f83-9eb2-4ea4-9314-175505bf0a7a PS:CellType myeloid progenitor cell PS:Description Leukotrienes are primarily known for their role in the chemotaxis of myeloid cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21307f83-9eb2-4ea4-9314-175505bf0a7a PS:NodeType Pathway PS:Notes Headnote: Leukotrienes are primarily known for their role in the chemotaxis of myeloid cells. Signaling description: LTB4 is a powerful chemoattractant for neutrophils. Leukotrienes LTD4 and LTE4, that signal via CYSLTR1 and CYSLTR2, can increase proliferation of mast cells through the activation of GNAI1/PRKCE/RAF1/MAPK3/MAPK1, which are downstream signals important for cell-cycle progression. In addition, CYSLTRs are direct chemoattractants for eosinophils and have been shown to enhance eosinophil migration in vivo. PGD2 is a potent stimulator of eosinophil chemotaxis. PGE2 induces both pro- and anti-inflammatory effects. PGE2 acts via PTGER3, PTGER4, PTGER2, and PTGER1 receptors. Outcome effects: PTGER3 and PTGER4 receptors are widely distributed throughout the body and signal through GNAS, which leads to increased cAMP levels and inhibition of myeloid cell function. Therefore, PGE2 decreases T-cell proliferation and lymphocyte migration via PTGER3 and PTGER4 signaling. PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Tissue bone marrow PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21338af0-169d-4df6-8905-1aacccd6015e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-21338af0-169d-4df6-8905-1aacccd6015e Monolignol storage and Gymnosperm transport template uuid-21338af0-169d-4df6-8905-1aacccd6015e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21338af0-169d-4df6-8905-1aacccd6015e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21462423-7710-431b-9540-b827838eeb08 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-21462423-7710-431b-9540-b827838eeb08 Gibberellin biosynthesis template uuid-21462423-7710-431b-9540-b827838eeb08 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21462423-7710-431b-9540-b827838eeb08 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Glomerulonephritis (GN) is an inflammation of the renal glomeruli. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-214ad502-48b9-428d-bdd0-34f1f42aa060 NodeType: Pathway Notes: Glomerulonephritis (GN) is an inflammation of the renal glomeruli. Endothelium damage is one of the factors in the development of GN. Overexpression of TNF, IL1B, IL6, KNG1 leads to increase of blood vessels permeability and excessive immune response. Organ: blood vessel Organ_System: urinary tract PMID: 15034086 PMID: 19436333 PMID: 22465480 PMID: 24406453 PMID: 24742784 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endothelium urn:agi-pathway:uuid-214ad502-48b9-428d-bdd0-34f1f42aa060 Endothelial Cell Dysfunction in Glomerulonephritis uuid-214ad502-48b9-428d-bdd0-34f1f42aa060 PS:CellType endothelial cell PS:Description Glomerulonephritis (GN) is an inflammation of the renal glomeruli. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-214ad502-48b9-428d-bdd0-34f1f42aa060 PS:NodeType Pathway PS:Notes Glomerulonephritis (GN) is an inflammation of the renal glomeruli. Endothelium damage is one of the factors in the development of GN. Overexpression of TNF, IL1B, IL6, KNG1 leads to increase of blood vessels permeability and excessive immune response. PS:Organ blood vessel PS:Organ_System urinary tract PS:PMID 15034086 PS:PMID 19436333 PS:PMID 22465480 PS:PMID 24406453 PS:PMID 24742784 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endothelium PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-214e3c80-b12e-4a17-8551-d9be08cb2965 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-214e3c80-b12e-4a17-8551-d9be08cb2965 INSR, IRS degradation uuid-214e3c80-b12e-4a17-8551-d9be08cb2965 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-214e3c80-b12e-4a17-8551-d9be08cb2965 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Transcription is the process in which a DNA sequence is enzymatically processed to produce a complementary RNA. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21513d90-97e3-47b9-84dd-537c37e674b9 NodeType: Pathway Notes: Headnote: Transcription is the process in which a DNA sequence is enzymatically processed to produce a complementary RNA. Signaling description: RNA Polymerase II transcribes messenger RNA (mRNA) and most small nuclear RNAs (snRNAs). Transcription is divided into three stages including initiation, elongation, and termination. To initiate transcription, the TBP subunit of TFIID transcription factor must recognize and bind to the TATA box, a core promoter element at the DNA. GTF2B and GTF2A1 stabilize this interaction between TATA and TFIID. RNA Polymerase II, along with transcription factors TFIIE, TFIIF, and TFIIH, is then recruited to form the initiation complex. Chromatin structure inhibition of transcriptional initiation is the process where the promoter is hidden by a chromatin structure. RNA Polymerase II catalyzes elongation upon clearing from the TFIID-complex. Once transcription begins, the 5' end of the initial RNA product synthesized by RNA Polymerase II is capped with 7-methyl-guanylate. The 3' end of a complete mRNA transcript is generated by endonucleolytic cleavage at a specific sequence, the Poly-A site, located at the 3' end the final exon. The transcriptional machinery continues up to 2kb beyond this signaling sequence and then dissociates. Outcome effects: The initial pre-mRNA product undergoes several processing steps including polyadenylation and splicing. Polyadenylation is the covalent linking of a polyadenylyl moiety to the 3' ends of mRNA molecule. CPSF forms an unstable complex with the upstream AU-rich poly(A) signal (AAUAAA sequence) and initiates cleavage resulting in free 3' ends that are rapidly polyadenylated by PABPN1. Finally, introns are removed by RNA splicing before the complete RNA is transported to the cytoplasm. Most introns start from the sequence GU and end with the sequence AG, in the 5' to 3' direction. Splicing can be broadly divided into two stages including recognition of consensus sequences and assembly of complex and reactions of cleavage and ligation that change the structure of substrate RNA. Splicing small nuclear ribonucleoprotein particles (snRNPs) such as U1, U2, U4, U5, and U6 associate with pre-mRNA and with each other in a certain order to form the spliceosome. This large ribonucleoprotein complex then catalyzes two transesterification reactions that result in splicing of the exons and excision of the intron. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-21513d90-97e3-47b9-84dd-537c37e674b9 mRNA Transcription and Processing uuid-21513d90-97e3-47b9-84dd-537c37e674b9 PS:CellType generic PS:Description Transcription is the process in which a DNA sequence is enzymatically processed to produce a complementary RNA. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21513d90-97e3-47b9-84dd-537c37e674b9 PS:NodeType Pathway PS:Notes Headnote: Transcription is the process in which a DNA sequence is enzymatically processed to produce a complementary RNA. Signaling description: RNA Polymerase II transcribes messenger RNA (mRNA) and most small nuclear RNAs (snRNAs). Transcription is divided into three stages including initiation, elongation, and termination. To initiate transcription, the TBP subunit of TFIID transcription factor must recognize and bind to the TATA box, a core promoter element at the DNA. GTF2B and GTF2A1 stabilize this interaction between TATA and TFIID. RNA Polymerase II, along with transcription factors TFIIE, TFIIF, and TFIIH, is then recruited to form the initiation complex. Chromatin structure inhibition of transcriptional initiation is the process where the promoter is hidden by a chromatin structure. RNA Polymerase II catalyzes elongation upon clearing from the TFIID-complex. Once transcription begins, the 5' end of the initial RNA product synthesized by RNA Polymerase II is capped with 7-methyl-guanylate. The 3' end of a complete mRNA transcript is generated by endonucleolytic cleavage at a specific sequence, the Poly-A site, located at the 3' end the final exon. The transcriptional machinery continues up to 2kb beyond this signaling sequence and then dissociates. Outcome effects: The initial pre-mRNA product undergoes several processing steps including polyadenylation and splicing. Polyadenylation is the covalent linking of a polyadenylyl moiety to the 3' ends of mRNA molecule. CPSF forms an unstable complex with the upstream AU-rich poly(A) signal (AAUAAA sequence) and initiates cleavage resulting in free 3' ends that are rapidly polyadenylated by PABPN1. Finally, introns are removed by RNA splicing before the complete RNA is transported to the cytoplasm. Most introns start from the sequence GU and end with the sequence AG, in the 5' to 3' direction. Splicing can be broadly divided into two stages including recognition of consensus sequences and assembly of complex and reactions of cleavage and ligation that change the structure of substrate RNA. Splicing small nuclear ribonucleoprotein particles (snRNPs) such as U1, U2, U4, U5, and U6 associate with pre-mRNA and with each other in a certain order to form the spliceosome. This large ribonucleoprotein complex then catalyzes two transesterification reactions that result in splicing of the exons and excision of the intron. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21591241-969c-4286-82df-40a072a2857a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-21591241-969c-4286-82df-40a072a2857a Cyanate degradation template uuid-21591241-969c-4286-82df-40a072a2857a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21591241-969c-4286-82df-40a072a2857a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-215be595-2a33-4c67-994e-a14c337c544a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-215be595-2a33-4c67-994e-a14c337c544a Coronavirus protein inhibitors uuid-215be595-2a33-4c67-994e-a14c337c544a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-215be595-2a33-4c67-994e-a14c337c544a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-217f0b23-a40b-4774-b7cb-9ecedbe43aa3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-217f0b23-a40b-4774-b7cb-9ecedbe43aa3 IL21 Expression Targets uuid-217f0b23-a40b-4774-b7cb-9ecedbe43aa3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-217f0b23-a40b-4774-b7cb-9ecedbe43aa3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-218b673a-097a-47aa-9af1-59a46d7746b6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-218b673a-097a-47aa-9af1-59a46d7746b6 VEGFR -> ATF/CREB/ELK-SRF Signaling uuid-218b673a-097a-47aa-9af1-59a46d7746b6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-218b673a-097a-47aa-9af1-59a46d7746b6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Impairment of K gradient due to gene mutations in the inner ear cell may cause hearing lowering. Pathway is built manually using published studies Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21923038-6f5a-44c1-8363-7efc9cc491f0 NodeType: Pathway Notes: Headnote: Age-related hearing loss ARHL is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. PCDH15 polymorphism was shown to be associated with ARHL. Outcome effects: K+ exits the hair cells through KCNQ4 and KCNMA1 channels, and KCNQ4 is a candidate gene for ARHL predisposition. In addition, KCNQ4 mutations are found in patients with autosomal dominant nonsyndromic hearing loss (ARNSHL). Following K+ efflux from the hair cell, it is taken up by supporting Deiters cells via KCNJ10 and then exported via SLC12A6 and SLC12A7. K+ passes fibrocytes of the lateral wall through gap junctions. The common GJB2 (Connexin 26, gap junction protein) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL). GJB2 mutations were also described in ARNSHL. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. Then, K+ exits through KCNQ1 and KCN1 apical channels back to the endolymph. SLC12A2, ATP1A1 and ATP1A2 heterozygous deletEion were shown to cause age-dependent hearing loss in mice. Organ: ear Organ_System: sensory system PMID: 16917933 PMID: 16990454 PMID: 17670895 PMID: 17909436 PMID: 18797286 PMID: 19925344 PMID: 23717403 PMID: 25116015 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-21923038-6f5a-44c1-8363-7efc9cc491f0 Potassium Cycling in the Inner Ear (Age-Related) uuid-21923038-6f5a-44c1-8363-7efc9cc491f0 PS:CellType sensory hair cell PS:Description Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Impairment of K gradient due to gene mutations in the inner ear cell may cause hearing lowering. Pathway is built manually using published studies PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21923038-6f5a-44c1-8363-7efc9cc491f0 PS:NodeType Pathway PS:Notes Headnote: Age-related hearing loss ARHL is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. PCDH15 polymorphism was shown to be associated with ARHL. Outcome effects: K+ exits the hair cells through KCNQ4 and KCNMA1 channels, and KCNQ4 is a candidate gene for ARHL predisposition. In addition, KCNQ4 mutations are found in patients with autosomal dominant nonsyndromic hearing loss (ARNSHL). Following K+ efflux from the hair cell, it is taken up by supporting Deiters cells via KCNJ10 and then exported via SLC12A6 and SLC12A7. K+ passes fibrocytes of the lateral wall through gap junctions. The common GJB2 (Connexin 26, gap junction protein) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL). GJB2 mutations were also described in ARNSHL. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. Then, K+ exits through KCNQ1 and KCN1 apical channels back to the endolymph. SLC12A2, ATP1A1 and ATP1A2 heterozygous deletEion were shown to cause age-dependent hearing loss in mice. PS:Organ ear PS:Organ_System sensory system PS:PMID 16917933 PS:PMID 16990454 PS:PMID 17670895 PS:PMID 17909436 PS:PMID 18797286 PS:PMID 19925344 PS:PMID 23717403 PS:PMID 25116015 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Both cortisol infusion and acute treatment with high doses of oral prednisolone acutely impair insulin secretion in healthy human volunteers. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-219947fc-5bc1-4d4d-ace5-2decbee8f2f2 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Pancreatic beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: Cortisol infusions as well as acute treatment with high doses of oral prednisolone severely impair insulin secretion in healthy human volunteers. Glucocorticoids (GCs) have been shown to induce beta-cell dysfunction in completely healthy males. GCs have been demonstrated to impair rodent beta-cell glucose metabolism by reducing the expression levels of SLC2A2 and GCK, and by enhancing the G6PC2 activity. Outcome effects: GCs may reduce glucose uptake and phosphorylation via the above mentioned mechanisms, and thereby decrease ATP synthesis and Ca2+ influx. Organ: pancreas Organ_System: endocrine system PMID: 19200161 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-219947fc-5bc1-4d4d-ace5-2decbee8f2f2 beta-Cell Dysfunction by Steroids in Diabetes Mellitus (Hypothesis) uuid-219947fc-5bc1-4d4d-ace5-2decbee8f2f2 PS:CellType insulin-secreting cell PS:Description Both cortisol infusion and acute treatment with high doses of oral prednisolone acutely impair insulin secretion in healthy human volunteers. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-219947fc-5bc1-4d4d-ace5-2decbee8f2f2 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Pancreatic beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: Cortisol infusions as well as acute treatment with high doses of oral prednisolone severely impair insulin secretion in healthy human volunteers. Glucocorticoids (GCs) have been shown to induce beta-cell dysfunction in completely healthy males. GCs have been demonstrated to impair rodent beta-cell glucose metabolism by reducing the expression levels of SLC2A2 and GCK, and by enhancing the G6PC2 activity. Outcome effects: GCs may reduce glucose uptake and phosphorylation via the above mentioned mechanisms, and thereby decrease ATP synthesis and Ca2+ influx. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19200161 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: gonadotroph Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-219af0f5-0ca1-4ef2-ba18-cfe114193d60 NodeType: Pathway Notes: Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a follow-on lack of sex steroids production. Loss-of-function mutations in GNRH1, GNRHR, LHB, and FSHB are the main cause of the hypogonadotrophic hypogonadism progression. Signaling description: Fertility in mammals is initiated at puberty by the pulsatile secretion of gonadotrophin releasing hormone (GNRH) from neurons in the hypothalamus. The GNRH acts on the anterior pituitary to stimulate the release of the gonadotrophic hormones, luteinizing hormone (LH), and follicle stimulating hormone (FSH). FSH is a dimmer and contains two subunits, FSHB and CGA. LH is also a dimmer and contains LHB and CGA. Upon GNRH binding to the GNRHR in the gonadotroph membrane GNRHR activates GNAS and GNAQ leading to activation of adenylyl cyclase (ADCY) and phospholipase C (PLC). ADCY generates cAMP, stimulating PKA which activates the transcription factor CREB1. PLC leads to activation of PKC, driving activation of MAPK and of MAPK-dependent transcription via EGR1 and JUN-FOS. It also elevates the cytoplasmic Ca2+ concentration, driving activation of calmodulin and its targets. A rise in Ca2+ is the key signal to trigger regulated exocytosis of FSH and LH.Mutated genes are shown in white-out style. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 18708085 PMID: 22229029 PMID: 24312080 PMID: 25071724 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-219af0f5-0ca1-4ef2-ba18-cfe114193d60 GNRH Signaling Impairment in Hypogonadotrophic Hypogonadism uuid-219af0f5-0ca1-4ef2-ba18-cfe114193d60 PS:CellType gonadotroph PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-219af0f5-0ca1-4ef2-ba18-cfe114193d60 PS:NodeType Pathway PS:Notes Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a follow-on lack of sex steroids production. Loss-of-function mutations in GNRH1, GNRHR, LHB, and FSHB are the main cause of the hypogonadotrophic hypogonadism progression. Signaling description: Fertility in mammals is initiated at puberty by the pulsatile secretion of gonadotrophin releasing hormone (GNRH) from neurons in the hypothalamus. The GNRH acts on the anterior pituitary to stimulate the release of the gonadotrophic hormones, luteinizing hormone (LH), and follicle stimulating hormone (FSH). FSH is a dimmer and contains two subunits, FSHB and CGA. LH is also a dimmer and contains LHB and CGA. Upon GNRH binding to the GNRHR in the gonadotroph membrane GNRHR activates GNAS and GNAQ leading to activation of adenylyl cyclase (ADCY) and phospholipase C (PLC). ADCY generates cAMP, stimulating PKA which activates the transcription factor CREB1. PLC leads to activation of PKC, driving activation of MAPK and of MAPK-dependent transcription via EGR1 and JUN-FOS. It also elevates the cytoplasmic Ca2+ concentration, driving activation of calmodulin and its targets. A rise in Ca2+ is the key signal to trigger regulated exocytosis of FSH and LH.Mutated genes are shown in white-out style. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 18708085 PS:PMID 22229029 PS:PMID 24312080 PS:PMID 25071724 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21ae9580-0a42-42b5-906b-8e5ad7c94401 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-21ae9580-0a42-42b5-906b-8e5ad7c94401 Genes with Mutations Associated with Urolithiasis uuid-21ae9580-0a42-42b5-906b-8e5ad7c94401 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21ae9580-0a42-42b5-906b-8e5ad7c94401 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21b2b709-0d3e-49d1-8562-51ccff7aadde NodeType: Pathway Organ: generic Organ_System: generic PMID: 12757749 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: generic urn:agi-pathway:uuid-21b2b709-0d3e-49d1-8562-51ccff7aadde Golgi to Endosome Transport uuid-21b2b709-0d3e-49d1-8562-51ccff7aadde PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21b2b709-0d3e-49d1-8562-51ccff7aadde PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 12757749 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: TSLP is highly expressed in ASM bundles from asthma and COPD patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c24c62-7db6-4c7a-b503-524df763cc35 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: TSLP protein is highly expressed in ASM (airway smooth muscle) bundles from asthma and COPD (chronic obstructive pulmonary disease) patients. TSLP is produced by epithelial cells, mast cells, ASM cells, and fibroblasts. The inflammatory mediators IL1b and TNFa regulate human TSLP gene expression. Human TSLP mRNA concentrations increase following exposure to TLR2, TLR3, TLR8, and TLR9 ligands in airway bronchial epithelial cells. Outcome effects: TSLP receptor (TSLPR) activation in bronchial epithelial cells involves Stat3 phosphorylation and induces IL13 production and cell proliferation. TSLP activates cellular senescentin in airway epithelium of patients with asthma. In dendritic cells, TSLP stimulates maturation, which facilitates the generation of effector T-cells, and triggers airway inflammation through subsequent adaptive T-cell responses. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 18724870 PMID: 20656951 PMID: 22052771 PMID: 24167583 PMID: 24348685 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-21c24c62-7db6-4c7a-b503-524df763cc35 TSLP Signaling in Bronchial Epithelial Cell in Asthma uuid-21c24c62-7db6-4c7a-b503-524df763cc35 PS:CellType epithelial cell PS:Description TSLP is highly expressed in ASM bundles from asthma and COPD patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c24c62-7db6-4c7a-b503-524df763cc35 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: TSLP protein is highly expressed in ASM (airway smooth muscle) bundles from asthma and COPD (chronic obstructive pulmonary disease) patients. TSLP is produced by epithelial cells, mast cells, ASM cells, and fibroblasts. The inflammatory mediators IL1b and TNFa regulate human TSLP gene expression. Human TSLP mRNA concentrations increase following exposure to TLR2, TLR3, TLR8, and TLR9 ligands in airway bronchial epithelial cells. Outcome effects: TSLP receptor (TSLPR) activation in bronchial epithelial cells involves Stat3 phosphorylation and induces IL13 production and cell proliferation. TSLP activates cellular senescentin in airway epithelium of patients with asthma. In dendritic cells, TSLP stimulates maturation, which facilitates the generation of effector T-cells, and triggers airway inflammation through subsequent adaptive T-cell responses. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18724870 PS:PMID 20656951 PS:PMID 22052771 PS:PMID 24167583 PS:PMID 24348685 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c62ac4-d41d-4045-9ac4-b05319389b0e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-21c62ac4-d41d-4045-9ac4-b05319389b0e Vitamin B5 (Pantothenate) Metabolism and Biosynthesis of CoA and Holo-ACP uuid-21c62ac4-d41d-4045-9ac4-b05319389b0e PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c62ac4-d41d-4045-9ac4-b05319389b0e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c9a336-8c7f-458b-a1cd-4f6c54a93d2d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-21c9a336-8c7f-458b-a1cd-4f6c54a93d2d Reductive TCA cycle template uuid-21c9a336-8c7f-458b-a1cd-4f6c54a93d2d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21c9a336-8c7f-458b-a1cd-4f6c54a93d2d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: The intrinsic signaling pathway for programmed cell death comprises non-receptor-mediated intracellular signals which induce activities in the mitochondria that initiate apoptosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21cef437-15e3-4a14-b7b9-cbec8a5ffbc4 NodeType: Pathway Notes: Headnote: The intrinsic signaling pathway for programmed cell death comprises non-receptor-mediated intracellular signals, which induce activities in the mitochondria that initiate apoptosis. Melatonin and its signaling effects can interfere with this apoptotic pathway, thus preventing apoptotic cell death. Signaling description: Melatonin-induced activation of NF-kB and JUN-FOS is responsible for the control of anti-apoptotic genes such as BCL2. The activation of NFE2L2 is responsible for the antioxidant response. Outcome effects: In addition to its receptor-mediated actions, melatonin also has direct free radical scavenging and receptor-independent effects. Melatonin detoxifies radicals via the mechanism of electron donation. Organ: brain Organ_System: nervous system PMID: 16678784 PMID: 19818070 PMID: 20534884 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-21cef437-15e3-4a14-b7b9-cbec8a5ffbc4 Melatonin in Cell Survival and Antioxidant Response uuid-21cef437-15e3-4a14-b7b9-cbec8a5ffbc4 PS:CellType neuron PS:Description The intrinsic signaling pathway for programmed cell death comprises non-receptor-mediated intracellular signals which induce activities in the mitochondria that initiate apoptosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21cef437-15e3-4a14-b7b9-cbec8a5ffbc4 PS:NodeType Pathway PS:Notes Headnote: The intrinsic signaling pathway for programmed cell death comprises non-receptor-mediated intracellular signals, which induce activities in the mitochondria that initiate apoptosis. Melatonin and its signaling effects can interfere with this apoptotic pathway, thus preventing apoptotic cell death. Signaling description: Melatonin-induced activation of NF-kB and JUN-FOS is responsible for the control of anti-apoptotic genes such as BCL2. The activation of NFE2L2 is responsible for the antioxidant response. Outcome effects: In addition to its receptor-mediated actions, melatonin also has direct free radical scavenging and receptor-independent effects. Melatonin detoxifies radicals via the mechanism of electron donation. PS:Organ brain PS:Organ_System nervous system PS:PMID 16678784 PS:PMID 19818070 PS:PMID 20534884 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21f7611f-8e2e-4960-86f2-d863fe5b3a9f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-21f7611f-8e2e-4960-86f2-d863fe5b3a9f Basement membrane damage+>CD147+>NFkB+>inflammation, ECM remodeling uuid-21f7611f-8e2e-4960-86f2-d863fe5b3a9f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-21f7611f-8e2e-4960-86f2-d863fe5b3a9f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22013d7c-2381-4dc8-a7f8-92d541b83d67 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-22013d7c-2381-4dc8-a7f8-92d541b83d67 Genes with Mutations Associated with Osteoarthritis uuid-22013d7c-2381-4dc8-a7f8-92d541b83d67 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22013d7c-2381-4dc8-a7f8-92d541b83d67 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Description: IL17 signaling activates NF-kB and MAPK pathways through the conserved SEF/IL-17R (SEFIR) domain containing the adaptor protein, Act1 (TRAF3IP2). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22089ec2-ba4f-4763-ba97-b698f46189dd NodeType: Pathway Notes: Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. Interleukin-17 is an essential element in the pathology of autoimmune diseases including psoriasis. Signaling description: IL17 signaling activates NF-kB and MAPK pathways through the conserved SEF/IL-17R (SEFIR) domain containing the adaptor protein, Act1 (TRAF3IP2). TRAF3IP2 further interacts with TRAF6 to promote signal transduction in addition to cytokine and chemokine secretion. Outcome effects: IL17 stimulates the production of chemokines CXCL1, CXCL5, IL8, CCL2, and CCL7 which are responsible for the recruitment of neutrophils to the site of inflammation. Signal transduction activation by IL17 positively regulates cell proliferation and activates the immune response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: TRAF3IP2 mutated in psoriasis is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 22673731 PMID: 22716185 PMID: 23122008 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-22089ec2-ba4f-4763-ba97-b698f46189dd IL17 Signaling in Psoriasis uuid-22089ec2-ba4f-4763-ba97-b698f46189dd PS:CellType keratinocyte PS:Description IL17 signaling activates NF-kB and MAPK pathways through the conserved SEF/IL-17R (SEFIR) domain containing the adaptor protein, Act1 (TRAF3IP2). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22089ec2-ba4f-4763-ba97-b698f46189dd PS:NodeType Pathway PS:Notes Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. Interleukin-17 is an essential element in the pathology of autoimmune diseases including psoriasis. Signaling description: IL17 signaling activates NF-kB and MAPK pathways through the conserved SEF/IL-17R (SEFIR) domain containing the adaptor protein, Act1 (TRAF3IP2). TRAF3IP2 further interacts with TRAF6 to promote signal transduction in addition to cytokine and chemokine secretion. Outcome effects: IL17 stimulates the production of chemokines CXCL1, CXCL5, IL8, CCL2, and CCL7 which are responsible for the recruitment of neutrophils to the site of inflammation. Signal transduction activation by IL17 positively regulates cell proliferation and activates the immune response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: TRAF3IP2 mutated in psoriasis is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 22673731 PS:PMID 22716185 PS:PMID 23122008 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22435414-8a21-46ba-a4cf-01ac1683d5e7 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-22435414-8a21-46ba-a4cf-01ac1683d5e7 TNFRSF6 -> HSF1 Signaling uuid-22435414-8a21-46ba-a4cf-01ac1683d5e7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22435414-8a21-46ba-a4cf-01ac1683d5e7 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: glucagon-secreting cell CellType: insulin-secreting cell Description: Four main hypotheses have been proposed regarding the origin of beta cells in adult mammals (mice). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-226489fc-1dee-4506-9ec4-6da8b4a23f7f NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. The major hypotheses for the origin of beta cells in adult mammals include replication of pre-existing beta cells, neogenesis from duct epithelium, acini-to-endocrine or acini-to-duct-to-endocrine transdifferentiation, endocrine cell interconversion, and trans-differentiation of pro-alpha-cells to-beta cells. Signaling description: Alpha cells produce glucagon and are similar to beta cells with regard to intracellular signaling. PCSK2 is an enzyme crucial for proglucagon processing in alpha cells. Fully-differentiated alpha cells express only PCSK2 and produce glucagon, whereas undifferentiated pro-alpha cells express PCSK1/3 as well as PCSK2 and produce GCG in addition to glucagon. The control of glucagon secretion in alpha cells is similar to insulin secretion control in beta cells. Glucagon is released by alpha cells through calcium (Ca2 )-dependent exocytosis of secretory granules. Insulin, somatostatin, GCG, and leptin inhibit whereas amino acids, low glucose, free fatty acids, and catecholamines stimulate glucagon release. Alpha cell development and glucagon gene expression are tightly linked. The differentiated alpha cell phenotype is determined by the expression of ARX, PAX6, POU3F4, IRX2, and FOXA2 as well as the absence of PDX1, PAX4, PCSK1/3, and GCG receptor. PAX6 regulates the expression of the glucagon gene as well as MAF, MAFB, PCSK2, and NEUROD1 genes. Specifically, ARX has been shown to affect alpha cell differentiation but not the glucagon gene expression. Outcome effects: Alpha cells may transdifferentiate into beta cells, and ARX is crucial for the suppression of beta cell phenotype through the control of PAX4. In addition, PAX4 directly inhibits the expression of ARX. Ectopic expression of PAX4 is sufficient to convert alpha cells into beta cells in vivo. MAFB is essentially absent from mature adult beta cells and its expression is restricted to alpha cells in the adult pancreas. Lastly, the signals that control alpha cell proliferation and their conversion into beta cells remain unknown. The production of GCG by alpha cells is initiated by factors secreted by beta cells in response to injuries, e.g. CXCL12. Organ: pancreas Organ_System: endocrine system PMID: 19665969 PMID: 20364121 PMID: 21337462 PMID: 21824254 PMID: 22847495 PMID: 23715541 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-226489fc-1dee-4506-9ec4-6da8b4a23f7f alpha-Cell to beta-Cell Interconversion (Hypothesis) uuid-226489fc-1dee-4506-9ec4-6da8b4a23f7f PS:CellType glucagon-secreting cell PS:CellType insulin-secreting cell PS:Description Four main hypotheses have been proposed regarding the origin of beta cells in adult mammals (mice). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-226489fc-1dee-4506-9ec4-6da8b4a23f7f PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. The major hypotheses for the origin of beta cells in adult mammals include replication of pre-existing beta cells, neogenesis from duct epithelium, acini-to-endocrine or acini-to-duct-to-endocrine transdifferentiation, endocrine cell interconversion, and trans-differentiation of pro-alpha-cells to-beta cells. Signaling description: Alpha cells produce glucagon and are similar to beta cells with regard to intracellular signaling. PCSK2 is an enzyme crucial for proglucagon processing in alpha cells. Fully-differentiated alpha cells express only PCSK2 and produce glucagon, whereas undifferentiated pro-alpha cells express PCSK1/3 as well as PCSK2 and produce GCG in addition to glucagon. The control of glucagon secretion in alpha cells is similar to insulin secretion control in beta cells. Glucagon is released by alpha cells through calcium (Ca2 )-dependent exocytosis of secretory granules. Insulin, somatostatin, GCG, and leptin inhibit whereas amino acids, low glucose, free fatty acids, and catecholamines stimulate glucagon release. Alpha cell development and glucagon gene expression are tightly linked. The differentiated alpha cell phenotype is determined by the expression of ARX, PAX6, POU3F4, IRX2, and FOXA2 as well as the absence of PDX1, PAX4, PCSK1/3, and GCG receptor. PAX6 regulates the expression of the glucagon gene as well as MAF, MAFB, PCSK2, and NEUROD1 genes. Specifically, ARX has been shown to affect alpha cell differentiation but not the glucagon gene expression. Outcome effects: Alpha cells may transdifferentiate into beta cells, and ARX is crucial for the suppression of beta cell phenotype through the control of PAX4. In addition, PAX4 directly inhibits the expression of ARX. Ectopic expression of PAX4 is sufficient to convert alpha cells into beta cells in vivo. MAFB is essentially absent from mature adult beta cells and its expression is restricted to alpha cells in the adult pancreas. Lastly, the signals that control alpha cell proliferation and their conversion into beta cells remain unknown. The production of GCG by alpha cells is initiated by factors secreted by beta cells in response to injuries, e.g. CXCL12. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19665969 PS:PMID 20364121 PS:PMID 21337462 PS:PMID 21824254 PS:PMID 22847495 PS:PMID 23715541 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Orexin A/B (HCRT) is a neuropeptide responsible for the regulation of sleep/arousal, feeding behavior, coordination of emotion, energy homeostasis, reward system, and drug addiction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2279aeea-febf-4f95-8124-187579d006f6 NodeType: Pathway Notes: Headnote: Orexin A/B (HCRT) is a neuropeptide responsible for the regulation of sleep/arousal, feeding behavior, coordination of emotion, energy homeostasis, reward system, and is also implicated in the mechanisms of drug addiction. Signaling description: Orexin is produced exclusively in orexinergic neurons in the lateral hypothalamic area and interacts with HCRTR1 and HCRTR2 receptors. The absence or deficiency of HCRT or HCRTR1/2 leads to narcolepsy. Individuals with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern. HCRTR1 and HCRTR2 are G protein-coupled receptors. HCRTR1 is coupled exclusively to GNAQ whereas HCRTR2 couples to Gi/o and/or GNAQ. One prominent method of signaling for these receptors is via phospholipase (PLC) cascades, with the most important one being phospholipase C (PLCB1). PLC signaling has multiple roles in orexin receptor responses. Diacylglycerol activates PKC, which in turn activates multiple calcium (Ca2+) transporters (voltage-gated Ca2+ channels, Ca2+/Na+ antiporters, TRPMs, TRPVs, and TRPCs) and inhibits inward rectifier potassium (K+) channels. Outcome effects: As a result of massive Ca2+ influx, depolarization occurs and neuron action potential is generated. PLA2G4A, activated by PKC, is a central enzyme for arachidonic acid production. PLA2G4A signaling contributes to Ca2+ influx into the cell. Orexins have an excitatory activity in monoaminergic neurons. Noradrenergic cells of the locus coeruleus, dopaminergic cells of the ventral tegmental area, serotonergic cells of the dorsal raphe, histaminergic cells from tuberomammillary nucleus, and cholinergic neurons of the basal forebrain have been shown to be activated by orexins and are implicated in the regulation of arousal. During sleep, orexin neurons and monoaminergic neurons are inhibited by GABAergic neurons of the ventrolateral preoptic nucleus (VLPO). While awake, monoaminergic neurons send inhibitory projections to the VLPO sleep center. Organ: brain Organ_System: nervous system PMID: 17910982 PMID: 19549926 PMID: 22550093 PMID: 22640606 PMID: 23034387 PMID: 23730297 PMID: 23810911 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-2279aeea-febf-4f95-8124-187579d006f6 Hypocretin (Orexin) in Arousal Regulation uuid-2279aeea-febf-4f95-8124-187579d006f6 PS:CellType neuron PS:Description Orexin A/B (HCRT) is a neuropeptide responsible for the regulation of sleep/arousal, feeding behavior, coordination of emotion, energy homeostasis, reward system, and drug addiction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2279aeea-febf-4f95-8124-187579d006f6 PS:NodeType Pathway PS:Notes Headnote: Orexin A/B (HCRT) is a neuropeptide responsible for the regulation of sleep/arousal, feeding behavior, coordination of emotion, energy homeostasis, reward system, and is also implicated in the mechanisms of drug addiction. Signaling description: Orexin is produced exclusively in orexinergic neurons in the lateral hypothalamic area and interacts with HCRTR1 and HCRTR2 receptors. The absence or deficiency of HCRT or HCRTR1/2 leads to narcolepsy. Individuals with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern. HCRTR1 and HCRTR2 are G protein-coupled receptors. HCRTR1 is coupled exclusively to GNAQ whereas HCRTR2 couples to Gi/o and/or GNAQ. One prominent method of signaling for these receptors is via phospholipase (PLC) cascades, with the most important one being phospholipase C (PLCB1). PLC signaling has multiple roles in orexin receptor responses. Diacylglycerol activates PKC, which in turn activates multiple calcium (Ca2+) transporters (voltage-gated Ca2+ channels, Ca2+/Na+ antiporters, TRPMs, TRPVs, and TRPCs) and inhibits inward rectifier potassium (K+) channels. Outcome effects: As a result of massive Ca2+ influx, depolarization occurs and neuron action potential is generated. PLA2G4A, activated by PKC, is a central enzyme for arachidonic acid production. PLA2G4A signaling contributes to Ca2+ influx into the cell. Orexins have an excitatory activity in monoaminergic neurons. Noradrenergic cells of the locus coeruleus, dopaminergic cells of the ventral tegmental area, serotonergic cells of the dorsal raphe, histaminergic cells from tuberomammillary nucleus, and cholinergic neurons of the basal forebrain have been shown to be activated by orexins and are implicated in the regulation of arousal. During sleep, orexin neurons and monoaminergic neurons are inhibited by GABAergic neurons of the ventrolateral preoptic nucleus (VLPO). While awake, monoaminergic neurons send inhibitory projections to the VLPO sleep center. PS:Organ brain PS:Organ_System nervous system PS:PMID 17910982 PS:PMID 19549926 PS:PMID 22550093 PS:PMID 22640606 PS:PMID 23034387 PS:PMID 23730297 PS:PMID 23810911 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22d87ebf-1b49-4abf-ac18-b0887818db1f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-22d87ebf-1b49-4abf-ac18-b0887818db1f Caudate nucleus defects in Huntington uuid-22d87ebf-1b49-4abf-ac18-b0887818db1f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22d87ebf-1b49-4abf-ac18-b0887818db1f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22f362ff-3933-4ea9-87ae-154497bdb50d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-22f362ff-3933-4ea9-87ae-154497bdb50d Cu2+ toxicity in Huntington uuid-22f362ff-3933-4ea9-87ae-154497bdb50d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22f362ff-3933-4ea9-87ae-154497bdb50d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Coagulation results in the formation of thrombus which is a blood clot that prevents further blood loss from damaged tissues. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22f9e7a9-3073-4f18-b273-5623c70aa07c NodeType: Pathway Notes: Headnote: Coagulation results in the formation of thrombus, which is a blood clot that prevents further blood loss from damaged tissues. The coagulation proteins form a cascade in a chain reaction. Signaling description: There are 12 coagulation factors from F1 to F12; the numbers refer to the order, in which the factors were discovered and not to the order in which they react. The purpose of the pathway is to generate thrombin (F2), which subsequently converts fibrinogen dissolved in plasma into fibrin to form a clot. The process of F2 generation can be divided into three phases including the intrinsic and extrinsic pathways which provide the alternative generation of activated F10 and the final common pathway which results in F2 formation. The intrinsic pathway begins with the formation of the primary complex of F12, KLKB1, and KNG1 on the surface of platelets. During activation, the single chain protein F12 is cleaved into two chains and the light chain (28kDa) is referred to as activated F12. The activated F12 remains in close contact with the activating surface and can activate F11. The subsequent step in the intrinsic pathway requires Ca2+ to proceed efficiently. F11 activates F9 which in turn, activates F10 to its active form through the interactions with Ca2+, membrane phospholipids, and F8. Outcome effects: The extrinsic pathway provides a very rapid response to tissue injury to activate F10. There are two unique components to the extrinsic pathway including tissue factor (F3) and F7. Following damage to the blood vessel, F7 leaves the circulation and comes into contact with F3 expressed on tissue factor-bearing cells such as stromal fibroblasts and leukocytes. The F3/F7 complex then rapidly activates F10. The activation of F10 is ultimately responsible for the production of F2 which converts fibrinogen to fibrin. In addition, F2 enhances the activation of F5 and F8 in a feedback manner. The polymerized fibrin is stabilized by F13 which is produced by the action of F2 on F13. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-22f9e7a9-3073-4f18-b273-5623c70aa07c Coagulation Cascade uuid-22f9e7a9-3073-4f18-b273-5623c70aa07c PS:CellType blood platelet PS:Description Coagulation results in the formation of thrombus which is a blood clot that prevents further blood loss from damaged tissues. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22f9e7a9-3073-4f18-b273-5623c70aa07c PS:NodeType Pathway PS:Notes Headnote: Coagulation results in the formation of thrombus, which is a blood clot that prevents further blood loss from damaged tissues. The coagulation proteins form a cascade in a chain reaction. Signaling description: There are 12 coagulation factors from F1 to F12; the numbers refer to the order, in which the factors were discovered and not to the order in which they react. The purpose of the pathway is to generate thrombin (F2), which subsequently converts fibrinogen dissolved in plasma into fibrin to form a clot. The process of F2 generation can be divided into three phases including the intrinsic and extrinsic pathways which provide the alternative generation of activated F10 and the final common pathway which results in F2 formation. The intrinsic pathway begins with the formation of the primary complex of F12, KLKB1, and KNG1 on the surface of platelets. During activation, the single chain protein F12 is cleaved into two chains and the light chain (28kDa) is referred to as activated F12. The activated F12 remains in close contact with the activating surface and can activate F11. The subsequent step in the intrinsic pathway requires Ca2+ to proceed efficiently. F11 activates F9 which in turn, activates F10 to its active form through the interactions with Ca2+, membrane phospholipids, and F8. Outcome effects: The extrinsic pathway provides a very rapid response to tissue injury to activate F10. There are two unique components to the extrinsic pathway including tissue factor (F3) and F7. Following damage to the blood vessel, F7 leaves the circulation and comes into contact with F3 expressed on tissue factor-bearing cells such as stromal fibroblasts and leukocytes. The F3/F7 complex then rapidly activates F10. The activation of F10 is ultimately responsible for the production of F2 which converts fibrinogen to fibrin. In addition, F2 enhances the activation of F5 and F8 in a feedback manner. The polymerized fibrin is stabilized by F13 which is produced by the action of F2 on F13. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuroglia CellType: neuron Description: IKBKB is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22fd50f9-e173-4280-a0f8-acbbc7979bf3 NodeType: Pathway Notes: Headnote: The IkB kinase beta (IKBKB) is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington disease (HD). IKBKB may directly regulate the cleavage and neurotoxicity of huntingtin. Signaling description: Activation of IKBKB by DNA damage triggers caspase-dependent cleavage of mutant huntingtin (mHTT) and enhances the accumulation of oligomeric fragments which have neurotoxic properties. Moreover, mHTT directly binds to and activate IKBKB thus forming a deleterious feed-forward loop. mHTT also may be cleaved to oligomeric fragments by caspase 3 and 6 (CASP3/6) and these caspases in turn may be activated by IKBKB. Activated caspases finally lead to apoptosis. IKBKB may activate NFkB and production of inflammatory cytokines and chemokines including IL6, IL8, IL1B, TNF, CCL2 inducing neuroinflammation. mHTT may also activate IKBKG leading to the same results.Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 19488402 PMID: 20026656 PMID: 21554955 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-22fd50f9-e173-4280-a0f8-acbbc7979bf3 NF-kB Signaling Activation in Huntington Disease uuid-22fd50f9-e173-4280-a0f8-acbbc7979bf3 PS:CellType neuroglia PS:CellType neuron PS:Description IKBKB is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-22fd50f9-e173-4280-a0f8-acbbc7979bf3 PS:NodeType Pathway PS:Notes Headnote: The IkB kinase beta (IKBKB) is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington disease (HD). IKBKB may directly regulate the cleavage and neurotoxicity of huntingtin. Signaling description: Activation of IKBKB by DNA damage triggers caspase-dependent cleavage of mutant huntingtin (mHTT) and enhances the accumulation of oligomeric fragments which have neurotoxic properties. Moreover, mHTT directly binds to and activate IKBKB thus forming a deleterious feed-forward loop. mHTT also may be cleaved to oligomeric fragments by caspase 3 and 6 (CASP3/6) and these caspases in turn may be activated by IKBKB. Activated caspases finally lead to apoptosis. IKBKB may activate NFkB and production of inflammatory cytokines and chemokines including IL6, IL8, IL1B, TNF, CCL2 inducing neuroinflammation. mHTT may also activate IKBKG leading to the same results.Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 19488402 PS:PMID 20026656 PS:PMID 21554955 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-231072af-fa03-43c1-bb67-bb12a2c90707 NodeType: Pathway PMID: 18187454 PMID: 18292776 PMID: 18497750 PMID: 19339545 PMID: 20029421 PMID: 22481923 PMID: 27563880 PMID: 27929432 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-231072af-fa03-43c1-bb67-bb12a2c90707 Integrins in Cancer Cells Motility, Invasion and Survival uuid-231072af-fa03-43c1-bb67-bb12a2c90707 PS:CellType cancer stem cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-231072af-fa03-43c1-bb67-bb12a2c90707 PS:NodeType Pathway PS:PMID 18187454 PS:PMID 18292776 PS:PMID 18497750 PS:PMID 19339545 PS:PMID 20029421 PS:PMID 22481923 PS:PMID 27563880 PS:PMID 27929432 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-231728dd-b16f-428c-9b94-f65f540fad44 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-231728dd-b16f-428c-9b94-f65f540fad44 IL13R -> STAT6 Signaling uuid-231728dd-b16f-428c-9b94-f65f540fad44 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-231728dd-b16f-428c-9b94-f65f540fad44 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SIRT2 regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2340f703-9b3c-44e4-8110-2305d814d4f4 NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT2 regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Signaling description: SIRT2 requires NAD for its deacetylase activity. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. Outcome effects: NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. SIRT2 is highly expressed in the brain and can be implicated in the brain aging probably by participation in neuron cytoskeleton regulation. The role of SIRT2 in the regulation of gluconeogenesis was also shown. Organ: generic Organ_System: generic PMID: 24019997 PMID: 26089639 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-2340f703-9b3c-44e4-8110-2305d814d4f4 SIRT2 Signaling in Aging uuid-2340f703-9b3c-44e4-8110-2305d814d4f4 PS:CellType generic PS:Description SIRT2 regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2340f703-9b3c-44e4-8110-2305d814d4f4 PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT2 regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Signaling description: SIRT2 requires NAD for its deacetylase activity. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. Outcome effects: NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. SIRT2 is highly expressed in the brain and can be implicated in the brain aging probably by participation in neuron cytoskeleton regulation. The role of SIRT2 in the regulation of gluconeogenesis was also shown. PS:Organ generic PS:Organ_System generic PS:PMID 24019997 PS:PMID 26089639 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-234885ed-baba-4b6c-b943-ab9517c35034 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-234885ed-baba-4b6c-b943-ab9517c35034 H2A Modification Sites uuid-234885ed-baba-4b6c-b943-ab9517c35034 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-234885ed-baba-4b6c-b943-ab9517c35034 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-236a49ad-2f5d-49fb-b35b-67abc1e66fbb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-236a49ad-2f5d-49fb-b35b-67abc1e66fbb Coagulation cascade in cancer uuid-236a49ad-2f5d-49fb-b35b-67abc1e66fbb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-236a49ad-2f5d-49fb-b35b-67abc1e66fbb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Link PS:NodeType PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23941a44-c31f-4d8e-b5cc-5db18e7c34de NodeType: Pathway Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-23941a44-c31f-4d8e-b5cc-5db18e7c34de SARS inhibits IFN response, lung edema uuid-23941a44-c31f-4d8e-b5cc-5db18e7c34de PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23941a44-c31f-4d8e-b5cc-5db18e7c34de PS:NodeType Pathway PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23944935-07d5-4d2d-b5fb-f5ea07caa834 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-23944935-07d5-4d2d-b5fb-f5ea07caa834 N(4)-benzyladenine stabilization template uuid-23944935-07d5-4d2d-b5fb-f5ea07caa834 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23944935-07d5-4d2d-b5fb-f5ea07caa834 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2396275c-3668-4157-834e-6c5dc2fb8dd4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-2396275c-3668-4157-834e-6c5dc2fb8dd4 Ca2+ Flux Regulation uuid-2396275c-3668-4157-834e-6c5dc2fb8dd4 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2396275c-3668-4157-834e-6c5dc2fb8dd4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-239807d0-502d-4117-9c08-e512e552f2a1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-239807d0-502d-4117-9c08-e512e552f2a1 NRG1 -> TP53 Expression Target uuid-239807d0-502d-4117-9c08-e512e552f2a1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-239807d0-502d-4117-9c08-e512e552f2a1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2398615e-7685-4215-b408-4277f471d627 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-2398615e-7685-4215-b408-4277f471d627 Proteins with Altered Expression in Cancer-Associated Histone Methylation uuid-2398615e-7685-4215-b408-4277f471d627 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2398615e-7685-4215-b408-4277f471d627 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer stem cell Description: Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to estrogen receptors (ESR1), preventing estrogen from binding. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23a42402-4f65-429f-913e-1504c4341ae7 NodeType: Pathway Notes: Headnote: Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to estrogen receptors (ESR1), preventing estrogen from binding. Signaling description: Tamoxifen inhibits or activates estrogen receptor targets depending on the cell type. In mast cells, tamoxifen suppresses estrogen-induced proliferation and promotes apoptosis which reduces tumor growth, the main effect of the drug. Conversely, in endometrial cells, tamoxifen inhibits apoptosis and induces proliferation resulting in an increased risk of endometrial cancer. Organ: uterus Organ_System: reproductive system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-23a42402-4f65-429f-913e-1504c4341ae7 Tamoxifen Induced Endometrial Cancer uuid-23a42402-4f65-429f-913e-1504c4341ae7 PS:CellType cancer stem cell PS:Description Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to estrogen receptors (ESR1), preventing estrogen from binding. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23a42402-4f65-429f-913e-1504c4341ae7 PS:NodeType Pathway PS:Notes Headnote: Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to estrogen receptors (ESR1), preventing estrogen from binding. Signaling description: Tamoxifen inhibits or activates estrogen receptor targets depending on the cell type. In mast cells, tamoxifen suppresses estrogen-induced proliferation and promotes apoptosis which reduces tumor growth, the main effect of the drug. Conversely, in endometrial cells, tamoxifen inhibits apoptosis and induces proliferation resulting in an increased risk of endometrial cancer. PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b08399-3829-426c-8703-a4a80d414faa NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-23b08399-3829-426c-8703-a4a80d414faa Nociception Expression Targets uuid-23b08399-3829-426c-8703-a4a80d414faa PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b08399-3829-426c-8703-a4a80d414faa PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte Description: Complement activation plays an important role in the pathogenesis of Alzheimer's disease (AD). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b24178-86ce-4071-bae1-e65460505a57 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Complement activation plays an important role in the pathogenesis of AD. Signaling description: The complement cascade is an essential component of the innate immune response which assists in the removal of invading pathogens and cellular debris as well as in the processing of immune complexes. In AD, extracellular aggregated Abeta binds to complement component C1q and so triggers the classical complement pathway. The pathway includes consequent C1S, C2, C4B, and C3 activation. Outcome effects: The interaction of C3 with CR1 and ITGAM on the surface of astrocytes promotes the phagocytosis of Abeta aggregates by the cell. The acquired polymorphisms in CR1 gene are associated with extracellular Abeta accumulation. Activated C3 also induces the inflammatory response through the activation of C3AR1. Therefore, complement activation is implicated in AD pathogenesis via initiation of chronic inflammation and, at the same time has a role in removing Abeta aggregates. Organ: brain Organ_System: nervous system PMID: 10899441 PMID: 21856034 PMID: 22957298 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-23b24178-86ce-4071-bae1-e65460505a57 Complement Activation in Alzheimer's Disease uuid-23b24178-86ce-4071-bae1-e65460505a57 PS:CellType astrocyte PS:Description Complement activation plays an important role in the pathogenesis of Alzheimer's disease (AD). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b24178-86ce-4071-bae1-e65460505a57 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Complement activation plays an important role in the pathogenesis of AD. Signaling description: The complement cascade is an essential component of the innate immune response which assists in the removal of invading pathogens and cellular debris as well as in the processing of immune complexes. In AD, extracellular aggregated Abeta binds to complement component C1q and so triggers the classical complement pathway. The pathway includes consequent C1S, C2, C4B, and C3 activation. Outcome effects: The interaction of C3 with CR1 and ITGAM on the surface of astrocytes promotes the phagocytosis of Abeta aggregates by the cell. The acquired polymorphisms in CR1 gene are associated with extracellular Abeta accumulation. Activated C3 also induces the inflammatory response through the activation of C3AR1. Therefore, complement activation is implicated in AD pathogenesis via initiation of chronic inflammation and, at the same time has a role in removing Abeta aggregates. PS:Organ brain PS:Organ_System nervous system PS:PMID 10899441 PS:PMID 21856034 PS:PMID 22957298 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b7dbce-bc3e-4338-afef-9826b2384d2e NodeType: Pathway Organ: breast Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-23b7dbce-bc3e-4338-afef-9826b2384d2e Genes with Mutations Associated with Breast Cancer uuid-23b7dbce-bc3e-4338-afef-9826b2384d2e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-23b7dbce-bc3e-4338-afef-9826b2384d2e PS:NodeType Pathway PS:Organ breast PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2401ae5e-e070-4daa-a158-2e09dfd21533 NodeType: Pathway Notes: Headnote: Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Signaling description: Adenosine is released from leptomeningeal cells of the basal forebrain following prostaglandin D2 stimulation. Adenosine activates ADORA2A and ADORA1 on neurons in the basal forebrain and the ventrolateral preoptic nucleus (VLPO). Outcome effects: Sleep-promoting neurons in the VLPO send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus (TMN), which contribute to arousal. Caffeine binds to ADORA2A and ADORA1 with similar high affinities and acts as an antagonist at both receptor subtypes. Organ: brain Organ_System: nervous system PMID: 12531135 PMID: 16885223 PMID: 17129762 PMID: 17468046 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-2401ae5e-e070-4daa-a158-2e09dfd21533 Adenosine Role in Sleep Regulation uuid-2401ae5e-e070-4daa-a158-2e09dfd21533 PS:CellType neuron PS:Description Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2401ae5e-e070-4daa-a158-2e09dfd21533 PS:NodeType Pathway PS:Notes Headnote: Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Signaling description: Adenosine is released from leptomeningeal cells of the basal forebrain following prostaglandin D2 stimulation. Adenosine activates ADORA2A and ADORA1 on neurons in the basal forebrain and the ventrolateral preoptic nucleus (VLPO). Outcome effects: Sleep-promoting neurons in the VLPO send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus (TMN), which contribute to arousal. Caffeine binds to ADORA2A and ADORA1 with similar high affinities and acts as an antagonist at both receptor subtypes. PS:Organ brain PS:Organ_System nervous system PS:PMID 12531135 PS:PMID 16885223 PS:PMID 17129762 PS:PMID 17468046 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: EPHA2 regulates processes of cell migration in the lens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-242bf59c-ef81-482e-9968-3028ba4dc48e NodeType: Pathway Notes: Headnote: Cataract is clouding of the eye's lens that affects vision. Mutations in the EPHA2 proteins gene cause congenital cataract and are associated with age-related cataract resulting in the posterior subcapsular form of the disease. Signaling description: EPHA2, a receptor of the ephrin receptor subfamily, regulates processes of cell migration in the lens independent of ligand stimulation. Normally, EPHA2 exerts its effects through the activation of AKT1. Outcome effects: AKT1 involves IKBK, which phosphorylates NFKBIA disrupting its interaction with NF-kB, which is then released from its inhibitor, NFKBIA and binds to the promoter regions of integrins. In addition, AKT1 phosphorylates CTNNB1 which interacts with proteins of the cytoskeleton leading to cell migration. Mutated proteins: Mutated genes are shown in white-out style. Organ: eye Organ_System: sensory system PMID: 19649315 PMID: 22570727 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-242bf59c-ef81-482e-9968-3028ba4dc48e EPHA2 Mutations in Cataract uuid-242bf59c-ef81-482e-9968-3028ba4dc48e PS:CellType epithelial cell PS:Description EPHA2 regulates processes of cell migration in the lens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-242bf59c-ef81-482e-9968-3028ba4dc48e PS:NodeType Pathway PS:Notes Headnote: Cataract is clouding of the eye's lens that affects vision. Mutations in the EPHA2 proteins gene cause congenital cataract and are associated with age-related cataract resulting in the posterior subcapsular form of the disease. Signaling description: EPHA2, a receptor of the ephrin receptor subfamily, regulates processes of cell migration in the lens independent of ligand stimulation. Normally, EPHA2 exerts its effects through the activation of AKT1. Outcome effects: AKT1 involves IKBK, which phosphorylates NFKBIA disrupting its interaction with NF-kB, which is then released from its inhibitor, NFKBIA and binds to the promoter regions of integrins. In addition, AKT1 phosphorylates CTNNB1 which interacts with proteins of the cytoskeleton leading to cell migration. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 19649315 PS:PMID 22570727 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2446ef5a-42ad-4648-8938-8a1b963fbd5e NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2446ef5a-42ad-4648-8938-8a1b963fbd5e Proteins with Altered Expression in Osteoarthritis uuid-2446ef5a-42ad-4648-8938-8a1b963fbd5e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2446ef5a-42ad-4648-8938-8a1b963fbd5e PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Lung disease is the major cause of mortality in cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2451c0e3-e08e-4c2e-bca3-811ff7438d1a NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. There are more than a thousand known mutations in the CFTR gene divided into 5 classes. Class III mutations affect Cl- channel regulation and gating, and in this case CFTR protein is trafficked to the cell membrane, but then fails to respond to cAMP stimulation. Classes I, II, and III usually lead to the classic CF phenotype with pancreatic insufficiency. Class IV mutations affect Cl- conductance, while class V mutations interfere with normal transcription and thereby reduce the amount of otherwise normal CFTR. The latter two classes are mostly associated with a milder expression of the disease. The diversity of mutations explains the penetrance of the disease. It is unclear how the disruption of ion transport causes lung disease in CF. There are several theories of how defects in the protein and cellular function cause the clinical effects. One theory is that the lack of Cl-, iodide, and thiocyanate exiting through the CFTR protein channel leads to the accumulation of a more viscous, nutrient-rich mucus in the lungs that allows bacteria, usually Staphylococcus aureus or Pseudomonas aeruginosa, to hide from the body's immune system. Another theory is that CFTR protein failure leads to an increase in Na+ and Cl- uptake, which results in increased water reabsorption and creates thick, dehydrated mucus. The subsequent decrease in periciliary water volume causes a reduction in the lubricating layer between epithelium and mucus with compression of cilia by mucus resulting in the inhibition of normal ciliary and cough clearance of the mucus. According to this (Hypothesis), mucus on the epithelium forms plaques with hypoxic niches that can harbor bacteria, particularly Pseudomonas aeruginosa. The prevailing (Hypothesis) for pathophysiology in the CF lung has been the disruption of CFTR-mediated negative regulation of ENaC, leading to Na+ hyperabsorption and dehydration of the airway. The adequate hydration of airway surface liquid (ASL) is determined by the balance between Na+ absorption of ENaC and Cl- secretion mediated by CFTR. Outcome effects: In the absence of CFTR function, unrestrained Na+ absorption and the deficiency of active Cl- secretion lead to decreased ASL volume and subsequent failure of normal mucociliary clearance. Chronic lung diseases burdened by considerable tissue damage recruit additional receptors (P2RY2) responding to higher ATP concentrations. In addition, the lung expresses several AQPs including AQP1 in microvascular endothelia, AQP3 in large airways, AQP4 in large- and small-airway epithelia, and AQP5 in type I alveolar epithelial cells. Furthermore, pathogens activate NF-kB signaling pathway causing chronic infection, neutrophilic inflammation, and progressive airway destruction. The elevated level of IL8 is a marker of CF. The decreased level of nitric oxide (NO) also serves as a marker of inflammation during CF. Other types of inflammation in the lung are usually accompanied by high NO levels. The reason for decreased NO levels in patients with CF remains unknown. One possible explanation may be the increased activity of ARG1, which competes with NOS3 for the substrate during NO synthesis. NO stimulates CFTR via NO-sensitive guanylate cyclase. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 17643962 PMID: 22481418 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-2451c0e3-e08e-4c2e-bca3-811ff7438d1a CFTR Related Ion-Channel Dysfunction in Cystic Fibrosis Airway Epithelium (Class III Mutations) uuid-2451c0e3-e08e-4c2e-bca3-811ff7438d1a PS:CellType epithelial cell PS:Description Lung disease is the major cause of mortality in cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2451c0e3-e08e-4c2e-bca3-811ff7438d1a PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. There are more than a thousand known mutations in the CFTR gene divided into 5 classes. Class III mutations affect Cl- channel regulation and gating, and in this case CFTR protein is trafficked to the cell membrane, but then fails to respond to cAMP stimulation. Classes I, II, and III usually lead to the classic CF phenotype with pancreatic insufficiency. Class IV mutations affect Cl- conductance, while class V mutations interfere with normal transcription and thereby reduce the amount of otherwise normal CFTR. The latter two classes are mostly associated with a milder expression of the disease. The diversity of mutations explains the penetrance of the disease. It is unclear how the disruption of ion transport causes lung disease in CF. There are several theories of how defects in the protein and cellular function cause the clinical effects. One theory is that the lack of Cl-, iodide, and thiocyanate exiting through the CFTR protein channel leads to the accumulation of a more viscous, nutrient-rich mucus in the lungs that allows bacteria, usually Staphylococcus aureus or Pseudomonas aeruginosa, to hide from the body's immune system. Another theory is that CFTR protein failure leads to an increase in Na+ and Cl- uptake, which results in increased water reabsorption and creates thick, dehydrated mucus. The subsequent decrease in periciliary water volume causes a reduction in the lubricating layer between epithelium and mucus with compression of cilia by mucus resulting in the inhibition of normal ciliary and cough clearance of the mucus. According to this (Hypothesis), mucus on the epithelium forms plaques with hypoxic niches that can harbor bacteria, particularly Pseudomonas aeruginosa. The prevailing (Hypothesis) for pathophysiology in the CF lung has been the disruption of CFTR-mediated negative regulation of ENaC, leading to Na+ hyperabsorption and dehydration of the airway. The adequate hydration of airway surface liquid (ASL) is determined by the balance between Na+ absorption of ENaC and Cl- secretion mediated by CFTR. Outcome effects: In the absence of CFTR function, unrestrained Na+ absorption and the deficiency of active Cl- secretion lead to decreased ASL volume and subsequent failure of normal mucociliary clearance. Chronic lung diseases burdened by considerable tissue damage recruit additional receptors (P2RY2) responding to higher ATP concentrations. In addition, the lung expresses several AQPs including AQP1 in microvascular endothelia, AQP3 in large airways, AQP4 in large- and small-airway epithelia, and AQP5 in type I alveolar epithelial cells. Furthermore, pathogens activate NF-kB signaling pathway causing chronic infection, neutrophilic inflammation, and progressive airway destruction. The elevated level of IL8 is a marker of CF. The decreased level of nitric oxide (NO) also serves as a marker of inflammation during CF. Other types of inflammation in the lung are usually accompanied by high NO levels. The reason for decreased NO levels in patients with CF remains unknown. One possible explanation may be the increased activity of ARG1, which competes with NOS3 for the substrate during NO synthesis. NO stimulates CFTR via NO-sensitive guanylate cyclase. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17643962 PS:PMID 22481418 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Hypothyroidism is a pathological state caused by a deficiency of thyroid hormones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24834908-007a-4a48-b921-d0b6376393c2 NodeType: Pathway Notes: Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. About 95% of hypothyroidism cases occur from problems that start in the thyroid gland. In such cases, the disorder is called primary hypothyroidism. The two most common causes of primary hypothyroidism are (1) Hashimoto's thyroiditis which is an autoimmune condition and (2) overtreatment of hyperthyroidism (an overactive thyroid). Primary hypothyroidism may also occur as a result of insufficient introduction of iodine into body (endemic goiter). Primary hypothyroidism may also occur as a result of hereditary defects TSHR, GNAS, NKX1 and congenital hyperthyroidism. Signaling description: Overt hypothyroidism is characterized by stable decrease synthesis of both T3 and T4. The growth of TSH level is a result of cancellation of T3 inhibitory effect on TSH synthesis in pituitary cell. The signaling through TSHR which activate synthesis of thyroid hormones is shown. TSHR activates directly CREB1 -regulator of thyroglobulin expression. TSHR can indirectly activate thyroid hormones synthesis providing cells proliferation in thyroid gland. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: thyroid gland Organ_System: endocrine system PMID: 16715098 PMID: 20093166 PMID: 23169673 PMID: 23455760 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-24834908-007a-4a48-b921-d0b6376393c2 Overt Hypothyroidism, Primary uuid-24834908-007a-4a48-b921-d0b6376393c2 PS:CellType thyroid cell PS:Description Hypothyroidism is a pathological state caused by a deficiency of thyroid hormones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24834908-007a-4a48-b921-d0b6376393c2 PS:NodeType Pathway PS:Notes Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. About 95% of hypothyroidism cases occur from problems that start in the thyroid gland. In such cases, the disorder is called primary hypothyroidism. The two most common causes of primary hypothyroidism are (1) Hashimoto's thyroiditis which is an autoimmune condition and (2) overtreatment of hyperthyroidism (an overactive thyroid). Primary hypothyroidism may also occur as a result of insufficient introduction of iodine into body (endemic goiter). Primary hypothyroidism may also occur as a result of hereditary defects TSHR, GNAS, NKX1 and congenital hyperthyroidism. Signaling description: Overt hypothyroidism is characterized by stable decrease synthesis of both T3 and T4. The growth of TSH level is a result of cancellation of T3 inhibitory effect on TSH synthesis in pituitary cell. The signaling through TSHR which activate synthesis of thyroid hormones is shown. TSHR activates directly CREB1 -regulator of thyroglobulin expression. TSHR can indirectly activate thyroid hormones synthesis providing cells proliferation in thyroid gland. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 16715098 PS:PMID 20093166 PS:PMID 23169673 PS:PMID 23455760 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24a399ed-fc02-4133-b631-51d56b972f8b NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-24a399ed-fc02-4133-b631-51d56b972f8b Proteins Involved in B-Cell Chronic Lymphocytic Leukemia uuid-24a399ed-fc02-4133-b631-51d56b972f8b PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24a399ed-fc02-4133-b631-51d56b972f8b PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24c4712b-5db9-4ec5-b04f-60bfb6e31146 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-24c4712b-5db9-4ec5-b04f-60bfb6e31146 Kinetin biosynthesis template uuid-24c4712b-5db9-4ec5-b04f-60bfb6e31146 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24c4712b-5db9-4ec5-b04f-60bfb6e31146 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24cead3a-c7e3-409f-9ecd-1cbea4988fe4 NodeType: Pathway Organ: bone Organ: joint Organ: skin Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-24cead3a-c7e3-409f-9ecd-1cbea4988fe4 Proteins with Altered Expression in Psoriatic Arthritis uuid-24cead3a-c7e3-409f-9ecd-1cbea4988fe4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24cead3a-c7e3-409f-9ecd-1cbea4988fe4 PS:NodeType Pathway PS:Organ bone PS:Organ joint PS:Organ skin PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: epithelial cell Description: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24db0d43-59d2-42d6-802f-22064bc5620d NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. The virus genome encodes 6 early proteins and 2 late proteins. The early proteins are required for viral replication (E1 and E2), virus particle release (E4), blocking of host immune response (E5) and host cell proliferation (E6 and E7). The late viral proteins (L1 and L2) are necessary for viral capsid formation. The HPV genome is surrounded by an icosahedral capsid consisting of two structural proteins: the major protein L1 and the minor capsid protein L2. The L1 proteins are highly conserved and form 72 five-fold capsomers. The L2 protein binds viral DNA; whereas, L1 can bind laminin-332 and syndecan-1 (SDC1). Conformational changes and proteolytic cleavage of L2 is essential for successful infection. Signaling description: The internalization of virus can occur via different pathways including clathrin and/or caveolae dependent /independent and lipid raft independent routes. In addition, L2 can interact with karyopherins (importins) and the viral DNA may enter the nucleus via import pathways mediated by karyopherins. The karyopherin beta/importin beta superfamily proteins interact with nucleoporins at the nuclear pore complex to transport the proteins into the nucleus. E1 binds to and recruits cellular replication proteins to the viral origin of replication including alpha DNA polymeraseprimase, replication factor A, and human topoisomerase I (TOP1). E2 binds DNA as a homodimer, with a helix of each monomer contacting two consecutive major grooves of its target site. Strong interactions of high-risk HPV E2 with CDC20 and CDH1, the activators of APC/C, result in the stabilization of some APC/C substrates including CCNB2 and AURKA. The overexpression of AURKA causes excessive centrosome duplication and genome instability. The blocking of APC/C by E2 also stabilizes SKP2, which leads to the increased levels of SKP2 prior to the cell reaching the G1/S transition. The accumulation of SKP2 by E2 leads to E2 degradation via the SCF/SKP2 complex through the negative feedback loop. SCF (SKP1/CUL1/F-box) is a ring-finger ubiquitin ligase composed of four subunits: three invariable components (RBX1, CUL1, and SKP1) and one variable component, specifically, F-box protein SKP2, that binds directly to the substrates. The overexpression of SKP2 also leads to the activation of E2F transcription factors required for G1/S transition. The interaction of E2 with BRD4 is necessary to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in HPV-infected cells. The E4 protein is detected in the amplification of the viral genome and its greatest amount is observed at the late stage of virus replication prior to assembly and release of viral particles. The protein contributes to viral genome replication and promotes the release of viral particles. E4 binds directly to keratin type I such as KRT18, but not keratin type II or vimentin. The binding is dependent on the 16 amino acids at the N-terminus of the E4 protein, with the leucine cluster being indispensable. The next protein interacting with E4 cellular protein is calpain. Protease calpain cleaves the E4 protein after the amino acid 17 to generate species that lack the N terminus. These C-terminal fragments are able to multimerize and form amyloid-like fibers. This can lead to accumulation of E4 and disruption of the normal dynamics of keratin networks. E4 is also phosphorylated by CDK (CCNB1/CDK1 and CCNA2/ CDK2) in the G2-phase-like/differentiating cells. This causes G2 cell cycle arrest by associating with and preventing the nuclear entry of the CDK1/CCNB1 complexes. E5 protein interacts with IPO5, and the IPO5/E5 complex plays an important role in vesicle trafficking. E5 protein binds and inhibits the activity of ATP6V0C, which alters the endosome PMID: 11753669 PMID: 14694114 PMID: 16597322 PMID: 16733063 PMID: 19007434 PMID: 19081593 PMID: 19828607 PMID: 19861444 PMID: 20089191 PMID: 21400034 PMID: 22078316 PMID: 23263171 PMID: 23689062 PMID: 24016539 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-24db0d43-59d2-42d6-802f-22064bc5620d HPV Infection and Cancer uuid-24db0d43-59d2-42d6-802f-22064bc5620d PS:CellType cancer cell PS:CellType epithelial cell PS:Description Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24db0d43-59d2-42d6-802f-22064bc5620d PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. The virus genome encodes 6 early proteins and 2 late proteins. The early proteins are required for viral replication (E1 and E2), virus particle release (E4), blocking of host immune response (E5) and host cell proliferation (E6 and E7). The late viral proteins (L1 and L2) are necessary for viral capsid formation. The HPV genome is surrounded by an icosahedral capsid consisting of two structural proteins: the major protein L1 and the minor capsid protein L2. The L1 proteins are highly conserved and form 72 five-fold capsomers. The L2 protein binds viral DNA; whereas, L1 can bind laminin-332 and syndecan-1 (SDC1). Conformational changes and proteolytic cleavage of L2 is essential for successful infection. Signaling description: The internalization of virus can occur via different pathways including clathrin and/or caveolae dependent /independent and lipid raft independent routes. In addition, L2 can interact with karyopherins (importins) and the viral DNA may enter the nucleus via import pathways mediated by karyopherins. The karyopherin beta/importin beta superfamily proteins interact with nucleoporins at the nuclear pore complex to transport the proteins into the nucleus. E1 binds to and recruits cellular replication proteins to the viral origin of replication including alpha DNA polymeraseprimase, replication factor A, and human topoisomerase I (TOP1). E2 binds DNA as a homodimer, with a helix of each monomer contacting two consecutive major grooves of its target site. Strong interactions of high-risk HPV E2 with CDC20 and CDH1, the activators of APC/C, result in the stabilization of some APC/C substrates including CCNB2 and AURKA. The overexpression of AURKA causes excessive centrosome duplication and genome instability. The blocking of APC/C by E2 also stabilizes SKP2, which leads to the increased levels of SKP2 prior to the cell reaching the G1/S transition. The accumulation of SKP2 by E2 leads to E2 degradation via the SCF/SKP2 complex through the negative feedback loop. SCF (SKP1/CUL1/F-box) is a ring-finger ubiquitin ligase composed of four subunits: three invariable components (RBX1, CUL1, and SKP1) and one variable component, specifically, F-box protein SKP2, that binds directly to the substrates. The overexpression of SKP2 also leads to the activation of E2F transcription factors required for G1/S transition. The interaction of E2 with BRD4 is necessary to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in HPV-infected cells. The E4 protein is detected in the amplification of the viral genome and its greatest amount is observed at the late stage of virus replication prior to assembly and release of viral particles. The protein contributes to viral genome replication and promotes the release of viral particles. E4 binds directly to keratin type I such as KRT18, but not keratin type II or vimentin. The binding is dependent on the 16 amino acids at the N-terminus of the E4 protein, with the leucine cluster being indispensable. The next protein interacting with E4 cellular protein is calpain. Protease calpain cleaves the E4 protein after the amino acid 17 to generate species that lack the N terminus. These C-terminal fragments are able to multimerize and form amyloid-like fibers. This can lead to accumulation of E4 and disruption of the normal dynamics of keratin networks. E4 is also phosphorylated by CDK (CCNB1/CDK1 and CCNA2/ CDK2) in the G2-phase-like/differentiating cells. This causes G2 cell cycle arrest by associating with and preventing the nuclear entry of the CDK1/CCNB1 complexes. E5 protein interacts with IPO5, and the IPO5/E5 complex plays an important role in vesicle trafficking. E5 protein binds and inhibits the activity of ATP6V0C, which alters the endosome PS:PMID 11753669 PS:PMID 14694114 PS:PMID 16597322 PS:PMID 16733063 PS:PMID 19007434 PS:PMID 19081593 PS:PMID 19828607 PS:PMID 19861444 PS:PMID 20089191 PS:PMID 21400034 PS:PMID 22078316 PS:PMID 23263171 PS:PMID 23689062 PS:PMID 24016539 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24ed122c-0dfb-4ff2-a095-a03b7fd0b0d0 NodeType: Pathway Notes: During general inflammation, there is an increase in the synthesis of interleukins and other mediators by different types of cells. The interleukins IL-6 and IL-22 and also activin B are thought to be the primary regulators of inflammatory anemia. Inflammatory mediators induce production of HAMP by hepatocytes. HAMP released to the blood from the liver regulates the systemic iron balance—it prevents iron release from enterocytes and macrophages (see Pathways 2 and 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-24ed122c-0dfb-4ff2-a095-a03b7fd0b0d0 1_Inflammatory mediators increase the production of hepcidin (HAMP) uuid-24ed122c-0dfb-4ff2-a095-a03b7fd0b0d0 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-24ed122c-0dfb-4ff2-a095-a03b7fd0b0d0 PS:NodeType Pathway PS:Notes During general inflammation, there is an increase in the synthesis of interleukins and other mediators by different types of cells. The interleukins IL-6 and IL-22 and also activin B are thought to be the primary regulators of inflammatory anemia. Inflammatory mediators induce production of HAMP by hepatocytes. HAMP released to the blood from the liver regulates the systemic iron balance—it prevents iron release from enterocytes and macrophages (see Pathways 2 and 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2529c7a9-3872-4c55-b785-9d8d6dad353b NodeType: Pathway urn:agi-pathway:uuid-2529c7a9-3872-4c55-b785-9d8d6dad353b Mitochondrial Fusion and Fission uuid-2529c7a9-3872-4c55-b785-9d8d6dad353b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2529c7a9-3872-4c55-b785-9d8d6dad353b PS:NodeType Pathway PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-252cc7c6-91f3-4415-8d74-6c8595b5b65d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-252cc7c6-91f3-4415-8d74-6c8595b5b65d Diterpenoid biosynthesis template uuid-252cc7c6-91f3-4415-8d74-6c8595b5b65d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-252cc7c6-91f3-4415-8d74-6c8595b5b65d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2545b73a-7f8b-496f-bdd9-d34f775da9a3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2545b73a-7f8b-496f-bdd9-d34f775da9a3 Benzoate biosynthesis template uuid-2545b73a-7f8b-496f-bdd9-d34f775da9a3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2545b73a-7f8b-496f-bdd9-d34f775da9a3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-254c4117-54a5-4ccf-a655-1b6aff3c5dd8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-254c4117-54a5-4ccf-a655-1b6aff3c5dd8 Lacrimal gland anatomical concepts uuid-254c4117-54a5-4ccf-a655-1b6aff3c5dd8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-254c4117-54a5-4ccf-a655-1b6aff3c5dd8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2560f94e-11e5-43e1-af85-d07703f4d2eb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2560f94e-11e5-43e1-af85-d07703f4d2eb Selenoamino acid metabolism template uuid-2560f94e-11e5-43e1-af85-d07703f4d2eb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2560f94e-11e5-43e1-af85-d07703f4d2eb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Mitochondria in mammals are organized into tubular networks that undergo frequent shape change. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-257cb9db-d67a-45e3-92bf-90d5fc1d71be NodeType: Pathway Notes: Headnote: Mitochondria in mammals are organized into tubular networks that undergo frequent shape change. Mitochondrial fusion and fission are the main components that mediate mitochondrial shape change. Signaling description: As soon as the mitochondrion has sufficient mtDNA, membrane area, and membrane proteins, it can undergo fission. Mitochondria can also fuse with each other in order to exchange genetic material. FIS1 supports the dynamic assembly of DNM1L on the mitochondrial surface. DNM1L self-assembles into curved filaments and its function is comparable to other dynamin family members that act in numerous intracellular membrane scission events. Outcome effects: During mitochondrial fusion, MFN1 and MFN2 bind via coiled-coil domain interactions between mitofusins that are anchored into the outer mitochondrial membrane, with their GTPase domains facing the cytosol. OPA1 is an intermembrane space protein anchored to the inner membrane. The coordinated activity of the machineries in the outer and inner membranes is necessary to ensure the reliability of double membrane fusion. The second step in membrane fusion is lipid bilayer mixing. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-257cb9db-d67a-45e3-92bf-90d5fc1d71be Mitochondrial Fusion and Fission uuid-257cb9db-d67a-45e3-92bf-90d5fc1d71be PS:CellType generic PS:Description Mitochondria in mammals are organized into tubular networks that undergo frequent shape change. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-257cb9db-d67a-45e3-92bf-90d5fc1d71be PS:NodeType Pathway PS:Notes Headnote: Mitochondria in mammals are organized into tubular networks that undergo frequent shape change. Mitochondrial fusion and fission are the main components that mediate mitochondrial shape change. Signaling description: As soon as the mitochondrion has sufficient mtDNA, membrane area, and membrane proteins, it can undergo fission. Mitochondria can also fuse with each other in order to exchange genetic material. FIS1 supports the dynamic assembly of DNM1L on the mitochondrial surface. DNM1L self-assembles into curved filaments and its function is comparable to other dynamin family members that act in numerous intracellular membrane scission events. Outcome effects: During mitochondrial fusion, MFN1 and MFN2 bind via coiled-coil domain interactions between mitofusins that are anchored into the outer mitochondrial membrane, with their GTPase domains facing the cytosol. OPA1 is an intermembrane space protein anchored to the inner membrane. The coordinated activity of the machineries in the outer and inner membranes is necessary to ensure the reliability of double membrane fusion. The second step in membrane fusion is lipid bilayer mixing. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25a81614-68db-4d7b-b41b-2a5d5e3cb809 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-25a81614-68db-4d7b-b41b-2a5d5e3cb809 Rett Syndrome Biomarkers uuid-25a81614-68db-4d7b-b41b-2a5d5e3cb809 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25a81614-68db-4d7b-b41b-2a5d5e3cb809 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25e06c69-4455-4327-b46e-a970cb3232bb NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-25e06c69-4455-4327-b46e-a970cb3232bb Vitamin B1 (Thiamine) Metabolism uuid-25e06c69-4455-4327-b46e-a970cb3232bb PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25e06c69-4455-4327-b46e-a970cb3232bb PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25fbf9ec-26ed-4c30-b3fe-b485b63cc8c8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-25fbf9ec-26ed-4c30-b3fe-b485b63cc8c8 FGF1 -> STAT Expression Targets uuid-25fbf9ec-26ed-4c30-b3fe-b485b63cc8c8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-25fbf9ec-26ed-4c30-b3fe-b485b63cc8c8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-262bb50f-2c0e-4f02-8fd5-0f6057c5f8df NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-262bb50f-2c0e-4f02-8fd5-0f6057c5f8df Proteins Involved in Mucinous Ovarian Carcinoma uuid-262bb50f-2c0e-4f02-8fd5-0f6057c5f8df PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-262bb50f-2c0e-4f02-8fd5-0f6057c5f8df PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: osteoblast Description: BMP and TGFB signaling are crucial for osteoblast differentiation and function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2639f218-230b-42e3-8569-415f4270f923 NodeType: Pathway Notes: Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, renal functional impairment, tophi and bone erosion. It has been shown that osteoblast viability and function are disrupted in gout. Signaling description: BMP and TGFB signaling are crucial for osteoblast differentiation and function. TGFB2 and BMP2 bind to their receptors and through SMAD pathway lead to RUNX2 activation. Outcome effects: In turn, RUNX2 promotes SP7, BGLAP, and IBSP expression which is responsible for osteoblast differentiation and function (biomineral formation). Further, RUNX2 along with PTH and calcitriol (vitamin D3) signaling regulates TNFSF11 and TNFRSF11B expression, thereby promoting osteoclast formation and function. In addition, monosodium urate crystal deposition results in decreased mineralization and reduced mRNA expression of genes related to all stages of osteoblast differentiation such as RUNX2, SP7, IBSP, and BGLAP. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: bone Organ_System: skeletal system PMID: 21403645 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-2639f218-230b-42e3-8569-415f4270f923 Osteoblast Function Decline in Gout uuid-2639f218-230b-42e3-8569-415f4270f923 PS:CellType osteoblast PS:Description BMP and TGFB signaling are crucial for osteoblast differentiation and function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2639f218-230b-42e3-8569-415f4270f923 PS:NodeType Pathway PS:Notes Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, renal functional impairment, tophi and bone erosion. It has been shown that osteoblast viability and function are disrupted in gout. Signaling description: BMP and TGFB signaling are crucial for osteoblast differentiation and function. TGFB2 and BMP2 bind to their receptors and through SMAD pathway lead to RUNX2 activation. Outcome effects: In turn, RUNX2 promotes SP7, BGLAP, and IBSP expression which is responsible for osteoblast differentiation and function (biomineral formation). Further, RUNX2 along with PTH and calcitriol (vitamin D3) signaling regulates TNFSF11 and TNFRSF11B expression, thereby promoting osteoclast formation and function. In addition, monosodium urate crystal deposition results in decreased mineralization and reduced mRNA expression of genes related to all stages of osteoblast differentiation such as RUNX2, SP7, IBSP, and BGLAP. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ bone PS:Organ_System skeletal system PS:PMID 21403645 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Description: Upon IFN-gamma (IFNG) and TNF-alpha (TNF) exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, show aberrant hyperproliferation, and terminal differentiation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-269b87c1-99cd-438e-9126-06f035083f28 NodeType: Pathway Notes: Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. IFN-gamma (IFNG) and TNF-alpha (TNF) induced inflammation is implicated in the development of psoriasis. Signaling description: SOCS1 and SOCS3 are abundantly expressed in IFNG/TNF-activated psoriatic keratinocytes which play an important role in maintaining anti-apoptosis. SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT1 pathway in keratinocytes. The latter determines the activation of the antiapoptotic NF-kB cascade and, in parallel, the inhibition of the proapoptotic BAD function in keratinocytes. SOCS3 binds RasGAP (RASA1), a negative regulator of Ras signaling, and reduces its activity, thereby promoting activation of the Ras pathway. Moreover, SOCS1 interacts with RASA1, and promotes its degradation after IFNG stimulation. Outcome effects: Upon IFN-gamma (IFNG) and TNF-alpha (TNF) exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, show aberrant hyperproliferation, and terminal differentiation. The thickening of psoriatic skin also results from an unusual resistance of keratinocytes to cytokine-induced apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: skin Organ_System: integumentary system PMID: 10792035 PMID: 15173123 PMID: 20644166 PMID: 22739986 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-269b87c1-99cd-438e-9126-06f035083f28 IFN-gamma/TNF-alpha Mediated Cell Proliferation in Psoriasis uuid-269b87c1-99cd-438e-9126-06f035083f28 PS:CellType keratinocyte PS:Description Upon IFN-gamma (IFNG) and TNF-alpha (TNF) exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, show aberrant hyperproliferation, and terminal differentiation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-269b87c1-99cd-438e-9126-06f035083f28 PS:NodeType Pathway PS:Notes Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. IFN-gamma (IFNG) and TNF-alpha (TNF) induced inflammation is implicated in the development of psoriasis. Signaling description: SOCS1 and SOCS3 are abundantly expressed in IFNG/TNF-activated psoriatic keratinocytes which play an important role in maintaining anti-apoptosis. SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT1 pathway in keratinocytes. The latter determines the activation of the antiapoptotic NF-kB cascade and, in parallel, the inhibition of the proapoptotic BAD function in keratinocytes. SOCS3 binds RasGAP (RASA1), a negative regulator of Ras signaling, and reduces its activity, thereby promoting activation of the Ras pathway. Moreover, SOCS1 interacts with RASA1, and promotes its degradation after IFNG stimulation. Outcome effects: Upon IFN-gamma (IFNG) and TNF-alpha (TNF) exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, show aberrant hyperproliferation, and terminal differentiation. The thickening of psoriatic skin also results from an unusual resistance of keratinocytes to cytokine-induced apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ skin PS:Organ_System integumentary system PS:PMID 10792035 PS:PMID 15173123 PS:PMID 20644166 PS:PMID 22739986 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: The level of serum IL17 is increased in patients with systemic lupus erythematosus (SLE). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26b75c9a-f8e5-43f9-890b-3ef52c0b68a5 NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. The level of serum IL17 is increased in SLE patients. The frequency of IL17-producing T- cells is increased in peripheral blood. T-cell differentiation into IL17-producing Th17 cells requires cytokines IL6, IL23, IL21, and TGFB. High levels of IFNA1, IL1B, and IL18 released from dendritic cells can promote Th17 cell activation. IL6, IL21, and IL23 receptors all activate STAT3, which can bind and activate IL17 and IL21 genes directly. The expression and activity of STAT3 is increased in SLE T-cells. IL17 gene transcription is regulated by the retinoid related orphan receptor, RORC transcription factor. RORC is expressed exclusively in Th17 cells and is necessary for IL17 production. In addition, altered T-cell receptor (TCR) signaling can also lead to Th17 expression. Outcome effects: There is evidence of an increased level of IL17 in the circulation and tissues of SLE patients. IL17 can induce the production of an array of inflammatory molecules such as cytokines, chemokines, and MMP from immune and non-immune cells, leading to the recruitment and activation of inflammatory cells along with tissue damage in SLE. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: lymphatic system PMID: 21457530 PMID: 21720245 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-26b75c9a-f8e5-43f9-890b-3ef52c0b68a5 Th17-Cell Function in Systemic Lupus Erythematosus uuid-26b75c9a-f8e5-43f9-890b-3ef52c0b68a5 PS:CellType T-cell PS:Description The level of serum IL17 is increased in patients with systemic lupus erythematosus (SLE). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26b75c9a-f8e5-43f9-890b-3ef52c0b68a5 PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. The level of serum IL17 is increased in SLE patients. The frequency of IL17-producing T- cells is increased in peripheral blood. T-cell differentiation into IL17-producing Th17 cells requires cytokines IL6, IL23, IL21, and TGFB. High levels of IFNA1, IL1B, and IL18 released from dendritic cells can promote Th17 cell activation. IL6, IL21, and IL23 receptors all activate STAT3, which can bind and activate IL17 and IL21 genes directly. The expression and activity of STAT3 is increased in SLE T-cells. IL17 gene transcription is regulated by the retinoid related orphan receptor, RORC transcription factor. RORC is expressed exclusively in Th17 cells and is necessary for IL17 production. In addition, altered T-cell receptor (TCR) signaling can also lead to Th17 expression. Outcome effects: There is evidence of an increased level of IL17 in the circulation and tissues of SLE patients. IL17 can induce the production of an array of inflammatory molecules such as cytokines, chemokines, and MMP from immune and non-immune cells, leading to the recruitment and activation of inflammatory cells along with tissue damage in SLE. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 21457530 PS:PMID 21720245 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c3366f-6408-49c8-9b8b-1de31be1bfd9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-26c3366f-6408-49c8-9b8b-1de31be1bfd9 Tyrosine degradation template uuid-26c3366f-6408-49c8-9b8b-1de31be1bfd9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c3366f-6408-49c8-9b8b-1de31be1bfd9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c78685-a7a4-44e2-9a53-afd3a0c30840 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-26c78685-a7a4-44e2-9a53-afd3a0c30840 Xylan reducing end synthesis uuid-26c78685-a7a4-44e2-9a53-afd3a0c30840 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c78685-a7a4-44e2-9a53-afd3a0c30840 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c87205-a805-42c8-a10c-0200c722e60f NodeType: Pathway Notes: Excess FFAs can be toxic for hepatocytes. Hepatocytes take up FFAs and usually process and store them as triglycerides (TGs). But when hepatic FFAs exceed the accumulation quota, they activate hepatocyte apoptosis and inflammation. Hepatocyte apoptosis and inflammation are crucial mechanisms that promote progression of steatosis in steatohepatitis. Dead hepatocytes are consumed by macrophages leading to the release of proinflammatory signals. These stimuli along with proinflammatory cytokines produced by hepatocytes activate the hepatic stellate cells involved in liver fibrosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-26c87205-a805-42c8-a10c-0200c722e60f 2_Lipotoxicity in NAFLD uuid-26c87205-a805-42c8-a10c-0200c722e60f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26c87205-a805-42c8-a10c-0200c722e60f PS:NodeType Pathway PS:Notes Excess FFAs can be toxic for hepatocytes. Hepatocytes take up FFAs and usually process and store them as triglycerides (TGs). But when hepatic FFAs exceed the accumulation quota, they activate hepatocyte apoptosis and inflammation. Hepatocyte apoptosis and inflammation are crucial mechanisms that promote progression of steatosis in steatohepatitis. Dead hepatocytes are consumed by macrophages leading to the release of proinflammatory signals. These stimuli along with proinflammatory cytokines produced by hepatocytes activate the hepatic stellate cells involved in liver fibrosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Mantle cell lymphoma (MCL) represents approximately 4-10? of all cases of non-Hodgkin lymphoma. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description:The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. At the same time, several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL has the highest degree of genomic instability among B-cell malignances and many secondary chromosomal alterations of cell-cycle regulation genes have been described in MCL. TP53, RB1, ATM, BCL2L11, SOCS1, CDKN2A, CDKN2C, HIC1, FAF1, TNFAIP3, and CHEK2 genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplifications deregulate additional genes including CDK4, BMI1, MDM2, BCL2, MYC, SYK, and PIK3CA while point mutations may activate NOTCH1. Furthermore, several signaling pathways contribute to MCL pathogenesis including constitutively activated PI3K/AKT1/MTOR, NF-kB, WNT, Hedgehog (SHH), Notch, and JAK/STAT pathways. Further, there are some indications that tumor-host interactions may be more important in MCL than currently believed. It has been shown that IL6, IL10, and CXCL12 may activate JAK/STAT3 pathway. The expression of CD40 and responsiveness to CD40LG suggest that MCL cells can interact with CD40LG-positive T cells. Furthermore, epigenetic changes in MCL are currently under investigation. Several hypomethylated and thereby upregulated genes including NOTCH1, CDK5, and HDAC1 could play a pathogenic role in disease development and progression. MCL is one of the most difficult B-cell lymphomas to treat. Although conventional chemotherapy induces high remission rates in previously untreated patients, relapse within a few years is common contributing to a rather short median survival of 3-4 years. Proteasome inhibitors (bortezomib), MTOR inhibitors (temsirolimus), immunomodulatory drugs (lenalidomide) and new alkylating agents (bendamustine) have recently been added to the treatment options for MCL. Outcome effects: In general, all of the described MCL-related signaling routes promote tumor cell proliferation and survival. The role of CCND1 in MCL lymphomagenesis is related to its function as a regulator of cyclin-dependent kinases, CDK4 and CDK6 during the cell cycle. The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promoting cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In addition, the microenvironment most likely plays an important role in the biology of MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 18410453 PMID: 19362399 PMID: 19880776 PMID: 20940415 PMID: 22224767 PMID: 23023712 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 Mantle Cell Lymphoma uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 PS:CellType B-cell PS:CellType cancer cell PS:Description Mantle cell lymphoma (MCL) represents approximately 4-10? of all cases of non-Hodgkin lymphoma. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description:The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. At the same time, several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL has the highest degree of genomic instability among B-cell malignances and many secondary chromosomal alterations of cell-cycle regulation genes have been described in MCL. TP53, RB1, ATM, BCL2L11, SOCS1, CDKN2A, CDKN2C, HIC1, FAF1, TNFAIP3, and CHEK2 genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplifications deregulate additional genes including CDK4, BMI1, MDM2, BCL2, MYC, SYK, and PIK3CA while point mutations may activate NOTCH1. Furthermore, several signaling pathways contribute to MCL pathogenesis including constitutively activated PI3K/AKT1/MTOR, NF-kB, WNT, Hedgehog (SHH), Notch, and JAK/STAT pathways. Further, there are some indications that tumor-host interactions may be more important in MCL than currently believed. It has been shown that IL6, IL10, and CXCL12 may activate JAK/STAT3 pathway. The expression of CD40 and responsiveness to CD40LG suggest that MCL cells can interact with CD40LG-positive T cells. Furthermore, epigenetic changes in MCL are currently under investigation. Several hypomethylated and thereby upregulated genes including NOTCH1, CDK5, and HDAC1 could play a pathogenic role in disease development and progression. MCL is one of the most difficult B-cell lymphomas to treat. Although conventional chemotherapy induces high remission rates in previously untreated patients, relapse within a few years is common contributing to a rather short median survival of 3-4 years. Proteasome inhibitors (bortezomib), MTOR inhibitors (temsirolimus), immunomodulatory drugs (lenalidomide) and new alkylating agents (bendamustine) have recently been added to the treatment options for MCL. Outcome effects: In general, all of the described MCL-related signaling routes promote tumor cell proliferation and survival. The role of CCND1 in MCL lymphomagenesis is related to its function as a regulator of cyclin-dependent kinases, CDK4 and CDK6 during the cell cycle. The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promoting cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In addition, the microenvironment most likely plays an important role in the biology of MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 18410453 PS:PMID 19362399 PS:PMID 19880776 PS:PMID 20940415 PS:PMID 22224767 PS:PMID 23023712 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26d1412c-0693-4f5b-8202-09d62e1443b3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-26d1412c-0693-4f5b-8202-09d62e1443b3 Insulin -> STAT Expression Targets uuid-26d1412c-0693-4f5b-8202-09d62e1443b3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26d1412c-0693-4f5b-8202-09d62e1443b3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell CellType: mesenchymal stem cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26d8c0b1-4eea-430c-a20e-8b9764e017a4 NodeType: Pathway PMID: 18719708 PMID: 21697900 PMID: 26186729 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-26d8c0b1-4eea-430c-a20e-8b9764e017a4 Lamellipodia and Filopodia Formation uuid-26d8c0b1-4eea-430c-a20e-8b9764e017a4 PS:CellType cancer stem cell PS:CellType mesenchymal stem cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26d8c0b1-4eea-430c-a20e-8b9764e017a4 PS:NodeType Pathway PS:PMID 18719708 PS:PMID 21697900 PS:PMID 26186729 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26e813ee-db40-441d-8525-55ca9037fb7f NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-26e813ee-db40-441d-8525-55ca9037fb7f CHRNA7 -> NOS1 Production uuid-26e813ee-db40-441d-8525-55ca9037fb7f PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26e813ee-db40-441d-8525-55ca9037fb7f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: leukocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26eae7a3-1f80-492f-8bf4-7cf18a27ce25 NodeType: Pathway Notes: An increase of IL6 and IL12 was observed in multiple sclerosis. These interleukins leads to activation of the transcription of cytokines through the JAK-STAT pathway. Organ_System: lymphatic system PMID: 22287540 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-26eae7a3-1f80-492f-8bf4-7cf18a27ce25 IL6/IL12 Signaling Activates Immune System in Multiple Sclerosis uuid-26eae7a3-1f80-492f-8bf4-7cf18a27ce25 PS:CellType leukocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26eae7a3-1f80-492f-8bf4-7cf18a27ce25 PS:NodeType Pathway PS:Notes An increase of IL6 and IL12 was observed in multiple sclerosis. These interleukins leads to activation of the transcription of cytokines through the JAK-STAT pathway. PS:Organ_System lymphatic system PS:PMID 22287540 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27206b72-b930-40ef-8872-793a49168025 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-27206b72-b930-40ef-8872-793a49168025 NSP1 inhibits protein synthesis and activates immunophilins uuid-27206b72-b930-40ef-8872-793a49168025 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27206b72-b930-40ef-8872-793a49168025 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2756c94b-edb8-4846-817a-094b4b1f759e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-2756c94b-edb8-4846-817a-094b4b1f759e TCR -> CREB/CREBBP/ATF Expression Targets uuid-2756c94b-edb8-4846-817a-094b4b1f759e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2756c94b-edb8-4846-817a-094b4b1f759e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27628d34-afd8-4b25-8651-2ec55c7cbfee NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-27628d34-afd8-4b25-8651-2ec55c7cbfee AREG -> SMAD1 Expression Target uuid-27628d34-afd8-4b25-8651-2ec55c7cbfee PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27628d34-afd8-4b25-8651-2ec55c7cbfee PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27acdbd2-7c6b-4d3f-9857-07d8a96a4e9d NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-27acdbd2-7c6b-4d3f-9857-07d8a96a4e9d Panic Disorder: Proteins Involved uuid-27acdbd2-7c6b-4d3f-9857-07d8a96a4e9d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27acdbd2-7c6b-4d3f-9857-07d8a96a4e9d PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27b9e945-b85d-44ea-820c-737116f3ac9e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-27b9e945-b85d-44ea-820c-737116f3ac9e SARS+>Filopodia uuid-27b9e945-b85d-44ea-820c-737116f3ac9e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27b9e945-b85d-44ea-820c-737116f3ac9e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27da22ca-0441-42d6-9679-e4a740feff60 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-27da22ca-0441-42d6-9679-e4a740feff60 NGF+>Cornea epithelium uuid-27da22ca-0441-42d6-9679-e4a740feff60 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-27da22ca-0441-42d6-9679-e4a740feff60 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28100734-b91e-431f-accb-516e672f81fc NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-28100734-b91e-431f-accb-516e672f81fc Genes with Mutations Associated with Primary Ovarian Insufficiency uuid-28100734-b91e-431f-accb-516e672f81fc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28100734-b91e-431f-accb-516e672f81fc PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: gonadotroph Description: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-281442b0-51c4-4dd7-986d-7951574cb637 NodeType: Pathway Notes: Headnote: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Signaling description: Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB). Inhibins are structurally related to activins. Activin is a homodimer of two b subunits, which antagonizes the effect of inhibin. The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. The gene products of INHA, INHBA and INHBB are restricted to granulosa cells from the primordial follicle stage. If there is any mutation in the INHA gene, the association of a and b will be severely diminished, the homodimerization of two b subunits will take place dominantly. In other words, the concentration of inhibin will diminish and concentration of activins will rise and ultimately FSH concentration will rise. Outcome effects: High FSH level resulting in increased number of primordial follicles being recruited for folliculogenesis, enhanced follicular development to antral stages with increased granulosa cell proliferation, cumulus cell differentiation and expansion, and a dysregulation in steroid hormone production at the theca and granulosa cell level. This condition may also lead to the rapid depletion of follicles, causing premature ovarian failure. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: brain Organ: pituitary gland Organ_System: reproductive system PMID: 19752047 PMID: 20382564 PMID: 20668067 PMID: 24696764 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-281442b0-51c4-4dd7-986d-7951574cb637 FSH Hyperproduction Due to INHA Mutation in Primary Ovarian Insufficiency uuid-281442b0-51c4-4dd7-986d-7951574cb637 PS:CellType gonadotroph PS:Description Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-281442b0-51c4-4dd7-986d-7951574cb637 PS:NodeType Pathway PS:Notes Headnote: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Signaling description: Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB). Inhibins are structurally related to activins. Activin is a homodimer of two b subunits, which antagonizes the effect of inhibin. The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. The gene products of INHA, INHBA and INHBB are restricted to granulosa cells from the primordial follicle stage. If there is any mutation in the INHA gene, the association of a and b will be severely diminished, the homodimerization of two b subunits will take place dominantly. In other words, the concentration of inhibin will diminish and concentration of activins will rise and ultimately FSH concentration will rise. Outcome effects: High FSH level resulting in increased number of primordial follicles being recruited for folliculogenesis, enhanced follicular development to antral stages with increased granulosa cell proliferation, cumulus cell differentiation and expansion, and a dysregulation in steroid hormone production at the theca and granulosa cell level. This condition may also lead to the rapid depletion of follicles, causing premature ovarian failure. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ pituitary gland PS:Organ_System reproductive system PS:PMID 19752047 PS:PMID 20382564 PS:PMID 20668067 PS:PMID 24696764 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28189eb3-1ff5-41b4-9abe-819723d7a559 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-28189eb3-1ff5-41b4-9abe-819723d7a559 TNFRSF5/13B -> NFATC1 Signaling uuid-28189eb3-1ff5-41b4-9abe-819723d7a559 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28189eb3-1ff5-41b4-9abe-819723d7a559 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The photoresponse persists until key phototransduction proteins become deactivated through regulatory enzymes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2821cf36-0459-4d7b-965e-699770c24cb6 NodeType: Pathway Notes: Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). The photoresponse persists until key phototransduction proteins become deactivated through regulatory enzymes. Outcome effects: The decrease in intracellular Ca2+ during light stimulation affects the level of recoverin (RCVRN). Normally, RCVRN inhibits the ability of G protein-coupled receptor kinase (GRK1) to phosphorylate and inactivate rhodopsin (RHO). When the level of Ca2+ decreases, this inhibition fails to occur and RHO is inactivated. Subsequently, arrestin 1 (SAG) binds to RHO with high affinity and completely blocks subsequent G-protein (transducin) activation. Similarly, G-protein and PDE6 remain active until G-protein hydrolyzes GTP. This hydrolysis is catalyzed by a complex of proteins consisting of RGS9, RGS9BP, and G-beta-5-L subunit of G-protein. It has been shown that illumination causes significant fractions of transducin and RCVRN to exit rod outer segments, whereas SAG translocates in the opposite direction. It is hypothesized that SAG is transported by microtubules and this reaction may be induced by PLC/PKC signaling. Outcome effects: The final point of photoreceptor cell recovery is restoration of cGMP levels by guanylate cyclases to its dark level. Highlighted proteins: Entities with decreased level are highlighted in blue. Organ: Retina Organ: eye Organ_System: sensory system PMID: 18379987 PMID: 19887106 PMID: 22074925 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-2821cf36-0459-4d7b-965e-699770c24cb6 RHO Signaling (Light Signal Termination and Photoreceptor Recovery) uuid-2821cf36-0459-4d7b-965e-699770c24cb6 PS:Description The photoresponse persists until key phototransduction proteins become deactivated through regulatory enzymes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2821cf36-0459-4d7b-965e-699770c24cb6 PS:NodeType Pathway PS:Notes Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). The photoresponse persists until key phototransduction proteins become deactivated through regulatory enzymes. Outcome effects: The decrease in intracellular Ca2+ during light stimulation affects the level of recoverin (RCVRN). Normally, RCVRN inhibits the ability of G protein-coupled receptor kinase (GRK1) to phosphorylate and inactivate rhodopsin (RHO). When the level of Ca2+ decreases, this inhibition fails to occur and RHO is inactivated. Subsequently, arrestin 1 (SAG) binds to RHO with high affinity and completely blocks subsequent G-protein (transducin) activation. Similarly, G-protein and PDE6 remain active until G-protein hydrolyzes GTP. This hydrolysis is catalyzed by a complex of proteins consisting of RGS9, RGS9BP, and G-beta-5-L subunit of G-protein. It has been shown that illumination causes significant fractions of transducin and RCVRN to exit rod outer segments, whereas SAG translocates in the opposite direction. It is hypothesized that SAG is transported by microtubules and this reaction may be induced by PLC/PKC signaling. Outcome effects: The final point of photoreceptor cell recovery is restoration of cGMP levels by guanylate cyclases to its dark level. Highlighted proteins: Entities with decreased level are highlighted in blue. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 18379987 PS:PMID 19887106 PS:PMID 22074925 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-282b9169-72d7-4b7b-9251-6d41cff03e9a NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-282b9169-72d7-4b7b-9251-6d41cff03e9a VEGFR -> STAT Signaling uuid-282b9169-72d7-4b7b-9251-6d41cff03e9a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-282b9169-72d7-4b7b-9251-6d41cff03e9a PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuroglia CellType: neuron Description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-284cb9e3-f2b8-4327-b408-92030de68d86 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Activated glia cells release the proinflammatory cytokine IL1B, and neurons release HMGB1, initiating a cascade of inflammatory events in glia cells via the activation of IL1R1 (IL1B) and TLR4 (HMGB1). Outcome effects: Ceramide/SRC-mediated phosphorylation of N-methyl-D-aspartate (NMDA) selective glutamate receptor results in the rapid increase in Ca2+ conductance via the receptor leading to neuronal hyperexcitability. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 21473909 PMID: 21793950 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-284cb9e3-f2b8-4327-b408-92030de68d86 HMGB1 and IL1B in Neuronal Hyperexcitation uuid-284cb9e3-f2b8-4327-b408-92030de68d86 PS:CellType neuroglia PS:CellType neuron PS:Description Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-284cb9e3-f2b8-4327-b408-92030de68d86 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Activated glia cells release the proinflammatory cytokine IL1B, and neurons release HMGB1, initiating a cascade of inflammatory events in glia cells via the activation of IL1R1 (IL1B) and TLR4 (HMGB1). Outcome effects: Ceramide/SRC-mediated phosphorylation of N-methyl-D-aspartate (NMDA) selective glutamate receptor results in the rapid increase in Ca2+ conductance via the receptor leading to neuronal hyperexcitability. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 21473909 PS:PMID 21793950 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-286f451e-12c6-401b-9570-42eee38ffc4c NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-286f451e-12c6-401b-9570-42eee38ffc4c H2BK120 Deubiquitination uuid-286f451e-12c6-401b-9570-42eee38ffc4c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-286f451e-12c6-401b-9570-42eee38ffc4c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-287dc643-177f-4f7a-8ceb-c4b3412ed5b6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-287dc643-177f-4f7a-8ceb-c4b3412ed5b6 CXCL1 Expression Targets uuid-287dc643-177f-4f7a-8ceb-c4b3412ed5b6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-287dc643-177f-4f7a-8ceb-c4b3412ed5b6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28856d53-4722-4ccf-b01b-bea9228d0950 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-28856d53-4722-4ccf-b01b-bea9228d0950 Ornithine biosynthesis template uuid-28856d53-4722-4ccf-b01b-bea9228d0950 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28856d53-4722-4ccf-b01b-bea9228d0950 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2897fae9-2b1a-48ac-8a5f-9756e9e3993c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-2897fae9-2b1a-48ac-8a5f-9756e9e3993c NSP14 interactions uuid-2897fae9-2b1a-48ac-8a5f-9756e9e3993c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2897fae9-2b1a-48ac-8a5f-9756e9e3993c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28a6a9bf-82b5-449f-98e7-858ba7a7fb8f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-28a6a9bf-82b5-449f-98e7-858ba7a7fb8f MDK/PTN Expression Targets uuid-28a6a9bf-82b5-449f-98e7-858ba7a7fb8f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28a6a9bf-82b5-449f-98e7-858ba7a7fb8f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28cc7670-5895-48f8-aded-d8d587bd0a05 NodeType: Pathway Notes: Headnote: Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. FPR2 is the receptor for stereospecific lipoxin A4 binding. The interaction between FPR2 and lipoxin A4 is primarily dependent on stereoselectivity and chirality, respectively. Human FPR2 is present in several types of leukocytes, including monocytes and T-cells, as well as resident cells such as macrophages, synovial fibroblasts, and intestinal epithelial cells. Signaling description: The anti-inflammatory action of lipoxin A4 is likely to be a summation of multiple lipid domain FPR2 signaling events in several cell types. In general, lipoxin A4 promotes the resolution of inflammation since it blocks polymorphonuclear neutrophil (PMN) transmigration and causes a reduction in their numbers, recruitment of monocytes to the sites of inflammation and injury, and clearance of apoptotic PMNs by macrophages. The current understanding of lipoxin A4/FPR2 intracellular signaling remains incomplete. In neutrophils, lipoxins fail to promote a sustained mobilization of intracellular Ca2+ or generation of cAMP. However, the binding of lipoxin A4 to its receptor triggers the activation of GTPase, phospholipase A2, and phospholipase D. In neutrophils, FPR2/ lipoxin A4 regulates presqualene-PP conversions. Presqualene-PP is a constituent of PMN cell membranes, which lack squalene cyclase, and therefore, cannot use it for cholesterol biosynthesis. The activating positive signals for PMN, such as LTB4, initiate the rapid degradation of presqualene-PP. Presqualene-PP directly inhibits PIK3CG and PLD1. Presqualene-PP degradation under LTB4 unlocks these regulatory enzymes and leads to neutrophil function activation. Presqualene-PP also interacts with GRB2 and blocks NAD(P)H oxidase assembly for reactive oxygen species (ROS) generation. FPR2 activation causes the accumulation of presqualene-PP and blocks neutrophil function, but the signaling mechanisms of this effect remain unknown. The degradation of neutrophil presqualene-PP does not occur when PPAPDC2 or PRKCB is inhibited. Outcome effects: Neutrophil exposure to 15-epi-lipoxin A4 triggers PRKCB phosphorylation and its interactions with PPAPDC2. It is hypothesized that FPR2-related accumulation of presqualene-PP is dependent on the phosphorylation status of PPAPDC2. Peptide PBP10, derived from PIP2, may participate in FPR2-signaling in PMN. PBP10 binds to gelsolin (GSN), which is a key regulator of actin filament assembly and disassembly. GSN also blocks granule mobilization and the secretion of oxygen radicals. Thus, FPR2 activation by lipoxin A4 in human neutrophils blocks ROS generation and migration. Lipoxin A4 causes low expression of NF-kB, JUN/FOS, and IL8. It is noted that lipoxins block the phosphorylation of LSP1 and upregulate NAB1. In addition, lipoxin A4/FPR2 signaling may inhibit LTB4-related proinflammatory pathway in neutrophils by uncoupling polyisoprenyl phosphate (PIPP) signaling pathway. This is demonstrated by the down-regulation of ITGAM/ITGB2-dependent PMN adhesion and decreased IP3 formation. In monocytes, lipoxin A4 stimulates chemotaxis and adherence. Lipoxin A4 stimulates the uptake of apoptotic PMN by monocyte-derived macrophages thus decreasing inflammation. This action seems to be coupled to changes in the actin cytoskeleton in macrophages. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-28cc7670-5895-48f8-aded-d8d587bd0a05 Lipoxin A4/FPR2-Related Neutrophil Depression uuid-28cc7670-5895-48f8-aded-d8d587bd0a05 PS:CellType neutrophil PS:Description Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28cc7670-5895-48f8-aded-d8d587bd0a05 PS:NodeType Pathway PS:Notes Headnote: Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. FPR2 is the receptor for stereospecific lipoxin A4 binding. The interaction between FPR2 and lipoxin A4 is primarily dependent on stereoselectivity and chirality, respectively. Human FPR2 is present in several types of leukocytes, including monocytes and T-cells, as well as resident cells such as macrophages, synovial fibroblasts, and intestinal epithelial cells. Signaling description: The anti-inflammatory action of lipoxin A4 is likely to be a summation of multiple lipid domain FPR2 signaling events in several cell types. In general, lipoxin A4 promotes the resolution of inflammation since it blocks polymorphonuclear neutrophil (PMN) transmigration and causes a reduction in their numbers, recruitment of monocytes to the sites of inflammation and injury, and clearance of apoptotic PMNs by macrophages. The current understanding of lipoxin A4/FPR2 intracellular signaling remains incomplete. In neutrophils, lipoxins fail to promote a sustained mobilization of intracellular Ca2+ or generation of cAMP. However, the binding of lipoxin A4 to its receptor triggers the activation of GTPase, phospholipase A2, and phospholipase D. In neutrophils, FPR2/ lipoxin A4 regulates presqualene-PP conversions. Presqualene-PP is a constituent of PMN cell membranes, which lack squalene cyclase, and therefore, cannot use it for cholesterol biosynthesis. The activating positive signals for PMN, such as LTB4, initiate the rapid degradation of presqualene-PP. Presqualene-PP directly inhibits PIK3CG and PLD1. Presqualene-PP degradation under LTB4 unlocks these regulatory enzymes and leads to neutrophil function activation. Presqualene-PP also interacts with GRB2 and blocks NAD(P)H oxidase assembly for reactive oxygen species (ROS) generation. FPR2 activation causes the accumulation of presqualene-PP and blocks neutrophil function, but the signaling mechanisms of this effect remain unknown. The degradation of neutrophil presqualene-PP does not occur when PPAPDC2 or PRKCB is inhibited. Outcome effects: Neutrophil exposure to 15-epi-lipoxin A4 triggers PRKCB phosphorylation and its interactions with PPAPDC2. It is hypothesized that FPR2-related accumulation of presqualene-PP is dependent on the phosphorylation status of PPAPDC2. Peptide PBP10, derived from PIP2, may participate in FPR2-signaling in PMN. PBP10 binds to gelsolin (GSN), which is a key regulator of actin filament assembly and disassembly. GSN also blocks granule mobilization and the secretion of oxygen radicals. Thus, FPR2 activation by lipoxin A4 in human neutrophils blocks ROS generation and migration. Lipoxin A4 causes low expression of NF-kB, JUN/FOS, and IL8. It is noted that lipoxins block the phosphorylation of LSP1 and upregulate NAB1. In addition, lipoxin A4/FPR2 signaling may inhibit LTB4-related proinflammatory pathway in neutrophils by uncoupling polyisoprenyl phosphate (PIPP) signaling pathway. This is demonstrated by the down-regulation of ITGAM/ITGB2-dependent PMN adhesion and decreased IP3 formation. In monocytes, lipoxin A4 stimulates chemotaxis and adherence. Lipoxin A4 stimulates the uptake of apoptotic PMN by monocyte-derived macrophages thus decreasing inflammation. This action seems to be coupled to changes in the actin cytoskeleton in macrophages. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28d6c5cf-a79a-4350-adb2-2aaeb51e2ea2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-28d6c5cf-a79a-4350-adb2-2aaeb51e2ea2 gamma Globulins Expression Targets uuid-28d6c5cf-a79a-4350-adb2-2aaeb51e2ea2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-28d6c5cf-a79a-4350-adb2-2aaeb51e2ea2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2901a260-4699-45f2-8471-ec6b346c810e NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2901a260-4699-45f2-8471-ec6b346c810e Proteins Involved in Hypoxia-Induced Pulmonary Hypertension uuid-2901a260-4699-45f2-8471-ec6b346c810e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2901a260-4699-45f2-8471-ec6b346c810e PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2906d5c4-4ee5-4223-95b1-a5b1ad74e5fa NodeType: Pathway Notes: Congenital hearing loss is most often associated with dysfunction of actin-myosin complex organization within the ear. The pathway reconstructed here reviews all known mutations together although usually one mutated gene underlies inborn hearing loss. Bending of higher stereocilia under the influence of a sound wave causes mechanical opening of the mechanoelectrical transducer (MET) channels on the membranes of lower stereocilia by tensioning the tip of each lower stereocilium with the side wall of its associated higher one. K+ and Ca2+ enter the stereocilium through MET channels and lead to the transformation of the mechanical impulse or sound wave into an electrical impulse or action potential. Dysfunctions in stereocilia proteins lead to the impairment of their movements, the inability of mechanoelectrical transducer channels to open, and the subsequent failure to transform a sound wave into an electric impulse. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: ear Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2906d5c4-4ee5-4223-95b1-a5b1ad74e5fa 1_Dysfunction of cochlear hair cell stereocilia proteins in hearing loss uuid-2906d5c4-4ee5-4223-95b1-a5b1ad74e5fa PS:CellType sensory hair cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2906d5c4-4ee5-4223-95b1-a5b1ad74e5fa PS:NodeType Pathway PS:Notes Congenital hearing loss is most often associated with dysfunction of actin-myosin complex organization within the ear. The pathway reconstructed here reviews all known mutations together although usually one mutated gene underlies inborn hearing loss. Bending of higher stereocilia under the influence of a sound wave causes mechanical opening of the mechanoelectrical transducer (MET) channels on the membranes of lower stereocilia by tensioning the tip of each lower stereocilium with the side wall of its associated higher one. K+ and Ca2+ enter the stereocilium through MET channels and lead to the transformation of the mechanical impulse or sound wave into an electrical impulse or action potential. Dysfunctions in stereocilia proteins lead to the impairment of their movements, the inability of mechanoelectrical transducer channels to open, and the subsequent failure to transform a sound wave into an electric impulse. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ ear PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-291ce224-f68a-41d2-9599-975a1ed4dde6 NodeType: Pathway Organ: colon Organ: small intestine Organ_System: digestive system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-291ce224-f68a-41d2-9599-975a1ed4dde6 Proteins Involved in Celiac Disease uuid-291ce224-f68a-41d2-9599-975a1ed4dde6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-291ce224-f68a-41d2-9599-975a1ed4dde6 PS:NodeType Pathway PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: Systemic osteoporosis is characterized by the pathology process by bone loss in many bones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2926a1b9-c68f-4fc8-9c53-da1234a7c695 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Systemic osteoporosis refers to pathological bone loss in numerous bones. The process can be triggered by several chronic inflammatory conditions. Inflammation has been shown to lead to excessive bone resorption as well as impaired bone formation. Signaling description: Under healthy conditions, essential pathways involved in osteoblast functioning are: the bone morphogenetic protein BMP2 and its receptors, which utilize SMAD proteins for direct or transcriptional activation of RUNX2 and subsequent downstream cellular events; the WNT-FZD pathway, which uses CTNNB1 for further activities; as well as parathyroid hormone (PTH) and its receptor signaling mediated by PKA. Pro-inflammatory cytokines promote osteoblast functioning disruption through several mechanisms. TNF causes the expression of SMURF proteins which block BMP2 signaling in osteoblasts by mediating the degradation of SMAD proteins. In addition, TNF induces DKK1 and SOST expression which are inhibitors of WNT signaling. The negative effects of pro-inflammatory cytokines on osteoblasts include IL6-mediated impairment of osteoclast differentiation through JAK-STAT pathway. Outcome effects: The cytokines activated during the course of inflammatory response have profound effects on the differentiation and activity of osteoblasts by affecting cell signaling. Highlighted proteins: Proteins with increased level or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 19171108 PMID: 22298955 PMID: 22378270 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2926a1b9-c68f-4fc8-9c53-da1234a7c695 Bone Loss in Osteoporosis uuid-2926a1b9-c68f-4fc8-9c53-da1234a7c695 PS:CellType osteoblast PS:Description Systemic osteoporosis is characterized by the pathology process by bone loss in many bones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2926a1b9-c68f-4fc8-9c53-da1234a7c695 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Systemic osteoporosis refers to pathological bone loss in numerous bones. The process can be triggered by several chronic inflammatory conditions. Inflammation has been shown to lead to excessive bone resorption as well as impaired bone formation. Signaling description: Under healthy conditions, essential pathways involved in osteoblast functioning are: the bone morphogenetic protein BMP2 and its receptors, which utilize SMAD proteins for direct or transcriptional activation of RUNX2 and subsequent downstream cellular events; the WNT-FZD pathway, which uses CTNNB1 for further activities; as well as parathyroid hormone (PTH) and its receptor signaling mediated by PKA. Pro-inflammatory cytokines promote osteoblast functioning disruption through several mechanisms. TNF causes the expression of SMURF proteins which block BMP2 signaling in osteoblasts by mediating the degradation of SMAD proteins. In addition, TNF induces DKK1 and SOST expression which are inhibitors of WNT signaling. The negative effects of pro-inflammatory cytokines on osteoblasts include IL6-mediated impairment of osteoclast differentiation through JAK-STAT pathway. Outcome effects: The cytokines activated during the course of inflammatory response have profound effects on the differentiation and activity of osteoblasts by affecting cell signaling. Highlighted proteins: Proteins with increased level or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 19171108 PS:PMID 22298955 PS:PMID 22378270 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: ameloblast Description: Dental enamel is a highly mineralised tissue.The formation of this highly organised tissue is rigorously controlled in ameloblasts through the interaction of a number proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29488928-c32a-47c5-af9d-48f02a39ee74 NodeType: Pathway Notes: Dental enamel is a highly mineralized tissue. The formation of this highly organized tissue is thoroughly controlled in ameloblasts through a number of protein interactions. Mutated genes: Mutated genes are shown in white-out style. Organ: Tooth Organ: mouth Organ_System: digestive system PMID: 17408482 PMID: 19913215 PMID: 22243224 PMID: 23539364 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: dental enamel urn:agi-pathway:uuid-29488928-c32a-47c5-af9d-48f02a39ee74 Enamel Formation Disruption uuid-29488928-c32a-47c5-af9d-48f02a39ee74 PS:CellType ameloblast PS:Description Dental enamel is a highly mineralised tissue.The formation of this highly organised tissue is rigorously controlled in ameloblasts through the interaction of a number proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29488928-c32a-47c5-af9d-48f02a39ee74 PS:NodeType Pathway PS:Notes Dental enamel is a highly mineralized tissue. The formation of this highly organized tissue is thoroughly controlled in ameloblasts through a number of protein interactions. Mutated genes: Mutated genes are shown in white-out style. PS:Organ Tooth PS:Organ mouth PS:Organ_System digestive system PS:PMID 17408482 PS:PMID 19913215 PS:PMID 22243224 PS:PMID 23539364 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue dental enamel PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: glial precursor cell Description: Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-295cdb39-237a-4a23-af04-515cbc0fa8bd NodeType: Pathway Notes: Headnote: Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord and generally does not affect other organs. Signaling description: The brain parenchyma has a unique composition, mainly hyaluronan, and is devoid of rigid protein barriers composed of collagen, fibronectin, and laminin. Invasion signaling in glioma is induced by several types of receptor tyrosine kinases (RTKs), integrins, CD44, and G-protein-coupled receptors. RTKs such as EGFR, PDGFR, MET, TIE1, DDR1, EPH, and AXL are expressed at very high levels in glioblastoma multiforme (GBM) and play a major role in glioma invasion. In addition, hyaluronic acid receptor (CD44) and hyaluronan-mediated motility receptor (HMMR) play a major role in glioma cell-matrix interactions since neoplastic cells use these receptors to adhere to and migrate along the components of the brain extracellular matrix (ECM). Glioma cells activate plasminogen (PLG) and plasminogen activator (PLAU). PLAU converts PLG to the active plasmin, whereas, plasmin as a proteolytic enzyme enhances the ability of PLAUR to localize the proteolytic activity of PLAU on the cell surface which is extremely important for the invasive ability of tumor cells. In addition, integrins, particularly vitronectin receptor and VLA-3 receptor, are overexpressed in gliomas and appear to be significant to processes of invasion and angiogenesis. Furthermore, gliomas overexpress ephrin receptors including EPHB2, EPHA2, and EPHA4 and their ligands, the ephrins, which also regulate migration and invasion. Lastly, plasmin activates protease activated receptor-1 (F2R) to enhance cell invasion and proliferation. Outcome effects: Plasmin, as a broad-specificity protease, degrades several ECM components such as fibronectin, laminin, and collagens. In addition, PLAU triggers a proteolytic cascade that involves the activation of MMP1, 2, 3, and 9, which are responsible for ECM degradation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 21856686 PMID: 24212955 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-295cdb39-237a-4a23-af04-515cbc0fa8bd Glioma Invasion Signaling uuid-295cdb39-237a-4a23-af04-515cbc0fa8bd PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType glial precursor cell PS:Description Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-295cdb39-237a-4a23-af04-515cbc0fa8bd PS:NodeType Pathway PS:Notes Headnote: Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord and generally does not affect other organs. Signaling description: The brain parenchyma has a unique composition, mainly hyaluronan, and is devoid of rigid protein barriers composed of collagen, fibronectin, and laminin. Invasion signaling in glioma is induced by several types of receptor tyrosine kinases (RTKs), integrins, CD44, and G-protein-coupled receptors. RTKs such as EGFR, PDGFR, MET, TIE1, DDR1, EPH, and AXL are expressed at very high levels in glioblastoma multiforme (GBM) and play a major role in glioma invasion. In addition, hyaluronic acid receptor (CD44) and hyaluronan-mediated motility receptor (HMMR) play a major role in glioma cell-matrix interactions since neoplastic cells use these receptors to adhere to and migrate along the components of the brain extracellular matrix (ECM). Glioma cells activate plasminogen (PLG) and plasminogen activator (PLAU). PLAU converts PLG to the active plasmin, whereas, plasmin as a proteolytic enzyme enhances the ability of PLAUR to localize the proteolytic activity of PLAU on the cell surface which is extremely important for the invasive ability of tumor cells. In addition, integrins, particularly vitronectin receptor and VLA-3 receptor, are overexpressed in gliomas and appear to be significant to processes of invasion and angiogenesis. Furthermore, gliomas overexpress ephrin receptors including EPHB2, EPHA2, and EPHA4 and their ligands, the ephrins, which also regulate migration and invasion. Lastly, plasmin activates protease activated receptor-1 (F2R) to enhance cell invasion and proliferation. Outcome effects: Plasmin, as a broad-specificity protease, degrades several ECM components such as fibronectin, laminin, and collagens. In addition, PLAU triggers a proteolytic cascade that involves the activation of MMP1, 2, 3, and 9, which are responsible for ECM degradation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 21856686 PS:PMID 24212955 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-296a5ac9-5873-4088-b8b7-6f3fcb04e465 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-296a5ac9-5873-4088-b8b7-6f3fcb04e465 IL1R -> NF-kB Signaling uuid-296a5ac9-5873-4088-b8b7-6f3fcb04e465 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-296a5ac9-5873-4088-b8b7-6f3fcb04e465 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-296fca64-1c69-4a75-9660-c6a0e142887b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-296fca64-1c69-4a75-9660-c6a0e142887b IL15R -> STAT Signaling uuid-296fca64-1c69-4a75-9660-c6a0e142887b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-296fca64-1c69-4a75-9660-c6a0e142887b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29705066-2bff-442b-9ead-95c2dde4fbb9 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-29705066-2bff-442b-9ead-95c2dde4fbb9 PTGFR -> Vasoconstriction uuid-29705066-2bff-442b-9ead-95c2dde4fbb9 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29705066-2bff-442b-9ead-95c2dde4fbb9 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Endothelial dysfunction in pulmonary arterial hypertension (PAH) is characterized by the decreased production of vasodilators and growth inhibitors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29a9af11-230e-4cf4-922d-8dfca2098a80 NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: Endothelial dysfunction in PAH is characterized by the decreased production of vasodilators and growth inhibitors such as nitric oxide (NO) and prostacyclin (PGI2) and the increased production of the vasoconstrictor/co-mitogens such as endothelin 1 (EDN1) and thromboxane A2 (TXA2) in endothelial cells (ECs). These factors act on ECs and pulmonary artery smooth muscle cells (PASMCs) in an autocrine and paracrine manner, leading to vasoconstriction and cell proliferation. In normal conditions, endothelial-specific nitric oxide synthase (NOS3) produces nitric oxide (NO) from arginine and oxygen (O2). Soluble guanylate cyclase (sGC) is activated in the presence of NO and produces cGMP. In the vascular endothelium, cGMP activates PKG, a cGMP kinase. Consequently, this process leads to a reduction of intracellular calcium (Ca2+) levels via the Ca2+-transporting ATPase, and finally vasodilation. Phosphodiesterase 5A (PDE5A), which is abundant in PAH, is an enzyme that hydrolyzes cGMP. The reduced NO bioavailability in PAH may be due to the decreased expression of NOS3, inhibition of NOS3 enzymatic activity, or the inactivation of NO by superoxide radical. The activity of arginase II (ARG2), a STAT1/STAT3-regulated gene, whose product reduces NO synthesis by competing with NOS3 for arginine, is increased in PAH ECs. Patients with PAH have increased plasma levels of the endogenous inhibitor of NOS3, N,N-dimethylarginine and decreased levels of the enzymes which are responsible for the degradation of dimethylarginine, such as dimethylarginine dimethylaminohydrolases (DDAH1/2). The decreased expression of PGI2 synthase (PTGIS) in PAH ECs has also been reported in patients with PAH. In addition, the local hyperproduction of reactive oxygen spices (ROS) by NADPH oxidases such as CYBB and NOX4, as well as xanthine dehydrogenase (XDH), also have a role in vasoconstriction. Angiopoietin 1 (ANGPT1) is overexpressed in most forms of non-familial PAH. Outcome effects: ANGPT1 exerts its effects through the endothelial-specific tyrosine kinase receptor (TEK) and stimulates ECs to produce and secrete serotonin and EDN1. The exact mechanism is not clear yet, however it has been shown that ANGPT1 increases the level of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme of serotonin synthesis, and endothelin converting enzyme 1 (ECE1). In addition, BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote EC proliferation, survival, and motility. In the case of canonical WNT-activation, BMP2 via BMPR2 activates MAPK1/3 in a SMAD-independent manner. MAPK1/3-mediated inhibition of GSK3B induces beta-catenin (CTNNB1) accumulation and transcriptional activity necessary for EC survival and proliferation in addition to the inhibition of apoptosis. In the case of non-canonical WNT-activation, BMP2 is responsible for SMAD1 phosphorylation, or with the loss of BMPR2 (as in some cases of familial and idiopathic PAH), ACVR2A/SMAD3-dependent recruitment of DVL1 to promote the RHOA/RAC1 signaling. Furthermore, the activation of G-protein-coupled receptors by vasoconstrictors leads to the activation of RHOA, which in turn activates ROCK1. RHOA/ROCK1, acting through LIMK1/2 and CFL1, increases the formation of F-actin stress fibers, cell contraction, and blood vessel permeability. RHOA activates NF-kB and CCND1 and thereby inhibits apoptosis and activates the proliferation of ECs.In addition, RHOA induces the production of SERPINE1, thromboplastin (F3), and selectin P (SELP) and also inhibits thrombomodulin (THBD) formation thereby facilitating thrombosis formation. In conclusion, the final common outcome in PAH is the elevation of pulmonary vascular resistance mediated by vasoconstriction and obstructive cellular proliferation of PASMCs and ECs. Highlighted proteins: Entities with increased levels or act Organ: lung Organ_System: cardiovascular system PMID: 16917117 PMID: 18596905 PMID: 19139264 PMID: 19286424 PMID: 19555855 PMID: 20833255 PMID: 21641060 PMID: 22401856 PMID: 23662189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-29a9af11-230e-4cf4-922d-8dfca2098a80 Endothelial Cell Dysfunction in Pulmonary Hypertension uuid-29a9af11-230e-4cf4-922d-8dfca2098a80 PS:CellType endothelial cell PS:Description Endothelial dysfunction in pulmonary arterial hypertension (PAH) is characterized by the decreased production of vasodilators and growth inhibitors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29a9af11-230e-4cf4-922d-8dfca2098a80 PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: Endothelial dysfunction in PAH is characterized by the decreased production of vasodilators and growth inhibitors such as nitric oxide (NO) and prostacyclin (PGI2) and the increased production of the vasoconstrictor/co-mitogens such as endothelin 1 (EDN1) and thromboxane A2 (TXA2) in endothelial cells (ECs). These factors act on ECs and pulmonary artery smooth muscle cells (PASMCs) in an autocrine and paracrine manner, leading to vasoconstriction and cell proliferation. In normal conditions, endothelial-specific nitric oxide synthase (NOS3) produces nitric oxide (NO) from arginine and oxygen (O2). Soluble guanylate cyclase (sGC) is activated in the presence of NO and produces cGMP. In the vascular endothelium, cGMP activates PKG, a cGMP kinase. Consequently, this process leads to a reduction of intracellular calcium (Ca2+) levels via the Ca2+-transporting ATPase, and finally vasodilation. Phosphodiesterase 5A (PDE5A), which is abundant in PAH, is an enzyme that hydrolyzes cGMP. The reduced NO bioavailability in PAH may be due to the decreased expression of NOS3, inhibition of NOS3 enzymatic activity, or the inactivation of NO by superoxide radical. The activity of arginase II (ARG2), a STAT1/STAT3-regulated gene, whose product reduces NO synthesis by competing with NOS3 for arginine, is increased in PAH ECs. Patients with PAH have increased plasma levels of the endogenous inhibitor of NOS3, N,N-dimethylarginine and decreased levels of the enzymes which are responsible for the degradation of dimethylarginine, such as dimethylarginine dimethylaminohydrolases (DDAH1/2). The decreased expression of PGI2 synthase (PTGIS) in PAH ECs has also been reported in patients with PAH. In addition, the local hyperproduction of reactive oxygen spices (ROS) by NADPH oxidases such as CYBB and NOX4, as well as xanthine dehydrogenase (XDH), also have a role in vasoconstriction. Angiopoietin 1 (ANGPT1) is overexpressed in most forms of non-familial PAH. Outcome effects: ANGPT1 exerts its effects through the endothelial-specific tyrosine kinase receptor (TEK) and stimulates ECs to produce and secrete serotonin and EDN1. The exact mechanism is not clear yet, however it has been shown that ANGPT1 increases the level of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme of serotonin synthesis, and endothelin converting enzyme 1 (ECE1). In addition, BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote EC proliferation, survival, and motility. In the case of canonical WNT-activation, BMP2 via BMPR2 activates MAPK1/3 in a SMAD-independent manner. MAPK1/3-mediated inhibition of GSK3B induces beta-catenin (CTNNB1) accumulation and transcriptional activity necessary for EC survival and proliferation in addition to the inhibition of apoptosis. In the case of non-canonical WNT-activation, BMP2 is responsible for SMAD1 phosphorylation, or with the loss of BMPR2 (as in some cases of familial and idiopathic PAH), ACVR2A/SMAD3-dependent recruitment of DVL1 to promote the RHOA/RAC1 signaling. Furthermore, the activation of G-protein-coupled receptors by vasoconstrictors leads to the activation of RHOA, which in turn activates ROCK1. RHOA/ROCK1, acting through LIMK1/2 and CFL1, increases the formation of F-actin stress fibers, cell contraction, and blood vessel permeability. RHOA activates NF-kB and CCND1 and thereby inhibits apoptosis and activates the proliferation of ECs.In addition, RHOA induces the production of SERPINE1, thromboplastin (F3), and selectin P (SELP) and also inhibits thrombomodulin (THBD) formation thereby facilitating thrombosis formation. In conclusion, the final common outcome in PAH is the elevation of pulmonary vascular resistance mediated by vasoconstriction and obstructive cellular proliferation of PASMCs and ECs. Highlighted proteins: Entities with increased levels or act PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 16917117 PS:PMID 18596905 PS:PMID 19139264 PS:PMID 19286424 PS:PMID 19555855 PS:PMID 20833255 PS:PMID 21641060 PS:PMID 22401856 PS:PMID 23662189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: CFL1 is an actin-binding protein that regulate actin dynamics and implicated in cancer cell motility. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29c55b72-8cb1-478b-b76f-bb4057ba0660 NodeType: Pathway Notes: Headnote: CFL1 is an actin-binding protein that can regulate actin dynamics in a number of ways. In highly invasive tumor cells, CFL1 has been shown to sever actin filaments thus generating new barbed ends accessible to monomers of G-actin promoting actin polymerization at invasive and locomotory protrusions._x000D __x000D_ Signaling description: RASGRF1 and ARHGAP35 are responsible for RHOC regulation in a spatiotemporal manner. RHOC is activated by RASGRF1 near the periphery of invadopodial cores. RHOC is inactivated by ARHGAP35 within the invadopodial cores, allowing active CFL1 to generate actin barbed ends and promote polymerization. CFL1 activity may be regulated by PLCG1/ PtdIns(3,4)P2 and CTTN. SLC9A1 increases the intracellular pH to disrupt the inhibitory pH-dependent interaction between CTTN and CFL1, allowing active CFL1 to be released. EZR-MSN-RDX complex and TLN1 regulate both SLC9A1 and F-actin spatial localization._x000D__x000D_ Outcome effects: Actin polymerization promotes invadopodia / lamellipodia formation and cancer cell invasion / migration._x000D__x000D_ Highlighted proteins: not shown due to different spatiotemporal expression of key proteins. Organ: oncogenic Organ_System: oncogenic PMID: 19862699 PMID: 21474314 PMID: 21514509 PMID: 23073633 PMID: 23778968 PMID: 24642482 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-29c55b72-8cb1-478b-b76f-bb4057ba0660 CFL1 in Cancer Cell Motility uuid-29c55b72-8cb1-478b-b76f-bb4057ba0660 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description CFL1 is an actin-binding protein that regulate actin dynamics and implicated in cancer cell motility. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29c55b72-8cb1-478b-b76f-bb4057ba0660 PS:NodeType Pathway PS:Notes Headnote: CFL1 is an actin-binding protein that can regulate actin dynamics in a number of ways. In highly invasive tumor cells, CFL1 has been shown to sever actin filaments thus generating new barbed ends accessible to monomers of G-actin promoting actin polymerization at invasive and locomotory protrusions._x000D __x000D_ Signaling description: RASGRF1 and ARHGAP35 are responsible for RHOC regulation in a spatiotemporal manner. RHOC is activated by RASGRF1 near the periphery of invadopodial cores. RHOC is inactivated by ARHGAP35 within the invadopodial cores, allowing active CFL1 to generate actin barbed ends and promote polymerization. CFL1 activity may be regulated by PLCG1/ PtdIns(3,4)P2 and CTTN. SLC9A1 increases the intracellular pH to disrupt the inhibitory pH-dependent interaction between CTTN and CFL1, allowing active CFL1 to be released. EZR-MSN-RDX complex and TLN1 regulate both SLC9A1 and F-actin spatial localization._x000D__x000D_ Outcome effects: Actin polymerization promotes invadopodia / lamellipodia formation and cancer cell invasion / migration._x000D__x000D_ Highlighted proteins: not shown due to different spatiotemporal expression of key proteins. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 19862699 PS:PMID 21474314 PS:PMID 21514509 PS:PMID 23073633 PS:PMID 23778968 PS:PMID 24642482 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuroglia CellType: neuron Description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29def2d9-a3af-4389-9116-7b24debb957c NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Activated glia cells release the proinflammatory cytokine IL1B, and neurons release HMGB1, initiating a cascade of inflammatory events in glia cells via the activation of IL1R1 (IL1B) and TLR4 (HMGB1), which activates the TRAF6/NF-kB pathway. Outcome effects: NF-kB activation results in the increased secretion of proinflammatory factors such as TNF, IL1B, HMGB1, IL6, and CCL2 which leads to the exacerbation of neuroinflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 21473909 PMID: 21793950 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-29def2d9-a3af-4389-9116-7b24debb957c HMGB1 and IL1B in Neuroinflammation uuid-29def2d9-a3af-4389-9116-7b24debb957c PS:CellType neuroglia PS:CellType neuron PS:Description Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29def2d9-a3af-4389-9116-7b24debb957c PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Proconvulsant events such as brain trauma or infection lead to the activation of microglia, astrocytes, and neurons. Activated glia cells release the proinflammatory cytokine IL1B, and neurons release HMGB1, initiating a cascade of inflammatory events in glia cells via the activation of IL1R1 (IL1B) and TLR4 (HMGB1), which activates the TRAF6/NF-kB pathway. Outcome effects: NF-kB activation results in the increased secretion of proinflammatory factors such as TNF, IL1B, HMGB1, IL6, and CCL2 which leads to the exacerbation of neuroinflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 21473909 PS:PMID 21793950 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29e5792a-4f9d-4d6f-9c0e-6cb97c7562a8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-29e5792a-4f9d-4d6f-9c0e-6cb97c7562a8 FGF7 -> FOXO3A Expression Target uuid-29e5792a-4f9d-4d6f-9c0e-6cb97c7562a8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29e5792a-4f9d-4d6f-9c0e-6cb97c7562a8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29ef88e3-4714-4d24-871b-28b456ff057d NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-29ef88e3-4714-4d24-871b-28b456ff057d DRD2 Expression Targets uuid-29ef88e3-4714-4d24-871b-28b456ff057d PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29ef88e3-4714-4d24-871b-28b456ff057d PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PMID Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29f5a608-907c-4b20-b785-ef3926d14561 NodeType: Pathway PMID: 18313409 urn:agi-pathway:uuid-29f5a608-907c-4b20-b785-ef3926d14561 TGFb+>apoptosis uuid-29f5a608-907c-4b20-b785-ef3926d14561 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-29f5a608-907c-4b20-b785-ef3926d14561 PS:NodeType Pathway PS:PMID 18313409 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The vesicle trafficking is a step of exocytosis required for the transportation of a vesicle to the cell surface area. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a02b841-6a19-4ca6-b78d-990730aa5b8c NodeType: Pathway Notes: Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle trafficking is required for the transportation of a vesicle to the cell surface area. Signaling description: Loaded secretory vesicles are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by specific RAB GTPases. The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: Kinesin proteins, RAB GTPases and cytoskeleton elements are required for the transportation of a vesicle to the cell surface area. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 19888562 PMID: 21936774 PMID: 28730385 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-2a02b841-6a19-4ca6-b78d-990730aa5b8c Exocytosis: Vesicle Trafficking uuid-2a02b841-6a19-4ca6-b78d-990730aa5b8c PS:CellType generic PS:Description The vesicle trafficking is a step of exocytosis required for the transportation of a vesicle to the cell surface area. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a02b841-6a19-4ca6-b78d-990730aa5b8c PS:NodeType Pathway PS:Notes Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle trafficking is required for the transportation of a vesicle to the cell surface area. Signaling description: Loaded secretory vesicles are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by specific RAB GTPases. The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: Kinesin proteins, RAB GTPases and cytoskeleton elements are required for the transportation of a vesicle to the cell surface area. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 19888562 PS:PMID 21936774 PS:PMID 28730385 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a0d8fa5-95b0-4b6a-9644-ed8d9e1d3eac NodeType: Pathway Notes: After contact with an antigen such as Staphylococcus aureus, cutaneous professional antigen-presenting cells (such as Langerhans cells) migrate to regional lymph nodes where they present processed peptides to naive T cells. Activated naive T lymphocytes then differentiate toward a Th2 phenotype and induce IgE production by B lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-2a0d8fa5-95b0-4b6a-9644-ed8d9e1d3eac 1_The onset of atopic dermatitis uuid-2a0d8fa5-95b0-4b6a-9644-ed8d9e1d3eac PS:CellType T-cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a0d8fa5-95b0-4b6a-9644-ed8d9e1d3eac PS:NodeType Pathway PS:Notes After contact with an antigen such as Staphylococcus aureus, cutaneous professional antigen-presenting cells (such as Langerhans cells) migrate to regional lymph nodes where they present processed peptides to naive T cells. Activated naive T lymphocytes then differentiate toward a Th2 phenotype and induce IgE production by B lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: The differentiation of naive T cells towards a Th17 phenotype is supported by several cytokines including transforming growth factor-B (TGFB1), IL1B, IL6, IL21, and IL23. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a305c23-f0ee-4491-a7f5-9ad39208c0f4 NodeType: Pathway Notes: Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. Studies have shown that dysregulation of the skin T-cells is involved in the development of psoriasis plaques. Signaling description: Psoriasis skin lesions contain increased amounts of T helper 17 (Th17) cells. Several cytokines are involved in Th17 differentiation. TGFB1 prevents Th1 and Th2 differentiation by suppressing STAT4 and GATA3 expression, thus allowing Th17 differentiation. However, Th17 development also occurs in the absence of TGFB1 signaling. IL18 synergizes with IL23 to promote IL17 production. IL1B negatively regulates Th1 differentiation by inducing cyclooxygenase (COX)-2, which subsequently increases the secretion of prostaglandin E2 (PGE2) that suppresses IFNG production thus allowing Th17 differentiation. In addition, the association between psoriasis and polymorphisms in IL12/23p40 and IL23R was recently discovered. Also, nuclear orphan receptor (RORC) functions to coordinate the diverse cytokine-induced signals and thus controls Th17 cell differentiation. Furthermore, the overreaction of psoriatic T cells to IFNA1 can be explained by the downregulation of SOCS3 and PTPN6. These two proteins are negative regulators of the IFNA1 signaling pathway. PTPN6 inhibits JAK1 and JAK2 that activate STAT1, STAT3, and STAT4 by the dephosphorylation of upstream cytokine receptors and receptor-associated tyrosine kinases. In turn, the suppressors of cytokine signaling (SOCS) constitute a family of STAT-induced negative regulators of cytokine signaling. These proteins inhibit the production of certain proinflammatory cytokines such as IL17. Finally, the deficiency of FOXP3 regulatory T (Treg) cells in psoriasis lesions may be responsible for an acute flare-up of the disease, and thus may predict severity and clinical course. Outcome effects: The differentiation of naive T-cells towards a Th17 phenotype is promoted by a number of cytokines including transforming growth factor-B (TGFB1), IL1B, IL6, IL21, and IL23. In turn, the interleukin-(IL)-23 and IL-17 expressing Th17 cells are thought to be the specific regulators of the inflammatory reactions in psoriasis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: IL12/23p40 and IL23R mutated in psoriasis are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 16389548 PMID: 18200064 PMID: 20130595 PMID: 22342740 PMID: 22705915 PMID: 23122008 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-2a305c23-f0ee-4491-a7f5-9ad39208c0f4 T-Cells Differentiation Block in Psoriasis uuid-2a305c23-f0ee-4491-a7f5-9ad39208c0f4 PS:CellType T-cell PS:Description The differentiation of naive T cells towards a Th17 phenotype is supported by several cytokines including transforming growth factor-B (TGFB1), IL1B, IL6, IL21, and IL23. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a305c23-f0ee-4491-a7f5-9ad39208c0f4 PS:NodeType Pathway PS:Notes Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. The pathogenesis of psoriasis is yet to be fully understood. Studies have shown that dysregulation of the skin T-cells is involved in the development of psoriasis plaques. Signaling description: Psoriasis skin lesions contain increased amounts of T helper 17 (Th17) cells. Several cytokines are involved in Th17 differentiation. TGFB1 prevents Th1 and Th2 differentiation by suppressing STAT4 and GATA3 expression, thus allowing Th17 differentiation. However, Th17 development also occurs in the absence of TGFB1 signaling. IL18 synergizes with IL23 to promote IL17 production. IL1B negatively regulates Th1 differentiation by inducing cyclooxygenase (COX)-2, which subsequently increases the secretion of prostaglandin E2 (PGE2) that suppresses IFNG production thus allowing Th17 differentiation. In addition, the association between psoriasis and polymorphisms in IL12/23p40 and IL23R was recently discovered. Also, nuclear orphan receptor (RORC) functions to coordinate the diverse cytokine-induced signals and thus controls Th17 cell differentiation. Furthermore, the overreaction of psoriatic T cells to IFNA1 can be explained by the downregulation of SOCS3 and PTPN6. These two proteins are negative regulators of the IFNA1 signaling pathway. PTPN6 inhibits JAK1 and JAK2 that activate STAT1, STAT3, and STAT4 by the dephosphorylation of upstream cytokine receptors and receptor-associated tyrosine kinases. In turn, the suppressors of cytokine signaling (SOCS) constitute a family of STAT-induced negative regulators of cytokine signaling. These proteins inhibit the production of certain proinflammatory cytokines such as IL17. Finally, the deficiency of FOXP3 regulatory T (Treg) cells in psoriasis lesions may be responsible for an acute flare-up of the disease, and thus may predict severity and clinical course. Outcome effects: The differentiation of naive T-cells towards a Th17 phenotype is promoted by a number of cytokines including transforming growth factor-B (TGFB1), IL1B, IL6, IL21, and IL23. In turn, the interleukin-(IL)-23 and IL-17 expressing Th17 cells are thought to be the specific regulators of the inflammatory reactions in psoriasis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: IL12/23p40 and IL23R mutated in psoriasis are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 16389548 PS:PMID 18200064 PS:PMID 20130595 PS:PMID 22342740 PS:PMID 22705915 PS:PMID 23122008 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a3fe1b5-2eec-49e9-af6a-ecb1b1528ed9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2a3fe1b5-2eec-49e9-af6a-ecb1b1528ed9 PGF -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-2a3fe1b5-2eec-49e9-af6a-ecb1b1528ed9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a3fe1b5-2eec-49e9-af6a-ecb1b1528ed9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Hyperplasia (cell number increase) and hypertrophy (cell size increase) are two mechanisms of adipose tissue growth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a546ee2-20d3-4a75-bcca-2fe322211cc5 NodeType: Pathway Notes: Headnote: Adipose tissue is one of the insulin-responsive tissues, and insulin stimulates storage of triglycerides in adipose tissue by multiple mechanisms, including promoting the differentiation of preadipocytes to adipocytes, increasing the uptake of glucose and fatty acids derived from circulating lipoproteins, lipogenesis in mature adipocytes, and inhibiting lipolysis. Signaling description: Hyperplasia (cell number increase) and hypertrophy (cell size increase) are two mechanisms of adipose tissue growth. The main transcription factors regulating adipocyte proliferation and making impact to adipocyte hyperplasia are PPARA, PPARG, CEBPA, and SREBF1.SREBF1 and PPARA also control expression of multiple lipogenic enzymes. Outcome effects: The final products of lipogenesis are triglycerides. Redundant accumulation of triglycerides leads to adipocyte hypertrophy. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: endocrine system PMID: 15814457 PMID: 17374880 PMID: 19194515 PMID: 21633177 PMID: 9421459 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-2a546ee2-20d3-4a75-bcca-2fe322211cc5 Adipocyte Hypertrophy and Hyperplasia uuid-2a546ee2-20d3-4a75-bcca-2fe322211cc5 PS:CellType adipocyte PS:Description Hyperplasia (cell number increase) and hypertrophy (cell size increase) are two mechanisms of adipose tissue growth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a546ee2-20d3-4a75-bcca-2fe322211cc5 PS:NodeType Pathway PS:Notes Headnote: Adipose tissue is one of the insulin-responsive tissues, and insulin stimulates storage of triglycerides in adipose tissue by multiple mechanisms, including promoting the differentiation of preadipocytes to adipocytes, increasing the uptake of glucose and fatty acids derived from circulating lipoproteins, lipogenesis in mature adipocytes, and inhibiting lipolysis. Signaling description: Hyperplasia (cell number increase) and hypertrophy (cell size increase) are two mechanisms of adipose tissue growth. The main transcription factors regulating adipocyte proliferation and making impact to adipocyte hyperplasia are PPARA, PPARG, CEBPA, and SREBF1.SREBF1 and PPARA also control expression of multiple lipogenic enzymes. Outcome effects: The final products of lipogenesis are triglycerides. Redundant accumulation of triglycerides leads to adipocyte hypertrophy. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System endocrine system PS:PMID 15814457 PS:PMID 17374880 PS:PMID 19194515 PS:PMID 21633177 PS:PMID 9421459 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a647acd-e7cf-4753-8521-7af54444206c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2a647acd-e7cf-4753-8521-7af54444206c WNT2 Expression Targets uuid-2a647acd-e7cf-4753-8521-7af54444206c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a647acd-e7cf-4753-8521-7af54444206c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a861cc5-ebd4-4398-944f-7a04bde54a13 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-2a861cc5-ebd4-4398-944f-7a04bde54a13 Metabolism of Triacylglycerols uuid-2a861cc5-ebd4-4398-944f-7a04bde54a13 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a861cc5-ebd4-4398-944f-7a04bde54a13 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a966a69-d663-4b3e-8508-2b3d6b85e3f8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2a966a69-d663-4b3e-8508-2b3d6b85e3f8 Tryptophan biosynthesis template uuid-2a966a69-d663-4b3e-8508-2b3d6b85e3f8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2a966a69-d663-4b3e-8508-2b3d6b85e3f8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2aa08353-9832-4bac-b604-ac569542481e NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-2aa08353-9832-4bac-b604-ac569542481e PTGDR -> Vasodilation uuid-2aa08353-9832-4bac-b604-ac569542481e PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2aa08353-9832-4bac-b604-ac569542481e PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ab0073d-c30c-4728-b5c6-59cb3e7a0d67 NodeType: Pathway Organ: liver Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-2ab0073d-c30c-4728-b5c6-59cb3e7a0d67 Proteins Involved in non-Alcoholic Fatty Liver Disease uuid-2ab0073d-c30c-4728-b5c6-59cb3e7a0d67 PS:CellType hepatocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ab0073d-c30c-4728-b5c6-59cb3e7a0d67 PS:NodeType Pathway PS:Organ liver PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Several proteins implicated in endosomal transport and autophagy may be mutated in ALS. Mutations in the alsin gene (ALS2) are associated with a form of autosomal recessive juvenile-onset ALS. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ac6e880-232c-44f2-b523-a197bc6356f1 NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: The dysregulation of endosomal trafficking and autophagy-endolysosomal pathway has been implicated in several genetic subtypes of ALS. Endocytosis is the process by which extracellular molecules are captured at the cell membrane and taken into the cell. Autophagy is a process which among other functions is responsible for protein degradation. Several proteins implicated in endosomal transport and autophagy may be mutated in ALS. Mutations in the alsin gene (ALS2) are associated with a form of autosomal recessive juvenile-onset ALS. ALS2 interacts with RAB5A and RAC1 and is involved in endosomal fusion/trafficking and microtubule assembly. FIG4 plays a role in the turnover of phosphatidylinositol-3,5-bisphosphate (PtdIns 3,5-P2) which is involved in endocytosis and autophagy. In addition, valosin containing protein (VCP) forms a complex with clathrin coat and is implicated in multiple cellular processes including endocytosis, autophagy, and ubiquitin-dependent protein degradation. Charged multivesicular protein 2B (CHMP2B) is a component of ESCRT-III complex. The ESCRT complexes are known to play a role in multivesicular body biogenesis and autophagosomal-endolysosomal maturation. Additionally, dynactin 1 (DCTN1) functions as an adaptor between dynein and various cargos, thereby regulating the efficiency of dynein motor and taking part in axonal cargo transport. There are also rare ALS-associated mutations that dysregulate endosomal trafficking including vesicle-associated membrane protein-associated protein B (VAPB), optineurin (OPTN), and microtubule-associated protein tau (MAPT). Outcome effects: Autophagy is impaired in ALS leading to the accumulation of insoluble protein aggregates which is one of the key pathological features of ALS. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 22051914 PMID: 22482452 PMID: 22852081 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-2ac6e880-232c-44f2-b523-a197bc6356f1 Endosomal Trafficking Dysregulation in Amyotrophic Lateral Sclerosis uuid-2ac6e880-232c-44f2-b523-a197bc6356f1 PS:CellType neuron PS:Description Several proteins implicated in endosomal transport and autophagy may be mutated in ALS. Mutations in the alsin gene (ALS2) are associated with a form of autosomal recessive juvenile-onset ALS. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ac6e880-232c-44f2-b523-a197bc6356f1 PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: The dysregulation of endosomal trafficking and autophagy-endolysosomal pathway has been implicated in several genetic subtypes of ALS. Endocytosis is the process by which extracellular molecules are captured at the cell membrane and taken into the cell. Autophagy is a process which among other functions is responsible for protein degradation. Several proteins implicated in endosomal transport and autophagy may be mutated in ALS. Mutations in the alsin gene (ALS2) are associated with a form of autosomal recessive juvenile-onset ALS. ALS2 interacts with RAB5A and RAC1 and is involved in endosomal fusion/trafficking and microtubule assembly. FIG4 plays a role in the turnover of phosphatidylinositol-3,5-bisphosphate (PtdIns 3,5-P2) which is involved in endocytosis and autophagy. In addition, valosin containing protein (VCP) forms a complex with clathrin coat and is implicated in multiple cellular processes including endocytosis, autophagy, and ubiquitin-dependent protein degradation. Charged multivesicular protein 2B (CHMP2B) is a component of ESCRT-III complex. The ESCRT complexes are known to play a role in multivesicular body biogenesis and autophagosomal-endolysosomal maturation. Additionally, dynactin 1 (DCTN1) functions as an adaptor between dynein and various cargos, thereby regulating the efficiency of dynein motor and taking part in axonal cargo transport. There are also rare ALS-associated mutations that dysregulate endosomal trafficking including vesicle-associated membrane protein-associated protein B (VAPB), optineurin (OPTN), and microtubule-associated protein tau (MAPT). Outcome effects: Autophagy is impaired in ALS leading to the accumulation of insoluble protein aggregates which is one of the key pathological features of ALS. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 22051914 PS:PMID 22482452 PS:PMID 22852081 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2af1eb17-aafa-416d-9f0e-a79467b1bff2 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone tissue urn:agi-pathway:uuid-2af1eb17-aafa-416d-9f0e-a79467b1bff2 GPCRs Family -> Expression Targets in Bone uuid-2af1eb17-aafa-416d-9f0e-a79467b1bff2 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2af1eb17-aafa-416d-9f0e-a79467b1bff2 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afa1c73-18a8-4ecf-84c0-4b4bf067760e NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-2afa1c73-18a8-4ecf-84c0-4b4bf067760e GRM1/5 (Postsynaptic) -> Ion Channels uuid-2afa1c73-18a8-4ecf-84c0-4b4bf067760e PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afa1c73-18a8-4ecf-84c0-4b4bf067760e PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afad23d-3b30-42b5-b65f-076792e94585 NodeType: Pathway Notes: Headnote: Cryptorchidism is one of the most frequent congenital abnormalities, with a recorded frequency of 3-4% among newborn males. Before sex determination, both female and male embryonic gonads are located in the same high intra-abdominal position. The developing testes migrate through a multiphase process of testicular descent (TD), first into a low abdominal position and then into the developing scrotum. A critical role in TD belongs to the gubernacular ligaments. Analysis of mouse mutants revealed a number of genes involved in this process. Signaling description: Insulin-like factor 3 (INSL3) controls the first abdominal phase of TD through its receptor, leucine-rich-containing repeats G protein-coupled receptor LGR8 (RXFP2). INSL3 signaling is essential for myogenic differentiation in the gubernaculum and involved genes of the WNT and NOTCH pathways. Mutation of INSL3 and RXFP2 result in high intraabdominal cryptorchidism and male sterility. The mutant by INSL3 and RXFP2 genes gubernaculum fails to differentiate. Several transcription factors, such as HOXA10, HOXA11, and ARID5B also were shown to cause the cryptorchidism in mice, suggesting an involvement of multiple signaling pathways in in the control of TD. Organ: gubernaculum Organ: testis Organ_System: reproductive system PMID: 17462055 PMID: 18032558 PMID: 18647820 PMID: 18989307 PMID: 19416188 PMID: 20550598 PMID: 21147849 PMID: 23100620 PMID: 23303914 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2afad23d-3b30-42b5-b65f-076792e94585 Cryptorchidism Molecular Mechanism (Hypothesis) uuid-2afad23d-3b30-42b5-b65f-076792e94585 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afad23d-3b30-42b5-b65f-076792e94585 PS:NodeType Pathway PS:Notes Headnote: Cryptorchidism is one of the most frequent congenital abnormalities, with a recorded frequency of 3-4% among newborn males. Before sex determination, both female and male embryonic gonads are located in the same high intra-abdominal position. The developing testes migrate through a multiphase process of testicular descent (TD), first into a low abdominal position and then into the developing scrotum. A critical role in TD belongs to the gubernacular ligaments. Analysis of mouse mutants revealed a number of genes involved in this process. Signaling description: Insulin-like factor 3 (INSL3) controls the first abdominal phase of TD through its receptor, leucine-rich-containing repeats G protein-coupled receptor LGR8 (RXFP2). INSL3 signaling is essential for myogenic differentiation in the gubernaculum and involved genes of the WNT and NOTCH pathways. Mutation of INSL3 and RXFP2 result in high intraabdominal cryptorchidism and male sterility. The mutant by INSL3 and RXFP2 genes gubernaculum fails to differentiate. Several transcription factors, such as HOXA10, HOXA11, and ARID5B also were shown to cause the cryptorchidism in mice, suggesting an involvement of multiple signaling pathways in in the control of TD. PS:Organ gubernaculum PS:Organ testis PS:Organ_System reproductive system PS:PMID 17462055 PS:PMID 18032558 PS:PMID 18647820 PS:PMID 18989307 PS:PMID 19416188 PS:PMID 20550598 PS:PMID 21147849 PS:PMID 23100620 PS:PMID 23303914 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afd3321-39c6-497a-9dcb-e187fa340f4b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2afd3321-39c6-497a-9dcb-e187fa340f4b CXCL12 Expression Targets uuid-2afd3321-39c6-497a-9dcb-e187fa340f4b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afd3321-39c6-497a-9dcb-e187fa340f4b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afd5b95-a71a-4add-a718-8574edcd430e NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-2afd5b95-a71a-4add-a718-8574edcd430e Proteins with Altered Expression in Atopic Dermatitis uuid-2afd5b95-a71a-4add-a718-8574edcd430e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2afd5b95-a71a-4add-a718-8574edcd430e PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b1b937e-0a6f-48b9-bfd7-624c2e3ac5cd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2b1b937e-0a6f-48b9-bfd7-624c2e3ac5cd HBEGF -> CREB/MYC Expression Targets uuid-2b1b937e-0a6f-48b9-bfd7-624c2e3ac5cd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b1b937e-0a6f-48b9-bfd7-624c2e3ac5cd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b269944-4b74-4063-bb6d-4d76f5107384 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2b269944-4b74-4063-bb6d-4d76f5107384 HGF -> AP-1/CREB/ELK/SRF/MYC Expression Targets uuid-2b269944-4b74-4063-bb6d-4d76f5107384 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b269944-4b74-4063-bb6d-4d76f5107384 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Dysfunction of mitochondria occurs in neurons in Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b29dafb-1ee7-4a46-beab-66bbefbed46f NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: It is not completely clear whether AD related mitochondrial dysfunction is a cause or a disease consequence.The aspects of mitochondrial dysfunction are as follows: mitochondria release higher amounts of reactive oxygen species (ROS) into the cytoplasm; mitochondrial respiratory chain produces lower amounts of ATP; and mitochondria extend in size. Amyloid precursor protein (APP) and Abeta can alter the transport of proteins and small molecules into the mitochondria through their interaction with the membrane and TOM pore complex. Abeta can stimulate the passage of small molecules into the intermembrane space through the mPTP pore complex. Calcium (Ca2 ) depolarizes the membrane and alters the respiratory chain activity. In addition, APP and Abeta can directly and indirectly alter the activity of mitochondrial metabolic enzymes causing an increase in the synthesis of reactive oxygen and hydrogen species and a decrease in the synthesis of ATP by the respiratory chain. APP also participates in the process of mitochondrial fusion which leads to the accumulation of mitochondrial dysfunction. Furthermore, cholesterol and estrogens play a neuroprotective role in AD through the inhibition of Abeta. Under certain conditions, Abeta can eliminate the neuroprotective role of estrogens. However, estrogens can also increase mitochondrial dysfunction by producing ROS during catechol-quinone redox cycling. Additionally, Ca2 and glucose that enter mitochondria from the cytoplasm can activate signaling pathways of apoptosis in neuronal mitochondria. Outcome effects: Finally, the poorly functioning enlarged mitochondria gradually displace normal organelles, eventually causing decreased ATP production and failing autophagocytosis. This triggers oxidative stress and apoptosis, resulting in degeneration and death of neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12695498 PMID: 17917162 PMID: 21545753 PMID: 22523685 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-2b29dafb-1ee7-4a46-beab-66bbefbed46f Mitochondrial Dysfunction in Alzheimer's Disease uuid-2b29dafb-1ee7-4a46-beab-66bbefbed46f PS:CellType neuron PS:Description Dysfunction of mitochondria occurs in neurons in Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b29dafb-1ee7-4a46-beab-66bbefbed46f PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: It is not completely clear whether AD related mitochondrial dysfunction is a cause or a disease consequence.The aspects of mitochondrial dysfunction are as follows: mitochondria release higher amounts of reactive oxygen species (ROS) into the cytoplasm; mitochondrial respiratory chain produces lower amounts of ATP; and mitochondria extend in size. Amyloid precursor protein (APP) and Abeta can alter the transport of proteins and small molecules into the mitochondria through their interaction with the membrane and TOM pore complex. Abeta can stimulate the passage of small molecules into the intermembrane space through the mPTP pore complex. Calcium (Ca2 ) depolarizes the membrane and alters the respiratory chain activity. In addition, APP and Abeta can directly and indirectly alter the activity of mitochondrial metabolic enzymes causing an increase in the synthesis of reactive oxygen and hydrogen species and a decrease in the synthesis of ATP by the respiratory chain. APP also participates in the process of mitochondrial fusion which leads to the accumulation of mitochondrial dysfunction. Furthermore, cholesterol and estrogens play a neuroprotective role in AD through the inhibition of Abeta. Under certain conditions, Abeta can eliminate the neuroprotective role of estrogens. However, estrogens can also increase mitochondrial dysfunction by producing ROS during catechol-quinone redox cycling. Additionally, Ca2 and glucose that enter mitochondria from the cytoplasm can activate signaling pathways of apoptosis in neuronal mitochondria. Outcome effects: Finally, the poorly functioning enlarged mitochondria gradually displace normal organelles, eventually causing decreased ATP production and failing autophagocytosis. This triggers oxidative stress and apoptosis, resulting in degeneration and death of neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12695498 PS:PMID 17917162 PS:PMID 21545753 PS:PMID 22523685 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b305855-b10f-4099-85cf-958b8ffa6f6d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-2b305855-b10f-4099-85cf-958b8ffa6f6d Regulation of IFI27 (biomarker for severe COVID-19) uuid-2b305855-b10f-4099-85cf-958b8ffa6f6d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b305855-b10f-4099-85cf-958b8ffa6f6d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b3a4128-9150-4379-99d3-379a80468811 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2b3a4128-9150-4379-99d3-379a80468811 Jasmonic acid biosynthesis template uuid-2b3a4128-9150-4379-99d3-379a80468811 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b3a4128-9150-4379-99d3-379a80468811 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b721494-38a9-4eea-9ff1-b70768af22b8 NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-lymphocytes from SLE patients show a number of abnormalities that cause hypercellular kinetics along with the production of defective interleukin-2 (IL2). The increased level of TNF secreted from dendritic cells activates the FAS/FASLG and CASP3-mediated apoptotic signaling pathways in SLE T-cells. Therefore, apoptosis of the T-cell subset in SLE patients increases. As a result of chronic activation, defective DNA methylation or impaired alternative splicing, the expression and function of proteins in the T-cell receptor (TCR) complex are altered. The exact details of this process are not known. The defective downstream signaling from TCR leads to the aberrant activation of T-cells and low levels of IL2 production. Outcome effects: SLE-related TCR signaling pathway alterations cause changes in the CD247 and FCER1G expression. As a result, reduced expression of CD247 leads to the increased activation of SYK. FCER1G-SYK signaling replaces normal CD247-ZAP70 signaling and leads to higher calcium levels in the T-cell. In addition, CREM activation leads to down-regulation of IL2. Aberrant DNA methylation affects a number of genes in SLE patients, such as those encoding CD40LG, CD70, CD11A (ITGAL), and PP2A. Finally, aberrant activation Th0-cell causes a reduction in the Th1 cell-mediated cytokine (IL2 and IFNG) secretion. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: lymphatic system PMID: 15286379 PMID: 16713714 PMID: 16808908 PMID: 21457530 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-2b721494-38a9-4eea-9ff1-b70768af22b8 Th0-Cell Aberrant Activation in Systemic Lupus Erythematosus uuid-2b721494-38a9-4eea-9ff1-b70768af22b8 PS:CellType T-cell PS:Description Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2b721494-38a9-4eea-9ff1-b70768af22b8 PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-lymphocytes from SLE patients show a number of abnormalities that cause hypercellular kinetics along with the production of defective interleukin-2 (IL2). The increased level of TNF secreted from dendritic cells activates the FAS/FASLG and CASP3-mediated apoptotic signaling pathways in SLE T-cells. Therefore, apoptosis of the T-cell subset in SLE patients increases. As a result of chronic activation, defective DNA methylation or impaired alternative splicing, the expression and function of proteins in the T-cell receptor (TCR) complex are altered. The exact details of this process are not known. The defective downstream signaling from TCR leads to the aberrant activation of T-cells and low levels of IL2 production. Outcome effects: SLE-related TCR signaling pathway alterations cause changes in the CD247 and FCER1G expression. As a result, reduced expression of CD247 leads to the increased activation of SYK. FCER1G-SYK signaling replaces normal CD247-ZAP70 signaling and leads to higher calcium levels in the T-cell. In addition, CREM activation leads to down-regulation of IL2. Aberrant DNA methylation affects a number of genes in SLE patients, such as those encoding CD40LG, CD70, CD11A (ITGAL), and PP2A. Finally, aberrant activation Th0-cell causes a reduction in the Th1 cell-mediated cytokine (IL2 and IFNG) secretion. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 15286379 PS:PMID 16713714 PS:PMID 16808908 PS:PMID 21457530 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bacbac9-e8d7-456f-a092-7343c36b2c6d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-2bacbac9-e8d7-456f-a092-7343c36b2c6d IGF1R ->EMT uuid-2bacbac9-e8d7-456f-a092-7343c36b2c6d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bacbac9-e8d7-456f-a092-7343c36b2c6d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bbeee7d-2d76-407d-a29a-b4f5935ae091 NodeType: Pathway PMID: 18406052 PMID: 18615630 PMID: 21258212 PMID: 21307399 PMID: 21697900 PMID: 23843616 PMID: 25113547 PMID: 25699257 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-2bbeee7d-2d76-407d-a29a-b4f5935ae091 Invadopodia Formation in Cancer Cells uuid-2bbeee7d-2d76-407d-a29a-b4f5935ae091 PS:CellType cancer stem cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bbeee7d-2d76-407d-a29a-b4f5935ae091 PS:NodeType Pathway PS:PMID 18406052 PS:PMID 18615630 PS:PMID 21258212 PS:PMID 21307399 PS:PMID 21697900 PS:PMID 23843616 PS:PMID 25113547 PS:PMID 25699257 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bda961b-4ac1-4d07-9ffc-7eb52895ba82 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-2bda961b-4ac1-4d07-9ffc-7eb52895ba82 ITGB1 -> Expression Targets in Skin uuid-2bda961b-4ac1-4d07-9ffc-7eb52895ba82 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2bda961b-4ac1-4d07-9ffc-7eb52895ba82 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2be55666-9c0d-4068-8224-c35e4c8c7ed1 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19812304 PMID: 25402640 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-2be55666-9c0d-4068-8224-c35e4c8c7ed1 mTOR Signaling_2 uuid-2be55666-9c0d-4068-8224-c35e4c8c7ed1 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2be55666-9c0d-4068-8224-c35e4c8c7ed1 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19812304 PS:PMID 25402640 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c05d68e-e921-4a70-862c-6db7e16566c7 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-2c05d68e-e921-4a70-862c-6db7e16566c7 Elevated Receptors -> Expression Targets in Nerve Tissue uuid-2c05d68e-e921-4a70-862c-6db7e16566c7 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c05d68e-e921-4a70-862c-6db7e16566c7 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c0f4967-d000-41b2-82fc-ba523db234db NodeType: Pathway Organ: stomach Organ_System: digestive system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-2c0f4967-d000-41b2-82fc-ba523db234db Proteins Involved in Helicobacter Infections uuid-2c0f4967-d000-41b2-82fc-ba523db234db PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c0f4967-d000-41b2-82fc-ba523db234db PS:NodeType Pathway PS:Organ stomach PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c1970ec-9350-48f8-999b-b696bfab853f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2c1970ec-9350-48f8-999b-b696bfab853f Leucine degradation template uuid-2c1970ec-9350-48f8-999b-b696bfab853f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c1970ec-9350-48f8-999b-b696bfab853f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c23938e-01dd-4dc5-9cf6-2b12eb2fa3e6 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-2c23938e-01dd-4dc5-9cf6-2b12eb2fa3e6 CD81 Expression Targets uuid-2c23938e-01dd-4dc5-9cf6-2b12eb2fa3e6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c23938e-01dd-4dc5-9cf6-2b12eb2fa3e6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c2ce97f-f919-4985-aa13-354b4cd03f50 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-2c2ce97f-f919-4985-aa13-354b4cd03f50 Proteins Involved in Rheumatoid Arthritis uuid-2c2ce97f-f919-4985-aa13-354b4cd03f50 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c2ce97f-f919-4985-aa13-354b4cd03f50 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors can recognize non-infectious endogenous molecules that are released during tissue damage and cellular injury. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c4ece37-e11d-4d60-94b0-1030188d0d39 NodeType: Pathway Notes: Headnote: Pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors can recognize non-infectious endogenous molecules that are released during tissue damage and cellular injury. These molecules are known as damage-associated molecular patterns (DAMPs). The most common DAMPs are HMGB1, heat shock proteins, SAP130, fragments of RNA and DNA, hyaluronic acid, VCAN, heparan sulfate, monosodium urate, IL33, and IL1A. Signaling description: DAMPs act similarly to pathogen pattern molecules that bind to TLRs and activate an immune response and trigger inflammation. TLRs are expressed on the surface of various cells of the immune system and can initiate inflammation after association with DAMPs originating from necrotic cells. TLRs are primarily expressed on the surface of monocytes, macrophages, and dendritic cells. Outcome effects: Downstream pathways that follow DAMP/TLR binding are similar to other TLR-activated pathways. These signaling pathways include the activation of MYD88, TIRAP, and TICAM which finally lead to the synthesis of inflammatory cytokines, interferon, and chemokines via the activation of NF-kB, IRFs, and Jun/Fos transcription factors. CD14, CD36, CD40, and CD91 are important co-activators of TLRs. CD14 and CD91 bind to heat shock proteins (HSPs) and promote the expression of IL1B, IL6, TNF, IL12, and NO production through TLR-mediated signaling. These molecules play different roles in the inflammation process. DAMP-specific receptor CD24, which can bind to both HMGB1 and HSPs, negatively regulates sterile inflammatory responses via the inhibition of TLR responses. Intracellular TLRs such as TLR3 and TLR9 can bind to fragments of DNA and RNA originating from dead cells and promote interferon synthesis. In certain cases, AGER may transduce signals by acting cooperatively with TLRs. HMGB1-bound DNA can form a complex with TLR9 and AGER to induce proinflammatory cytokines. Finally, similarly to microbially-induced inflammation, sterile inflammation mediated by TLRs is marked by the recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines, particularly TNF and IL1. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-2c4ece37-e11d-4d60-94b0-1030188d0d39 Toll-like Receptors in Sterile Inflammation uuid-2c4ece37-e11d-4d60-94b0-1030188d0d39 PS:CellType generic PS:Description Pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors can recognize non-infectious endogenous molecules that are released during tissue damage and cellular injury. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2c4ece37-e11d-4d60-94b0-1030188d0d39 PS:NodeType Pathway PS:Notes Headnote: Pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors can recognize non-infectious endogenous molecules that are released during tissue damage and cellular injury. These molecules are known as damage-associated molecular patterns (DAMPs). The most common DAMPs are HMGB1, heat shock proteins, SAP130, fragments of RNA and DNA, hyaluronic acid, VCAN, heparan sulfate, monosodium urate, IL33, and IL1A. Signaling description: DAMPs act similarly to pathogen pattern molecules that bind to TLRs and activate an immune response and trigger inflammation. TLRs are expressed on the surface of various cells of the immune system and can initiate inflammation after association with DAMPs originating from necrotic cells. TLRs are primarily expressed on the surface of monocytes, macrophages, and dendritic cells. Outcome effects: Downstream pathways that follow DAMP/TLR binding are similar to other TLR-activated pathways. These signaling pathways include the activation of MYD88, TIRAP, and TICAM which finally lead to the synthesis of inflammatory cytokines, interferon, and chemokines via the activation of NF-kB, IRFs, and Jun/Fos transcription factors. CD14, CD36, CD40, and CD91 are important co-activators of TLRs. CD14 and CD91 bind to heat shock proteins (HSPs) and promote the expression of IL1B, IL6, TNF, IL12, and NO production through TLR-mediated signaling. These molecules play different roles in the inflammation process. DAMP-specific receptor CD24, which can bind to both HMGB1 and HSPs, negatively regulates sterile inflammatory responses via the inhibition of TLR responses. Intracellular TLRs such as TLR3 and TLR9 can bind to fragments of DNA and RNA originating from dead cells and promote interferon synthesis. In certain cases, AGER may transduce signals by acting cooperatively with TLRs. HMGB1-bound DNA can form a complex with TLR9 and AGER to induce proinflammatory cytokines. Finally, similarly to microbially-induced inflammation, sterile inflammation mediated by TLRs is marked by the recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines, particularly TNF and IL1. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of NFKB signaling pathway contributes to uncontrolled cell proliferation, inhibition of apoptosis and induction of inflammation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ca58b3f-cbc6-4dda-a07c-2db4ceac5e2f NodeType: Pathway Notes: Headnote: NFKB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NFKB plays a key role in regulating the immune response to infection. Incorrect regulation of NFKB has been linked to cancer. Signaling description: Mammalian NFKB dimers are generated via homodimeric and heterodimeric interactions of 5 REL subunits expressed from distinct but related genes: RELA, RELB, REL, NFKB1 and NFKB2. The canonical NFKB activation pathway results in activation of gene transcription by the RELA/NFKB1 dimer. This heterodimer cycles between the cytoplasm and the nucleus complexed with the inhibitory protein NFKBIA which reduces the efficiency of its nuclear transport and prevents binding of RELA/NFKB1 to DNA. Extracellular stimuli including bacterial LPS and TNFA activate RELA/NFKB1 dimer via a number of signaling steps facilitated by the IKK complex. This complex is comprised of three major components known as IKBKA (CHUK), IKBKB and IKBKG. The general consensus is that the catalytic component IKBKB and the scaffold component IKBKG transduce signals to the canonical pathway. IKBKB catalyzes NFKBIA phosphorylation which leads to its poly-ubiquitination and degradation by the 26S proteasome to generate "free" RELA/NFKB1 and transcriptional activation of target genes. NFKB activation is reported to be associated with tumorigenesis. Inactivation of natural NFKB signaling inhibitors NFKBIA, NFKBIE, FAF1, CYLD, TNFAIP3, TRAF3 leads to constant NFKB activation and cancer progression. Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation, inhibition of apoptosis and provokes inflammation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15102437 PMID: 16485028 PMID: 17072331 PMID: 18056430 PMID: 20001209 PMID: 20066113 PMID: 23056468 PMID: 23915189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-2ca58b3f-cbc6-4dda-a07c-2db4ceac5e2f NFKB Signaling Activation by Blocking of Tumor Suppressors uuid-2ca58b3f-cbc6-4dda-a07c-2db4ceac5e2f PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of NFKB signaling pathway contributes to uncontrolled cell proliferation, inhibition of apoptosis and induction of inflammation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ca58b3f-cbc6-4dda-a07c-2db4ceac5e2f PS:NodeType Pathway PS:Notes Headnote: NFKB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NFKB plays a key role in regulating the immune response to infection. Incorrect regulation of NFKB has been linked to cancer. Signaling description: Mammalian NFKB dimers are generated via homodimeric and heterodimeric interactions of 5 REL subunits expressed from distinct but related genes: RELA, RELB, REL, NFKB1 and NFKB2. The canonical NFKB activation pathway results in activation of gene transcription by the RELA/NFKB1 dimer. This heterodimer cycles between the cytoplasm and the nucleus complexed with the inhibitory protein NFKBIA which reduces the efficiency of its nuclear transport and prevents binding of RELA/NFKB1 to DNA. Extracellular stimuli including bacterial LPS and TNFA activate RELA/NFKB1 dimer via a number of signaling steps facilitated by the IKK complex. This complex is comprised of three major components known as IKBKA (CHUK), IKBKB and IKBKG. The general consensus is that the catalytic component IKBKB and the scaffold component IKBKG transduce signals to the canonical pathway. IKBKB catalyzes NFKBIA phosphorylation which leads to its poly-ubiquitination and degradation by the 26S proteasome to generate "free" RELA/NFKB1 and transcriptional activation of target genes. NFKB activation is reported to be associated with tumorigenesis. Inactivation of natural NFKB signaling inhibitors NFKBIA, NFKBIE, FAF1, CYLD, TNFAIP3, TRAF3 leads to constant NFKB activation and cancer progression. Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation, inhibition of apoptosis and provokes inflammation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15102437 PS:PMID 16485028 PS:PMID 17072331 PS:PMID 18056430 PS:PMID 20001209 PS:PMID 20066113 PS:PMID 23056468 PS:PMID 23915189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cb32c66-8580-4e92-9af3-04d4a4f3153b NodeType: Pathway Notes: Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The lectin-induced complement pathway can activate the complement system in an antibody-independent manner and is activated by the binding of mannose-binding lectin (MBL) to carbohydrates on the surfaces of pathogens. MBL consists of oligomers of several sizes. The C-type lectin domain of MBL is capable of recognizing N-acetylglucosamine or mannose structures on the pathogen surface, resulting in the activation of MBL-associated serine proteases (MASPs). In humans, three types of MASPs (MASP1, MASP2, and MASP3) form complexes with MBL. C3 and C2 are cleaved by activated MASP1, while C4B and C2 are cleaved by MASP2. The cascade is similar to the classical complement cascade following activation. Outcome effects: The major consequence of complement system activation is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments. The lectin pathway of complement activation is important not only for killing microorganisms through the interaction of carbohydrates on their surfaces and mannan-binding protein (MBP) or other collectins, which are humoral lectins found in humans and other mammals, but may also significantly contribute to the pathophysiology of cerebral, myocardial and gut infarction, septic shock syndrome, and possibly autoimmune disease. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-2cb32c66-8580-4e92-9af3-04d4a4f3153b Complement Activation by Lectin uuid-2cb32c66-8580-4e92-9af3-04d4a4f3153b PS:CellType generic PS:Description The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cb32c66-8580-4e92-9af3-04d4a4f3153b PS:NodeType Pathway PS:Notes Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or as binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The lectin-induced complement pathway can activate the complement system in an antibody-independent manner and is activated by the binding of mannose-binding lectin (MBL) to carbohydrates on the surfaces of pathogens. MBL consists of oligomers of several sizes. The C-type lectin domain of MBL is capable of recognizing N-acetylglucosamine or mannose structures on the pathogen surface, resulting in the activation of MBL-associated serine proteases (MASPs). In humans, three types of MASPs (MASP1, MASP2, and MASP3) form complexes with MBL. C3 and C2 are cleaved by activated MASP1, while C4B and C2 are cleaved by MASP2. The cascade is similar to the classical complement cascade following activation. Outcome effects: The major consequence of complement system activation is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments. The lectin pathway of complement activation is important not only for killing microorganisms through the interaction of carbohydrates on their surfaces and mannan-binding protein (MBP) or other collectins, which are humoral lectins found in humans and other mammals, but may also significantly contribute to the pathophysiology of cerebral, myocardial and gut infarction, septic shock syndrome, and possibly autoimmune disease. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cb62dba-d3fb-468b-9738-900bb6506698 NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: During phagocytosis, neutrophils engulf and take up microbes into specialized compartments known as phagosomes in a receptor-mediated, clathrin-independent process. Neutrophils absorb pathogens tagged with opsonins, which are molecules that bind the cell surface and facilitate phagocytosis. One of the main opsonins, IgG, promotes neutrophil phagocytosis through the activation of Fc-gamma receptors. Unlike macrophages, neutrophils express a low affinity to FCGR3B and FCGR2A receptors. FCGR-dependent phagocytosis is associated with pseudopod extension. When activated by IgG, these receptors facilitate the polymerization of actin filaments, membrane extension outward to surround the particle, and particle engulfment. The initial tyrosine phosphorylation event is carried out by HCK and LYN. Tyrosine kinase SYK is then recruited to the phosphorylated ITAM domain. Active SYK then transmits downstream signals leading to actin polymerization and particle internalization. Outcome effects: The downstream effectors of SYK are PI3K and PLCG1. Further, VAV1 and motor proteins are involved in the polymerization of actin and phagosome formation. Various members of the Rho family, including RAC1, CDC42, and RHOA, are activated by VAV1. CDC42 participates in the formation of filopodia while RAC1 and RHOA stimulate membrane ruffling. VCL and PXN can also be activated via PI3K/ARF6 signaling and can participate in the organization of polymerized microfilaments. Occasionally, myosin participates in the process of pseudopod extension and phagosome formation. All of these events culminate in actin nucleation, reorganization, and actin-dependent extension of the plasma membrane around the particle. The synthesis of arachidonic acid derivatives also stimulates membrane motility during phagocytosis. The pathogen, absorbed by neutrophils, undergoes respiratory burst in phagolysosomes. In addition, the synthesis of ROS can be activated as the result of the FCGR-related cascade. In addition, the fusion of neutrophil granules with a phagosome results in the formation of a phagolysosome and allows for the assembly of the NAD(P)H oxidase complex, which is a transmembrane multi-protein complex that generates superoxide anions into the lumen of the phagolysosome. Superoxide is generated following the activation of CYBB in the NAD(P)H oxidase complex by RAC1 and RAC2 at the plasma membrane and as a result of the FCGR-related cascade. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-2cb62dba-d3fb-468b-9738-900bb6506698 Neutrophil Activation via FCGR3B uuid-2cb62dba-d3fb-468b-9738-900bb6506698 PS:CellType neutrophil PS:Description Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cb62dba-d3fb-468b-9738-900bb6506698 PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: During phagocytosis, neutrophils engulf and take up microbes into specialized compartments known as phagosomes in a receptor-mediated, clathrin-independent process. Neutrophils absorb pathogens tagged with opsonins, which are molecules that bind the cell surface and facilitate phagocytosis. One of the main opsonins, IgG, promotes neutrophil phagocytosis through the activation of Fc-gamma receptors. Unlike macrophages, neutrophils express a low affinity to FCGR3B and FCGR2A receptors. FCGR-dependent phagocytosis is associated with pseudopod extension. When activated by IgG, these receptors facilitate the polymerization of actin filaments, membrane extension outward to surround the particle, and particle engulfment. The initial tyrosine phosphorylation event is carried out by HCK and LYN. Tyrosine kinase SYK is then recruited to the phosphorylated ITAM domain. Active SYK then transmits downstream signals leading to actin polymerization and particle internalization. Outcome effects: The downstream effectors of SYK are PI3K and PLCG1. Further, VAV1 and motor proteins are involved in the polymerization of actin and phagosome formation. Various members of the Rho family, including RAC1, CDC42, and RHOA, are activated by VAV1. CDC42 participates in the formation of filopodia while RAC1 and RHOA stimulate membrane ruffling. VCL and PXN can also be activated via PI3K/ARF6 signaling and can participate in the organization of polymerized microfilaments. Occasionally, myosin participates in the process of pseudopod extension and phagosome formation. All of these events culminate in actin nucleation, reorganization, and actin-dependent extension of the plasma membrane around the particle. The synthesis of arachidonic acid derivatives also stimulates membrane motility during phagocytosis. The pathogen, absorbed by neutrophils, undergoes respiratory burst in phagolysosomes. In addition, the synthesis of ROS can be activated as the result of the FCGR-related cascade. In addition, the fusion of neutrophil granules with a phagosome results in the formation of a phagolysosome and allows for the assembly of the NAD(P)H oxidase complex, which is a transmembrane multi-protein complex that generates superoxide anions into the lumen of the phagolysosome. Superoxide is generated following the activation of CYBB in the NAD(P)H oxidase complex by RAC1 and RAC2 at the plasma membrane and as a result of the FCGR-related cascade. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cc8f508-9c73-4155-98f7-4fbdb7241357 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-2cc8f508-9c73-4155-98f7-4fbdb7241357 Ubiquinoine Biosynthesis in Rats uuid-2cc8f508-9c73-4155-98f7-4fbdb7241357 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cc8f508-9c73-4155-98f7-4fbdb7241357 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ce783a8-6d5d-4b16-ad60-ddc78812ce36 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-2ce783a8-6d5d-4b16-ad60-ddc78812ce36 ORF7a interactions uuid-2ce783a8-6d5d-4b16-ad60-ddc78812ce36 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ce783a8-6d5d-4b16-ad60-ddc78812ce36 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in cochlear sensory hair cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cf2a61d-c0b0-49df-a8d7-3f6b56031b7c NodeType: Pathway Notes: Headnote: Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in cochlear sensory hair cells. Generation of reactive oxygen species (ROS) is regarded as one the key events in noise-induced hearing loss. Signaling description: The probable trigger for elevated ROS is Ca2+. Free Ca2+ increases in outer hair cells immediately after acoustic overstimulation, probably both via entry through ion channels and liberation from intracellular stores. In agreement with Ca2+ as a decisive factor in noise trauma is the success of attenuating noise-induced hearing loss through a blockade of L-type or T-type voltage-gated calcium channels. At the same time, previous observational studies investigating the role of race and hearing loss have consistently demonstrated that black race is associated with a 60-70% lower odd of noise-induced hearing loss and AHL compared to white subjects. Melanin produced by strial melanocytes (intermediate cells) in the cochlea has been hypothesized to serve a protective role as a free radical scavenger. Further, traumatic noise induces transient ATP depletion probably through mitochondrial mechanisms. AMPK is an energy sensor; when cellular ATP levels decrease, the levels of AMP increase and AMPK is activated. This leads to RAC1 increases and RHOA decrease. The increase in activated RAC1 leads to ROS formation through activation of NOX3. Traumatic noise diminishes both RHOA/DIAPH1 complex and total DIAPH1. The mammalian homolog of diaphanous (DIAPH1) is a RHO effector that regulates F-actin polymerization. Diminished levels of RHOA decrease ROCK2 levels. Phosphorylation of ezrin (EZR)-radixin(RDX)-moesin (MSN) by ROCK2 normally allows EZR-RDX-MSN to cross-link actin filaments and the plasma membrane. Noise-decreased levels of ROCK results in reduction of phosphorylation of EZR-RDX-MSN leading to depolymerization of actin filaments. Outcome effects: Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is activated following noise exposure and can, in turn, activate mitochondria-mediated cell death pathways via BAD. Oxidative stress can damage mitochondria which, in turn, release pro-apoptotic factors AIFM1 and ENDOG. ROS induce DNA damage and upregulates TP53 causing chronic activation of the mitochondrial BAK1. Noise-induced ROS produce vasoactive lipid peroxidation products such as isoprostanes, which may contribute to the decrease in cochlear blood flow observed following exposure to noise. The resulting ischemia and subsequent reperfusion would add to increased mitochondrial ROS formation and oxidative stress in a self-enhancing cycle. Noise exposure also induces up-regulation of NOX1 and DUOX2 in the cochlea. The activity of antioxidant defenders such as SOD2, GSTM1, GSTT1 and UCP2 may diminish with age and may be implicated in mechanisms of hearing loss. Traumatic noise was shown to induce hair cell apoptosis through transient cellular energy depletion. Finally, actin rearrangements following traumatic noise appear to change the gross morphology of hair cell structure. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: ear Organ_System: sensory system PMID: 21782914 PMID: 21906645 PMID: 22956833 PMID: 23899412 PMID: 25683353 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2cf2a61d-c0b0-49df-a8d7-3f6b56031b7c Apoptosis of Cochlear Hair Cells (Noise-Induced, Mouse Model) uuid-2cf2a61d-c0b0-49df-a8d7-3f6b56031b7c PS:CellType sensory hair cell PS:Description Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in cochlear sensory hair cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2cf2a61d-c0b0-49df-a8d7-3f6b56031b7c PS:NodeType Pathway PS:Notes Headnote: Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in cochlear sensory hair cells. Generation of reactive oxygen species (ROS) is regarded as one the key events in noise-induced hearing loss. Signaling description: The probable trigger for elevated ROS is Ca2+. Free Ca2+ increases in outer hair cells immediately after acoustic overstimulation, probably both via entry through ion channels and liberation from intracellular stores. In agreement with Ca2+ as a decisive factor in noise trauma is the success of attenuating noise-induced hearing loss through a blockade of L-type or T-type voltage-gated calcium channels. At the same time, previous observational studies investigating the role of race and hearing loss have consistently demonstrated that black race is associated with a 60-70% lower odd of noise-induced hearing loss and AHL compared to white subjects. Melanin produced by strial melanocytes (intermediate cells) in the cochlea has been hypothesized to serve a protective role as a free radical scavenger. Further, traumatic noise induces transient ATP depletion probably through mitochondrial mechanisms. AMPK is an energy sensor; when cellular ATP levels decrease, the levels of AMP increase and AMPK is activated. This leads to RAC1 increases and RHOA decrease. The increase in activated RAC1 leads to ROS formation through activation of NOX3. Traumatic noise diminishes both RHOA/DIAPH1 complex and total DIAPH1. The mammalian homolog of diaphanous (DIAPH1) is a RHO effector that regulates F-actin polymerization. Diminished levels of RHOA decrease ROCK2 levels. Phosphorylation of ezrin (EZR)-radixin(RDX)-moesin (MSN) by ROCK2 normally allows EZR-RDX-MSN to cross-link actin filaments and the plasma membrane. Noise-decreased levels of ROCK results in reduction of phosphorylation of EZR-RDX-MSN leading to depolymerization of actin filaments. Outcome effects: Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is activated following noise exposure and can, in turn, activate mitochondria-mediated cell death pathways via BAD. Oxidative stress can damage mitochondria which, in turn, release pro-apoptotic factors AIFM1 and ENDOG. ROS induce DNA damage and upregulates TP53 causing chronic activation of the mitochondrial BAK1. Noise-induced ROS produce vasoactive lipid peroxidation products such as isoprostanes, which may contribute to the decrease in cochlear blood flow observed following exposure to noise. The resulting ischemia and subsequent reperfusion would add to increased mitochondrial ROS formation and oxidative stress in a self-enhancing cycle. Noise exposure also induces up-regulation of NOX1 and DUOX2 in the cochlea. The activity of antioxidant defenders such as SOD2, GSTM1, GSTT1 and UCP2 may diminish with age and may be implicated in mechanisms of hearing loss. Traumatic noise was shown to induce hair cell apoptosis through transient cellular energy depletion. Finally, actin rearrangements following traumatic noise appear to change the gross morphology of hair cell structure. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ ear PS:Organ_System sensory system PS:PMID 21782914 PS:PMID 21906645 PS:PMID 22956833 PS:PMID 23899412 PS:PMID 25683353 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: B-cell receptor (BCR) can recognize free (soluble) protein antigens in the blood or lymph with their membrane bound-immunoglobulin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d04614a-9163-47a9-95e5-8d3492e31bcd NodeType: Pathway Notes: Headnote: B-cell receptor (BCR) can recognize free (soluble) protein antigens in the blood or lymph with their membrane bound-immunoglobulin. BCR is a transmembrane protein complex composed of membrane immunoglobulin and disulfide-linked heterodimers CD79A/CD79B. Signaling description: Activated by antigen, the BCR complex stimulates B-cell proliferation and differentiation. BCR can influence intracellular signaling through the PLCG2/calcium/NFATC2, PI3K, IKBK/NF-kB, and canonical ERK (MAPK) signaling. Many non-protein antigens such as polysaccharides and lipids stimulate antibody production and B-cell activation in the absence of helper T-cells and activate BCR signaling. Non-protein T-cell independent type I antigens such as LPS stimulates polyclonal B-cell activation directly by binding to CD14 and TLR4 receptors. T-cell independent type I antigens provide a second signal of B-cell activation. The complement fragment, C3 binds to the antigen and provides a second signal of B-cell activation after stimulating complement cascade by soluble immunoglobulin. The secondary responses are very rapid and generate low affinity antibodies, which consist mainly of IgM without isotype switching or affinity maturation. C3 simultaneously binds and engages CR2, CD19, and CD81 complement receptors and the membrane immunoglobulin on the surface of B-cells. Outcome effects: This leads to the initiation of signaling cascades from both the BCR complex and the CR2 complex. T-cell independent type 2 antigens such as polysaccharides are molecules with multiple repeating subunits that engage the BCR and thus induce antigen-specific B-cell responses. T-cell independent type 2 antigens provide long-lasting humoral immunity and the generation of memory B-cells. FCGR2B is a monomeric receptor with immunoreceptor tyrosine-based inhibition motif in the cytoplasmic region. The FCGR2B1 isoform, which is predominantly expressed on B-cells, is cross-linked with BCR by IgG immune complexes. FCGR2B1 acts as a negative feedback regulator by inhibiting BCR signaling through the immunoreceptor tyrosine-based inhibition motif. Signaling through TNFSF13 and TNFSF13B stimulates B-lymphocytes to undergo proliferation. TNFRSF13C, as a nuclear receptor, participates in AICDA production and thereby in the process of isotype switching of immunoglobulin genes. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-2d04614a-9163-47a9-95e5-8d3492e31bcd T-Cell Independent B-Cell Activation uuid-2d04614a-9163-47a9-95e5-8d3492e31bcd PS:CellType B-cell PS:Description B-cell receptor (BCR) can recognize free (soluble) protein antigens in the blood or lymph with their membrane bound-immunoglobulin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d04614a-9163-47a9-95e5-8d3492e31bcd PS:NodeType Pathway PS:Notes Headnote: B-cell receptor (BCR) can recognize free (soluble) protein antigens in the blood or lymph with their membrane bound-immunoglobulin. BCR is a transmembrane protein complex composed of membrane immunoglobulin and disulfide-linked heterodimers CD79A/CD79B. Signaling description: Activated by antigen, the BCR complex stimulates B-cell proliferation and differentiation. BCR can influence intracellular signaling through the PLCG2/calcium/NFATC2, PI3K, IKBK/NF-kB, and canonical ERK (MAPK) signaling. Many non-protein antigens such as polysaccharides and lipids stimulate antibody production and B-cell activation in the absence of helper T-cells and activate BCR signaling. Non-protein T-cell independent type I antigens such as LPS stimulates polyclonal B-cell activation directly by binding to CD14 and TLR4 receptors. T-cell independent type I antigens provide a second signal of B-cell activation. The complement fragment, C3 binds to the antigen and provides a second signal of B-cell activation after stimulating complement cascade by soluble immunoglobulin. The secondary responses are very rapid and generate low affinity antibodies, which consist mainly of IgM without isotype switching or affinity maturation. C3 simultaneously binds and engages CR2, CD19, and CD81 complement receptors and the membrane immunoglobulin on the surface of B-cells. Outcome effects: This leads to the initiation of signaling cascades from both the BCR complex and the CR2 complex. T-cell independent type 2 antigens such as polysaccharides are molecules with multiple repeating subunits that engage the BCR and thus induce antigen-specific B-cell responses. T-cell independent type 2 antigens provide long-lasting humoral immunity and the generation of memory B-cells. FCGR2B is a monomeric receptor with immunoreceptor tyrosine-based inhibition motif in the cytoplasmic region. The FCGR2B1 isoform, which is predominantly expressed on B-cells, is cross-linked with BCR by IgG immune complexes. FCGR2B1 acts as a negative feedback regulator by inhibiting BCR signaling through the immunoreceptor tyrosine-based inhibition motif. Signaling through TNFSF13 and TNFSF13B stimulates B-lymphocytes to undergo proliferation. TNFRSF13C, as a nuclear receptor, participates in AICDA production and thereby in the process of isotype switching of immunoglobulin genes. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: CD4+ T-cell CellType: antigen-presenting cell CellType: cancer cell CellType: cancer stem cell CellType: regulatory T-cell Description: Adenosine and cAMP play major role in Treg-cell-mediated suppression of CD4+ T-cells and antigen-presenting cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d21c199-62af-4b9b-a418-1b516cb6118d NodeType: Pathway Notes: Headnote: Adenosine and cAMP are important for Treg-cell-mediated suppression of CD4+ T-cells and antigen-presenting cells. Signaling description: High intracellular cAMP levels are generated in Treg cells by FOXP3-mediated downregulation of the PDE3B. Furthermore, FOXP3 also down-regulates MIR-142 targeting ADCY9 resulting in upregulated cAMP production. cAMP is transferred from nTreg cells into activated target CD4+ T cells and/or antigen-presenting cells (APCs) via gap junctions to suppress these cells. cAMP facilitates the expression of CREM transcription factor, resulting in the suppression IL-2 directly or via NFATC1. ENTPD1 (CD39) and NT5E (CD73) ectoenzymes on nTreg cells generate extracellular immunosuppressive adenosine from ATP, which adds to the suppressive effects of inflamed-tissue hypoxic adenosinergic signaling on conventional CD4+ T cells acting via ADORA2A. ADORA2A signaling enhances the levels of intracellular cAMP and enforces nuclear localization of CREM. Outcome effects: Elevated level of intracellular cAMP down-regulates IL2 production which is necessary for CD4+ T-cell and antigen-presenting cell activation thereby providing an immunosuppressive effect. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 22678893 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-2d21c199-62af-4b9b-a418-1b516cb6118d Adenosine/cAMP Promote Immunosuppression by Treg Cells uuid-2d21c199-62af-4b9b-a418-1b516cb6118d PS:CellType CD4+ T-cell PS:CellType antigen-presenting cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType regulatory T-cell PS:Description Adenosine and cAMP play major role in Treg-cell-mediated suppression of CD4+ T-cells and antigen-presenting cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d21c199-62af-4b9b-a418-1b516cb6118d PS:NodeType Pathway PS:Notes Headnote: Adenosine and cAMP are important for Treg-cell-mediated suppression of CD4+ T-cells and antigen-presenting cells. Signaling description: High intracellular cAMP levels are generated in Treg cells by FOXP3-mediated downregulation of the PDE3B. Furthermore, FOXP3 also down-regulates MIR-142 targeting ADCY9 resulting in upregulated cAMP production. cAMP is transferred from nTreg cells into activated target CD4+ T cells and/or antigen-presenting cells (APCs) via gap junctions to suppress these cells. cAMP facilitates the expression of CREM transcription factor, resulting in the suppression IL-2 directly or via NFATC1. ENTPD1 (CD39) and NT5E (CD73) ectoenzymes on nTreg cells generate extracellular immunosuppressive adenosine from ATP, which adds to the suppressive effects of inflamed-tissue hypoxic adenosinergic signaling on conventional CD4+ T cells acting via ADORA2A. ADORA2A signaling enhances the levels of intracellular cAMP and enforces nuclear localization of CREM. Outcome effects: Elevated level of intracellular cAMP down-regulates IL2 production which is necessary for CD4+ T-cell and antigen-presenting cell activation thereby providing an immunosuppressive effect. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 22678893 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuroendocrine cell CellType: neuron Description: In neuronal exocytosis the priming of the secretory vesicle is mediated by Ca2+ influx after initial docking and triggers vesicle fusion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d2dbe62-b975-4c86-954d-6a620135fedd NodeType: Pathway Notes: Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle priming is defined as a Ca2+-dependent mechanism restoring secretion. Signaling description: In neuronal exocytosis, the priming of the secretory vesicle is mediated by molecular rearrangements and modifications that take place following initial docking of a synaptic vesicle but prior to exocytosis. In other cell types, whose secretion is constitutive (calcium ion independent, non-triggered) there is no priming. The influx of calcium into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor, synaptotagmin (SYT1), and the partially assembled SNARE complex (SNAP25/STX1A/VAMP2). The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: The influx of calcium ions in the priming step is needed to trigger vesicle fusion and nearly instantaneous neurotransmitter release in neurons. Animal data: Some of the data was revealed from animal model experiments. PMID: 17110340 PMID: 22026965 PMID: 24363652 PMID: 26498108 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-2d2dbe62-b975-4c86-954d-6a620135fedd Exocytosis: Vesicle Priming uuid-2d2dbe62-b975-4c86-954d-6a620135fedd PS:CellType neuroendocrine cell PS:CellType neuron PS:Description In neuronal exocytosis the priming of the secretory vesicle is mediated by Ca2+ influx after initial docking and triggers vesicle fusion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d2dbe62-b975-4c86-954d-6a620135fedd PS:NodeType Pathway PS:Notes Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle priming is defined as a Ca2+-dependent mechanism restoring secretion. Signaling description: In neuronal exocytosis, the priming of the secretory vesicle is mediated by molecular rearrangements and modifications that take place following initial docking of a synaptic vesicle but prior to exocytosis. In other cell types, whose secretion is constitutive (calcium ion independent, non-triggered) there is no priming. The influx of calcium into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor, synaptotagmin (SYT1), and the partially assembled SNARE complex (SNAP25/STX1A/VAMP2). The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: The influx of calcium ions in the priming step is needed to trigger vesicle fusion and nearly instantaneous neurotransmitter release in neurons. Animal data: Some of the data was revealed from animal model experiments. PS:PMID 17110340 PS:PMID 22026965 PS:PMID 24363652 PS:PMID 26498108 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d32d3e6-6f5e-45f8-b71d-283b465fd300 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2d32d3e6-6f5e-45f8-b71d-283b465fd300 Overview. Diseases of the skin (chapter 11) uuid-2d32d3e6-6f5e-45f8-b71d-283b465fd300 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d32d3e6-6f5e-45f8-b71d-283b465fd300 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Increased levels of EGFR in the nucleus enhances cell proliferation and contributes to drug resistance in cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d47273a-039e-4f0f-b5a0-8a83ed0c3b8b NodeType: Pathway Notes: Headnote: Increased levels of nuclear epidermal growth factor receptor (EGFR) were found in the nuclei in a variety of tumors such as skin, breast, and thyroid tumors. The accumulation of EGFR in the nucleus enhances cell proliferation and contributes to drug resistance. Signaling description: Although the exact mechanism of EGFR transport from the cellular membrane to the nucleus is unknown, several players involved in its internalization and trafficking have been recently discovered. First, EGFR has to undergo endocytosis and then is redistributed to the Golgi complex and endoplasmic reticulum. Finally, with the interaction of importins and nuclear pore complex, EGFR enters the nucleus using Sec61 to detach from the membrane. The downstream targets of nuclear EGFR can be used as markers of EGFR translocation. Outcome effects: Nuclear EGFR phosphorylates PCNA and PRKDC, which affects cell proliferation and DNA repair. Also, EGFR interacts with transcription factors, STAT3, STAT5A, and E2F1, and increases their activity. Organ: colon Organ: intestine Organ_System: integumentary system PMID: 26077270 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-2d47273a-039e-4f0f-b5a0-8a83ed0c3b8b EGFR Nuclear Signaling in Colorectal Cancer uuid-2d47273a-039e-4f0f-b5a0-8a83ed0c3b8b PS:CellType cancer cell PS:Description Increased levels of EGFR in the nucleus enhances cell proliferation and contributes to drug resistance in cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d47273a-039e-4f0f-b5a0-8a83ed0c3b8b PS:NodeType Pathway PS:Notes Headnote: Increased levels of nuclear epidermal growth factor receptor (EGFR) were found in the nuclei in a variety of tumors such as skin, breast, and thyroid tumors. The accumulation of EGFR in the nucleus enhances cell proliferation and contributes to drug resistance. Signaling description: Although the exact mechanism of EGFR transport from the cellular membrane to the nucleus is unknown, several players involved in its internalization and trafficking have been recently discovered. First, EGFR has to undergo endocytosis and then is redistributed to the Golgi complex and endoplasmic reticulum. Finally, with the interaction of importins and nuclear pore complex, EGFR enters the nucleus using Sec61 to detach from the membrane. The downstream targets of nuclear EGFR can be used as markers of EGFR translocation. Outcome effects: Nuclear EGFR phosphorylates PCNA and PRKDC, which affects cell proliferation and DNA repair. Also, EGFR interacts with transcription factors, STAT3, STAT5A, and E2F1, and increases their activity. PS:Organ colon PS:Organ intestine PS:Organ_System integumentary system PS:PMID 26077270 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d487a98-af0d-4c88-aa15-8042509e74ad NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2d487a98-af0d-4c88-aa15-8042509e74ad BTC -> EP300/ETS/ETV/SP1 Expression Targets uuid-2d487a98-af0d-4c88-aa15-8042509e74ad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d487a98-af0d-4c88-aa15-8042509e74ad PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Duchenne muscular dystrophy (DMD) is caused by mutations in the gene coding for dystrophin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d555c19-32af-4f56-b262-5458401bebab NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: One of the functions of dystrophin is the proper scaffolding of various proteins including members of signaling cascades. The lack of DGC results in mislocalization and changes in the activity of proteins normally associated with DGC. NOS1 activity becomes decreased in dystrophin-deficient muscles. Caveolin 3 (CAV3) levels are also increased in dystrophin-deficient muscles. It has been documented that such an increase can alone cause Duchenne-like symptoms. DGKZ, calmodulin, and GRB2 also interact with DGC and may represent a link between DGC impairment and muscle cell survival. Outcome effects: Nitric oxide (NO) produced by NOS1 is an important anti-inflammatory and cytoprotective agent. The restoration of NO synthesis or treatment with NO donors improves symptoms of dystrophin deficiency in models of DMD. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-2d555c19-32af-4f56-b262-5458401bebab Dystrophin Glycoprotein Complex Signaling in Muscular Dystrophies uuid-2d555c19-32af-4f56-b262-5458401bebab PS:CellType muscle cell PS:Description Duchenne muscular dystrophy (DMD) is caused by mutations in the gene coding for dystrophin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d555c19-32af-4f56-b262-5458401bebab PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: One of the functions of dystrophin is the proper scaffolding of various proteins including members of signaling cascades. The lack of DGC results in mislocalization and changes in the activity of proteins normally associated with DGC. NOS1 activity becomes decreased in dystrophin-deficient muscles. Caveolin 3 (CAV3) levels are also increased in dystrophin-deficient muscles. It has been documented that such an increase can alone cause Duchenne-like symptoms. DGKZ, calmodulin, and GRB2 also interact with DGC and may represent a link between DGC impairment and muscle cell survival. Outcome effects: Nitric oxide (NO) produced by NOS1 is an important anti-inflammatory and cytoprotective agent. The restoration of NO synthesis or treatment with NO donors improves symptoms of dystrophin deficiency in models of DMD. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d5a892b-1808-4ce9-8231-c9dbd2f42076 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-2d5a892b-1808-4ce9-8231-c9dbd2f42076 CD8 -> AP-1 Expression Targets uuid-2d5a892b-1808-4ce9-8231-c9dbd2f42076 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d5a892b-1808-4ce9-8231-c9dbd2f42076 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: odontoblast Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d6cc50e-7241-47d9-b80a-8e64118d1473 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: Tooth Organ: mouth Organ_System: digestive system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-2d6cc50e-7241-47d9-b80a-8e64118d1473 Vitamine D Deficite and Dentin Formation uuid-2d6cc50e-7241-47d9-b80a-8e64118d1473 PS:CellType odontoblast PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d6cc50e-7241-47d9-b80a-8e64118d1473 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ Tooth PS:Organ mouth PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d7240e5-65bb-4a48-9f0e-f3dbd9ef6ca5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2d7240e5-65bb-4a48-9f0e-f3dbd9ef6ca5 FGF7 -> RUNX Expression Targets uuid-2d7240e5-65bb-4a48-9f0e-f3dbd9ef6ca5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d7240e5-65bb-4a48-9f0e-f3dbd9ef6ca5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d7de054-9543-4a85-ba8f-7ac3916e0eb7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2d7de054-9543-4a85-ba8f-7ac3916e0eb7 Thromboxane A2 Expression Targets uuid-2d7de054-9543-4a85-ba8f-7ac3916e0eb7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2d7de054-9543-4a85-ba8f-7ac3916e0eb7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: granulosa cell CellType: theca cell Description: Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2da1a7dc-1fae-4b48-8cd3-23800c090054 NodeType: Pathway Notes: Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Signaling description: Normally, androgens are synthesized in the theca cells of ovarian follicles under the exposure to luteinizing hormone (LH) to be later converted into estrogens by CYP19A1 in granulosa cells. In PCOS, elevated LH or LH/FSH ratio is observed. Gonadotropin-releasing hormone (GNRH1) has increased amplitude of secretion in the pathology. The hormone provokes LH release in the pituitary and elevated LH triggers steroid hormone synthesis by binding to its receptor, LHCGR. It promotes STAR involvement in the process through PRKAR1A activation. STAR is a protein, which transports cholesterol (the substrate for hormone synthesis) into the mitochondrion where the process occurs. Several proteins, including CYP11A1, CYP17A1, HSD3B2, and HSD17B1, are involved in the subsequent conversion of cholesterol into testosterone in the theca cells. In addition, insulin (INS) synergistically increases LH action. INS induces the expression of steroidogenic enzymes through the activation of NR5A1 transcription factor and also promotes LDLR synthesis in the theca cells. LDLR transports cholesterol into the cell. IGF1 and IGF2 are involved in PCOS pathogenesis by activating the expression of steroidogenic enzymes through MAPK1/MAPK3 pathway. RBP4, which is also elevated in PCOS, delivers retinol to the follicle. Retinol uptake into the cell, where it contributes to CYP17A1 expression, occurs via STRA6. The next step of steroidogenesis in women occurs in granulosa cells where testosterone and its derivatives are converted into estrogens. Normally, the conversion is promoted by CYP19A1. The lack of the enzyme due to a deficiency of stimulatory signals from FSH leads to androgen excess. In some cases, testosterone may be converted into dihydrotestosterone by SRD5A1, when the protein is elevated. Outcome effects: The excess of androgens, particularly dihydrotestosterone, explain hirsutism and acne in PCOS women. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: ovary Organ_System: reproductive system PMID: 18440223 PMID: 19078868 PMID: 21606667 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-2da1a7dc-1fae-4b48-8cd3-23800c090054 Steroidogenesis Impairement in Polycystic Ovary Syndrome uuid-2da1a7dc-1fae-4b48-8cd3-23800c090054 PS:CellType granulosa cell PS:CellType theca cell PS:Description Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2da1a7dc-1fae-4b48-8cd3-23800c090054 PS:NodeType Pathway PS:Notes Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Signaling description: Normally, androgens are synthesized in the theca cells of ovarian follicles under the exposure to luteinizing hormone (LH) to be later converted into estrogens by CYP19A1 in granulosa cells. In PCOS, elevated LH or LH/FSH ratio is observed. Gonadotropin-releasing hormone (GNRH1) has increased amplitude of secretion in the pathology. The hormone provokes LH release in the pituitary and elevated LH triggers steroid hormone synthesis by binding to its receptor, LHCGR. It promotes STAR involvement in the process through PRKAR1A activation. STAR is a protein, which transports cholesterol (the substrate for hormone synthesis) into the mitochondrion where the process occurs. Several proteins, including CYP11A1, CYP17A1, HSD3B2, and HSD17B1, are involved in the subsequent conversion of cholesterol into testosterone in the theca cells. In addition, insulin (INS) synergistically increases LH action. INS induces the expression of steroidogenic enzymes through the activation of NR5A1 transcription factor and also promotes LDLR synthesis in the theca cells. LDLR transports cholesterol into the cell. IGF1 and IGF2 are involved in PCOS pathogenesis by activating the expression of steroidogenic enzymes through MAPK1/MAPK3 pathway. RBP4, which is also elevated in PCOS, delivers retinol to the follicle. Retinol uptake into the cell, where it contributes to CYP17A1 expression, occurs via STRA6. The next step of steroidogenesis in women occurs in granulosa cells where testosterone and its derivatives are converted into estrogens. Normally, the conversion is promoted by CYP19A1. The lack of the enzyme due to a deficiency of stimulatory signals from FSH leads to androgen excess. In some cases, testosterone may be converted into dihydrotestosterone by SRD5A1, when the protein is elevated. Outcome effects: The excess of androgens, particularly dihydrotestosterone, explain hirsutism and acne in PCOS women. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18440223 PS:PMID 19078868 PS:PMID 21606667 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage CellType: neutrophil Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dbceb8b-e1ec-4d43-a9ed-7d1f3aa8998c NodeType: Pathway Organ: generic Organ_System: generic PMID: 20363321 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-2dbceb8b-e1ec-4d43-a9ed-7d1f3aa8998c SARS-Kawasaki disease uuid-2dbceb8b-e1ec-4d43-a9ed-7d1f3aa8998c PS:CellType dendritic cell PS:CellType macrophage PS:CellType neutrophil PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dbceb8b-e1ec-4d43-a9ed-7d1f3aa8998c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 20363321 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Basophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dcb1e91-f90d-4fcb-9e85-59d5157f8f93 NodeType: Pathway Notes: Headnote: Basophils belong to a subtype of leukocytes that contain granules known as granulocytes. There are very few basophils in blood which account for less than 1% of all leukocytes. Moreover, there are virtually no basophils in a healthy organism since they appear as a response to disorders generally caused by allergic reactions. Signaling description: Basophils, the largest granulocytes, are very similar to mast cells and originate from the same precursor. The activation of basophils, similarly that of mast cells, is primarily characterized by degranulation and the release of heparin, histamine, and leukotrienes from granules which leads to immediate hypersensitivity reactions. Unlike mast cells, basophils are introduced into blood in a mature state, so their effects are faster than those of mast cells. Unlike mast cells, basophils express MHC class II and co-stimulatory molecules which can transmit haptens and peptide antigens to Th2 cells and therefore stimulate their differentiation. Similarly to mast cells, which also express the high-affinity IgE receptor FCERI, basophils release inflammatory mediators such as histamine and LTC4 in response to IgE-mediated activation. FCER1 is expressed on mast cells and basophils as tetramers (FCER1A/MS4A2/2 of FCER1G). Antigen binding to IgE cross-links two FCERI leading to LYN phosphorylation. The multi-molecular complex, which includes GRAP2, LCP2, PLCG, and VAV1, form on LAT. FCERI aggregation induces PI3K, MAPK1, MAPK8, NF-kB, PLC, and PKC activation. An increase in calcium (Ca2+) also leads to the synthesis of arachidonic acid and lysophospholipid that support the fusion of mast cell granules with the membrane and release of their contents. In addition to the well-characterized ability of basophils to be activated by antigen-IgE complexes, basophils have also been shown to become activated by the IgD antibody class. IgD is a class of antibodies that is produced during the early phases of B-cell development, but its biological functions remain poorly defined. IL3, the key cytokine that activates the maturation of basophils, appears to have a prominent pro-survival effect on basophils that are influenced by the kinase PIM1. IL3 also enhances the production of IL4 and IL13 by basophils in response to IgE-mediated activation. In basophils, IL4 and IL13 production is also induced by TLR2-related signaling. IL18 and IL33 are also specific to the activation of basophils. IL18 is produced by macrophages, Kupffer cells, and mast cells and is associated with allergic disease and immunity to helminth parasites. In human basophils, the role of IL18 in basophil activation is not well established. IL33 is expressed by dermal fibroblasts, airway epithelial cells, and bronchial smooth muscle cells and is associated with IL4, IL13, and IL6. In addition, human basophils express the complement receptors CR1, CR3, CR4, and C5AR1. Outcome effects: Human basophils produce histamine in response to the complement component C5a in an IgE-independent manner. Basophils are known to contribute to allergic responses by inducing smooth muscle contraction once they migrate to the area of inflammation during the late phase response. Leukotrienes LTC4, LTD4, and LTE4 are smooth muscle constrictors. Like mast cells, basophils synthesize large amounts of cytokines, growth factors, and proinflammatory mediators. Most basophil-specific mediators include IL13, IL6, IL4, TNF, CD80, CD40, and TSLP. In the absence of pro-survival factors, neutrophils, eosinophils, and basophils all die by intrinsic apoptosis within a short time following maturation. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-2dcb1e91-f90d-4fcb-9e85-59d5157f8f93 Basophil Activation uuid-2dcb1e91-f90d-4fcb-9e85-59d5157f8f93 PS:CellType T-cell PS:Description Basophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dcb1e91-f90d-4fcb-9e85-59d5157f8f93 PS:NodeType Pathway PS:Notes Headnote: Basophils belong to a subtype of leukocytes that contain granules known as granulocytes. There are very few basophils in blood which account for less than 1% of all leukocytes. Moreover, there are virtually no basophils in a healthy organism since they appear as a response to disorders generally caused by allergic reactions. Signaling description: Basophils, the largest granulocytes, are very similar to mast cells and originate from the same precursor. The activation of basophils, similarly that of mast cells, is primarily characterized by degranulation and the release of heparin, histamine, and leukotrienes from granules which leads to immediate hypersensitivity reactions. Unlike mast cells, basophils are introduced into blood in a mature state, so their effects are faster than those of mast cells. Unlike mast cells, basophils express MHC class II and co-stimulatory molecules which can transmit haptens and peptide antigens to Th2 cells and therefore stimulate their differentiation. Similarly to mast cells, which also express the high-affinity IgE receptor FCERI, basophils release inflammatory mediators such as histamine and LTC4 in response to IgE-mediated activation. FCER1 is expressed on mast cells and basophils as tetramers (FCER1A/MS4A2/2 of FCER1G). Antigen binding to IgE cross-links two FCERI leading to LYN phosphorylation. The multi-molecular complex, which includes GRAP2, LCP2, PLCG, and VAV1, form on LAT. FCERI aggregation induces PI3K, MAPK1, MAPK8, NF-kB, PLC, and PKC activation. An increase in calcium (Ca2+) also leads to the synthesis of arachidonic acid and lysophospholipid that support the fusion of mast cell granules with the membrane and release of their contents. In addition to the well-characterized ability of basophils to be activated by antigen-IgE complexes, basophils have also been shown to become activated by the IgD antibody class. IgD is a class of antibodies that is produced during the early phases of B-cell development, but its biological functions remain poorly defined. IL3, the key cytokine that activates the maturation of basophils, appears to have a prominent pro-survival effect on basophils that are influenced by the kinase PIM1. IL3 also enhances the production of IL4 and IL13 by basophils in response to IgE-mediated activation. In basophils, IL4 and IL13 production is also induced by TLR2-related signaling. IL18 and IL33 are also specific to the activation of basophils. IL18 is produced by macrophages, Kupffer cells, and mast cells and is associated with allergic disease and immunity to helminth parasites. In human basophils, the role of IL18 in basophil activation is not well established. IL33 is expressed by dermal fibroblasts, airway epithelial cells, and bronchial smooth muscle cells and is associated with IL4, IL13, and IL6. In addition, human basophils express the complement receptors CR1, CR3, CR4, and C5AR1. Outcome effects: Human basophils produce histamine in response to the complement component C5a in an IgE-independent manner. Basophils are known to contribute to allergic responses by inducing smooth muscle contraction once they migrate to the area of inflammation during the late phase response. Leukotrienes LTC4, LTD4, and LTE4 are smooth muscle constrictors. Like mast cells, basophils synthesize large amounts of cytokines, growth factors, and proinflammatory mediators. Most basophil-specific mediators include IL13, IL6, IL4, TNF, CD80, CD40, and TSLP. In the absence of pro-survival factors, neutrophils, eosinophils, and basophils all die by intrinsic apoptosis within a short time following maturation. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dd76db5-facd-4cf8-81f5-726793f3f3dd NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-2dd76db5-facd-4cf8-81f5-726793f3f3dd KIT -> MITF Signaling uuid-2dd76db5-facd-4cf8-81f5-726793f3f3dd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dd76db5-facd-4cf8-81f5-726793f3f3dd PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Beta cells in the islets of Langerhans release insulin in two phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dedb52e-8926-450e-94e2-71de9a114c7f NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: Insulin release from pancreatic beta-cells proceeds in two steps. Increased blood glucose levels rapidly trigger the first step of insulin release. Upregulation of glucose metabolism activates the ATP/ADP ratio in beta-cells, which promotes the ATP-sensitive potassium channel (KCNJ11) closure, membrane depolarization, and opens voltage-gated calcium (Ca2 ) channels. Outcome effects: Insulin is stored in large dense-core secretory granules known as beta-granules, which constantly turn over: if a beta-granule does not undergo exocytosis, it is retired by intracellular degradation with a half-life of 3 to 5 days. The release of insulin from the pancreas is not continuous, and oscillates with a period of 3 to 6 minutes. Pulsatile insulin secretion from individual beta-cells is driven by oscillations of Ca2+ concentration in the cell, as well as cyclic variations of the cell metabolism and ATP/ADP ratio. An increase of intracellular Ca2+ concentrations triggers the exocytosis of insulin granules, which occurs at different rates and is controlled by two Ca2+ sensing mechanisms: the low affinity Ca2+ sensor and the high affinity Ca2+ sensor. Exocytosis which occurs at high Ca2+ is controlled by the low affinity Ca2+ sensor. SYT9 has been identified as the high-affinity Ca2+ sensor in beta cells, whereas PCLO may act as a low-affinity Ca2+ sensor. PCLO facilitates rapid Ca2+-induced exocytosis by its interacting with RAPGEF3/RAPGEF4. The fusion of granules involves a complex interaction between SNAP25 and STX1A at the plasma membrane, and VAMP2 probably modulated by synaptotagmin V and VII. Upon stimulation, proteolysis of SNAP25 seems to be crucial for the secretion of insulin. In addition, cyclic AMP (cAMP) promotes insulin exocytosis by facilitating the generation of Ca2+ signals by stimulating the mobilization and priming of granules via PKA- and RAPGEF4/RAPGEF3-dependent pathways. In addition, both cAMP and Ca2+ are dependent on the intracellular ATP level. RAPGEF4/RAPGEF3 may increase the intracellular Ca2+ channel sensitivity to Ca2+ or Ca2+ mobilizing signals. RAPGEF4 may act through RAP1A, ABCC8, and RIMS2. Only 1% of insulin granules are immediately available for the glucose triggered release (readily releasable pool). The remaining 99% of granules belong to the reserve pool which has to undergo preparatory reactions before release. L-type Ca2+V1.2 channels (CACNA1C) are responsible for the immediate release of insulin, while R-type CaV2.3 channels (CACNA1E) are insufficient to initiate insulin exocytosis, but accelerate granule mobilization. UNC13A is vital for the second wave of secretion. KIAA1244-deficient insulin-secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation. Organ: pancreas Organ_System: endocrine system PMID: 21127054 PMID: 24711543 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-2dedb52e-8926-450e-94e2-71de9a114c7f beta-Cell Granules Exocytois uuid-2dedb52e-8926-450e-94e2-71de9a114c7f PS:CellType insulin-secreting cell PS:Description Beta cells in the islets of Langerhans release insulin in two phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2dedb52e-8926-450e-94e2-71de9a114c7f PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: Insulin release from pancreatic beta-cells proceeds in two steps. Increased blood glucose levels rapidly trigger the first step of insulin release. Upregulation of glucose metabolism activates the ATP/ADP ratio in beta-cells, which promotes the ATP-sensitive potassium channel (KCNJ11) closure, membrane depolarization, and opens voltage-gated calcium (Ca2 ) channels. Outcome effects: Insulin is stored in large dense-core secretory granules known as beta-granules, which constantly turn over: if a beta-granule does not undergo exocytosis, it is retired by intracellular degradation with a half-life of 3 to 5 days. The release of insulin from the pancreas is not continuous, and oscillates with a period of 3 to 6 minutes. Pulsatile insulin secretion from individual beta-cells is driven by oscillations of Ca2+ concentration in the cell, as well as cyclic variations of the cell metabolism and ATP/ADP ratio. An increase of intracellular Ca2+ concentrations triggers the exocytosis of insulin granules, which occurs at different rates and is controlled by two Ca2+ sensing mechanisms: the low affinity Ca2+ sensor and the high affinity Ca2+ sensor. Exocytosis which occurs at high Ca2+ is controlled by the low affinity Ca2+ sensor. SYT9 has been identified as the high-affinity Ca2+ sensor in beta cells, whereas PCLO may act as a low-affinity Ca2+ sensor. PCLO facilitates rapid Ca2+-induced exocytosis by its interacting with RAPGEF3/RAPGEF4. The fusion of granules involves a complex interaction between SNAP25 and STX1A at the plasma membrane, and VAMP2 probably modulated by synaptotagmin V and VII. Upon stimulation, proteolysis of SNAP25 seems to be crucial for the secretion of insulin. In addition, cyclic AMP (cAMP) promotes insulin exocytosis by facilitating the generation of Ca2+ signals by stimulating the mobilization and priming of granules via PKA- and RAPGEF4/RAPGEF3-dependent pathways. In addition, both cAMP and Ca2+ are dependent on the intracellular ATP level. RAPGEF4/RAPGEF3 may increase the intracellular Ca2+ channel sensitivity to Ca2+ or Ca2+ mobilizing signals. RAPGEF4 may act through RAP1A, ABCC8, and RIMS2. Only 1% of insulin granules are immediately available for the glucose triggered release (readily releasable pool). The remaining 99% of granules belong to the reserve pool which has to undergo preparatory reactions before release. L-type Ca2+V1.2 channels (CACNA1C) are responsible for the immediate release of insulin, while R-type CaV2.3 channels (CACNA1E) are insufficient to initiate insulin exocytosis, but accelerate granule mobilization. UNC13A is vital for the second wave of secretion. KIAA1244-deficient insulin-secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 21127054 PS:PMID 24711543 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: Ependymomas are glial tumors that arise from ependymal cells within the central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2def2d33-a7db-44b3-a7ef-6b2964943656 NodeType: Pathway Notes: Headnote: Ependymomas are glial tumors that arise from ependymal cells within the central nervous system. Signaling description: Notch, Sonic hedgehog homolog (SHH), ERBB/EPHB, IGF1R, and TP53 signaling pathways are implicated in the pathogenesis of ependymomas. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 18676356 PMID: 19531565 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-2def2d33-a7db-44b3-a7ef-6b2964943656 Ependymoma uuid-2def2d33-a7db-44b3-a7ef-6b2964943656 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description Ependymomas are glial tumors that arise from ependymal cells within the central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2def2d33-a7db-44b3-a7ef-6b2964943656 PS:NodeType Pathway PS:Notes Headnote: Ependymomas are glial tumors that arise from ependymal cells within the central nervous system. Signaling description: Notch, Sonic hedgehog homolog (SHH), ERBB/EPHB, IGF1R, and TP53 signaling pathways are implicated in the pathogenesis of ependymomas. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 18676356 PS:PMID 19531565 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e025aef-6154-49b7-8d74-d07c6a4c6df8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2e025aef-6154-49b7-8d74-d07c6a4c6df8 PLAU -> ELK-SRF/AP-1 Expression Targets uuid-2e025aef-6154-49b7-8d74-d07c6a4c6df8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e025aef-6154-49b7-8d74-d07c6a4c6df8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e2b2370-8694-4b30-929d-316a5c2afb79 NodeType: Pathway Notes: Oxidative stress and the toxicity of all-trans-retinal and lipofuscin may lead to RPE cell apoptosis, retinal inflammation, autoimmune response, retinal drusen formation or choroidal neovascularization resulting in retina degradation, and vision loss. Lipofuscin granules are by-products of photoreceptor outer segment turnover and are seen within both healthy and pathological RPE cells. Lipofuscin in RPE cells accumulates throughout life and is readily detectable after age 40. Accumulation of lipofuscin results in a significant increase in retinal phototoxicity. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2e2b2370-8694-4b30-929d-316a5c2afb79 2_Oxidative stress, all-trans-retinal, and lipofuscin toxicity in agerelated macular degeneration uuid-2e2b2370-8694-4b30-929d-316a5c2afb79 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e2b2370-8694-4b30-929d-316a5c2afb79 PS:NodeType Pathway PS:Notes Oxidative stress and the toxicity of all-trans-retinal and lipofuscin may lead to RPE cell apoptosis, retinal inflammation, autoimmune response, retinal drusen formation or choroidal neovascularization resulting in retina degradation, and vision loss. Lipofuscin granules are by-products of photoreceptor outer segment turnover and are seen within both healthy and pathological RPE cells. Lipofuscin in RPE cells accumulates throughout life and is readily detectable after age 40. Accumulation of lipofuscin results in a significant increase in retinal phototoxicity. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e2fee0d-4247-46a0-860c-a4e637dcfaa2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-2e2fee0d-4247-46a0-860c-a4e637dcfaa2 Cornea Efflux transporters uuid-2e2fee0d-4247-46a0-860c-a4e637dcfaa2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e2fee0d-4247-46a0-860c-a4e637dcfaa2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e301f31-61bc-4748-9af0-3a3b63c1d133 NodeType: Pathway Organ: generic Organ_System: generic PMID: 22917651 PMID: 26936847 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-2e301f31-61bc-4748-9af0-3a3b63c1d133 NOTCH Receptors Signaling uuid-2e301f31-61bc-4748-9af0-3a3b63c1d133 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e301f31-61bc-4748-9af0-3a3b63c1d133 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 22917651 PS:PMID 26936847 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e361223-d49e-447c-90e2-afca40107ce4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-2e361223-d49e-447c-90e2-afca40107ce4 Fibrinogen Expression Targets uuid-2e361223-d49e-447c-90e2-afca40107ce4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e361223-d49e-447c-90e2-afca40107ce4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e5c369b-fb51-4c81-8e5f-7cfa9393b50a NodeType: Pathway Organ: colon Organ: small intestine Organ_System: digestive system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-2e5c369b-fb51-4c81-8e5f-7cfa9393b50a Genes with Mutations Associated with Celiac Disease uuid-2e5c369b-fb51-4c81-8e5f-7cfa9393b50a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e5c369b-fb51-4c81-8e5f-7cfa9393b50a PS:NodeType Pathway PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: killer cell Description: GIP release is induced by fatty acids and glucose absorption system in K-cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e6de638-6e05-42c0-81b9-22feb0c49c2c NodeType: Pathway Notes: Headnote: K-cells of the proximal small intestine are activated by fatty acids. K-cells absorb glucose from intestine. The major product of K-cells is GIP. Signaling description: Fatty acids interact with FFAR1, FFAR4 and GPR119 G-protein-coupled receptor on the K-cell surface. Through G-proteins, they activate cAMP/PKA signaling. Activated PKA phosphorylates transcription factors GATA4 and CREB1. In turn, CREB1 interacts with ISL1 and activates the expression of PDX1 and PAX6. All these transcription factors are necessary for GIP gene expression activation. PKA activates the expression of Na+/glucose cotransporter (SLC5A1), the major glucose transporter and critical regulator of GIP release. The ATP-activated inward rectifier potassium channel, the second major regulator of GIP release, is also activated by PKA. The Na+/K+-exchanging ATPase regulate Na+/K+ balance through glucose absorption and is necessary for accurate work of ATP-activated inward rectifier potassium channel. Outcome effects: The GIP release stimulates synthesis and release of insulin by pancreatic beta-cells. Organ: colon Organ: intestine Organ: small intestine Organ_System: digestive system PMID: 21094898 PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-2e6de638-6e05-42c0-81b9-22feb0c49c2c K-cell: GIP Production uuid-2e6de638-6e05-42c0-81b9-22feb0c49c2c PS:CellType killer cell PS:Description GIP release is induced by fatty acids and glucose absorption system in K-cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e6de638-6e05-42c0-81b9-22feb0c49c2c PS:NodeType Pathway PS:Notes Headnote: K-cells of the proximal small intestine are activated by fatty acids. K-cells absorb glucose from intestine. The major product of K-cells is GIP. Signaling description: Fatty acids interact with FFAR1, FFAR4 and GPR119 G-protein-coupled receptor on the K-cell surface. Through G-proteins, they activate cAMP/PKA signaling. Activated PKA phosphorylates transcription factors GATA4 and CREB1. In turn, CREB1 interacts with ISL1 and activates the expression of PDX1 and PAX6. All these transcription factors are necessary for GIP gene expression activation. PKA activates the expression of Na+/glucose cotransporter (SLC5A1), the major glucose transporter and critical regulator of GIP release. The ATP-activated inward rectifier potassium channel, the second major regulator of GIP release, is also activated by PKA. The Na+/K+-exchanging ATPase regulate Na+/K+ balance through glucose absorption and is necessary for accurate work of ATP-activated inward rectifier potassium channel. Outcome effects: The GIP release stimulates synthesis and release of insulin by pancreatic beta-cells. PS:Organ colon PS:Organ intestine PS:Organ small intestine PS:Organ_System digestive system PS:PMID 21094898 PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e6f0b0b-32ba-4fc5-81fc-4305ca707ace NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-2e6f0b0b-32ba-4fc5-81fc-4305ca707ace Proteins Involved in Vasospasm uuid-2e6f0b0b-32ba-4fc5-81fc-4305ca707ace PS:CellType endothelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e6f0b0b-32ba-4fc5-81fc-4305ca707ace PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e801546-3a5f-41d0-a832-ef2e1695b59e NodeType: Pathway Organ: generic Organ_System: generic PMID: 21167873 PMID: 22569528 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-2e801546-3a5f-41d0-a832-ef2e1695b59e ERK/MAPK Canonical Signaling uuid-2e801546-3a5f-41d0-a832-ef2e1695b59e PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e801546-3a5f-41d0-a832-ef2e1695b59e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21167873 PS:PMID 22569528 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e9b8778-ed78-4d21-afa4-4e18031c7b96 NodeType: Pathway Notes: Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. NK cell stimulatory receptors with immunoreceptor tyrosine-based activation motif (ITAM) are the strongest NK cell activator receptors. Signaling description: The ITAM motif of NK cell activator receptors binds to cytoplasmic adaptor, TYROBP and becomes phosphorylated. The phosphorylation of the ITAM motif of NK cell activator receptors induces the recruitment of the kinases, SYK and ZAP70. SYK and ZAP70 signaling results in the release of calcium and activation of JUN/FOS and NFATC2 transcription factors. NK cell activator receptors such as FCGR3B and FCGR3A induce the phosphorylation of VAV2 and VAV3, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to additional VAV phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. Outcome effects: Finally, the two main NK cell-mediated responses are activated including the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes lead to the death of target cells. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-2e9b8778-ed78-4d21-afa4-4e18031c7b96 Natural Killer Cell Activation through ITAM-Containing Receptors uuid-2e9b8778-ed78-4d21-afa4-4e18031c7b96 PS:CellType natural killer cell PS:Description Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2e9b8778-ed78-4d21-afa4-4e18031c7b96 PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. NK cell stimulatory receptors with immunoreceptor tyrosine-based activation motif (ITAM) are the strongest NK cell activator receptors. Signaling description: The ITAM motif of NK cell activator receptors binds to cytoplasmic adaptor, TYROBP and becomes phosphorylated. The phosphorylation of the ITAM motif of NK cell activator receptors induces the recruitment of the kinases, SYK and ZAP70. SYK and ZAP70 signaling results in the release of calcium and activation of JUN/FOS and NFATC2 transcription factors. NK cell activator receptors such as FCGR3B and FCGR3A induce the phosphorylation of VAV2 and VAV3, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to additional VAV phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. Outcome effects: Finally, the two main NK cell-mediated responses are activated including the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes lead to the death of target cells. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2eaf8d24-ef18-47d2-899f-42b2f1c1c242 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-2eaf8d24-ef18-47d2-899f-42b2f1c1c242 Drugs re-purposed against COVID19 PMID:32149769 uuid-2eaf8d24-ef18-47d2-899f-42b2f1c1c242 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2eaf8d24-ef18-47d2-899f-42b2f1c1c242 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2eba1414-a871-4743-86b3-e204f54e9d6d NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-2eba1414-a871-4743-86b3-e204f54e9d6d Genes with Mutations in Cancer Metabolic Reprogramming (Krebs Cycle) uuid-2eba1414-a871-4743-86b3-e204f54e9d6d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2eba1414-a871-4743-86b3-e204f54e9d6d PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: oxLDL/LOX-1 activates signaling pathways that promote angiogenesis and cell proliferation and inhibit apoptosis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ee414f5-da4a-4d28-a4fd-8010c47e3a44 NodeType: Pathway Notes: Headnote: oxLDL/LOX-1 activates signaling pathways that promote angiogenesis and cell proliferation and inhibit apoptosis. Overexpression of LOX-1 was shown in prostate, breast and some other types of cancer. Signaling description: LOX-1 stimulated by oxLDL activates NFkB. The precise mechanism of this is not clear. The molecular path probably involves NAD(P)H oxidase/ROS signaling. Outcome effects: NFkB activation leads to overexpression of VEGFA, MMP2, MMP9 (they induce angiogenesis), BCL-2, BCL2A1, TNFAIP3 (inhibit apoptosis) and CCND2 (activates cell proliferation). All these events promote tumor progression. Animal data: not shown. All the data were obtained on human cancer specimens and cancer cell lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21637860 PMID: 25170920 PMID: 25566960 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-2ee414f5-da4a-4d28-a4fd-8010c47e3a44 Oxidized LDL/OLR1 Activates Cell Proliferation in Cancer uuid-2ee414f5-da4a-4d28-a4fd-8010c47e3a44 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description oxLDL/LOX-1 activates signaling pathways that promote angiogenesis and cell proliferation and inhibit apoptosis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ee414f5-da4a-4d28-a4fd-8010c47e3a44 PS:NodeType Pathway PS:Notes Headnote: oxLDL/LOX-1 activates signaling pathways that promote angiogenesis and cell proliferation and inhibit apoptosis. Overexpression of LOX-1 was shown in prostate, breast and some other types of cancer. Signaling description: LOX-1 stimulated by oxLDL activates NFkB. The precise mechanism of this is not clear. The molecular path probably involves NAD(P)H oxidase/ROS signaling. Outcome effects: NFkB activation leads to overexpression of VEGFA, MMP2, MMP9 (they induce angiogenesis), BCL-2, BCL2A1, TNFAIP3 (inhibit apoptosis) and CCND2 (activates cell proliferation). All these events promote tumor progression. Animal data: not shown. All the data were obtained on human cancer specimens and cancer cell lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21637860 PS:PMID 25170920 PS:PMID 25566960 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Kynurenine pathway (KP) is responsible for tryptophan turnover creating multiple intermediate metabolites. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ee86113-d1da-42d9-87dd-1d1a0243558c NodeType: Pathway Notes: Headnote: Kynurenine pathway (KP) is responsible for tryptophan turnover creating multiple intermediate metabolites. Signaling description: Among KP metabolites, kynurenine (KYN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QUIN) were fond to be immunosuppressive: in micromolar concentrations they were found to inhibit T-cell proliferation in vitro. The same substances induced selective apoptosis of thymocytes and of antigen-specific CD4 T-helper 1 cells. Another notable effect 3-HAA has on T-cells is its ability to cause a reduction in CD4 TH17 cells and a reciprocal increase in the fraction of Tregs. Organ: lymph node Organ_System: lymphatic system PMID: 20972599 PMID: 21744051 PMID: 23103127 PMID: 25400638 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-2ee86113-d1da-42d9-87dd-1d1a0243558c Kynurenine Metabolites in T-Cell Apoptosis uuid-2ee86113-d1da-42d9-87dd-1d1a0243558c PS:CellType T-cell PS:Description Kynurenine pathway (KP) is responsible for tryptophan turnover creating multiple intermediate metabolites. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ee86113-d1da-42d9-87dd-1d1a0243558c PS:NodeType Pathway PS:Notes Headnote: Kynurenine pathway (KP) is responsible for tryptophan turnover creating multiple intermediate metabolites. Signaling description: Among KP metabolites, kynurenine (KYN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QUIN) were fond to be immunosuppressive: in micromolar concentrations they were found to inhibit T-cell proliferation in vitro. The same substances induced selective apoptosis of thymocytes and of antigen-specific CD4 T-helper 1 cells. Another notable effect 3-HAA has on T-cells is its ability to cause a reduction in CD4 TH17 cells and a reciprocal increase in the fraction of Tregs. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 20972599 PS:PMID 21744051 PS:PMID 23103127 PS:PMID 25400638 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f04fab4-33e0-47f9-96ec-38f65b10e4c9 NodeType: Pathway Notes: The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. The E1 and E2 viral proteins are required for replication of the virus, cell cycle activation, and maintenance of the nononcogenic status of the infected cell. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organelle: cytosol Organelle: nucleus PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2f04fab4-33e0-47f9-96ec-38f65b10e4c9 2_Human papilloma virus E1 and E2 proteins in virus replication uuid-2f04fab4-33e0-47f9-96ec-38f65b10e4c9 PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f04fab4-33e0-47f9-96ec-38f65b10e4c9 PS:NodeType Pathway PS:Notes The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. The E1 and E2 viral proteins are required for replication of the virus, cell cycle activation, and maintenance of the nononcogenic status of the infected cell. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organelle cytosol PS:Organelle nucleus PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f22d951-678f-4cbf-b8ae-e698a709b76e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-2f22d951-678f-4cbf-b8ae-e698a709b76e FcIgER -> NFATC1 Signaling uuid-2f22d951-678f-4cbf-b8ae-e698a709b76e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f22d951-678f-4cbf-b8ae-e698a709b76e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f4bfd4f-661d-4317-ae38-aa60846b5126 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: stomach Organ_System: digestive system PMID: 14755326 PMID: 20938460 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-2f4bfd4f-661d-4317-ae38-aa60846b5126 Apoptosis through VacA in Helicobacter Pylori Infection uuid-2f4bfd4f-661d-4317-ae38-aa60846b5126 PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f4bfd4f-661d-4317-ae38-aa60846b5126 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ stomach PS:Organ_System digestive system PS:PMID 14755326 PS:PMID 20938460 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: enteroendocrine cell Description: Activated by seversl fatty acids ARRB2 blocks TLR signaling. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f4ff4d3-0da9-496a-9358-80ece637c197 NodeType: Pathway Notes: Headnote: Arrestin-beta 2 (ARRB2) can block the TLR signaling through the activation of fatty acid receptor signaling by several fatty acids (omega-3 etc.). Signaling description: The activation of fatty acid receptors (FFAR1, FFAR4 and GPR119) by omega-3 fatty acid or oleic acid induces ARRB2 coupling to these receptors. The ARRB2 coupling leads to the internalization of these receptors. ARRB2 can interact with the TAB1 protein, which blocks MAP3K7/TAB1 association. This, in turn disrupts the activation of classic TLR signaling pathway and blocks NF kappa B dependent mechanism of immune system activation and inflammatory response. Outcome effects: ARRB2 activated by fatty acids blocks TLR signaling and inhibits the inflammatory response. Animal data: Role of omega-3 in the inhibition of TLR signaling was established in animal models. Organ: colon Organ: intestine Organ_System: digestive system PMID: 24061204 PMID: 27000704 PMID: 27023530 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-2f4ff4d3-0da9-496a-9358-80ece637c197 Fatty Acids Block TLR Signaling in Enteroendocrine Cell uuid-2f4ff4d3-0da9-496a-9358-80ece637c197 PS:CellType enteroendocrine cell PS:Description Activated by seversl fatty acids ARRB2 blocks TLR signaling. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f4ff4d3-0da9-496a-9358-80ece637c197 PS:NodeType Pathway PS:Notes Headnote: Arrestin-beta 2 (ARRB2) can block the TLR signaling through the activation of fatty acid receptor signaling by several fatty acids (omega-3 etc.). Signaling description: The activation of fatty acid receptors (FFAR1, FFAR4 and GPR119) by omega-3 fatty acid or oleic acid induces ARRB2 coupling to these receptors. The ARRB2 coupling leads to the internalization of these receptors. ARRB2 can interact with the TAB1 protein, which blocks MAP3K7/TAB1 association. This, in turn disrupts the activation of classic TLR signaling pathway and blocks NF kappa B dependent mechanism of immune system activation and inflammatory response. Outcome effects: ARRB2 activated by fatty acids blocks TLR signaling and inhibits the inflammatory response. Animal data: Role of omega-3 in the inhibition of TLR signaling was established in animal models. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 27000704 PS:PMID 27023530 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f735e52-a959-4edf-9958-9e3a4d53b48e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2f735e52-a959-4edf-9958-9e3a4d53b48e PTS systems template uuid-2f735e52-a959-4edf-9958-9e3a4d53b48e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f735e52-a959-4edf-9958-9e3a4d53b48e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f7ddc74-3f5a-4c6c-872d-b70d33b42b80 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-2f7ddc74-3f5a-4c6c-872d-b70d33b42b80 Proteins Involved in Neuroblastoma uuid-2f7ddc74-3f5a-4c6c-872d-b70d33b42b80 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f7ddc74-3f5a-4c6c-872d-b70d33b42b80 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Retrograde transport is movement of molecules from the tip of cilium to the cell body for the formation and maintenance of eukaryotic cilia and flagella. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f909fcb-b561-458b-9a3f-63bd1249768d NodeType: Pathway Notes: Headnote: Intraflagellar transport (IFT) is a specialized intracellular process essential for the formation and maintenance of eukaryotic cilia and flagella. IFT is a bidirectional transport (anterograde or orthograde and retrograde transport) along axonemal microtubules. Anterograde activities deliver IFT particles (IFT subcomplexes, IFT trains) to the tip of cilium and retrograde activities return them back to the cell body. Both motilities are tightly regulated to keep cilia intact and maintain them at their specified lengths. Signaling description: The retrograde transport of individual cargoes along the doublet microtubules of the flagellar axoneme is mediated by dynein motor (DYNC2LI1/DYNC2H1). Dynein motor moves IFT-associated proteins and cargo, BBSome and IFT-A/B subcomplexes. In cooperation with this motor, IFT-A subcomplex binds to protein cargo through protein interaction domains. For many cargoes it is not yet understood how they interact with the IFT machinery. IFT-A subcomplex contains IFT144 (WDR19), IFT140, IFT139 (TTC21B), IFT122, IFT121 (WDR35) and IFT43. IFT144 (WDR19) is required for the association of IFT-A subcomplex with dynein motor. BBSome may play a role in holding IFT-A and IFT-B together. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: Dynein motor, IFT-A subcomplex and BBSome are involved in retrograde transport. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 22683354 PMID: 23945166 PMID: 28342295 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-2f909fcb-b561-458b-9a3f-63bd1249768d Intraflagellar Transport: Retrograde Transport uuid-2f909fcb-b561-458b-9a3f-63bd1249768d PS:CellType generic PS:Description Retrograde transport is movement of molecules from the tip of cilium to the cell body for the formation and maintenance of eukaryotic cilia and flagella. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2f909fcb-b561-458b-9a3f-63bd1249768d PS:NodeType Pathway PS:Notes Headnote: Intraflagellar transport (IFT) is a specialized intracellular process essential for the formation and maintenance of eukaryotic cilia and flagella. IFT is a bidirectional transport (anterograde or orthograde and retrograde transport) along axonemal microtubules. Anterograde activities deliver IFT particles (IFT subcomplexes, IFT trains) to the tip of cilium and retrograde activities return them back to the cell body. Both motilities are tightly regulated to keep cilia intact and maintain them at their specified lengths. Signaling description: The retrograde transport of individual cargoes along the doublet microtubules of the flagellar axoneme is mediated by dynein motor (DYNC2LI1/DYNC2H1). Dynein motor moves IFT-associated proteins and cargo, BBSome and IFT-A/B subcomplexes. In cooperation with this motor, IFT-A subcomplex binds to protein cargo through protein interaction domains. For many cargoes it is not yet understood how they interact with the IFT machinery. IFT-A subcomplex contains IFT144 (WDR19), IFT140, IFT139 (TTC21B), IFT122, IFT121 (WDR35) and IFT43. IFT144 (WDR19) is required for the association of IFT-A subcomplex with dynein motor. BBSome may play a role in holding IFT-A and IFT-B together. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: Dynein motor, IFT-A subcomplex and BBSome are involved in retrograde transport. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22683354 PS:PMID 23945166 PS:PMID 28342295 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fa7c385-efff-4d77-b214-b2d240d82fa5 NodeType: Pathway Notes: Cell cycle progression is needed for the reproduction of virus particles. Accordingly the tax protein actively interacts with and blocks host T-cell proteins responsible for the regulation of the mitotic spindle checkpoint, vacuole 14 protein (VAC14), RAN-binding protein 1 (RANBP1), and MAX dimerization protein 1 (MXD1). Expression of the viral tax protein ultimately disrupts the mitotic spindle checkpoint, leading to incorrect chromosome segregation, and results in aneuploidy. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-2fa7c385-efff-4d77-b214-b2d240d82fa5 3_Tax-induced aneuploidy in T-cell infected with HTLV-1 uuid-2fa7c385-efff-4d77-b214-b2d240d82fa5 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fa7c385-efff-4d77-b214-b2d240d82fa5 PS:NodeType Pathway PS:Notes Cell cycle progression is needed for the reproduction of virus particles. Accordingly the tax protein actively interacts with and blocks host T-cell proteins responsible for the regulation of the mitotic spindle checkpoint, vacuole 14 protein (VAC14), RAN-binding protein 1 (RANBP1), and MAX dimerization protein 1 (MXD1). Expression of the viral tax protein ultimately disrupts the mitotic spindle checkpoint, leading to incorrect chromosome segregation, and results in aneuploidy. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2faf1c56-872c-4055-bfa8-6ab0c7e54012 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-2faf1c56-872c-4055-bfa8-6ab0c7e54012 Ins->Protein Synthesis uuid-2faf1c56-872c-4055-bfa8-6ab0c7e54012 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2faf1c56-872c-4055-bfa8-6ab0c7e54012 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fb2d280-fc51-41d0-874f-47815f75242c NodeType: Pathway Notes: Disruption of cell-to-cell junctions in cardiomyocytes due to mutations in several genes can be the cause of at least some cases of ARVD. Unstable contacts between cardiomyocytes due to mutations of the supportive proteins in adherens junctions provoke cardiomyocyte detachment, impair mechanical junctions and intercellular electrical conductivity, and probably can lead to heart arrhythmias. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: heart Organ_System: cardiovascular system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: myocardium urn:agi-pathway:uuid-2fb2d280-fc51-41d0-874f-47815f75242c 1_Adherens junction dysfunction in cardiomyocytes in ARVD uuid-2fb2d280-fc51-41d0-874f-47815f75242c PS:CellType cardiac myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fb2d280-fc51-41d0-874f-47815f75242c PS:NodeType Pathway PS:Notes Disruption of cell-to-cell junctions in cardiomyocytes due to mutations in several genes can be the cause of at least some cases of ARVD. Unstable contacts between cardiomyocytes due to mutations of the supportive proteins in adherens junctions provoke cardiomyocyte detachment, impair mechanical junctions and intercellular electrical conductivity, and probably can lead to heart arrhythmias. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ heart PS:Organ_System cardiovascular system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: hepatocyte Description: The primary function of adipose tissue is to store energy in a triacylglycerol form, neutralizing the excess of circulating lipids and saving non-adipose tissues of a fat overload. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fd4693f-f625-413d-84f9-5a73e8508545 NodeType: Pathway Notes: Headnote: The primary function of adipose tissue is to store energy in a triacylglycerol form, neutralizing the excess of circulating lipids and saving non-adipose tissues of a fat overload. Thyroid hormone excess is associated with weight loss and reduced muscle and fat mass, demonstrating that thyroid hormones play a central role in regulating adipose tissue metabolism. Signaling description: Triiodothyronine (T3) can influence the metabolism of cholesterol at several critical proteins in the liver including LDLR which mediates cholesterol uptake from the circulation, ACACA which controls cholesterol biosynthesis, and CYP7A1 which is the rate-limiting enzyme in the synthesis of bile acids where cholesterol is used as a substrate. All of these proteins are regulated on the transcriptional level by thyroid hormone receptor activation. A potential interaction between leptin (LEP) and thyroid hormones has been suggested since both hormones are associated with body weight and energy expenditure regulation. The role of thyroid hormones in LEP modulation remains controversial. In hyperthyroid patients, serum LEP was found to be increased, decreased or unchanged when compared with euthyroid patients. In addition, thyroid hormones appear to regulate resistin (RETN). Some studies report that patients with hyperthyroidism have elevated RETN concentrations when compared to euthyroid control individuals. Furthermore, the levels of G6PD, ME1, and FASN are also increased in hyperthyroidism. Outcome effects: Finally, a high level of thyroid hormones leads to hypermetabolism and weight loss despite increased energy intake. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Thyroid Hormone. Edited by Neeraj Kumar Agrawal (2012) InTech. 386 p. ISBN 978-953-51-0678-4. Organ: liver PMID: 20015660 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-2fd4693f-f625-413d-84f9-5a73e8508545 Thyroid Hormones in Adipose Tissue Metabolism uuid-2fd4693f-f625-413d-84f9-5a73e8508545 PS:CellType adipocyte PS:CellType hepatocyte PS:Description The primary function of adipose tissue is to store energy in a triacylglycerol form, neutralizing the excess of circulating lipids and saving non-adipose tissues of a fat overload. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2fd4693f-f625-413d-84f9-5a73e8508545 PS:NodeType Pathway PS:Notes Headnote: The primary function of adipose tissue is to store energy in a triacylglycerol form, neutralizing the excess of circulating lipids and saving non-adipose tissues of a fat overload. Thyroid hormone excess is associated with weight loss and reduced muscle and fat mass, demonstrating that thyroid hormones play a central role in regulating adipose tissue metabolism. Signaling description: Triiodothyronine (T3) can influence the metabolism of cholesterol at several critical proteins in the liver including LDLR which mediates cholesterol uptake from the circulation, ACACA which controls cholesterol biosynthesis, and CYP7A1 which is the rate-limiting enzyme in the synthesis of bile acids where cholesterol is used as a substrate. All of these proteins are regulated on the transcriptional level by thyroid hormone receptor activation. A potential interaction between leptin (LEP) and thyroid hormones has been suggested since both hormones are associated with body weight and energy expenditure regulation. The role of thyroid hormones in LEP modulation remains controversial. In hyperthyroid patients, serum LEP was found to be increased, decreased or unchanged when compared with euthyroid patients. In addition, thyroid hormones appear to regulate resistin (RETN). Some studies report that patients with hyperthyroidism have elevated RETN concentrations when compared to euthyroid control individuals. Furthermore, the levels of G6PD, ME1, and FASN are also increased in hyperthyroidism. Outcome effects: Finally, a high level of thyroid hormones leads to hypermetabolism and weight loss despite increased energy intake. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Thyroid Hormone. Edited by Neeraj Kumar Agrawal (2012) InTech. 386 p. ISBN 978-953-51-0678-4. PS:Organ liver PS:PMID 20015660 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ff52995-bfd0-41e4-9aa1-1ea40386ba8b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-2ff52995-bfd0-41e4-9aa1-1ea40386ba8b Aerobactin biosynthesis template uuid-2ff52995-bfd0-41e4-9aa1-1ea40386ba8b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-2ff52995-bfd0-41e4-9aa1-1ea40386ba8b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-300a46cd-e269-4dff-80d6-92ab7efa67d4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-300a46cd-e269-4dff-80d6-92ab7efa67d4 PTPRF -> CTNNB Signaling uuid-300a46cd-e269-4dff-80d6-92ab7efa67d4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-300a46cd-e269-4dff-80d6-92ab7efa67d4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Polymorphisms / mutations in several circadian clock genes (PER2, PER3, CLOCK) and their regulator CSNK1D were associated with sleep disturbances. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-301a6c0e-2bd3-43e0-a7b7-da5aaeff985e NodeType: Pathway Notes: Headnote: Polymorphisms/mutations in several circadian clock genes (PER2, PER3, CLOCK) and their regulator CSNK1D were associated with sleep disturbances. Signaling description: PER2 gene mutation was found to cause advanced sleep phase disorder. PER3 genotype was shown to contribute variance in predicting insomnia severity in alcoholic desease patients. CLOCK gene polymorphisms probably plays role in depression-associated insomnia. CLOCK genotype was shown to influences the time course of insomnia during antidepressant treatment. Casein kinase I isoform delta (CSNK1D) mutation is associated with familial advanced sleep phase syndrome. Organ: brain Organ_System: nervous system PMID: 15952199 PMID: 17346965 PMID: 19660984 PMID: 19716732 PMID: 22467995 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-301a6c0e-2bd3-43e0-a7b7-da5aaeff985e Circadian Clock Genes Mutations Cause Insomnia uuid-301a6c0e-2bd3-43e0-a7b7-da5aaeff985e PS:CellType neuron PS:Description Polymorphisms / mutations in several circadian clock genes (PER2, PER3, CLOCK) and their regulator CSNK1D were associated with sleep disturbances. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-301a6c0e-2bd3-43e0-a7b7-da5aaeff985e PS:NodeType Pathway PS:Notes Headnote: Polymorphisms/mutations in several circadian clock genes (PER2, PER3, CLOCK) and their regulator CSNK1D were associated with sleep disturbances. Signaling description: PER2 gene mutation was found to cause advanced sleep phase disorder. PER3 genotype was shown to contribute variance in predicting insomnia severity in alcoholic desease patients. CLOCK gene polymorphisms probably plays role in depression-associated insomnia. CLOCK genotype was shown to influences the time course of insomnia during antidepressant treatment. Casein kinase I isoform delta (CSNK1D) mutation is associated with familial advanced sleep phase syndrome. PS:Organ brain PS:Organ_System nervous system PS:PMID 15952199 PS:PMID 17346965 PS:PMID 19660984 PS:PMID 19716732 PS:PMID 22467995 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-304af782-b214-4aed-83e8-a756099e0658 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-304af782-b214-4aed-83e8-a756099e0658 IL2R -> ELK/SRF/MYC Signaling uuid-304af782-b214-4aed-83e8-a756099e0658 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-304af782-b214-4aed-83e8-a756099e0658 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: Glucose overload in the lens epithelium leads to the oxidative cell stress. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-304b6703-4d63-4925-8345-8fe65339b3b0 NodeType: Pathway Notes: Headnote: Cataract is clouding of the eye's lens that affects vision. Diabetes-induced cataract is a common complication of the diabetes. Signaling description: Lens glucose uptake is an insulin-independent process. Glucose enters the lens epithelium through the SLC2A1 inwardly-directed gradient. In diabetes, hexokinase, the primary enzyme in the cell glucose metabolism, becomes saturated and excess glucose enters the sorbitol pathway which includes two reactions. In the first step, the AKR1B1 catalysis occurs via the NADPH-dependent reduction of glucose to its sugar alcohol, sorbitol. This reaction has a central role in diabetic cataract formation. In addition, sorbitol dehydrogenase (SORD) catalyzes NAD -dependent oxidation of sorbitol to fructose. The increased sorbitol pathway activity in the lens leads to intracellular sorbitol accumulation. Sorbitol is hydrophilic and does not diffuse through the cell membrane; therefore it accumulates intracellularly causing osmotic stress to the cell. The fructose produced by the polyol pathway can be phosphorylated to fructose-3-P, which is broken down to 3-deoxyglucosone. Both compounds are powerful glycosylating agents that are involved in the formation of advanced glycation end products. When they accumulate, they can modify structural proteins such as crystallins in the cataractous lenses of human subjects with diabetes mellitus and provoke lens opacities. The usage of NADPH by AKR1B1 may result in less cofactor available for glutathione reductase (GSR), which is critical for the maintenance of the intracellular pool of reduced glutathione. Outcome effects: Decreased antioxidant defenses and the generation of oxidant species initiate multiple mechanisms of cellular damage including structural protein modification, dysfunction of membrane proteins, and Ca2+ toxicity. Glucose-induced elevation of diacylglycerol concentration leads to PRKCG activation which phosphorylates GJA3, disrupting lens gap junction transfer activity. It causes the impairment of water circulation that leads to its accumulation and thereby provokes lens opacities. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. Organ: eye Organ_System: sensory system PMID: 20474067 PMID: 20634936 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-304b6703-4d63-4925-8345-8fe65339b3b0 Diabetes Induced Cataract uuid-304b6703-4d63-4925-8345-8fe65339b3b0 PS:CellType epithelial cell PS:Description Glucose overload in the lens epithelium leads to the oxidative cell stress. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-304b6703-4d63-4925-8345-8fe65339b3b0 PS:NodeType Pathway PS:Notes Headnote: Cataract is clouding of the eye's lens that affects vision. Diabetes-induced cataract is a common complication of the diabetes. Signaling description: Lens glucose uptake is an insulin-independent process. Glucose enters the lens epithelium through the SLC2A1 inwardly-directed gradient. In diabetes, hexokinase, the primary enzyme in the cell glucose metabolism, becomes saturated and excess glucose enters the sorbitol pathway which includes two reactions. In the first step, the AKR1B1 catalysis occurs via the NADPH-dependent reduction of glucose to its sugar alcohol, sorbitol. This reaction has a central role in diabetic cataract formation. In addition, sorbitol dehydrogenase (SORD) catalyzes NAD -dependent oxidation of sorbitol to fructose. The increased sorbitol pathway activity in the lens leads to intracellular sorbitol accumulation. Sorbitol is hydrophilic and does not diffuse through the cell membrane; therefore it accumulates intracellularly causing osmotic stress to the cell. The fructose produced by the polyol pathway can be phosphorylated to fructose-3-P, which is broken down to 3-deoxyglucosone. Both compounds are powerful glycosylating agents that are involved in the formation of advanced glycation end products. When they accumulate, they can modify structural proteins such as crystallins in the cataractous lenses of human subjects with diabetes mellitus and provoke lens opacities. The usage of NADPH by AKR1B1 may result in less cofactor available for glutathione reductase (GSR), which is critical for the maintenance of the intracellular pool of reduced glutathione. Outcome effects: Decreased antioxidant defenses and the generation of oxidant species initiate multiple mechanisms of cellular damage including structural protein modification, dysfunction of membrane proteins, and Ca2+ toxicity. Glucose-induced elevation of diacylglycerol concentration leads to PRKCG activation which phosphorylates GJA3, disrupting lens gap junction transfer activity. It causes the impairment of water circulation that leads to its accumulation and thereby provokes lens opacities. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 20474067 PS:PMID 20634936 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30762fcc-162a-4818-bab9-dc3240b79ee6 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-30762fcc-162a-4818-bab9-dc3240b79ee6 Genes with Mutations Associated with Retinitis Pigmentosa uuid-30762fcc-162a-4818-bab9-dc3240b79ee6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30762fcc-162a-4818-bab9-dc3240b79ee6 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is a group of diseases that affects breast tissue. BC is linked to the overexpression of NOTCH1 leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30a625d5-e1dc-41a8-b3ea-16e8e7cf0fd3 NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. The transmembrane receptors NOTCH (1-4) interact with surface-bound ligands including JAG1, JAG2, DLL1, and DLL4. NOTCH1 has been identified as a proto-oncogene. Outcome effects: The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. Activated membrane-bound NOTCH1 receptor is cleaved by gamma-secretase complex and ADAM metallopeptidase domain 17 (ADAM17). NOTCH intracellular domain (NICD) is transported to the nucleus and participates in the formation the chromatin remodeling complexes, KAT2B/MYSM1 and KAT2A/TADA2A/TADA3. In addition, NICD interacts with LEF1/TCF7/CTNNB1 and SMAD family members 2/3/4 (SMAD2/3/4) complexes which induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ: breast Organ_System: integumentary system PMID: 21785827 PMID: 23593544 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-30a625d5-e1dc-41a8-b3ea-16e8e7cf0fd3 NOTCH1 Signaling in Breast Cancer uuid-30a625d5-e1dc-41a8-b3ea-16e8e7cf0fd3 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is a group of diseases that affects breast tissue. BC is linked to the overexpression of NOTCH1 leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30a625d5-e1dc-41a8-b3ea-16e8e7cf0fd3 PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. The transmembrane receptors NOTCH (1-4) interact with surface-bound ligands including JAG1, JAG2, DLL1, and DLL4. NOTCH1 has been identified as a proto-oncogene. Outcome effects: The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. Activated membrane-bound NOTCH1 receptor is cleaved by gamma-secretase complex and ADAM metallopeptidase domain 17 (ADAM17). NOTCH intracellular domain (NICD) is transported to the nucleus and participates in the formation the chromatin remodeling complexes, KAT2B/MYSM1 and KAT2A/TADA2A/TADA3. In addition, NICD interacts with LEF1/TCF7/CTNNB1 and SMAD family members 2/3/4 (SMAD2/3/4) complexes which induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ breast PS:Organ_System integumentary system PS:PMID 21785827 PS:PMID 23593544 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: The recurrent bleeding that is a hallmark feature of endometriosis leads to continual thrombin (F2) generation, which can subsequently stimulate proliferation of endometriotic cells via F2R. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30afcbfc-a5bd-4976-a245-bc10e030baf2 NodeType: Pathway Notes: Headnote: Proteinase-activated receptors (PARs) are G protein-coupled receptors activated by various proteinases. PARs play important roles in haemostasis, thrombosis, and inflammation in endometrium. Signaling description: PAR1 (F2R) and PAR2 (F2RL1) are expressed in endometrial cells from the eutopic endometrium and endometriotic cells derived from endometriotic lesions. A typical activator of F2R, thrombin (F2), and a typical activator of F2RL1, tryptase (TPSAB1), are produced in the endometrium as well as endometriotic lesions. Activation of PARS related signaling in endometrial cells induces production of VEGFA, IL6, IL8, TNF, CCL2, PTGS2 and proliferation of the cells. The recurrent bleeding that is a hallmark feature of endometriosis leads to continual thrombin (F2) generation, which can subsequently stimulate proliferation of endometriotic cells via F2R. Tissue factor (F3) expression is significantly higher in ectopic and eutopic endometrium of women with endometriosis when compared with controls. F3 forms complexes with F7 and F10 and they may activate both F2R and PAR2 F2RL1. Organ: uterus Organ_System: reproductive system PMID: 18443336 PMID: 19619892 PMID: 22652866 PMID: 22672593 PMID: 24278684 PMID: 24927773 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-30afcbfc-a5bd-4976-a245-bc10e030baf2 Coagulation Factors and PAR1/2 Receptors (F2R/F2RL1) in Endometriosis uuid-30afcbfc-a5bd-4976-a245-bc10e030baf2 PS:CellType endometrium cell PS:Description The recurrent bleeding that is a hallmark feature of endometriosis leads to continual thrombin (F2) generation, which can subsequently stimulate proliferation of endometriotic cells via F2R. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30afcbfc-a5bd-4976-a245-bc10e030baf2 PS:NodeType Pathway PS:Notes Headnote: Proteinase-activated receptors (PARs) are G protein-coupled receptors activated by various proteinases. PARs play important roles in haemostasis, thrombosis, and inflammation in endometrium. Signaling description: PAR1 (F2R) and PAR2 (F2RL1) are expressed in endometrial cells from the eutopic endometrium and endometriotic cells derived from endometriotic lesions. A typical activator of F2R, thrombin (F2), and a typical activator of F2RL1, tryptase (TPSAB1), are produced in the endometrium as well as endometriotic lesions. Activation of PARS related signaling in endometrial cells induces production of VEGFA, IL6, IL8, TNF, CCL2, PTGS2 and proliferation of the cells. The recurrent bleeding that is a hallmark feature of endometriosis leads to continual thrombin (F2) generation, which can subsequently stimulate proliferation of endometriotic cells via F2R. Tissue factor (F3) expression is significantly higher in ectopic and eutopic endometrium of women with endometriosis when compared with controls. F3 forms complexes with F7 and F10 and they may activate both F2R and PAR2 F2RL1. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 18443336 PS:PMID 19619892 PS:PMID 22652866 PS:PMID 22672593 PS:PMID 24278684 PS:PMID 24927773 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: pituitary cell Description: Congenital secondary or central hypothyroidism generally results from defects of thyroid-stimulating hormone (TSH) production. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30bd55ff-28f1-4e78-a766-c1e3923b4a0b NodeType: Pathway Notes: Headnote: Congenital secondary or central hypothyroidism generally results from defects of thyroid-stimulating hormone (TSH) production and is most commonly part of a disorder causing congenital hypopituitarism. Congenital hypopituitarism is often associated with midline defects such as septo-optic dysplasia or cleft lip and/or palate, and can be part of a larger genetic syndrome. Signaling description: Mutations in genes regulating pituitary gland development, which include HESX1, LHX3, LHX4, PIT1, and PROP1, have been reported to be a cause of familial hypopituitarism. The mechanism of their action is poorly understood. In addition to TSH deficiency, other pituitary hormones are often deficient including growth hormone, adrenocorticotrophic hormone, and antidiuretic hormone. Yet again, the mechanism of their decrease is not clearly understood. Here, several possible signaling routes are shown. Outcome effects: In some cases, specific gene defects lead to central hypothyroidism. These include isolated TSH deficiency (autosomal recessive caused by mutations in the TSH ß subunit (TSHB) gene), and thyrotropin releasing hormone (TRH) resistance resulting from mutations in the TRH receptor gene. Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary that is responsible for pituitary deficiency. Mutations in the transcription factors, HESX1 and LHX4 have been associated with PSIS. PSIS is diagnosed on the basis of clinical findings and a low growth hormone (GH) peak after stimulation test and low insulin-like growth factor 1 (IGF1). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 18279788 PMID: 18941435 PMID: 19762173 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-30bd55ff-28f1-4e78-a766-c1e3923b4a0b Hypothyroidism, Secondary (Central) uuid-30bd55ff-28f1-4e78-a766-c1e3923b4a0b PS:CellType pituitary cell PS:Description Congenital secondary or central hypothyroidism generally results from defects of thyroid-stimulating hormone (TSH) production. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30bd55ff-28f1-4e78-a766-c1e3923b4a0b PS:NodeType Pathway PS:Notes Headnote: Congenital secondary or central hypothyroidism generally results from defects of thyroid-stimulating hormone (TSH) production and is most commonly part of a disorder causing congenital hypopituitarism. Congenital hypopituitarism is often associated with midline defects such as septo-optic dysplasia or cleft lip and/or palate, and can be part of a larger genetic syndrome. Signaling description: Mutations in genes regulating pituitary gland development, which include HESX1, LHX3, LHX4, PIT1, and PROP1, have been reported to be a cause of familial hypopituitarism. The mechanism of their action is poorly understood. In addition to TSH deficiency, other pituitary hormones are often deficient including growth hormone, adrenocorticotrophic hormone, and antidiuretic hormone. Yet again, the mechanism of their decrease is not clearly understood. Here, several possible signaling routes are shown. Outcome effects: In some cases, specific gene defects lead to central hypothyroidism. These include isolated TSH deficiency (autosomal recessive caused by mutations in the TSH ß subunit (TSHB) gene), and thyrotropin releasing hormone (TRH) resistance resulting from mutations in the TRH receptor gene. Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary that is responsible for pituitary deficiency. Mutations in the transcription factors, HESX1 and LHX4 have been associated with PSIS. PSIS is diagnosed on the basis of clinical findings and a low growth hormone (GH) peak after stimulation test and low insulin-like growth factor 1 (IGF1). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 18279788 PS:PMID 18941435 PS:PMID 19762173 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30c0e0c5-d677-4961-ba6c-564dd1ab7789 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-30c0e0c5-d677-4961-ba6c-564dd1ab7789 SARS exonuclease (NSP14) inhibitors uuid-30c0e0c5-d677-4961-ba6c-564dd1ab7789 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30c0e0c5-d677-4961-ba6c-564dd1ab7789 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d24d48-9ff3-4766-b0f9-9d3f11513870 NodeType: Pathway Notes: Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located in the uppermost portion of the lateral plasma membrane apical to adherens junctions. The tight junctions hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Claudins have two extracellular loops and four hydrophobic transmembrane domains. The extracellular loops vary in different claudins and may additionally contribute to the formation of ion-selective channels. The proteins that form a complex with the C-terminus of claudins include TJP1, TJP2, TJP3, MPDZ, MLLT4, EPB41, CSDA, INADL, and spectrin/fodrin. INADL and MPDZ interact with CRB1 and CRB3 to form a tight junction complex involved in epithelial cell polarity. The PARD3/PARD6A/ atypical PKC/CRB/INADL/TIAM1 polarity complex interacts with GTP-bound CDC42, a key modulator of the actin cytoskeleton, polarizing membrane transport and tight junction assembly. Furthermore, atypical PKC, PARD6A, and LLGL1 form another multi-protein complex that is required for regulating direct protein trafficking. Outcome effects: Tight junctions regulate epithelial proliferation by different molecular mechanisms which generally suppress proliferation and increase cell density. TJP1 regulates proliferation and interacts with CSDA which regulates G1/S phase progression by the reduction of nuclear CDK4. CSDA functions in the transcriptional regulation of cell cycle regulators. TJP2 enters the nucleus in proliferating cells and subsequently binds with mRNA-binding proteins. SAFB binds Jun/Fos to regulate epithelial cell proliferation and differentiation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-30d24d48-9ff3-4766-b0f9-9d3f11513870 Tight Junction Assembly (Claudins) uuid-30d24d48-9ff3-4766-b0f9-9d3f11513870 PS:CellType generic PS:Description Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d24d48-9ff3-4766-b0f9-9d3f11513870 PS:NodeType Pathway PS:Notes Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located in the uppermost portion of the lateral plasma membrane apical to adherens junctions. The tight junctions hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Claudins have two extracellular loops and four hydrophobic transmembrane domains. The extracellular loops vary in different claudins and may additionally contribute to the formation of ion-selective channels. The proteins that form a complex with the C-terminus of claudins include TJP1, TJP2, TJP3, MPDZ, MLLT4, EPB41, CSDA, INADL, and spectrin/fodrin. INADL and MPDZ interact with CRB1 and CRB3 to form a tight junction complex involved in epithelial cell polarity. The PARD3/PARD6A/ atypical PKC/CRB/INADL/TIAM1 polarity complex interacts with GTP-bound CDC42, a key modulator of the actin cytoskeleton, polarizing membrane transport and tight junction assembly. Furthermore, atypical PKC, PARD6A, and LLGL1 form another multi-protein complex that is required for regulating direct protein trafficking. Outcome effects: Tight junctions regulate epithelial proliferation by different molecular mechanisms which generally suppress proliferation and increase cell density. TJP1 regulates proliferation and interacts with CSDA which regulates G1/S phase progression by the reduction of nuclear CDK4. CSDA functions in the transcriptional regulation of cell cycle regulators. TJP2 enters the nucleus in proliferating cells and subsequently binds with mRNA-binding proteins. SAFB binds Jun/Fos to regulate epithelial cell proliferation and differentiation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: enterocyte CellType: fibroblast Description: GUCY2C is a transmembrane enzyme expressed in the intestine and brain. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d27c72-c45e-4899-b8b1-8b58fc80b013 NodeType: Pathway Notes: Headnote: Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme expressed in the intestine and brain. Its two ligands, guanylin (GUCA2A) and uroguanylin (GUCA2B) are secreted in the intestine and regulate electrolyte and water transport in intestinal epithelia which has an anti-proliferative effect. Signaling description: Following ligand binding, GUCY2C becomes activated and converts GTP to cGMP. The increase of cGMP levels results in the activation of downstream effectors including PRKG1, the main intracellular mediator of cGMP signaling. Increased cGMP levels activate PTEN which reduces the levels of phosphorylated AKT1. CDX2 is the transcription factor for several intestinal lineage genes including GUCY2C. CDX2 mutations may cause the inactivation of GUCY2C signaling. Normally, GUCY2C suppresses tumorigenesis by maintaining DNA damage repair mechanisms and restricting proliferation. The loss of GUCA2A/B paracrine hormone expression is a universal early event in colonic neoplasia. Therefore, the anti-proliferative activity of GUCY2C may perhaps be restored by the administration of GUCY2C agonists or by the elevation of intracellular cGMP following inhibition of cyclic nucleotide phosphodiesterases, such as PDE5A, which normally degrade cGMP. In addition, a characteristic feature of most colorectal cancers is the high level of activity of SRC tyrosine kinase observed in colon carcinoma cells. GUCY2C is regulated by SRC-mediated inhibitory phosphorylation. Thus, a combinatorial therapy of SRC inhibitors along with activators of GUCY2C may be an effective regimen in the treatment of colon cancers. Outcome effects: By means of decreasing AKT1 activation, GUCY2C signaling suppresses cell proliferation and helps to protect the tight junctional protein assemblies and intestinal barrier integrity. GUCY2C-induced AKT1 inhibition also prevents MDM2-dependent degradation of the tumor suppressor TP53 and promotes DNA damage repair and genomic stability. Furthermore, GUCY2C signaling reduces the levels of key proteins that promote cell proliferation and cell cycle progression such as CTNNB1 and CCND1. GUCY2C signaling also promotes mitochondrial biogenesis which induces the expression of transcription factors including PPARGC1A, TFAM, and NRF1. Silencing of the GUCY2C signaling reduces mitochondrion number and oxygen consumption in addition to elevating SLC2A1 expression, glucose uptake, and aerobic glycolysis which recapitulates a tumor metabolic phenotype. Silencing GUCY2C in human colon cancer cells increases AKT1-dependent TGFB1 secretion and activates fibroblasts through TGFBR1 and SMAD3 phosphorylation. In turn, activating TGFB1 signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through MET-dependent signaling.Highlighted protein: Proteins with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 17681179 PMID: 19771320 PMID: 20021465 PMID: 22731908 PMID: 23375388 PMID: 24085786 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-30d27c72-c45e-4899-b8b1-8b58fc80b013 GUCY2C Signaling in Colorectal Cancer uuid-30d27c72-c45e-4899-b8b1-8b58fc80b013 PS:CellType cancer cell PS:CellType enterocyte PS:CellType fibroblast PS:Description GUCY2C is a transmembrane enzyme expressed in the intestine and brain. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d27c72-c45e-4899-b8b1-8b58fc80b013 PS:NodeType Pathway PS:Notes Headnote: Guanylyl cyclase C (GUCY2C) is a transmembrane enzyme expressed in the intestine and brain. Its two ligands, guanylin (GUCA2A) and uroguanylin (GUCA2B) are secreted in the intestine and regulate electrolyte and water transport in intestinal epithelia which has an anti-proliferative effect. Signaling description: Following ligand binding, GUCY2C becomes activated and converts GTP to cGMP. The increase of cGMP levels results in the activation of downstream effectors including PRKG1, the main intracellular mediator of cGMP signaling. Increased cGMP levels activate PTEN which reduces the levels of phosphorylated AKT1. CDX2 is the transcription factor for several intestinal lineage genes including GUCY2C. CDX2 mutations may cause the inactivation of GUCY2C signaling. Normally, GUCY2C suppresses tumorigenesis by maintaining DNA damage repair mechanisms and restricting proliferation. The loss of GUCA2A/B paracrine hormone expression is a universal early event in colonic neoplasia. Therefore, the anti-proliferative activity of GUCY2C may perhaps be restored by the administration of GUCY2C agonists or by the elevation of intracellular cGMP following inhibition of cyclic nucleotide phosphodiesterases, such as PDE5A, which normally degrade cGMP. In addition, a characteristic feature of most colorectal cancers is the high level of activity of SRC tyrosine kinase observed in colon carcinoma cells. GUCY2C is regulated by SRC-mediated inhibitory phosphorylation. Thus, a combinatorial therapy of SRC inhibitors along with activators of GUCY2C may be an effective regimen in the treatment of colon cancers. Outcome effects: By means of decreasing AKT1 activation, GUCY2C signaling suppresses cell proliferation and helps to protect the tight junctional protein assemblies and intestinal barrier integrity. GUCY2C-induced AKT1 inhibition also prevents MDM2-dependent degradation of the tumor suppressor TP53 and promotes DNA damage repair and genomic stability. Furthermore, GUCY2C signaling reduces the levels of key proteins that promote cell proliferation and cell cycle progression such as CTNNB1 and CCND1. GUCY2C signaling also promotes mitochondrial biogenesis which induces the expression of transcription factors including PPARGC1A, TFAM, and NRF1. Silencing of the GUCY2C signaling reduces mitochondrion number and oxygen consumption in addition to elevating SLC2A1 expression, glucose uptake, and aerobic glycolysis which recapitulates a tumor metabolic phenotype. Silencing GUCY2C in human colon cancer cells increases AKT1-dependent TGFB1 secretion and activates fibroblasts through TGFBR1 and SMAD3 phosphorylation. In turn, activating TGFB1 signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through MET-dependent signaling.Highlighted protein: Proteins with increased expression or activity is highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 17681179 PS:PMID 19771320 PS:PMID 20021465 PS:PMID 22731908 PS:PMID 23375388 PS:PMID 24085786 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Adiponectin (ADIPOQ) is a protein hormone secreted from adipose tissue. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d5edb5-5096-4134-9bdc-8b6562cbc2f5 NodeType: Pathway Notes: Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Adiponectin (ADIPOQ) is a protein hormone secreted from adipose tissue. It plays a regulatory role in glucose and lipid homeostasis (fatty acid oxidation), preventing insulin resistance. ADIPOQ acts through its receptors, ADIPOR1 and ADIPOR2. Following its binding to ADIPOR2, the hormone induces the peroxisome proliferator-activated receptor alpha (PPARA) expression. Outcome effects: PRARA binds to the promoter regions of lipoprotein lipase (LPL), acyl-CoA oxidase 1 (ACOX1), and uncoupling protein 2 (UCP2) genes promoting their transcription, and thus, up-regulating fatty acid oxidation. ADIPOR1 receptor interacts with adaptor protein (APPL1) to transduce the signal from adiponectin to specific proteins, AMP-dependent protein kinases (AMPK), which negatively regulate the transcription of proteins involved in gluconeogenesis and activate coactivator 1 alpha (PPARGC1A), which is important for the synthesis of proteins participating in mitochondrial organization and biogenesis. In addition, APPL1 provides GLUT4 (SLC2A4) translocation into the cell membrane through AKT1 and MAPK cascade leading to increased glucose intake. Organ: liver Organ_System: endocrine system Organ_System: generic PMID: 18854421 PMID: 19466213 PMID: 22450341 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue Tissue: muscle urn:agi-pathway:uuid-30d5edb5-5096-4134-9bdc-8b6562cbc2f5 Adiponectin in Insulin Resistance Prevention uuid-30d5edb5-5096-4134-9bdc-8b6562cbc2f5 PS:Description Adiponectin (ADIPOQ) is a protein hormone secreted from adipose tissue. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30d5edb5-5096-4134-9bdc-8b6562cbc2f5 PS:NodeType Pathway PS:Notes Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Adiponectin (ADIPOQ) is a protein hormone secreted from adipose tissue. It plays a regulatory role in glucose and lipid homeostasis (fatty acid oxidation), preventing insulin resistance. ADIPOQ acts through its receptors, ADIPOR1 and ADIPOR2. Following its binding to ADIPOR2, the hormone induces the peroxisome proliferator-activated receptor alpha (PPARA) expression. Outcome effects: PRARA binds to the promoter regions of lipoprotein lipase (LPL), acyl-CoA oxidase 1 (ACOX1), and uncoupling protein 2 (UCP2) genes promoting their transcription, and thus, up-regulating fatty acid oxidation. ADIPOR1 receptor interacts with adaptor protein (APPL1) to transduce the signal from adiponectin to specific proteins, AMP-dependent protein kinases (AMPK), which negatively regulate the transcription of proteins involved in gluconeogenesis and activate coactivator 1 alpha (PPARGC1A), which is important for the synthesis of proteins participating in mitochondrial organization and biogenesis. In addition, APPL1 provides GLUT4 (SLC2A4) translocation into the cell membrane through AKT1 and MAPK cascade leading to increased glucose intake. PS:Organ liver PS:Organ_System endocrine system PS:Organ_System generic PS:PMID 18854421 PS:PMID 19466213 PS:PMID 22450341 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue muscle PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30effba0-0f9c-4290-93fd-bd23580b5306 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-30effba0-0f9c-4290-93fd-bd23580b5306 COVID19-|RAS-Bradykinin uuid-30effba0-0f9c-4290-93fd-bd23580b5306 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30effba0-0f9c-4290-93fd-bd23580b5306 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Epithelial-to-mesenchymal transition, a process guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30f3113f-8f2d-4b41-b4f2-82b4a5e5ef9f NodeType: Pathway Notes: Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. Signaling description: The induction of EMT in cancer cells can occur as a result of embryonic pathway signaling. SHH, WNT, NOTCH, BMP or TGFB signaling activation leads to the up-regulation of transcriptional factors that drive EMT. WNT driven transcriptional factors that induce EMT include CTNNB1 and LEF1 and some others. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins inhibiting cell adhesion and activating cell migration (ex., CDH2, VIM, FN1, TNC, MMP2/9/15). Outcome effects: This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17645776 PMID: 19487818 PMID: 21672282 PMID: 23344542 PMID: 23589827 PMID: 24556840 PMID: 25107915 PMID: 25240174 PMID: 25249658 PMID: 25482613 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: epithelium urn:agi-pathway:uuid-30f3113f-8f2d-4b41-b4f2-82b4a5e5ef9f WNT in Epithelial to Mesenchymal Transition in Cancer uuid-30f3113f-8f2d-4b41-b4f2-82b4a5e5ef9f PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Epithelial-to-mesenchymal transition, a process guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-30f3113f-8f2d-4b41-b4f2-82b4a5e5ef9f PS:NodeType Pathway PS:Notes Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. Signaling description: The induction of EMT in cancer cells can occur as a result of embryonic pathway signaling. SHH, WNT, NOTCH, BMP or TGFB signaling activation leads to the up-regulation of transcriptional factors that drive EMT. WNT driven transcriptional factors that induce EMT include CTNNB1 and LEF1 and some others. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins inhibiting cell adhesion and activating cell migration (ex., CDH2, VIM, FN1, TNC, MMP2/9/15). Outcome effects: This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17645776 PS:PMID 19487818 PS:PMID 21672282 PS:PMID 23344542 PS:PMID 23589827 PS:PMID 24556840 PS:PMID 25107915 PS:PMID 25240174 PS:PMID 25249658 PS:PMID 25482613 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Many receptor tyrosine-kinases, TAM-receptors, estrogen and androgen receptor as well as adapter proteins are overexpressed in different types of cancer and play important role in cancer progression. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3101cb17-cb63-4a83-8ac2-a35f9df711a9 NodeType: Pathway Notes: Headnote: A large number of receptor tyrosine-kinases (RTKs), TAM-receptors, estrogen and androgen receptor as well as adapter proteins are overexpressed in different types of cancer and have important roles in cancer progression. Signaling description: Receptors and adapter proteins can be over-activated due to activating mutations, hyperexpression or chromosomal translocations. Receptors transmit signals through adaptor proteins and activate downstream signaling pathways including PI3K/AKT, RAS/MAPK, PLCG, JAK/STAT pathways and others. Outcome effects: The abovementioned events lead to uncontrolled proliferation of malignant cells. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17374994 PMID: 19534786 PMID: 20179300 PMID: 20602996 PMID: 21776389 PMID: 22128289 PMID: 24060861 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-3101cb17-cb63-4a83-8ac2-a35f9df711a9 Receptors and Adaptor Proteins Activated in Cancer uuid-3101cb17-cb63-4a83-8ac2-a35f9df711a9 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Many receptor tyrosine-kinases, TAM-receptors, estrogen and androgen receptor as well as adapter proteins are overexpressed in different types of cancer and play important role in cancer progression. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3101cb17-cb63-4a83-8ac2-a35f9df711a9 PS:NodeType Pathway PS:Notes Headnote: A large number of receptor tyrosine-kinases (RTKs), TAM-receptors, estrogen and androgen receptor as well as adapter proteins are overexpressed in different types of cancer and have important roles in cancer progression. Signaling description: Receptors and adapter proteins can be over-activated due to activating mutations, hyperexpression or chromosomal translocations. Receptors transmit signals through adaptor proteins and activate downstream signaling pathways including PI3K/AKT, RAS/MAPK, PLCG, JAK/STAT pathways and others. Outcome effects: The abovementioned events lead to uncontrolled proliferation of malignant cells. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17374994 PS:PMID 19534786 PS:PMID 20179300 PS:PMID 20602996 PS:PMID 21776389 PS:PMID 22128289 PS:PMID 24060861 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-312e4c21-311e-4801-b370-ed896f2b349b NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-312e4c21-311e-4801-b370-ed896f2b349b Proteins Involved in Fragile X Syndrome uuid-312e4c21-311e-4801-b370-ed896f2b349b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-312e4c21-311e-4801-b370-ed896f2b349b PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-313cee02-db24-4621-a6b0-9e547da2971c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-313cee02-db24-4621-a6b0-9e547da2971c limbal epithelial stem cells-|neutrophils uuid-313cee02-db24-4621-a6b0-9e547da2971c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-313cee02-db24-4621-a6b0-9e547da2971c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-313eff6c-ec77-42af-bfbe-aac885d5008c NodeType: Pathway Organ_System: cardiovascular system Organ_System: hematological system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-313eff6c-ec77-42af-bfbe-aac885d5008c Proteins Involved in Thrombophilia uuid-313eff6c-ec77-42af-bfbe-aac885d5008c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-313eff6c-ec77-42af-bfbe-aac885d5008c PS:NodeType Pathway PS:Organ_System cardiovascular system PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3153d669-486f-4901-9e8f-865d0e8e6eff NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3153d669-486f-4901-9e8f-865d0e8e6eff LPA+>myofibroblats uuid-3153d669-486f-4901-9e8f-865d0e8e6eff PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3153d669-486f-4901-9e8f-865d0e8e6eff PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3159107d-0a9e-46e5-be82-39062ba9b264 NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. HIV infection of macrophages is crucial for the disease pathogenesis and progression. Signaling description: Normally, CCR5 is activated by its peptide ligands and regulates leukocyte chemotaxis and macrophage proliferation during inflammation. In the pathology, CCR5 serves as a coreceptor for macrophage tropic HIV entry. Infected cells serve as a reservoir for viral persistence and participate in person-to-person transmission. The chemokine receptor, CCR5 in macrophages is activated by HIV envelope glycoprotein Gp120 during HIV infection. CCR5 transduces its downstream signals through GNAQ promoting calcium (Ca2) influx into the cell through store-operated Ca2 channels. The signal from GNAQ to the channel is transduced through PLCG2 and IP3. Elevated intracellular Ca2 is required for the activation of calmodulin and the subsequent downstream activation of PTK2B. PTK2B activates two MAPK signaling cascades (including RAC1/MAP3K11 and CDC42/MAP3K1) through SRC and VAV2. Concurrently, MAPK1, MAPK14, MAPK8, MAPK9, and MAPK10 which are downstream of MAP2K4, MAP2K7, MAP2K3, and MAP2K6, are stimulated. Outcome effects: Stress-activated kinases enhance the transcriptional activity of the key transcription factors including NF-kB, JUN, and FOS, and these promote the proliferation of virally infected cells and lead to the secretion of cellular cytokines which may induce the recruitment of target cells and infected-cell proliferation through paracrine mechanisms. FASLG is also expressed in macrophages during HIV infection (the signal transduction from CCR5 to FASLG occurs through JAK/STAT).Therefore, in HIV infection, macrophages are the reservoir for viral persistence and death signal producers. Finally, mutations in CCR5 gene prevent HIV infection in humans. Organ_System: lymphatic system PMID: 18785842 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-3159107d-0a9e-46e5-be82-39062ba9b264 CCR5 Signaling in Macrophages uuid-3159107d-0a9e-46e5-be82-39062ba9b264 PS:CellType macrophage PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3159107d-0a9e-46e5-be82-39062ba9b264 PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. HIV infection of macrophages is crucial for the disease pathogenesis and progression. Signaling description: Normally, CCR5 is activated by its peptide ligands and regulates leukocyte chemotaxis and macrophage proliferation during inflammation. In the pathology, CCR5 serves as a coreceptor for macrophage tropic HIV entry. Infected cells serve as a reservoir for viral persistence and participate in person-to-person transmission. The chemokine receptor, CCR5 in macrophages is activated by HIV envelope glycoprotein Gp120 during HIV infection. CCR5 transduces its downstream signals through GNAQ promoting calcium (Ca2) influx into the cell through store-operated Ca2 channels. The signal from GNAQ to the channel is transduced through PLCG2 and IP3. Elevated intracellular Ca2 is required for the activation of calmodulin and the subsequent downstream activation of PTK2B. PTK2B activates two MAPK signaling cascades (including RAC1/MAP3K11 and CDC42/MAP3K1) through SRC and VAV2. Concurrently, MAPK1, MAPK14, MAPK8, MAPK9, and MAPK10 which are downstream of MAP2K4, MAP2K7, MAP2K3, and MAP2K6, are stimulated. Outcome effects: Stress-activated kinases enhance the transcriptional activity of the key transcription factors including NF-kB, JUN, and FOS, and these promote the proliferation of virally infected cells and lead to the secretion of cellular cytokines which may induce the recruitment of target cells and infected-cell proliferation through paracrine mechanisms. FASLG is also expressed in macrophages during HIV infection (the signal transduction from CCR5 to FASLG occurs through JAK/STAT).Therefore, in HIV infection, macrophages are the reservoir for viral persistence and death signal producers. Finally, mutations in CCR5 gene prevent HIV infection in humans. PS:Organ_System lymphatic system PS:PMID 18785842 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations: a-Tregs, r-Tregs, and non-Tregs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-315c07fc-8d7f-41f4-88d9-a6d3d648b4eb NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: CD4 FOXP3 T-cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA FOXP3 low resting Tregs (r-Tregs), CD45RA-FOXP3 high activated Tregs (a-Tregs) and CD45RA-FOXP3 low non-suppressive T cells (non-Tregs). Outcome effects: Non-Tregs, which can produce IL2, IFNG, and IL17A, are not able to suppress the responder cells. Genetic defects in non-Tregs in type 1 diabetes do not reduce the non-suppressive function, yet they increase the expression of proinflammatory cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PMID: 21301480 PMID: 23607886 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-315c07fc-8d7f-41f4-88d9-a6d3d648b4eb non-Suppressive Treg-Cell in Diabetes Mellitus Type 1 uuid-315c07fc-8d7f-41f4-88d9-a6d3d648b4eb PS:CellType T-cell PS:Description FOXP3 regulatory T cells (Treg) can be divided into three different subpopulations: a-Tregs, r-Tregs, and non-Tregs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-315c07fc-8d7f-41f4-88d9-a6d3d648b4eb PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: CD4 FOXP3 T-cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA FOXP3 low resting Tregs (r-Tregs), CD45RA-FOXP3 high activated Tregs (a-Tregs) and CD45RA-FOXP3 low non-suppressive T cells (non-Tregs). Outcome effects: Non-Tregs, which can produce IL2, IFNG, and IL17A, are not able to suppress the responder cells. Genetic defects in non-Tregs in type 1 diabetes do not reduce the non-suppressive function, yet they increase the expression of proinflammatory cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:PMID 21301480 PS:PMID 23607886 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-317450f2-b82d-4fe7-bd26-c45f8ad51b4e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-317450f2-b82d-4fe7-bd26-c45f8ad51b4e OR1A1 -> GNAS Signaling uuid-317450f2-b82d-4fe7-bd26-c45f8ad51b4e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-317450f2-b82d-4fe7-bd26-c45f8ad51b4e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: The serum and glucocorticoid-regulated kinase 1 (SGK1) is a member of the AGC family of serine/threonine protein kinases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-318122a7-c400-4d9e-9a65-af3c887096e8 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The serum and glucocorticoid-regulated kinase 1 (SGK1) is a member of the AGC family of serine/threonine protein kinases. The SGK1 gene is one of the targets of androgen receptor (AR) and its mRNA level is upregulated after androgen stimulation. SGK1 can impact cell physiology through various mechanisms. It can regulate cell cycle and apoptosis indirectly through the inhibition of FOXO3 (forkhead box 03) transcription factor which is responsible for cell cycle arrest and apoptosis. In addition, SGK1 can control cyclin D1 (CCND1) and entry into the cell cycle by regulating the activity of the mammalian target of rapamycin protein (MTOR). Outcome effects: MTOR regulation can be performed by activating various cellular transporters such as members of solute carrier families (SLC43A2, SLC2A5, SLC2A4, and SLC1A1) and the subsequent influx of nutrients and amino acids (e.g., L-glutamine and D-glucose), which are positive regulators of mTOR. Organ: prostate Organ_System: urinary tract PMID: 17932503 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-318122a7-c400-4d9e-9a65-af3c887096e8 Androgen Receptor/SGK1 Signaling uuid-318122a7-c400-4d9e-9a65-af3c887096e8 PS:CellType cancer cell PS:Description The serum and glucocorticoid-regulated kinase 1 (SGK1) is a member of the AGC family of serine/threonine protein kinases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-318122a7-c400-4d9e-9a65-af3c887096e8 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The serum and glucocorticoid-regulated kinase 1 (SGK1) is a member of the AGC family of serine/threonine protein kinases. The SGK1 gene is one of the targets of androgen receptor (AR) and its mRNA level is upregulated after androgen stimulation. SGK1 can impact cell physiology through various mechanisms. It can regulate cell cycle and apoptosis indirectly through the inhibition of FOXO3 (forkhead box 03) transcription factor which is responsible for cell cycle arrest and apoptosis. In addition, SGK1 can control cyclin D1 (CCND1) and entry into the cell cycle by regulating the activity of the mammalian target of rapamycin protein (MTOR). Outcome effects: MTOR regulation can be performed by activating various cellular transporters such as members of solute carrier families (SLC43A2, SLC2A5, SLC2A4, and SLC1A1) and the subsequent influx of nutrients and amino acids (e.g., L-glutamine and D-glucose), which are positive regulators of mTOR. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 17932503 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3199bd18-adc8-455c-ba8b-5bff17d110f7 NodeType: Pathway Notes: Headnote: Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries and is characterized by extensive loss of the retinal pigment epithelium cells (RPE) and overlying photoreceptors. Oxidative stress is regarded to be one of the major factors in the development of AMD. Cigarette smoking is a well-known rick factor for AMD and generates a lot of chemical components, some of which are strong oxidants. Signaling description: A high flux of retinoids through the retinoid cycle, as occurs during intense light exposure, can cause elevated levels of toxic retinoid intermediates, especially all-trans-retinal, that can trigger retinal pigment epithelium cells (RPE) degeneration. All-trans-retinal was found to induce NADPH oxidase-mediated ROS generation. It was shown that all-trans-retinal may acts via G-protein coupled HTR2A and CHRM3 to induce NADPH oxidase. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the immune system. Oxidative damage, mediated by reactive oxygen species, generates deleterious reactive aldehydic byproducts including carboxyethylpyrrole (CEP), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and advanced glycation end (AGE) products such as carboxymethyllysine and pentosidine. Outcome effects: Proteins modified with aldehydic adducts (MDA, 4-HNE) or CEP adducts become more immunogenic. Therefore, oxidation of lipids and proteins could induce the generation of new autoantigens to which the immune system has not been "tolerized". CEP is a byproduct generated from the oxidation of docosahexaenoic (DHA) acid in the retina. DHA is typically a precursor for neuroprotective factors neuroprotectin D1 and resolvin D1 that normally inhibit apoptosis and inflammation, but oxidative damage in the retina is capable of diverting DHA for use in these protective functions towards generation of pathogenic intermediates. Normally neuroprotectin D1 represses amyloid-beta-42-triggered activation of pro-inflammatory genes and upregulated the antiapoptotic genes encoding BCL2, BCL2L1, and BCL2A1. When the level of neuroprotectin D1 is decreased, it does not happen.Lipofuscin granules are byproducts of photoreceptor outer segment turnover and are seen within both healthy and pathological RPE. Lipofuscin in RPE accumulates throughout life, and is readily detectable after age 40. Lipofuscin pigments are generated from random non-enzymatic reactions of retinaldehyde in photoreceptors throughout life and enter RPE via phagocytosis, from which point pigment-containing phagosomes fuse with lysosomes. However, the random nature of lipofuscin pigment generation results in compounds that evade lysosomal digestion and thus accumulate within the RPE. Accumulation of lipofuscin results in a significant increase in retinal phototoxicity with age. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2 (NFE2L2). NFE2L2 controls target antioxidant genes HMOX1, NQO1, GCLM. Aging can reduce NFE2L2 activity. Impaired NFE2L2 signaling can lead to oxidative damage and RPE apoptosis. HIF1A was shown to be induced by ROS and hypoxia in AMD and controls expression of VEGFA making impact to choroidal neovascularization.Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: eye Organ_System: sensory system PMID: 15780767 PMID: 19589398 PMID: 19703486 PMID: 21875030 PMID: 22184108 PMID: 22503691 PMID: 23847393 PMID: 23933169 PMID: 24216314 PMID: 24876950 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3199bd18-adc8-455c-ba8b-5bff17d110f7 Oxidative Stress, All-Trans-Retinal and Lipofuscin Toxicity in AMD uuid-3199bd18-adc8-455c-ba8b-5bff17d110f7 PS:CellType epithelial cell PS:Description Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3199bd18-adc8-455c-ba8b-5bff17d110f7 PS:NodeType Pathway PS:Notes Headnote: Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries and is characterized by extensive loss of the retinal pigment epithelium cells (RPE) and overlying photoreceptors. Oxidative stress is regarded to be one of the major factors in the development of AMD. Cigarette smoking is a well-known rick factor for AMD and generates a lot of chemical components, some of which are strong oxidants. Signaling description: A high flux of retinoids through the retinoid cycle, as occurs during intense light exposure, can cause elevated levels of toxic retinoid intermediates, especially all-trans-retinal, that can trigger retinal pigment epithelium cells (RPE) degeneration. All-trans-retinal was found to induce NADPH oxidase-mediated ROS generation. It was shown that all-trans-retinal may acts via G-protein coupled HTR2A and CHRM3 to induce NADPH oxidase. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the immune system. Oxidative damage, mediated by reactive oxygen species, generates deleterious reactive aldehydic byproducts including carboxyethylpyrrole (CEP), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and advanced glycation end (AGE) products such as carboxymethyllysine and pentosidine. Outcome effects: Proteins modified with aldehydic adducts (MDA, 4-HNE) or CEP adducts become more immunogenic. Therefore, oxidation of lipids and proteins could induce the generation of new autoantigens to which the immune system has not been "tolerized". CEP is a byproduct generated from the oxidation of docosahexaenoic (DHA) acid in the retina. DHA is typically a precursor for neuroprotective factors neuroprotectin D1 and resolvin D1 that normally inhibit apoptosis and inflammation, but oxidative damage in the retina is capable of diverting DHA for use in these protective functions towards generation of pathogenic intermediates. Normally neuroprotectin D1 represses amyloid-beta-42-triggered activation of pro-inflammatory genes and upregulated the antiapoptotic genes encoding BCL2, BCL2L1, and BCL2A1. When the level of neuroprotectin D1 is decreased, it does not happen.Lipofuscin granules are byproducts of photoreceptor outer segment turnover and are seen within both healthy and pathological RPE. Lipofuscin in RPE accumulates throughout life, and is readily detectable after age 40. Lipofuscin pigments are generated from random non-enzymatic reactions of retinaldehyde in photoreceptors throughout life and enter RPE via phagocytosis, from which point pigment-containing phagosomes fuse with lysosomes. However, the random nature of lipofuscin pigment generation results in compounds that evade lysosomal digestion and thus accumulate within the RPE. Accumulation of lipofuscin results in a significant increase in retinal phototoxicity with age. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2 (NFE2L2). NFE2L2 controls target antioxidant genes HMOX1, NQO1, GCLM. Aging can reduce NFE2L2 activity. Impaired NFE2L2 signaling can lead to oxidative damage and RPE apoptosis. HIF1A was shown to be induced by ROS and hypoxia in AMD and controls expression of VEGFA making impact to choroidal neovascularization.Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ eye PS:Organ_System sensory system PS:PMID 15780767 PS:PMID 19589398 PS:PMID 19703486 PS:PMID 21875030 PS:PMID 22184108 PS:PMID 22503691 PS:PMID 23847393 PS:PMID 23933169 PS:PMID 24216314 PS:PMID 24876950 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-319cad15-a63b-44bf-a24f-3f634edf96ce NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-319cad15-a63b-44bf-a24f-3f634edf96ce HRH2/4 -> IL6/10 Production uuid-319cad15-a63b-44bf-a24f-3f634edf96ce PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-319cad15-a63b-44bf-a24f-3f634edf96ce PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31a81166-a1b6-4502-b3d9-62b3e9c9927a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-31a81166-a1b6-4502-b3d9-62b3e9c9927a TNF -> CREB Expression Targets uuid-31a81166-a1b6-4502-b3d9-62b3e9c9927a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31a81166-a1b6-4502-b3d9-62b3e9c9927a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31b20fdd-e886-4f2e-be61-b3876d2cafc0 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-31b20fdd-e886-4f2e-be61-b3876d2cafc0 Fatty acid omega-oxidation template uuid-31b20fdd-e886-4f2e-be61-b3876d2cafc0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31b20fdd-e886-4f2e-be61-b3876d2cafc0 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31bc73b4-dda6-489e-98a5-7b5c01dabbac NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-31bc73b4-dda6-489e-98a5-7b5c01dabbac NRG1 -> AP-1/ATF Expression Targets uuid-31bc73b4-dda6-489e-98a5-7b5c01dabbac PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31bc73b4-dda6-489e-98a5-7b5c01dabbac PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31d7a39d-0e54-46b4-8df9-91e109da56ea NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-31d7a39d-0e54-46b4-8df9-91e109da56ea PAF Expression Targets uuid-31d7a39d-0e54-46b4-8df9-91e109da56ea PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31d7a39d-0e54-46b4-8df9-91e109da56ea PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31e0b976-6e72-4c00-a89d-d611f7863b25 NodeType: Pathway Notes: Headnote: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Alternative end-joining (A-EJ) is a double-strand break (DSB) repair process that occurs in the absence of certain classical non-homologous end-joining components. Signaling description: Presumably, A-EJ depends on the MRN complex, RBBP8, and/or PARP1 to produce a microhomology region between the ends of DSBs for end-joining. The ligation of the DSB ends by one or more DNA ligases, which have yet to be identified, yields S-S junctions that show more extensive microhomology than those formed in classical non-homologous end-joining. Outcome effects: A-EJ is frequently associated with chromosomal translocations and is influenced by the expression of TP53BP1, which protects DSB ends from resection for A-EJ and by the presence of Ku70 (XRCC6) and Ku86 (XRCC5) which inhibit RBBP8. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-31e0b976-6e72-4c00-a89d-d611f7863b25 Immunoglobulin Class-Switch Recombination via Alternative End-Joining uuid-31e0b976-6e72-4c00-a89d-d611f7863b25 PS:CellType B-cell PS:Description Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31e0b976-6e72-4c00-a89d-d611f7863b25 PS:NodeType Pathway PS:Notes Headnote: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Alternative end-joining (A-EJ) is a double-strand break (DSB) repair process that occurs in the absence of certain classical non-homologous end-joining components. Signaling description: Presumably, A-EJ depends on the MRN complex, RBBP8, and/or PARP1 to produce a microhomology region between the ends of DSBs for end-joining. The ligation of the DSB ends by one or more DNA ligases, which have yet to be identified, yields S-S junctions that show more extensive microhomology than those formed in classical non-homologous end-joining. Outcome effects: A-EJ is frequently associated with chromosomal translocations and is influenced by the expression of TP53BP1, which protects DSB ends from resection for A-EJ and by the presence of Ku70 (XRCC6) and Ku86 (XRCC5) which inhibit RBBP8. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31e5b0a2-c777-4138-87c5-de86c622ce0c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-31e5b0a2-c777-4138-87c5-de86c622ce0c Glucose->IMPK->IR uuid-31e5b0a2-c777-4138-87c5-de86c622ce0c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31e5b0a2-c777-4138-87c5-de86c622ce0c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31f3f18c-a565-47e2-aac9-58a6c14b11ed NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-31f3f18c-a565-47e2-aac9-58a6c14b11ed IGF2/MEF/MYOD Expression Targets uuid-31f3f18c-a565-47e2-aac9-58a6c14b11ed PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-31f3f18c-a565-47e2-aac9-58a6c14b11ed PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3206e920-3599-49d1-9aee-54f2d7c77d59 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3206e920-3599-49d1-9aee-54f2d7c77d59 HGFR -> AP-1/CREB/MYC Signaling uuid-3206e920-3599-49d1-9aee-54f2d7c77d59 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3206e920-3599-49d1-9aee-54f2d7c77d59 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: NOTCH signaling may be oncogenic or tumor suppressive in different cancers. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3243a696-473e-431e-a464-e6b90594891d NodeType: Pathway Notes: Headnote: NOTCH signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during embryonic development and maintains adult tissue homeostasis. NOTCH signaling may be oncogenic or tumor suppressive in different cancers. Signaling description: NOTCH receptors are single-pass transmembrane proteins composed of functional extracellular (NECD), transmembrane (TM), and intracellular (NICD) domains. Delta-like (DLL) and the Jagged (JAG) families serve as ligands for Notch signaling receptors. Upon ligand binding, the NECD is cleaved from the TM-NICD domain by ADAM17. Further, the NECD domain stays bound to the ligand and the NECD-ligand complex undergoes endocytosis and recycling in the signal-emitting cell. Meanwhile, in the signal-perceiving cell, gamma-secretase separates NICD from the TM, which allows for the nuclear translocation of NICD where it associates with the RBPJ transcription factor complex. This leads to activation of target genes of the canonical Notch pathway: MYC, HES-family members and other genes. NOTCH signaling may be oncogenic or tumor suppressive in different cancers. The precise mechanism of this dual action is not clear and seems to be disease-, tissue- and context-dependent. NOTCH1 is hyperactivated due to mutations and serves as an oncogene in T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia, non-small cell lung cancer. Also, in T-ALL, inactivating mutations in FBXW7, an E3 ubiquitin ligase responsible for ICN1 degradation and subsequent termination of NOTCH1 signaling were identified. In head and neck squamous cell carcinoma, inactivating mutations in NOTCH1/2/3 are typical. Moreover, in chronic myelomonocytic leukemia, inactivating mutations in NCSTN, APH1A, MAML1 or NOTCH2 (NCSTN, APH1A are components of the gamma-secretase complex) were identified. This confirms the role of NOTCH proteins as tumor suppressors. Outcome effects: The activation of proliferation and induction of epithelial-mesenchymal transition happen as a result of NOTCH signaling deregulation. Animal data: The majority of the data were obtained in human cancer lines/specimens. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20041844 PMID: 21948802 PMID: 23033986 PMID: 23585460 PMID: 23973264 PMID: 24168187 PMID: 26341688 PMID: 26767041 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-3243a696-473e-431e-a464-e6b90594891d NOTCH Signaling Deregulation in Cancer uuid-3243a696-473e-431e-a464-e6b90594891d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description NOTCH signaling may be oncogenic or tumor suppressive in different cancers. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3243a696-473e-431e-a464-e6b90594891d PS:NodeType Pathway PS:Notes Headnote: NOTCH signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during embryonic development and maintains adult tissue homeostasis. NOTCH signaling may be oncogenic or tumor suppressive in different cancers. Signaling description: NOTCH receptors are single-pass transmembrane proteins composed of functional extracellular (NECD), transmembrane (TM), and intracellular (NICD) domains. Delta-like (DLL) and the Jagged (JAG) families serve as ligands for Notch signaling receptors. Upon ligand binding, the NECD is cleaved from the TM-NICD domain by ADAM17. Further, the NECD domain stays bound to the ligand and the NECD-ligand complex undergoes endocytosis and recycling in the signal-emitting cell. Meanwhile, in the signal-perceiving cell, gamma-secretase separates NICD from the TM, which allows for the nuclear translocation of NICD where it associates with the RBPJ transcription factor complex. This leads to activation of target genes of the canonical Notch pathway: MYC, HES-family members and other genes. NOTCH signaling may be oncogenic or tumor suppressive in different cancers. The precise mechanism of this dual action is not clear and seems to be disease-, tissue- and context-dependent. NOTCH1 is hyperactivated due to mutations and serves as an oncogene in T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia, non-small cell lung cancer. Also, in T-ALL, inactivating mutations in FBXW7, an E3 ubiquitin ligase responsible for ICN1 degradation and subsequent termination of NOTCH1 signaling were identified. In head and neck squamous cell carcinoma, inactivating mutations in NOTCH1/2/3 are typical. Moreover, in chronic myelomonocytic leukemia, inactivating mutations in NCSTN, APH1A, MAML1 or NOTCH2 (NCSTN, APH1A are components of the gamma-secretase complex) were identified. This confirms the role of NOTCH proteins as tumor suppressors. Outcome effects: The activation of proliferation and induction of epithelial-mesenchymal transition happen as a result of NOTCH signaling deregulation. Animal data: The majority of the data were obtained in human cancer lines/specimens. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20041844 PS:PMID 21948802 PS:PMID 23033986 PS:PMID 23585460 PS:PMID 23973264 PS:PMID 24168187 PS:PMID 26341688 PS:PMID 26767041 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: Blood vessel sprouting is a process necessary for physiological and pathological angiogenesis. The main signallings involved in sprouting angiogenesis regulation are VEGFA/KDR, DLL4/NOTCH1 and WNT. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-326b8a11-8ea1-469a-b963-1e86a3985178 NodeType: Pathway Notes: Headnote: Blood vessel sprouting is a process necessary for physiological and pathological angiogenesis. The pathology of this process in cancers is characterized by blood vessel hypersprouting and hyperbranching induced by hyperproduced angiogenic factors as well as by inhibition of negative feedback loops. Signaling description: Sprouting endothelial cells (ECs) are hierarchically organized into leading 'tip cells' and trailing 'stalk cells' (TCs and SCs). TCs lead and guide the blood vessel sprout, while neighbouring SCs proliferate and form the vascular lumen. The formation of TCs is induced by VEGFA signaling; whereas, DLL4/NOTCH1 signaling path represses the VEGFA/KDR signaling and TC differentiation. Outcome effects: NOTCH1 signaling in SCs down-regulates the expression of FLT4 and up-regulates FLT1 expression. NOTCH1 activation also induces DLL4 expression in SCs to propagate the DLL4 Notch-mediated lateral inhibition of KDR. NOTCH1-induced NRARP expression enhances WNT signaling in SCs, which maintains EC-EC junctions, promotes proliferation and may augment DLL4 expression via CTNNB1. NRARP also promotes the feedback inhibition of NOTCH1 signaling. The role of DLL4-Notch signaling in suppressing TC specification is not only critical for physiological blood vessel formation but also controls tumor angiogenesis. Tumours are extensively vascularized due to antibody-mediated reduction of DLL4-Notch interactions but vessels are hypoperfused and poorly functional, resulting in tumor hypoxia and decreased growth. Hence, DLL4 is considered to be a promising target for anticancer therapeutics. Animal data: The majority of the data regarding the role of WNT, DLL4/NOTCH1 in blood vessel sprouting and branching as well as the interplay between VEGFA and DLL4/NOTCH1 was obtained from animal model (mice and zebrafish) experiments. Organ: blood vessel Organ_System: cardiovascular system PMID: 19217422 PMID: 20627076 PMID: 21860391 PMID: 22020130 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-326b8a11-8ea1-469a-b963-1e86a3985178 VEGFA/NOTCH1/WNT Cross-talk in Blood Vessel Sprouting and Branching in Cancer uuid-326b8a11-8ea1-469a-b963-1e86a3985178 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description Blood vessel sprouting is a process necessary for physiological and pathological angiogenesis. The main signallings involved in sprouting angiogenesis regulation are VEGFA/KDR, DLL4/NOTCH1 and WNT. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-326b8a11-8ea1-469a-b963-1e86a3985178 PS:NodeType Pathway PS:Notes Headnote: Blood vessel sprouting is a process necessary for physiological and pathological angiogenesis. The pathology of this process in cancers is characterized by blood vessel hypersprouting and hyperbranching induced by hyperproduced angiogenic factors as well as by inhibition of negative feedback loops. Signaling description: Sprouting endothelial cells (ECs) are hierarchically organized into leading 'tip cells' and trailing 'stalk cells' (TCs and SCs). TCs lead and guide the blood vessel sprout, while neighbouring SCs proliferate and form the vascular lumen. The formation of TCs is induced by VEGFA signaling; whereas, DLL4/NOTCH1 signaling path represses the VEGFA/KDR signaling and TC differentiation. Outcome effects: NOTCH1 signaling in SCs down-regulates the expression of FLT4 and up-regulates FLT1 expression. NOTCH1 activation also induces DLL4 expression in SCs to propagate the DLL4 Notch-mediated lateral inhibition of KDR. NOTCH1-induced NRARP expression enhances WNT signaling in SCs, which maintains EC-EC junctions, promotes proliferation and may augment DLL4 expression via CTNNB1. NRARP also promotes the feedback inhibition of NOTCH1 signaling. The role of DLL4-Notch signaling in suppressing TC specification is not only critical for physiological blood vessel formation but also controls tumor angiogenesis. Tumours are extensively vascularized due to antibody-mediated reduction of DLL4-Notch interactions but vessels are hypoperfused and poorly functional, resulting in tumor hypoxia and decreased growth. Hence, DLL4 is considered to be a promising target for anticancer therapeutics. Animal data: The majority of the data regarding the role of WNT, DLL4/NOTCH1 in blood vessel sprouting and branching as well as the interplay between VEGFA and DLL4/NOTCH1 was obtained from animal model (mice and zebrafish) experiments. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 19217422 PS:PMID 20627076 PS:PMID 21860391 PS:PMID 22020130 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3270e46c-daa2-46ac-92d7-11d2555059ae NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3270e46c-daa2-46ac-92d7-11d2555059ae LTA Expression Targets uuid-3270e46c-daa2-46ac-92d7-11d2555059ae PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3270e46c-daa2-46ac-92d7-11d2555059ae PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-329f7b83-0554-4102-9cac-8c54f9ed7172 NodeType: Pathway Notes: Hypothyroidism is treated with levothyroxine, a drug that can cause different unwanted side effects related to hyperthyroidism. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-329f7b83-0554-4102-9cac-8c54f9ed7172 2_3_Effects of thyroid hormone deficiency: levothyroxine systemic effects uuid-329f7b83-0554-4102-9cac-8c54f9ed7172 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-329f7b83-0554-4102-9cac-8c54f9ed7172 PS:NodeType Pathway PS:Notes Hypothyroidism is treated with levothyroxine, a drug that can cause different unwanted side effects related to hyperthyroidism. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32aaddfc-ea35-4b03-8739-ddf79d274c05 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-32aaddfc-ea35-4b03-8739-ddf79d274c05 Thrombopoietin -> SP1 Expression Targets uuid-32aaddfc-ea35-4b03-8739-ddf79d274c05 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32aaddfc-ea35-4b03-8739-ddf79d274c05 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32b31f96-efa7-4971-82fa-1d7bff0919a8 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-32b31f96-efa7-4971-82fa-1d7bff0919a8 EPHB -> NMDA Receptor Activation uuid-32b31f96-efa7-4971-82fa-1d7bff0919a8 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32b31f96-efa7-4971-82fa-1d7bff0919a8 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32c5995e-cc11-465f-bbeb-144962202e55 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-32c5995e-cc11-465f-bbeb-144962202e55 Interleukin Receptors -> Expression Targets in Lymphoid System and Blood uuid-32c5995e-cc11-465f-bbeb-144962202e55 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32c5995e-cc11-465f-bbeb-144962202e55 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32d4c089-f4f7-4e73-9036-191660502555 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-32d4c089-f4f7-4e73-9036-191660502555 Coagulation Factors->fibroblasts uuid-32d4c089-f4f7-4e73-9036-191660502555 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32d4c089-f4f7-4e73-9036-191660502555 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32feaf27-2ea7-4b78-96b1-1c4a941e4973 NodeType: Pathway Notes: Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Citrullinemia type I is caused by mutations in ASS1 gene. Organ: liver PMID: 11941481 PMID: 19006241 PMID: 20301396 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-32feaf27-2ea7-4b78-96b1-1c4a941e4973 Citrullinemia Type I uuid-32feaf27-2ea7-4b78-96b1-1c4a941e4973 PS:CellType hepatocyte PS:Description Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-32feaf27-2ea7-4b78-96b1-1c4a941e4973 PS:NodeType Pathway PS:Notes Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Citrullinemia type I is caused by mutations in ASS1 gene. PS:Organ liver PS:PMID 11941481 PS:PMID 19006241 PS:PMID 20301396 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33090c88-c63c-43c5-a2c8-9bd8f6261678 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-33090c88-c63c-43c5-a2c8-9bd8f6261678 Overview. Infectious and parasitic diseases (chapter 2) uuid-33090c88-c63c-43c5-a2c8-9bd8f6261678 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33090c88-c63c-43c5-a2c8-9bd8f6261678 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-331311b5-27c8-4a86-b733-e5d9188d5537 NodeType: Pathway Notes: The HTLVs need cell cycle progression and transition through the mitotic phases for viral reproduction. The viral tax protein actively interacts with and regulates some of T-cell proteins that regulate phase changes in the cell cycle and thereby stimulate mitosis in the host cell. The activation of cell cycle progression diminishes the effectiveness of DNA repair, and consequently, mutations accumulate in the host cell’s genome. Persistent DNA repair mechanisms and related cellular processes lead to T-cell death or transformation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-331311b5-27c8-4a86-b733-e5d9188d5537 4_Tax-induced disruption of the G1/S transition in HTLV-1 infected T-cell uuid-331311b5-27c8-4a86-b733-e5d9188d5537 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-331311b5-27c8-4a86-b733-e5d9188d5537 PS:NodeType Pathway PS:Notes The HTLVs need cell cycle progression and transition through the mitotic phases for viral reproduction. The viral tax protein actively interacts with and regulates some of T-cell proteins that regulate phase changes in the cell cycle and thereby stimulate mitosis in the host cell. The activation of cell cycle progression diminishes the effectiveness of DNA repair, and consequently, mutations accumulate in the host cell’s genome. Persistent DNA repair mechanisms and related cellular processes lead to T-cell death or transformation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using iPTMnet database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3325c1d0-ed94-4bd6-8b8f-979e774d3e52 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-3325c1d0-ed94-4bd6-8b8f-979e774d3e52 CREB1 Arginine Modification Site uuid-3325c1d0-ed94-4bd6-8b8f-979e774d3e52 PS:Description Pathway is build using iPTMnet database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3325c1d0-ed94-4bd6-8b8f-979e774d3e52 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: smooth muscle myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3327fded-8f96-4c45-b5d0-a7f308c579c4 NodeType: Pathway Notes: Familial pulmonary arterial hypertension (FPAH) is associated with mutations in the genes encoding bone morphogenetic protein receptor type 2 (BMPR2), activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and some other genes. In FPAH and IPAH the BMP and TGFB1 signaling pathways are not fully activated, and the balance between PASMC proliferation and differentiation shifts toward proliferation. Excessive PASMC proliferation leads to pulmonary artery wall thickening, lumen narrowing, elevation of pulmonary vascular resistance, and the development of pulmonary hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3327fded-8f96-4c45-b5d0-a7f308c579c4 3_Increased proliferation of pulmonary artery smooth muscle cells (PASMCs) in familial forms of pulmonary hypertension uuid-3327fded-8f96-4c45-b5d0-a7f308c579c4 PS:CellType smooth muscle myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3327fded-8f96-4c45-b5d0-a7f308c579c4 PS:NodeType Pathway PS:Notes Familial pulmonary arterial hypertension (FPAH) is associated with mutations in the genes encoding bone morphogenetic protein receptor type 2 (BMPR2), activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and some other genes. In FPAH and IPAH the BMP and TGFB1 signaling pathways are not fully activated, and the balance between PASMC proliferation and differentiation shifts toward proliferation. Excessive PASMC proliferation leads to pulmonary artery wall thickening, lumen narrowing, elevation of pulmonary vascular resistance, and the development of pulmonary hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:NodeType PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Source: Atlas urn:agi-pathway:uuid-332952ce-136a-414f-9380-b230c70d7e9a Guide and legend (figure 5) uuid-332952ce-136a-414f-9380-b230c70d7e9a PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3339129a-d345-46c0-a579-952f45cbdb6e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-3339129a-d345-46c0-a579-952f45cbdb6e MRAS-RAFs-MAPK1/3 uuid-3339129a-d345-46c0-a579-952f45cbdb6e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3339129a-d345-46c0-a579-952f45cbdb6e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-335976b1-a79c-40b4-bde4-9c6e96d8b12a NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-335976b1-a79c-40b4-bde4-9c6e96d8b12a Pterine Biosynthesis uuid-335976b1-a79c-40b4-bde4-9c6e96d8b12a PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-335976b1-a79c-40b4-bde4-9c6e96d8b12a PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Description: Increased keratinocyte proliferation is a key element in the pathogenesis of acne vulgaris. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3363e146-9b2b-401c-9787-ddd53d538759 NodeType: Pathway Notes: Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Increased keratinocyte proliferation is a key element in the pathogenesis of acne vulgaris. Signaling description: Hyperkeratinization occurs when the cells of the follicle become cohesive and do not shed normally onto the skin surface. The process caused by keratin excess and is observed in the primary stages of the disease and causes obstruction of the sebaceous gland duct, which provokes sebum storage in the gland and increases the gland size. The main agents inducing hyperkeratinization are IL1A and androgens. Androgens bind to AR causing increased cell proliferation; whereas, IL1A participates in MAPK pathway activation through MYD88/TRAF6 and RAC1. Outcome effects: As a result of MAPK pathway activation, NF-kB induction similarly causes increased keratinocyte proliferation leading to hyperkeratinization and ultimately the enlargement of sebaceous gland. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 15788147 PMID: 19555434 PMID: 24575836 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-3363e146-9b2b-401c-9787-ddd53d538759 Keratinocyte Proliferation in Acne Vulgaris uuid-3363e146-9b2b-401c-9787-ddd53d538759 PS:CellType keratinocyte PS:Description Increased keratinocyte proliferation is a key element in the pathogenesis of acne vulgaris. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3363e146-9b2b-401c-9787-ddd53d538759 PS:NodeType Pathway PS:Notes Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Increased keratinocyte proliferation is a key element in the pathogenesis of acne vulgaris. Signaling description: Hyperkeratinization occurs when the cells of the follicle become cohesive and do not shed normally onto the skin surface. The process caused by keratin excess and is observed in the primary stages of the disease and causes obstruction of the sebaceous gland duct, which provokes sebum storage in the gland and increases the gland size. The main agents inducing hyperkeratinization are IL1A and androgens. Androgens bind to AR causing increased cell proliferation; whereas, IL1A participates in MAPK pathway activation through MYD88/TRAF6 and RAC1. Outcome effects: As a result of MAPK pathway activation, NF-kB induction similarly causes increased keratinocyte proliferation leading to hyperkeratinization and ultimately the enlargement of sebaceous gland. Highlighted proteins: Entities with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15788147 PS:PMID 19555434 PS:PMID 24575836 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Focal adhesions are large protein complexes through which the cytoskeleton of a cell connects to the extracellular matrix (ECM). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33703282-eba1-435c-ae7e-7db8095b7276 NodeType: Pathway Notes: Headnote: The focal adhesions are large protein complexes that connect the cell cytoskeleton to the extracellular matrix (ECM). Signaling description: Focal adhesions are formed around a transmembrane core of an alpha/beta integrin heterodimer which binds to a component of the ECM on its extracellular region, constitutes the site of anchorage of the actin cytoskeletons to the cytoplasmic side of the membrane, and mediates various intracellular signaling pathways. Integrins bind to ECM proteins such as fibronectin (FN1), laminin, vitronectin (VTN), or collagen. The intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as TLN1, ACTN1, filamin, VCL, and PXN. TLN1, a key component of focal adhesions, is required for the initial link between integrins and the cytoskeleton. Outcome effects: TLN1 binding to the integrin cytoplasmic tail promotes focal adhesion clustering. Integrin adapter proteins, including filamin and ITGB1BP1, regulate integrin activation at the plasma membrane. Filamin binding inhibits cell migration and is also implicated in the sensing of mechanical forces and adhesion strengthening. Tyrosine phosphorylation is required for focal adhesion assembly. The two major kinases found in focal adhesions are PTK2 and SRC. Phosphorylated PIP5K1C binds to TLN1 and inhibits its ability to bind integrin. This, along with the phosphorylation of integrin leads to focal adhesion disassembly. PTPN12 is a major phosphatase found in focal adhesions. BCAR1 and PXN function as signaling scaffolds for the components of focal adhesions. Calpain (CAPN1), through the interaction with PTK2, cleaves several proteins found within focal adhesions. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-33703282-eba1-435c-ae7e-7db8095b7276 Focal Junction Assembly uuid-33703282-eba1-435c-ae7e-7db8095b7276 PS:CellType generic PS:Description Focal adhesions are large protein complexes through which the cytoskeleton of a cell connects to the extracellular matrix (ECM). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33703282-eba1-435c-ae7e-7db8095b7276 PS:NodeType Pathway PS:Notes Headnote: The focal adhesions are large protein complexes that connect the cell cytoskeleton to the extracellular matrix (ECM). Signaling description: Focal adhesions are formed around a transmembrane core of an alpha/beta integrin heterodimer which binds to a component of the ECM on its extracellular region, constitutes the site of anchorage of the actin cytoskeletons to the cytoplasmic side of the membrane, and mediates various intracellular signaling pathways. Integrins bind to ECM proteins such as fibronectin (FN1), laminin, vitronectin (VTN), or collagen. The intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as TLN1, ACTN1, filamin, VCL, and PXN. TLN1, a key component of focal adhesions, is required for the initial link between integrins and the cytoskeleton. Outcome effects: TLN1 binding to the integrin cytoplasmic tail promotes focal adhesion clustering. Integrin adapter proteins, including filamin and ITGB1BP1, regulate integrin activation at the plasma membrane. Filamin binding inhibits cell migration and is also implicated in the sensing of mechanical forces and adhesion strengthening. Tyrosine phosphorylation is required for focal adhesion assembly. The two major kinases found in focal adhesions are PTK2 and SRC. Phosphorylated PIP5K1C binds to TLN1 and inhibits its ability to bind integrin. This, along with the phosphorylation of integrin leads to focal adhesion disassembly. PTPN12 is a major phosphatase found in focal adhesions. BCAR1 and PXN function as signaling scaffolds for the components of focal adhesions. Calpain (CAPN1), through the interaction with PTK2, cleaves several proteins found within focal adhesions. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33773829-15f4-4b9e-91e0-460dded3a27f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-33773829-15f4-4b9e-91e0-460dded3a27f -|P4H->Cardiotoxicity AOP uuid-33773829-15f4-4b9e-91e0-460dded3a27f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33773829-15f4-4b9e-91e0-460dded3a27f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33808969-978c-41a1-9bc5-719bcf504aed NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-33808969-978c-41a1-9bc5-719bcf504aed ANS->M1-M2 macrophage balance uuid-33808969-978c-41a1-9bc5-719bcf504aed PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33808969-978c-41a1-9bc5-719bcf504aed PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage CellType: neutrophil Description: DC-SIGN (CD209) is a transmembrane receptor on the surface of dendritic cells and macrophages. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3392c88d-8ed5-4459-ba14-58c5f4a2d285 NodeType: Pathway Notes: Headnote: DC-SIGN (CD209) is a transmembrane receptor on the surface of dendritic cells and macrophages. Signaling description: CD209 functions as a pattern recognition receptor that recognizes carbohydrate antigens of viruses, bacteria, and protozoa and modulates TLR4 signaling. Upon ligand binding, CD209 activates RAF1. Outcome effects: RAF1 activation leads to the modulation of TLR-induced NF-kB activation resulting in an augmented production of the immunosuppressive cytokine, IL10. Organ: generic Organ_System: generic PMID: 20363321 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-3392c88d-8ed5-4459-ba14-58c5f4a2d285 DC-SIGN (CD209) Signaling uuid-3392c88d-8ed5-4459-ba14-58c5f4a2d285 PS:CellType dendritic cell PS:CellType macrophage PS:CellType neutrophil PS:Description DC-SIGN (CD209) is a transmembrane receptor on the surface of dendritic cells and macrophages. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3392c88d-8ed5-4459-ba14-58c5f4a2d285 PS:NodeType Pathway PS:Notes Headnote: DC-SIGN (CD209) is a transmembrane receptor on the surface of dendritic cells and macrophages. Signaling description: CD209 functions as a pattern recognition receptor that recognizes carbohydrate antigens of viruses, bacteria, and protozoa and modulates TLR4 signaling. Upon ligand binding, CD209 activates RAF1. Outcome effects: RAF1 activation leads to the modulation of TLR-induced NF-kB activation resulting in an augmented production of the immunosuppressive cytokine, IL10. PS:Organ generic PS:Organ_System generic PS:PMID 20363321 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: The interruption of axonal transport and neurotrophic factor (NTF) deprivation due to elevated intraocular pressure are believed to cause retinal ganglion cell (RGC) apoptotic death in glaucoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33b9492c-7f4d-487f-acc6-da9609f221de NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: The interruption of axonal transport and neurotrophic factor (NTF) deprivation due to elevated intraocular pressure are believed to cause retinal ganglion cell (RGC) apoptosis in glaucoma. A range of NTFs, including BDNF, NTF3/4, NGF, and CNTF, are implicated in this process. The presence of NTFs supports cell survival and NTF deprivation may lead to apoptosis. The selective activation of NTRK1 by NGF promotes the survival of injured RGCs. The co-expression of NGFR and NTRK1 increases NGF binding and enhances NGF-mediated NTRK1 activation. Outcome effects: However, when NTRK1/NGFR ratios are low or when neurotrophin levels are limited, NGFR activation leads to neuronal death. Pro-NGF may initiate cell apoptosis by binding to NGFR-SORT1 receptor complex. In addition, CNTF has been shown to stimulate axonal regeneration via STAT3 signaling. NTF4 may be absent due to mutation in rare cases of glaucoma. The knockdown of endogenous OPTN induces apoptotic cell death due to the reduced secretion of NTF3 and CNTF. NTFs are regarded as potential therapeutic agents in glaucoma. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 19217904 PMID: 21702001 PMID: 21896272 PMID: 22155051 PMID: 22182585 PMID: 24052073 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-33b9492c-7f4d-487f-acc6-da9609f221de Neurotrophic Factor Deprivation in Retinal Ganglion Cell Death uuid-33b9492c-7f4d-487f-acc6-da9609f221de PS:CellType retina cell PS:Description The interruption of axonal transport and neurotrophic factor (NTF) deprivation due to elevated intraocular pressure are believed to cause retinal ganglion cell (RGC) apoptotic death in glaucoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33b9492c-7f4d-487f-acc6-da9609f221de PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: The interruption of axonal transport and neurotrophic factor (NTF) deprivation due to elevated intraocular pressure are believed to cause retinal ganglion cell (RGC) apoptosis in glaucoma. A range of NTFs, including BDNF, NTF3/4, NGF, and CNTF, are implicated in this process. The presence of NTFs supports cell survival and NTF deprivation may lead to apoptosis. The selective activation of NTRK1 by NGF promotes the survival of injured RGCs. The co-expression of NGFR and NTRK1 increases NGF binding and enhances NGF-mediated NTRK1 activation. Outcome effects: However, when NTRK1/NGFR ratios are low or when neurotrophin levels are limited, NGFR activation leads to neuronal death. Pro-NGF may initiate cell apoptosis by binding to NGFR-SORT1 receptor complex. In addition, CNTF has been shown to stimulate axonal regeneration via STAT3 signaling. NTF4 may be absent due to mutation in rare cases of glaucoma. The knockdown of endogenous OPTN induces apoptotic cell death due to the reduced secretion of NTF3 and CNTF. NTFs are regarded as potential therapeutic agents in glaucoma. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 19217904 PS:PMID 21702001 PS:PMID 21896272 PS:PMID 22155051 PS:PMID 22182585 PS:PMID 24052073 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33da5579-4ae8-4ee8-baaf-ef84b7cfedab NodeType: Pathway Notes: Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors, whose type and copy number vary from cell to cell. NK stimulatory receptors belong to lectin-like type II transmembrane proteins that have a C-type lectin domain. Signaling description: The C-type lectin superfamily consists of a disulfide-linked heterodimer of CD94 glycoprotein (KLRD1) and one member of NKG2-D (KLRK1). KLRK1 acts as a receptor for the recognition of MHC class I HLA molecules expressed by NK cells and some cytotoxic T-cells. Activated KLRK1 induces the phosphorylation of VAV1, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to more VAV1 phosphorylation, inducing a positive feedback loop, which ultimately results in NK cell cytotoxicity. Outcome effects: The YINM motif of KLRK1 adaptor, HCST is phosphorylated by Src family kinases (LCK) and can recruit PI3K and VAV1 via GRB2. These proteins activate two main NK cell-mediated responses which are transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes result in the death of target cells. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-33da5579-4ae8-4ee8-baaf-ef84b7cfedab Natural Killer Cell Activation through C-Type Lectin-like Receptors uuid-33da5579-4ae8-4ee8-baaf-ef84b7cfedab PS:CellType natural killer cell PS:Description Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33da5579-4ae8-4ee8-baaf-ef84b7cfedab PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors, whose type and copy number vary from cell to cell. NK stimulatory receptors belong to lectin-like type II transmembrane proteins that have a C-type lectin domain. Signaling description: The C-type lectin superfamily consists of a disulfide-linked heterodimer of CD94 glycoprotein (KLRD1) and one member of NKG2-D (KLRK1). KLRK1 acts as a receptor for the recognition of MHC class I HLA molecules expressed by NK cells and some cytotoxic T-cells. Activated KLRK1 induces the phosphorylation of VAV1, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to more VAV1 phosphorylation, inducing a positive feedback loop, which ultimately results in NK cell cytotoxicity. Outcome effects: The YINM motif of KLRK1 adaptor, HCST is phosphorylated by Src family kinases (LCK) and can recruit PI3K and VAV1 via GRB2. These proteins activate two main NK cell-mediated responses which are transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes result in the death of target cells. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: One of the hypothetical causes of of mitochondria's failure in AD is a decrease in the activity of the tricarboxylic acid (TCA) cycle enzymes by amyloid beta. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33e24119-b230-40e1-af30-ae9b133e340f NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). In AD, alterations in the energetic function of mitochondria are observed. Signaling description: Abeta is thought to decrease the activity of the tricarboxylic acid (TCA) cycle enzymes in AD. Abeta causes a decrease in the activity of pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (OGDH), decreasing NADH reduction and hydrogen traffic from the matrix to the intermembrane space. This impairs the mitochondrial membrane potential. Conversely, the expression of mitochondrial Abeta-binding alcohol dehydrogenase (HSD17B10), which participates in the TCA cycle in the mitochondrial matrix, is increased in AD. Cytotoxic forms of Abeta and amyloid precursor protein (APP) stimulate the passage of calcium (Ca2+) and other small molecules into the intermembrane space through the mPTP pore complex. Ca2+ causes membrane depolarization and decreases activity of the respiratory chain. Outcome effects: As a result, the respiratory chain of mitochondria produces less ATP and more reactive oxygen species (ROS) in the presence of cytotoxic effects of Abeta, causing oxidative stress. Organ: brain Organ_System: nervous system PMID: 12695498 PMID: 15087549 PMID: 15840571 PMID: 17917162 PMID: 21545753 PMID: 21547208 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-33e24119-b230-40e1-af30-ae9b133e340f Tricarboxylic Acid Cycle Enzymes Involvement in Alzheimer Disease uuid-33e24119-b230-40e1-af30-ae9b133e340f PS:CellType neuron PS:Description One of the hypothetical causes of of mitochondria's failure in AD is a decrease in the activity of the tricarboxylic acid (TCA) cycle enzymes by amyloid beta. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33e24119-b230-40e1-af30-ae9b133e340f PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). In AD, alterations in the energetic function of mitochondria are observed. Signaling description: Abeta is thought to decrease the activity of the tricarboxylic acid (TCA) cycle enzymes in AD. Abeta causes a decrease in the activity of pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (OGDH), decreasing NADH reduction and hydrogen traffic from the matrix to the intermembrane space. This impairs the mitochondrial membrane potential. Conversely, the expression of mitochondrial Abeta-binding alcohol dehydrogenase (HSD17B10), which participates in the TCA cycle in the mitochondrial matrix, is increased in AD. Cytotoxic forms of Abeta and amyloid precursor protein (APP) stimulate the passage of calcium (Ca2+) and other small molecules into the intermembrane space through the mPTP pore complex. Ca2+ causes membrane depolarization and decreases activity of the respiratory chain. Outcome effects: As a result, the respiratory chain of mitochondria produces less ATP and more reactive oxygen species (ROS) in the presence of cytotoxic effects of Abeta, causing oxidative stress. PS:Organ brain PS:Organ_System nervous system PS:PMID 12695498 PS:PMID 15087549 PS:PMID 15840571 PS:PMID 17917162 PS:PMID 21545753 PS:PMID 21547208 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Histamine is a small molecule which is produced primarily by mast cells and basophils. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33f21dd1-1bd9-45ca-90ed-d1e286c40db4 NodeType: Pathway Notes: Headnote: Histamine is a small molecule, which is produced primarily by mast cells and basophils. Antibodies, mechanical stress, and inflammatory mediators stimulate the release of histamine from secretory granules. Signaling description: Histamine is produced and stored in granules of mast cells and basophils and released upon stimulation. IL3 or glucocorticoid can augment histamine synthesis in mast cells. Histamine is synthesized by the pyridoxal phosphate (vitamin B6)-containing L-histidine decarboxylase (HDC) from the amino acid histidine. Once formed, histamine is rapidly inactivated by ABP1 or HNMT. MAOB processes the immediate metabolites of histamine for excretion or recycling. The main effects of histamine are associated with allergic and inflammatory reactions and include relaxation of smooth muscles, vasodilation of vessels, and increased blood flow. These effects are caused by the activation of histamine receptors such as HRH1, HRH2, HRH3, and HRH4. HRH1 couples to GNA11, which stimulates phospholipase C (PLC), whereas HRH2 interacts with Gs to activate adenylate cyclase (ADCY). HRH3 and HRH4 couple to Gi proteins to inhibit ADCY and stimulate MAPK in the case of HRH3. HRH1 is widely expressed in different cells, but most specifically in smooth muscles, vascular endothelial cells, heart, and neurons. Outcome effects: The activation of HRH1, through PLCB1-associated increase in intracellular Ca2+, leads to both smooth muscle contraction and relaxation through nitric oxide (NO) synthesis. The effect of vasodilation prevails in the case of an inflammatory response when NO comes from other cells. In addition, HRH2 effects also lead to vasodilation and relaxation of vascular smooth muscle cells. HRH2 activation leads to PKA-related phosphorylation of MYLK, which decreases its activity and results in contraction inhibition. Histamine is also produced by enterochromaffin-like (ECL) cells of the stomach, where it controls hydrochloric acid synthesis through HRH2 receptor signaling. In addition, HRH3 is expressed in neurons of the central nervous system and in presynaptic histaminergic neurons in the peripheral nervous system. HRH3 activation prohibits the release of neurotransmitters into the synapse. HRH3 signaling also regulates the sleep-wake cycle. HRH4 is highly expressed in bone marrow cells, intestine, liver, lung, spleen, trachea, thymus, and scrotum. During inflammatory reactions, HRH4 activation leads to neutrophil attraction from the bone marrow. All histamine receptors act through G proteins to activate cellular signaling. HRH1, HRH4, and HRH3 can inhibit intracellular cascades via ADCY inhibition and activate them via PI3K cascade. The release of phosphatidylinositol-triphosphate (PIP3) activates many cellular responses, the principal of which during inflammation are cytokine synthesis and cell growth stimulation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-33f21dd1-1bd9-45ca-90ed-d1e286c40db4 Histamine Effects in Inflammation uuid-33f21dd1-1bd9-45ca-90ed-d1e286c40db4 PS:CellType generic PS:Description Histamine is a small molecule which is produced primarily by mast cells and basophils. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33f21dd1-1bd9-45ca-90ed-d1e286c40db4 PS:NodeType Pathway PS:Notes Headnote: Histamine is a small molecule, which is produced primarily by mast cells and basophils. Antibodies, mechanical stress, and inflammatory mediators stimulate the release of histamine from secretory granules. Signaling description: Histamine is produced and stored in granules of mast cells and basophils and released upon stimulation. IL3 or glucocorticoid can augment histamine synthesis in mast cells. Histamine is synthesized by the pyridoxal phosphate (vitamin B6)-containing L-histidine decarboxylase (HDC) from the amino acid histidine. Once formed, histamine is rapidly inactivated by ABP1 or HNMT. MAOB processes the immediate metabolites of histamine for excretion or recycling. The main effects of histamine are associated with allergic and inflammatory reactions and include relaxation of smooth muscles, vasodilation of vessels, and increased blood flow. These effects are caused by the activation of histamine receptors such as HRH1, HRH2, HRH3, and HRH4. HRH1 couples to GNA11, which stimulates phospholipase C (PLC), whereas HRH2 interacts with Gs to activate adenylate cyclase (ADCY). HRH3 and HRH4 couple to Gi proteins to inhibit ADCY and stimulate MAPK in the case of HRH3. HRH1 is widely expressed in different cells, but most specifically in smooth muscles, vascular endothelial cells, heart, and neurons. Outcome effects: The activation of HRH1, through PLCB1-associated increase in intracellular Ca2+, leads to both smooth muscle contraction and relaxation through nitric oxide (NO) synthesis. The effect of vasodilation prevails in the case of an inflammatory response when NO comes from other cells. In addition, HRH2 effects also lead to vasodilation and relaxation of vascular smooth muscle cells. HRH2 activation leads to PKA-related phosphorylation of MYLK, which decreases its activity and results in contraction inhibition. Histamine is also produced by enterochromaffin-like (ECL) cells of the stomach, where it controls hydrochloric acid synthesis through HRH2 receptor signaling. In addition, HRH3 is expressed in neurons of the central nervous system and in presynaptic histaminergic neurons in the peripheral nervous system. HRH3 activation prohibits the release of neurotransmitters into the synapse. HRH3 signaling also regulates the sleep-wake cycle. HRH4 is highly expressed in bone marrow cells, intestine, liver, lung, spleen, trachea, thymus, and scrotum. During inflammatory reactions, HRH4 activation leads to neutrophil attraction from the bone marrow. All histamine receptors act through G proteins to activate cellular signaling. HRH1, HRH4, and HRH3 can inhibit intracellular cascades via ADCY inhibition and activate them via PI3K cascade. The release of phosphatidylinositol-triphosphate (PIP3) activates many cellular responses, the principal of which during inflammation are cytokine synthesis and cell growth stimulation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33f2f73f-4353-46d4-9bea-0bbc7724cb50 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-33f2f73f-4353-46d4-9bea-0bbc7724cb50 Glycosylphosphatidylinositol(GPI)-Anchor Biosynthesis uuid-33f2f73f-4353-46d4-9bea-0bbc7724cb50 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-33f2f73f-4353-46d4-9bea-0bbc7724cb50 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-340512eb-5cef-4b3f-b5d4-8c78d251151e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-340512eb-5cef-4b3f-b5d4-8c78d251151e KRAS-RAFs-MAPK1/3 uuid-340512eb-5cef-4b3f-b5d4-8c78d251151e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-340512eb-5cef-4b3f-b5d4-8c78d251151e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3419ab8f-1ef8-4346-9112-9cc228a1dc7d NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-3419ab8f-1ef8-4346-9112-9cc228a1dc7d Proteins Involved in Medulloblastoma uuid-3419ab8f-1ef8-4346-9112-9cc228a1dc7d PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3419ab8f-1ef8-4346-9112-9cc228a1dc7d PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34277c2b-50ef-47ca-9cac-a1ab6ebd18a2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-34277c2b-50ef-47ca-9cac-a1ab6ebd18a2 COVID19 viral budding uuid-34277c2b-50ef-47ca-9cac-a1ab6ebd18a2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34277c2b-50ef-47ca-9cac-a1ab6ebd18a2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-343289d9-45e0-4808-87f1-8474e8f3b6d9 NodeType: Pathway Notes: Headnote: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Platelet activation and coagulation normally do not occur within an intact blood vessel. Signaling description: Following vessel wall injury, platelet-plug formation is initiated by the adherence of platelets to subendothelial collagen. Platelet activation is a dynamic process involving several different pathways. Platelet adhesion receptors are the key initiators of platelet activation at sites of vascular injury, where platelets become exposed to adhesive proteins in the matrix or on endothelial cells. Initial platelet adhesion requires the binding of immobilized VWF from endothelial cells to its platelet receptor, GP1BA. Collagen mediates platelet activation signaling through glycoprotein GP6 and integrin ITGA2B (a2ß1). Fibrinogen also induces platelet activation. All of the major platelet adhesion receptors involve Src family kinases, PI3K, and immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway. ITAM phosphorylation leads to the binding and activation of the tyrosine kinase SYK, which phosphorylates downstream targets such as LAT. This induces the formation of a signaling complex including LAT, LCP2, and BTK, which further activates PLCG2 leading to TXA2 synthesis, granule secretion, and integrin activation. Outcome effects: A common platelet response to agonists is the secretion of granule contents. Platelets contain three major types of granules including alpha-granules (containing adhesion proteins, coagulation and fibrinolytic factors, cytokines, growth factors, and adhesion receptors), dense granules (containing nucleotides like ADP, ATP and GTP, serotonin, histamine, pyrophosphates, divalent cations, etc.), and lysosomes. There are multiple pathways that are important for stimulating granule secretion including calcium signaling, PKC-dependent phosphorylation and regulation of SNAP receptor complexes, signaling via small GTPases such as RAC1 and RHOA, the PI3K/AKT1 signaling pathway, and the signaling pathways of MAPK isoforms p38, integrin activation, the NO/cGMP/PKG pathway (not shown), and others. Finally, platelet activation contributes to the inflammatory response by the release of proinflammatory mediator, CD40LG inducing F3 synthesis and increasing IL6 and IL8 levels. Organ: generic Organ_System: hematological system PMID: 23704217 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-343289d9-45e0-4808-87f1-8474e8f3b6d9 Platelet Activation via Adhesion Molecules uuid-343289d9-45e0-4808-87f1-8474e8f3b6d9 PS:CellType blood platelet PS:Description The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-343289d9-45e0-4808-87f1-8474e8f3b6d9 PS:NodeType Pathway PS:Notes Headnote: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Platelet activation and coagulation normally do not occur within an intact blood vessel. Signaling description: Following vessel wall injury, platelet-plug formation is initiated by the adherence of platelets to subendothelial collagen. Platelet activation is a dynamic process involving several different pathways. Platelet adhesion receptors are the key initiators of platelet activation at sites of vascular injury, where platelets become exposed to adhesive proteins in the matrix or on endothelial cells. Initial platelet adhesion requires the binding of immobilized VWF from endothelial cells to its platelet receptor, GP1BA. Collagen mediates platelet activation signaling through glycoprotein GP6 and integrin ITGA2B (a2ß1). Fibrinogen also induces platelet activation. All of the major platelet adhesion receptors involve Src family kinases, PI3K, and immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway. ITAM phosphorylation leads to the binding and activation of the tyrosine kinase SYK, which phosphorylates downstream targets such as LAT. This induces the formation of a signaling complex including LAT, LCP2, and BTK, which further activates PLCG2 leading to TXA2 synthesis, granule secretion, and integrin activation. Outcome effects: A common platelet response to agonists is the secretion of granule contents. Platelets contain three major types of granules including alpha-granules (containing adhesion proteins, coagulation and fibrinolytic factors, cytokines, growth factors, and adhesion receptors), dense granules (containing nucleotides like ADP, ATP and GTP, serotonin, histamine, pyrophosphates, divalent cations, etc.), and lysosomes. There are multiple pathways that are important for stimulating granule secretion including calcium signaling, PKC-dependent phosphorylation and regulation of SNAP receptor complexes, signaling via small GTPases such as RAC1 and RHOA, the PI3K/AKT1 signaling pathway, and the signaling pathways of MAPK isoforms p38, integrin activation, the NO/cGMP/PKG pathway (not shown), and others. Finally, platelet activation contributes to the inflammatory response by the release of proinflammatory mediator, CD40LG inducing F3 synthesis and increasing IL6 and IL8 levels. PS:Organ generic PS:Organ_System hematological system PS:PMID 23704217 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34411f70-4345-402b-9d67-245a04d33008 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-34411f70-4345-402b-9d67-245a04d33008 Pentose-Phosphate Shunt uuid-34411f70-4345-402b-9d67-245a04d33008 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34411f70-4345-402b-9d67-245a04d33008 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vascular endothelial cell (EC) permeability is the capacity of a blood vessel wall to allow for the flow of small molecules and whole cells such as lymphocytes in and out of the vessel. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34629eaa-518d-4cce-b30b-eaed0959b917 NodeType: Pathway Notes: Headnote: Vascular endothelial cell (EC) permeability is the capacity of a blood vessel wall to allow the flow of small molecules and whole cells such as lymphocytes in and out of the vessel. Signaling description: Blood vessel walls are lined by a single layer of ECs. The regulation of cell junctions between a single layer of ECs and therefore permeability is a function of the balance between competing adhesive and contractile forces. VEGFA, F2, and histamine are the main activators of vascular EC permeability. These mediators inhibit the function of primary cell junction proteins including TJP1, CDH5, and OCLN through the increase in intracellular calcium (Ca2+) or interaction with the cytoskeleton. Outcome effects: Subsequently, RHOA/ROCK1 and myosin light chain kinase (MYLK) signaling pathways activate MYL9 to induce cytoskeleton contraction in ECs and dissociation of cell-cell junctions. As a result, the association between epithelial cells in the blood vessel wall weakens. Additionally, the synthesis of nitric oxide (NO) is stimulated which acts as a muscle relaxant for vascular muscles. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-34629eaa-518d-4cce-b30b-eaed0959b917 Vascular Endothelial Cell Permeability Activation uuid-34629eaa-518d-4cce-b30b-eaed0959b917 PS:CellType endothelial cell PS:Description Vascular endothelial cell (EC) permeability is the capacity of a blood vessel wall to allow for the flow of small molecules and whole cells such as lymphocytes in and out of the vessel. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34629eaa-518d-4cce-b30b-eaed0959b917 PS:NodeType Pathway PS:Notes Headnote: Vascular endothelial cell (EC) permeability is the capacity of a blood vessel wall to allow the flow of small molecules and whole cells such as lymphocytes in and out of the vessel. Signaling description: Blood vessel walls are lined by a single layer of ECs. The regulation of cell junctions between a single layer of ECs and therefore permeability is a function of the balance between competing adhesive and contractile forces. VEGFA, F2, and histamine are the main activators of vascular EC permeability. These mediators inhibit the function of primary cell junction proteins including TJP1, CDH5, and OCLN through the increase in intracellular calcium (Ca2+) or interaction with the cytoskeleton. Outcome effects: Subsequently, RHOA/ROCK1 and myosin light chain kinase (MYLK) signaling pathways activate MYL9 to induce cytoskeleton contraction in ECs and dissociation of cell-cell junctions. As a result, the association between epithelial cells in the blood vessel wall weakens. Additionally, the synthesis of nitric oxide (NO) is stimulated which acts as a muscle relaxant for vascular muscles. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-346cd91c-767f-4947-beb7-8add5d7443d6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-346cd91c-767f-4947-beb7-8add5d7443d6 TLR7 Expression Targets uuid-346cd91c-767f-4947-beb7-8add5d7443d6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-346cd91c-767f-4947-beb7-8add5d7443d6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage Description: Familial cold autoinflammatory syndrome 2 (FCAS2; MIM 611762) is rare and the causative mutations have been defined in NLRP12 (also known as NALP12), which encodes another member of the NLR family. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-346cffd1-b846-40dd-bac4-9f6ee35ab83f NodeType: Pathway Notes: Headnote: Familial cold autoinflammatory syndrome 2 (FCAS2; MIM 611762) is a rare disease caused by mutations in NLRP12 (also known as NALP12) gene, which encodes a member of the NLR family. The clinical features of these patients resemble familial cold autoinflammatory syndrome (FCAS). The reported patients describe attacks of fever and arthralgia lasting 2 to10 days and are induced by exposure to cold. Some attacks are accompanied by urticaria, abdominal pain, and lymphadenopathy. Hearing loss has been observed in at least two patients. Signaling description: NLRP12 has been shown to associate with ASC and activate CASP-1. In addition, NLRP12 can block the hyperphosphorylation of IRAK, eventually limiting downstream NF-kB signaling. Outcome effects: NF-kB signaling pathway regulates the production of cytokines involved in inflammatory responses. Activated CASP1 can convert pro-IL-1beta to its mature form (IL1B). IL-1beta maturation and secretion activates inflammatory response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 18230725 PMID: 24282415 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone tissue Tissue: epidermis urn:agi-pathway:uuid-346cffd1-b846-40dd-bac4-9f6ee35ab83f Familial Cold Autoinflammatory Syndrome 2 uuid-346cffd1-b846-40dd-bac4-9f6ee35ab83f PS:CellType dendritic cell PS:CellType macrophage PS:Description Familial cold autoinflammatory syndrome 2 (FCAS2; MIM 611762) is rare and the causative mutations have been defined in NLRP12 (also known as NALP12), which encodes another member of the NLR family. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-346cffd1-b846-40dd-bac4-9f6ee35ab83f PS:NodeType Pathway PS:Notes Headnote: Familial cold autoinflammatory syndrome 2 (FCAS2; MIM 611762) is a rare disease caused by mutations in NLRP12 (also known as NALP12) gene, which encodes a member of the NLR family. The clinical features of these patients resemble familial cold autoinflammatory syndrome (FCAS). The reported patients describe attacks of fever and arthralgia lasting 2 to10 days and are induced by exposure to cold. Some attacks are accompanied by urticaria, abdominal pain, and lymphadenopathy. Hearing loss has been observed in at least two patients. Signaling description: NLRP12 has been shown to associate with ASC and activate CASP-1. In addition, NLRP12 can block the hyperphosphorylation of IRAK, eventually limiting downstream NF-kB signaling. Outcome effects: NF-kB signaling pathway regulates the production of cytokines involved in inflammatory responses. Activated CASP1 can convert pro-IL-1beta to its mature form (IL1B). IL-1beta maturation and secretion activates inflammatory response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 18230725 PS:PMID 24282415 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone tissue PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-347513c3-3979-4084-99f9-62357b9e151d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-347513c3-3979-4084-99f9-62357b9e151d PRL/GHR -> NF/kB/ELK/SRF/MYC Expression Targets uuid-347513c3-3979-4084-99f9-62357b9e151d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-347513c3-3979-4084-99f9-62357b9e151d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-347c4c17-08dc-40d1-9a68-c6a81e6a7bda NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-347c4c17-08dc-40d1-9a68-c6a81e6a7bda EctodysplasinR -> AP-1 Signaling uuid-347c4c17-08dc-40d1-9a68-c6a81e6a7bda PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-347c4c17-08dc-40d1-9a68-c6a81e6a7bda PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: leukocyte Description: Circulating T cells bearing integrin-alpha(4)beta(7) bind to colonic endothelial cells of the microvasculature through the mucosal vascular addressin-cell adhesion molecule 1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3481d973-0c2b-4994-9713-733dc97236cd NodeType: Pathway Notes: Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Circulating T-cells bearing integrin-alpha(4)beta(7) bind to colonic endothelial cells of the microvasculature through the mucosal vascular addressin-cell adhesion molecule 1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 22914296 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-3481d973-0c2b-4994-9713-733dc97236cd Leukocyte Migration toward the Endothelial Cell in Ulcerative Colitis uuid-3481d973-0c2b-4994-9713-733dc97236cd PS:CellType endothelial cell PS:CellType leukocyte PS:Description Circulating T cells bearing integrin-alpha(4)beta(7) bind to colonic endothelial cells of the microvasculature through the mucosal vascular addressin-cell adhesion molecule 1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3481d973-0c2b-4994-9713-733dc97236cd PS:NodeType Pathway PS:Notes Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Circulating T-cells bearing integrin-alpha(4)beta(7) bind to colonic endothelial cells of the microvasculature through the mucosal vascular addressin-cell adhesion molecule 1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 22914296 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34852e75-148a-4036-b13f-0f8545d34f0e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-34852e75-148a-4036-b13f-0f8545d34f0e Peroxisome activation inhibits fibroblasts uuid-34852e75-148a-4036-b13f-0f8545d34f0e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34852e75-148a-4036-b13f-0f8545d34f0e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell CellType: stem cell Description: Hematopoietic stem cells (HSCs) are progenitor cells which differentiate to B-cell during lymphoid lineage cells related hematopoiesis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34aabc25-1b17-4580-b725-88e93c7d7712 NodeType: Pathway Notes: Headnote: Hematopoietic stem cells (HSCs) are progenitor cells that differentiate into all other blood cell types via the process of hematopoiesis. Signaling description: Classically, HSCs are thought to differentiate into two distinct leneages, i.e. llymphoid and myelo-erythroid cells. Hematopoetic lineage cell can be identified by the expression of specific cell surface lineage markers. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-34aabc25-1b17-4580-b725-88e93c7d7712 Hematopoietic Cell Lineage: B-cell uuid-34aabc25-1b17-4580-b725-88e93c7d7712 PS:CellType B-cell PS:CellType stem cell PS:Description Hematopoietic stem cells (HSCs) are progenitor cells which differentiate to B-cell during lymphoid lineage cells related hematopoiesis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34aabc25-1b17-4580-b725-88e93c7d7712 PS:NodeType Pathway PS:Notes Headnote: Hematopoietic stem cells (HSCs) are progenitor cells that differentiate into all other blood cell types via the process of hematopoiesis. Signaling description: Classically, HSCs are thought to differentiate into two distinct leneages, i.e. llymphoid and myelo-erythroid cells. Hematopoetic lineage cell can be identified by the expression of specific cell surface lineage markers. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34cfcf2f-9def-4a24-b049-deba9c0cbc49 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-34cfcf2f-9def-4a24-b049-deba9c0cbc49 Purine salvage pathway template uuid-34cfcf2f-9def-4a24-b049-deba9c0cbc49 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34cfcf2f-9def-4a24-b049-deba9c0cbc49 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34ddfc90-0453-4529-a240-162d80bb6d1d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-34ddfc90-0453-4529-a240-162d80bb6d1d Monolignol Angiosperm transport and lignin polymerization template uuid-34ddfc90-0453-4529-a240-162d80bb6d1d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34ddfc90-0453-4529-a240-162d80bb6d1d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: enterocyte Description: In osteoporosis, impaired intestinal calcium (Ca2 ) absorption may occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34f90007-d917-4385-b035-f1281283f4a5 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. Signaling description: Ca2+ transport is an active process and Ca2+ transport proteins are localized in the outer and inner enterocyte membranes. The process begins with Ca2+ entry in to the cell via TRPV5/6 proteins. The expression of TRPV proteins is under the control of VDR and ESR1 transcription factors. In the absence of their ligands (estrogens and/or calcitriol) or due to polymorphisms in the genes, TRPV synthesis can be impaired causing decreased Ca2+ absorption in the intestine. Outcome effects: Following its entry in to the cell, Ca2+ is transported to the inner membrane by CALB1 protein, and then excreted by the ATP2B1 and SLC8A1 transporters to the blood. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 12520535 PMID: 12520541 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-34f90007-d917-4385-b035-f1281283f4a5 Ca2+ Absorption Decline in Intestine in Osteoporosis uuid-34f90007-d917-4385-b035-f1281283f4a5 PS:CellType enterocyte PS:Description In osteoporosis, impaired intestinal calcium (Ca2 ) absorption may occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-34f90007-d917-4385-b035-f1281283f4a5 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. Signaling description: Ca2+ transport is an active process and Ca2+ transport proteins are localized in the outer and inner enterocyte membranes. The process begins with Ca2+ entry in to the cell via TRPV5/6 proteins. The expression of TRPV proteins is under the control of VDR and ESR1 transcription factors. In the absence of their ligands (estrogens and/or calcitriol) or due to polymorphisms in the genes, TRPV synthesis can be impaired causing decreased Ca2+ absorption in the intestine. Outcome effects: Following its entry in to the cell, Ca2+ is transported to the inner membrane by CALB1 protein, and then excreted by the ATP2B1 and SLC8A1 transporters to the blood. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 12520535 PS:PMID 12520541 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Gap junctions are specialized contacts between cells that mediate the direct exchange of ions and metabolites under approximately 1000Da between cells in contact. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-352448de-805b-46d5-8a8d-f89bc72e8ea5 NodeType: Pathway Notes: Headnote: The gap junctions are specialized contacts between cells that mediate the direct exchange of ions and metabolites under approximately 1000Da between the cells. Signaling description: The gap junctions of vertebrates are composed of the connexin family. One connexon consists of six connexin molecules. Gap junction connexon channels are formed from both heterotypic (different connexins in opposed cells) and heteromeric (different connexins in the same cell) channels. There are different types of interactions between connexins. GJA1 is the most widespread connexin in mammalian cells and can oligomerize with other connexins such as GJB2 (hepatocytes and keratinocytes), GJB3 (keratinocytes), and GJC1 (cardiomyocytes). Gap junction channels are unusual among ion channels since they typically remain open at rest and only close under specific circumstances. They close in response to a number of stimuli that generally reflect the poor health of a cell including low pH, high intracellular Ca2+ concentration and voltage differences between cells, and a number of physiological stimuli that are typically associated with increased cell division. Gap junctional communication is controlled by neurotransmitters, cytokines, growth factors, and other bioactive compounds such as LPA. Outcome effects: These biomolecules activate downstream kinases including PKG, PKA, PKC, casein kinase, MAPK3, MAPK1, and MAPK7. The kinase activators then significantly increase levels of GJA1 phosphorylation at specific sites leading to channel opening. When dopamine/DRD1 and noradrenaline/ADRB1 are coupled to G-protein it leads to cAMP production. In contrast, when dopamine/DRD2 binds to G-protein, ADCY activity is blocked and cAMP production is reduced. Other neurotransmitters such as serotonin and glutamate activate PLC which leads to the generation of IP3 and diacylglycerol. Diacylglycerol activates PKC, whereas the association of IP3 and IP3 receptor (ITPR1) promotes the release of Ca2 from endoplasmic reticulum. Gating is also controlled by a short-lived free radical gas NO through the ADCY-cGMP route activating PKG. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-352448de-805b-46d5-8a8d-f89bc72e8ea5 Gap Junction Assembly uuid-352448de-805b-46d5-8a8d-f89bc72e8ea5 PS:CellType generic PS:Description Gap junctions are specialized contacts between cells that mediate the direct exchange of ions and metabolites under approximately 1000Da between cells in contact. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-352448de-805b-46d5-8a8d-f89bc72e8ea5 PS:NodeType Pathway PS:Notes Headnote: The gap junctions are specialized contacts between cells that mediate the direct exchange of ions and metabolites under approximately 1000Da between the cells. Signaling description: The gap junctions of vertebrates are composed of the connexin family. One connexon consists of six connexin molecules. Gap junction connexon channels are formed from both heterotypic (different connexins in opposed cells) and heteromeric (different connexins in the same cell) channels. There are different types of interactions between connexins. GJA1 is the most widespread connexin in mammalian cells and can oligomerize with other connexins such as GJB2 (hepatocytes and keratinocytes), GJB3 (keratinocytes), and GJC1 (cardiomyocytes). Gap junction channels are unusual among ion channels since they typically remain open at rest and only close under specific circumstances. They close in response to a number of stimuli that generally reflect the poor health of a cell including low pH, high intracellular Ca2+ concentration and voltage differences between cells, and a number of physiological stimuli that are typically associated with increased cell division. Gap junctional communication is controlled by neurotransmitters, cytokines, growth factors, and other bioactive compounds such as LPA. Outcome effects: These biomolecules activate downstream kinases including PKG, PKA, PKC, casein kinase, MAPK3, MAPK1, and MAPK7. The kinase activators then significantly increase levels of GJA1 phosphorylation at specific sites leading to channel opening. When dopamine/DRD1 and noradrenaline/ADRB1 are coupled to G-protein it leads to cAMP production. In contrast, when dopamine/DRD2 binds to G-protein, ADCY activity is blocked and cAMP production is reduced. Other neurotransmitters such as serotonin and glutamate activate PLC which leads to the generation of IP3 and diacylglycerol. Diacylglycerol activates PKC, whereas the association of IP3 and IP3 receptor (ITPR1) promotes the release of Ca2 from endoplasmic reticulum. Gating is also controlled by a short-lived free radical gas NO through the ADCY-cGMP route activating PKG. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3525a2d6-f346-43e6-b780-1ea4cbda734e NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-3525a2d6-f346-43e6-b780-1ea4cbda734e Proteins Involved in Systemic Scleroderma uuid-3525a2d6-f346-43e6-b780-1ea4cbda734e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3525a2d6-f346-43e6-b780-1ea4cbda734e PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: endothelial cell Description: The penetration of CD4 T-cells through the blood-brain barrier in multiple sclerosis is occurs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35344f11-74f7-4977-8d5b-d6c26ef4336d NodeType: Pathway Notes: Multiple sclerosis pathogenesis is associated with the increase of blood-brain barrier permeability. Myelin basic protein (MBP) specific CD4 T-cells are among those CD4 T-cells that migrate through the blood-brain barrier in multiple sclerosis. This leads to myelin destruction. Organ: blood vessel Organ_System: cardiovascular system PMID: 19444308 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-35344f11-74f7-4977-8d5b-d6c26ef4336d T-Cells Passage through the Blood-Brain Barrier uuid-35344f11-74f7-4977-8d5b-d6c26ef4336d PS:CellType T-cell PS:CellType endothelial cell PS:Description The penetration of CD4 T-cells through the blood-brain barrier in multiple sclerosis is occurs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35344f11-74f7-4977-8d5b-d6c26ef4336d PS:NodeType Pathway PS:Notes Multiple sclerosis pathogenesis is associated with the increase of blood-brain barrier permeability. Myelin basic protein (MBP) specific CD4 T-cells are among those CD4 T-cells that migrate through the blood-brain barrier in multiple sclerosis. This leads to myelin destruction. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 19444308 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: goblet cell Description: The overproduction of mucin, the chief glycoprotein component of mucus, is a pathological feature of COPD. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3542dfbf-1f1b-4229-a484-0dec2ad38dfd NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Mucus production is a primary defense mechanism for maintaining lung health. However, the overproduction of mucin, the chief glycoprotein component of mucus, is a pathological feature in COPD. The most abundant gel forming mucins in tracheobronchial human epithelium are MUC5AC, produced by surface epithelial mucus secreting cells (mainly goblet cells) and MUC5B, mainly produced by submucosal glands. The activation of epidermal growth factor receptor (EGFR) by EGF and TGFA plays a pivotal role in the synthesis and secretion of mucins. ELANE and ADAM17 are involved in the cleavage and activation of TGFA. Outcome effects: EGFR activates MAPK- and SP1-dependent signaling pathways leading to MUC5AC and MUC5B production. IL1B, IL13, TNF, and activation of TLRs by pathogens also have a role in mucin production activation. Excessive mucus production and impaired mucociliary clearance contribute to airway obstruction and respiratory infections in patients with COPD. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16371599 PMID: 16543607 PMID: 19059283 PMID: 19201713 PMID: 20493919 PMID: 21121836 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3542dfbf-1f1b-4229-a484-0dec2ad38dfd Mucin Hyperproduction in Goblet and Mucous Cells uuid-3542dfbf-1f1b-4229-a484-0dec2ad38dfd PS:CellType goblet cell PS:Description The overproduction of mucin, the chief glycoprotein component of mucus, is a pathological feature of COPD. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3542dfbf-1f1b-4229-a484-0dec2ad38dfd PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Mucus production is a primary defense mechanism for maintaining lung health. However, the overproduction of mucin, the chief glycoprotein component of mucus, is a pathological feature in COPD. The most abundant gel forming mucins in tracheobronchial human epithelium are MUC5AC, produced by surface epithelial mucus secreting cells (mainly goblet cells) and MUC5B, mainly produced by submucosal glands. The activation of epidermal growth factor receptor (EGFR) by EGF and TGFA plays a pivotal role in the synthesis and secretion of mucins. ELANE and ADAM17 are involved in the cleavage and activation of TGFA. Outcome effects: EGFR activates MAPK- and SP1-dependent signaling pathways leading to MUC5AC and MUC5B production. IL1B, IL13, TNF, and activation of TLRs by pathogens also have a role in mucin production activation. Excessive mucus production and impaired mucociliary clearance contribute to airway obstruction and respiratory infections in patients with COPD. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16371599 PS:PMID 16543607 PS:PMID 19059283 PS:PMID 19201713 PS:PMID 20493919 PS:PMID 21121836 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: monoblast CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3542e839-b703-48e4-8791-8619c9431e68 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-3542e839-b703-48e4-8791-8619c9431e68 Monoblast -> Promonocyte Surface Expression Markers uuid-3542e839-b703-48e4-8791-8619c9431e68 PS:CellType monoblast PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3542e839-b703-48e4-8791-8619c9431e68 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3546a408-2b3d-4882-a369-83cf0f1403a5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3546a408-2b3d-4882-a369-83cf0f1403a5 InsR->GLUT4 with weights uuid-3546a408-2b3d-4882-a369-83cf0f1403a5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3546a408-2b3d-4882-a369-83cf0f1403a5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3558d2c5-e6a8-4692-a3ff-742aacd3f833 NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 protein is involved in PAH as it regulates pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. BMP2 can act through the canonical or non-canonical WNT-pathway. In the case of canonical WNT-activation, BMP2, via BMPR2, activates MAPK1/3 in a SMAD-independent manner. Outcome effects: MAPK1/3-mediated inhibition of GSK3B induces beta-catenin (CTNNB1) accumulation and transcriptional activity necessary for PAEC survival and proliferation in addition to the inhibition of apoptosis. Organ: lung Organ_System: cardiovascular system PMID: 19139264 PMID: 19329555 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3558d2c5-e6a8-4692-a3ff-742aacd3f833 BMP2 and Canonical WNT Signaling in Pulmonary Artery Endothelial Cells uuid-3558d2c5-e6a8-4692-a3ff-742aacd3f833 PS:CellType endothelial cell PS:Description BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3558d2c5-e6a8-4692-a3ff-742aacd3f833 PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 protein is involved in PAH as it regulates pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. BMP2 can act through the canonical or non-canonical WNT-pathway. In the case of canonical WNT-activation, BMP2, via BMPR2, activates MAPK1/3 in a SMAD-independent manner. Outcome effects: MAPK1/3-mediated inhibition of GSK3B induces beta-catenin (CTNNB1) accumulation and transcriptional activity necessary for PAEC survival and proliferation in addition to the inhibition of apoptosis. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 19139264 PS:PMID 19329555 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: There are three major classes of intracellular RNA-degrading enzymes (ribonucleases or RNases) including endonucleases, 5' exonucleases, and 3' exonucleases that degrade RNA from the 3' end. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35659ebe-245e-4875-94e9-8f368039b4f3 NodeType: Pathway Notes: Headnote: The three major classes of intracellular RNA-degrading enzymes (ribonucleases or RNases) include endonucleases which cut RNA internally, 5' exonucleases which hydrolyze RNA from the 5' end, and 3' exonucleases which degrade RNA from the 3' end. Signaling description: Nearly all mRNA degradation mechanisms are initiated by the shortening of mRNA 3'-poly(A) tails removed by deadenylases. The major deadenylase activity in yeast and humans is most likely the CCR4-NOT transcription complex. Another deadenylase (PARN) may play a more important role in regulated deadenylation. Following poly(A) tail removal, the mRNA body may be subject to 3' degradation. In eukaryotes, 3' degradation activity is provided by the exosome complex. TRAMP polyadenylation complexes act as major cofactors for the exosome complex. In human cells, homologs of TRAMP components are PAPD7, PAPD5, and ZCCHC3. The TRAMP-exosome combination exhibits exonuclease and endonuclease activities and function together with helicase family members such as SKIV2L2, SUPV3L1, and SKIV2L. Outcome effects: Eukaryotic mRNAs carry protective 5'-cap structures that must be removed prior to 5' exonuclease degradation by decapping enzymes DCP1A and XRN1. Individual LSM proteins assemble into a seven-member ring (torus), which usually binds to a small RNA molecule to form a ribonucleoprotein complex. Ring-shaped complexes LSM 1-7 act as chaperones promoting RNA degradation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-35659ebe-245e-4875-94e9-8f368039b4f3 mRNA Degradation uuid-35659ebe-245e-4875-94e9-8f368039b4f3 PS:CellType generic PS:Description There are three major classes of intracellular RNA-degrading enzymes (ribonucleases or RNases) including endonucleases, 5' exonucleases, and 3' exonucleases that degrade RNA from the 3' end. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35659ebe-245e-4875-94e9-8f368039b4f3 PS:NodeType Pathway PS:Notes Headnote: The three major classes of intracellular RNA-degrading enzymes (ribonucleases or RNases) include endonucleases which cut RNA internally, 5' exonucleases which hydrolyze RNA from the 5' end, and 3' exonucleases which degrade RNA from the 3' end. Signaling description: Nearly all mRNA degradation mechanisms are initiated by the shortening of mRNA 3'-poly(A) tails removed by deadenylases. The major deadenylase activity in yeast and humans is most likely the CCR4-NOT transcription complex. Another deadenylase (PARN) may play a more important role in regulated deadenylation. Following poly(A) tail removal, the mRNA body may be subject to 3' degradation. In eukaryotes, 3' degradation activity is provided by the exosome complex. TRAMP polyadenylation complexes act as major cofactors for the exosome complex. In human cells, homologs of TRAMP components are PAPD7, PAPD5, and ZCCHC3. The TRAMP-exosome combination exhibits exonuclease and endonuclease activities and function together with helicase family members such as SKIV2L2, SUPV3L1, and SKIV2L. Outcome effects: Eukaryotic mRNAs carry protective 5'-cap structures that must be removed prior to 5' exonuclease degradation by decapping enzymes DCP1A and XRN1. Individual LSM proteins assemble into a seven-member ring (torus), which usually binds to a small RNA molecule to form a ribonucleoprotein complex. Ring-shaped complexes LSM 1-7 act as chaperones promoting RNA degradation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35919f79-13e6-4b72-b079-29a95e2dbb3a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-35919f79-13e6-4b72-b079-29a95e2dbb3a malonyl-CoA biosynthesis template uuid-35919f79-13e6-4b72-b079-29a95e2dbb3a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35919f79-13e6-4b72-b079-29a95e2dbb3a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35968575-bb6c-484b-8e56-21d30b4007bf NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-35968575-bb6c-484b-8e56-21d30b4007bf Overview. Diseases of the musculoskeletal system (chapter 12) uuid-35968575-bb6c-484b-8e56-21d30b4007bf PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35968575-bb6c-484b-8e56-21d30b4007bf PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35a35311-a3b7-4fed-94d7-9653649b6dcd NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-35a35311-a3b7-4fed-94d7-9653649b6dcd TGFb-|COX2 uuid-35a35311-a3b7-4fed-94d7-9653649b6dcd PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35a35311-a3b7-4fed-94d7-9653649b6dcd PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35aa1c0f-b7d2-4427-998f-cb1199ebcc02 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-35aa1c0f-b7d2-4427-998f-cb1199ebcc02 PPARG signaling after laser treatment uuid-35aa1c0f-b7d2-4427-998f-cb1199ebcc02 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35aa1c0f-b7d2-4427-998f-cb1199ebcc02 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35f4a34b-2540-4f74-9930-6795e942cbe6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-35f4a34b-2540-4f74-9930-6795e942cbe6 Neutrophils and T-cells recruitment uuid-35f4a34b-2540-4f74-9930-6795e942cbe6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35f4a34b-2540-4f74-9930-6795e942cbe6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35ff12c4-c83d-4d83-bef9-f49a4034adc8 NodeType: Pathway Notes: Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway depicts thyroid gland development in relation to mutations in NKX2-1. The proteins regulated by NKX2-1 were added following the analysis of existing neighbors of NKX2-1 in Pathway Studio. Only those that are significant in the development of thyroid cells were included. Outcome effects: Mutations in NKX2-1 also known as thyroid transcription factor 1 (TTF-1), have been associated with congenital hypothyroidism, hyaline membrane disease (HMD) (more commonly called respiratory distress syndrome (RDS)), and the type of ataxia also known as choreoathetosis. Recent reports describe an NKX2-1 mutation with congenital hypothyroidism and benign chorea. . Mutated genes: Mutated genes are shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 15665157 PMID: 23169673 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-35ff12c4-c83d-4d83-bef9-f49a4034adc8 NKX2-1 in Thyroid Dysgenesis (Hypothesis) uuid-35ff12c4-c83d-4d83-bef9-f49a4034adc8 PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-35ff12c4-c83d-4d83-bef9-f49a4034adc8 PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway depicts thyroid gland development in relation to mutations in NKX2-1. The proteins regulated by NKX2-1 were added following the analysis of existing neighbors of NKX2-1 in Pathway Studio. Only those that are significant in the development of thyroid cells were included. Outcome effects: Mutations in NKX2-1 also known as thyroid transcription factor 1 (TTF-1), have been associated with congenital hypothyroidism, hyaline membrane disease (HMD) (more commonly called respiratory distress syndrome (RDS)), and the type of ataxia also known as choreoathetosis. Recent reports describe an NKX2-1 mutation with congenital hypothyroidism and benign chorea. . Mutated genes: Mutated genes are shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15665157 PS:PMID 23169673 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Frontotemporal dementia (FTD) is a group of related conditions resulting from the progressive degeneration of the temporal and frontal lobes of the brain. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-362a1c71-c4d2-4a8b-b009-fb6e15ef4860 NodeType: Pathway Notes: Frontotemporal dementia (FTD) is a group of related conditions resulting from the progressive degeneration of the temporal and frontal lobes of the brain. FTD is associated with microtubule depolymerization and impaired axonal transport. Organ: brain Organ_System: nervous system PMID: 17003069 PMID: 24600223 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-362a1c71-c4d2-4a8b-b009-fb6e15ef4860 Microtubule Organization Dysregulation (Hypothesis) uuid-362a1c71-c4d2-4a8b-b009-fb6e15ef4860 PS:CellType neuron PS:Description Frontotemporal dementia (FTD) is a group of related conditions resulting from the progressive degeneration of the temporal and frontal lobes of the brain. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-362a1c71-c4d2-4a8b-b009-fb6e15ef4860 PS:NodeType Pathway PS:Notes Frontotemporal dementia (FTD) is a group of related conditions resulting from the progressive degeneration of the temporal and frontal lobes of the brain. FTD is associated with microtubule depolymerization and impaired axonal transport. PS:Organ brain PS:Organ_System nervous system PS:PMID 17003069 PS:PMID 24600223 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-363bd932-d64c-4e68-b2d4-2dbf5b8463cb NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-363bd932-d64c-4e68-b2d4-2dbf5b8463cb Proteins with Altered Expression in Urolithiasis uuid-363bd932-d64c-4e68-b2d4-2dbf5b8463cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-363bd932-d64c-4e68-b2d4-2dbf5b8463cb PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/FBXO11 complex regulates cell cycle progression, response to DNA damage, apoposis and epithelial to mesenchymal transition. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-363f66bc-3471-4386-a0d7-faa25f2401bd NodeType: Pathway Notes: Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXO11 complex, FBXO11 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/FBXO11 related signaling leads to cell cycle progression, apoptosis and epithelial-mesenchymal transition (EMT). The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SCF/FBXO11 targets SNAI1, DTL and TP53. SNAI1 degradation by SCF/FBXO11 is dependent upon phosphorylation by PKD1. SCF/FBXO11 blocks SNAI1-induced EMT, tumor initiation and metastasis in multiple cancer models. During S and G2/M phases, SCF/FBXO11 promotes proteasomal degradation of DTL, a protein that controls cell cycle progression and response to DNA damage. CAND1 modulates the assembly of FBXO11 into cullin 1-RING ubiquitin ligase and NEDD8 leads to neddylation of TP53 and suppression of its function. Animal data: Role of SCF/FBXO11 in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 17098746 PMID: 23478441 PMID: 25203322 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-363f66bc-3471-4386-a0d7-faa25f2401bd SCF/FBXO11 Complex uuid-363f66bc-3471-4386-a0d7-faa25f2401bd PS:CellType generic PS:Description SCF/FBXO11 complex regulates cell cycle progression, response to DNA damage, apoposis and epithelial to mesenchymal transition. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-363f66bc-3471-4386-a0d7-faa25f2401bd PS:NodeType Pathway PS:Notes Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXO11 complex, FBXO11 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/FBXO11 related signaling leads to cell cycle progression, apoptosis and epithelial-mesenchymal transition (EMT). The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SCF/FBXO11 targets SNAI1, DTL and TP53. SNAI1 degradation by SCF/FBXO11 is dependent upon phosphorylation by PKD1. SCF/FBXO11 blocks SNAI1-induced EMT, tumor initiation and metastasis in multiple cancer models. During S and G2/M phases, SCF/FBXO11 promotes proteasomal degradation of DTL, a protein that controls cell cycle progression and response to DNA damage. CAND1 modulates the assembly of FBXO11 into cullin 1-RING ubiquitin ligase and NEDD8 leads to neddylation of TP53 and suppression of its function. Animal data: Role of SCF/FBXO11 in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17098746 PS:PMID 23478441 PS:PMID 25203322 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: The cause of this HM consists of mutations in SLC1A3 gene which encodes a high affinity glutamate transporter. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-366d4b03-7071-4bf2-b9db-dd46762ccc3c NodeType: Pathway Notes: Headnote: One type of hemiplegic migraine is caused by mutations in the SLC1A3 gene which encodes a high affinity glutamate transporter. This type of glutamate transporter is presented on the surface of astrocytes. Organ: brain Organ_System: nervous system PMID: 16116111 PMID: 17691981 PMID: 19499287 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-366d4b03-7071-4bf2-b9db-dd46762ccc3c Glutamate Overdose and Aura Effect Caused by Mutations in SLC1A3 Gene uuid-366d4b03-7071-4bf2-b9db-dd46762ccc3c PS:CellType astrocyte PS:CellType neuron PS:Description The cause of this HM consists of mutations in SLC1A3 gene which encodes a high affinity glutamate transporter. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-366d4b03-7071-4bf2-b9db-dd46762ccc3c PS:NodeType Pathway PS:Notes Headnote: One type of hemiplegic migraine is caused by mutations in the SLC1A3 gene which encodes a high affinity glutamate transporter. This type of glutamate transporter is presented on the surface of astrocytes. PS:Organ brain PS:Organ_System nervous system PS:PMID 16116111 PS:PMID 17691981 PS:PMID 19499287 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3689c98d-ae1e-408c-bca6-016851165f1b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3689c98d-ae1e-408c-bca6-016851165f1b TGFBR -> CREB/ELK-SRF Signaling uuid-3689c98d-ae1e-408c-bca6-016851165f1b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3689c98d-ae1e-408c-bca6-016851165f1b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-368b9d93-c2c0-4c82-85f2-eda6d7aca0db NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-368b9d93-c2c0-4c82-85f2-eda6d7aca0db IL15R -> NF-kB/NFATC Signaling uuid-368b9d93-c2c0-4c82-85f2-eda6d7aca0db PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-368b9d93-c2c0-4c82-85f2-eda6d7aca0db PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Cardiac hypoxia is the initial step in ischemia/reperfusion injury that ends in cardiomyocyte death by apoptosis or necrosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36919278-217a-4d07-9889-65ab45d643ca NodeType: Pathway Notes: Headnote: Cardiac hypoxia is the initial step in ischemia/reperfusion injury that results in cardiomyocyte death via apoptosis or necrosis. Signaling description: Oxygen deficiency triggers the transition of the cells to anaerobic metabolism, which results in lactic acidosis. The accumulation of hydrogen ions (H+) activates the Na+/H+ exchanger (SLC9A1), leading to Na+ and subsequent Ca2+ overload. In mitochondria, Ca2+ induces nitric oxide (NO) production and the opening of mitochondrial permeability transition pore (mPTP). This causes the burst of superoxide radical production, peroxynitrite and hydrogen peroxide (H2O2) formation, followed by the inhibition of TCA cycle enzymes and ATP depletion. Outcome effects: Peroxynitrite- and H2O2-induced DNA damage activates PARP1. This results in further drastic NAD and ATP depletion, which leads to energy collapse and necrosis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-36919278-217a-4d07-9889-65ab45d643ca Mitochondrial Damage Induced by Hypoxia uuid-36919278-217a-4d07-9889-65ab45d643ca PS:CellType generic PS:Description Cardiac hypoxia is the initial step in ischemia/reperfusion injury that ends in cardiomyocyte death by apoptosis or necrosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36919278-217a-4d07-9889-65ab45d643ca PS:NodeType Pathway PS:Notes Headnote: Cardiac hypoxia is the initial step in ischemia/reperfusion injury that results in cardiomyocyte death via apoptosis or necrosis. Signaling description: Oxygen deficiency triggers the transition of the cells to anaerobic metabolism, which results in lactic acidosis. The accumulation of hydrogen ions (H+) activates the Na+/H+ exchanger (SLC9A1), leading to Na+ and subsequent Ca2+ overload. In mitochondria, Ca2+ induces nitric oxide (NO) production and the opening of mitochondrial permeability transition pore (mPTP). This causes the burst of superoxide radical production, peroxynitrite and hydrogen peroxide (H2O2) formation, followed by the inhibition of TCA cycle enzymes and ATP depletion. Outcome effects: Peroxynitrite- and H2O2-induced DNA damage activates PARP1. This results in further drastic NAD and ATP depletion, which leads to energy collapse and necrosis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-369bbc08-40c9-4f38-8cff-a17fe6ec5226 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-369bbc08-40c9-4f38-8cff-a17fe6ec5226 INHBA/ACVR2/ACVR1 Expression Targets uuid-369bbc08-40c9-4f38-8cff-a17fe6ec5226 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-369bbc08-40c9-4f38-8cff-a17fe6ec5226 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36a8794d-650a-4001-a451-5229c0a4b1f8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-36a8794d-650a-4001-a451-5229c0a4b1f8 Riboflavin, FAD, FMN biosynthesis template uuid-36a8794d-650a-4001-a451-5229c0a4b1f8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36a8794d-650a-4001-a451-5229c0a4b1f8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36ac8e2d-a8cc-48e8-8ffc-f4a2cfcd2184 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-36ac8e2d-a8cc-48e8-8ffc-f4a2cfcd2184 LIF Expression Targets uuid-36ac8e2d-a8cc-48e8-8ffc-f4a2cfcd2184 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36ac8e2d-a8cc-48e8-8ffc-f4a2cfcd2184 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell CellType: macrophage Description: Endometriosis is an estrogen-dependent gynecological disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36b710fd-e000-4105-8f8b-9cc76c675185 NodeType: Pathway Notes: Headnote: Endometriosis is an estrogen-dependent gynecological disease characterized by endometrial-like tissue growing outside the uterine cavity, typically on the pelvic peritoneum, in the ovaries and in the rectovaginal septum. Endometriosis typically results in extensive pelvic adhesions and deformation of pelvic anatomy, often leading to pain and infertility. The incidence of endometriosis is estimated to be up to 10% in women of reproductive age. Signaling description: Endometriotic tissue proliferates in response to both systemic and locally produced estrogens. Endometriotic cells were shown to have their own estrogen production, which enhances the growth of the diseased tissue. Ectopic endometrium induces inflammation within the peritoneal cavity, which results in the release of cytokines. IL-1B and the VEGF produced by macrophages or endometriotic lesions induce COX-2 (PTGS2). PTGS2 catalyzes in macrophages and ectopic endometrial cells the formation of prostaglandin (PG) G2, which is further converted to PGE2. PGE2 increases estrogen synthesis by up-regulating steroidogenic acute regulatory protein (STAR), aromatase (CYP19A1) and other steroidogenic enzymes. In the endometrium of healthy women STAR and CYP19A1 are not expressed because NR5A1 is switched off and inhibitory factors (NR2F1/2, WT-1) are present. These inhibitory factors are down-regulated in endometriosis. Endometriosis is able to locally release hormones and pro-hormones from their sulfate conjugates (estrone from estrone sulfate, estradiol from estradiol sulfate and dehydroepiandrosterone from dehydroepiandrosterone sulfate) due to the presence of steroid sulfatase (STS) activity. Estrogen receptor beta (ESR2) was shown to be up-regulated in endometriosis and inhibits expression of estrogen receptor alpha (ESR1) and progesterone receptor (PGR). Outcome effects: PTGS2 induction increases local concentration of estradiol (E2), which further up-regulates PTGS2 and CYP19A1 and establishes a positive-feedback loop, as a vicious cycle in favor of continuous estrogen and PG formation. Normally E2 can be inactivated also by sulfate conjugation catalyzed by estrogen sulfotransferase (SULT1E1). SULT1E1 was shown to be down-regulated in endometriosis. Also E2 can be inactivated through conversion to estrone by oxidative HSD17B2 -activity, and via the formation of sulfate- or glucorine conjugates. In the healthy endometrium, the expression of HSD17B2 is highly increased in the secretory phase, due to its regulation by progesterone. Its aberrant expression, i.e. the lack of increase at the secretory phase, has been confirmed in endometriosis. The aberrant expression of HSD17B2 in endometriosis is assumed to be caused by an impaired action of progesterone in the endometriotic cells. Organ: uterus Organ_System: reproductive system PMID: 16123052 PMID: 18762229 PMID: 19524121 PMID: 20104427 PMID: 21875644 PMID: 22003899 PMID: 22271293 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-36b710fd-e000-4105-8f8b-9cc76c675185 Local Estrogen Production in Endometriosis uuid-36b710fd-e000-4105-8f8b-9cc76c675185 PS:CellType endometrium cell PS:CellType macrophage PS:Description Endometriosis is an estrogen-dependent gynecological disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36b710fd-e000-4105-8f8b-9cc76c675185 PS:NodeType Pathway PS:Notes Headnote: Endometriosis is an estrogen-dependent gynecological disease characterized by endometrial-like tissue growing outside the uterine cavity, typically on the pelvic peritoneum, in the ovaries and in the rectovaginal septum. Endometriosis typically results in extensive pelvic adhesions and deformation of pelvic anatomy, often leading to pain and infertility. The incidence of endometriosis is estimated to be up to 10% in women of reproductive age. Signaling description: Endometriotic tissue proliferates in response to both systemic and locally produced estrogens. Endometriotic cells were shown to have their own estrogen production, which enhances the growth of the diseased tissue. Ectopic endometrium induces inflammation within the peritoneal cavity, which results in the release of cytokines. IL-1B and the VEGF produced by macrophages or endometriotic lesions induce COX-2 (PTGS2). PTGS2 catalyzes in macrophages and ectopic endometrial cells the formation of prostaglandin (PG) G2, which is further converted to PGE2. PGE2 increases estrogen synthesis by up-regulating steroidogenic acute regulatory protein (STAR), aromatase (CYP19A1) and other steroidogenic enzymes. In the endometrium of healthy women STAR and CYP19A1 are not expressed because NR5A1 is switched off and inhibitory factors (NR2F1/2, WT-1) are present. These inhibitory factors are down-regulated in endometriosis. Endometriosis is able to locally release hormones and pro-hormones from their sulfate conjugates (estrone from estrone sulfate, estradiol from estradiol sulfate and dehydroepiandrosterone from dehydroepiandrosterone sulfate) due to the presence of steroid sulfatase (STS) activity. Estrogen receptor beta (ESR2) was shown to be up-regulated in endometriosis and inhibits expression of estrogen receptor alpha (ESR1) and progesterone receptor (PGR). Outcome effects: PTGS2 induction increases local concentration of estradiol (E2), which further up-regulates PTGS2 and CYP19A1 and establishes a positive-feedback loop, as a vicious cycle in favor of continuous estrogen and PG formation. Normally E2 can be inactivated also by sulfate conjugation catalyzed by estrogen sulfotransferase (SULT1E1). SULT1E1 was shown to be down-regulated in endometriosis. Also E2 can be inactivated through conversion to estrone by oxidative HSD17B2 -activity, and via the formation of sulfate- or glucorine conjugates. In the healthy endometrium, the expression of HSD17B2 is highly increased in the secretory phase, due to its regulation by progesterone. Its aberrant expression, i.e. the lack of increase at the secretory phase, has been confirmed in endometriosis. The aberrant expression of HSD17B2 in endometriosis is assumed to be caused by an impaired action of progesterone in the endometriotic cells. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 16123052 PS:PMID 18762229 PS:PMID 19524121 PS:PMID 20104427 PS:PMID 21875644 PS:PMID 22003899 PS:PMID 22271293 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Iron is necessary for microbial growth and the competition for iron between a host cell and microorganism is a critical issue during infectious processes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36c3f6bd-36a4-4e89-bc48-9199d05a3271 NodeType: Pathway Notes: Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Iron is necessary for microbial growth and the competition for iron between a host cell and microorganism is a critical issue during infectious processes. Signaling description: Macrophage iron uptake is accomplished through the action of TFRC and ITLN1 receptors via erythrophagocytosis and hemoglobin/haptoglobin capture by CD163. TFRC, ITLN1, and CD163-mediated endocytic process, together with erythrophagocytosis, brings iron or hemoglobin into the cytoplasm. Heme oxygenase (HMOX1) catalyzes heme degradation into equimolar amounts of iron, carbon monoxide, and biliverdin. STEAP4 functions as a metalloreductase that has the ability to reduce Fe3+ to Fe2+, using NAD as an acceptor. Macrophages accumulate iron in complexes with ferritin or release it via SLC40A1 on the plasma membrane. M1 macrophages are characterized by high levels of ferritin, which results in iron retention. This may lead to bacteriostatic effects, but also represents the cellular basis for anemia in chronic diseases. M2 macrophages are characterized by high levels of CD163, SLC40A1, and HMOX1 that support iron donation to the microenvironment. This may contribute to tissue repair by providing iron to proliferating parenchymal cells and to fibroblasts for collagen synthesis. Outcome effects: The levels of iron and iron-related metabolites in macrophages influence their function during activation. The activation of HMOX1 at the resolution phase of inflammation protects tissues from microbial-initiated inflammatory damage and switches macrophages from a proinflammatory state M1 to M2 macrophages. Carbon monoxide can inhibit LPS-induced production of IL1B, IL6, CSF2, TNF, and NO in macrophages and monocyte-derived dendritic cells, possibly by preventing CHUK degradation. Biliverdin exhibits anti-oxidant and anti-inflammatory activities. Iron loading of macrophages inhibits IFNG-mediated secretion of proinflammatory cytokines and reduces microbicidal action of macrophages. The inhibitory effect of iron on CEBPB and HIF1A, which mediate NOS2 inducibility by cytokines, further contributes to the diminished microbicidal activity of iron-loaded macrophages. Furthermore, since NO contributes to the inhibition of ferritin translation, iron further contributes to increased iron accumulation through a feedback loop. Lastly, iron regulatory proteins including ACO1 and IREB2 post-transcriptionally regulate mRNA modification of several iron genes. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-36c3f6bd-36a4-4e89-bc48-9199d05a3271 Macrophage Related Iron Uptake and Release uuid-36c3f6bd-36a4-4e89-bc48-9199d05a3271 PS:CellType macrophage PS:Description Iron is necessary for microbial growth and the competition for iron between a host cell and microorganism is a critical issue during infectious processes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36c3f6bd-36a4-4e89-bc48-9199d05a3271 PS:NodeType Pathway PS:Notes Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Iron is necessary for microbial growth and the competition for iron between a host cell and microorganism is a critical issue during infectious processes. Signaling description: Macrophage iron uptake is accomplished through the action of TFRC and ITLN1 receptors via erythrophagocytosis and hemoglobin/haptoglobin capture by CD163. TFRC, ITLN1, and CD163-mediated endocytic process, together with erythrophagocytosis, brings iron or hemoglobin into the cytoplasm. Heme oxygenase (HMOX1) catalyzes heme degradation into equimolar amounts of iron, carbon monoxide, and biliverdin. STEAP4 functions as a metalloreductase that has the ability to reduce Fe3+ to Fe2+, using NAD as an acceptor. Macrophages accumulate iron in complexes with ferritin or release it via SLC40A1 on the plasma membrane. M1 macrophages are characterized by high levels of ferritin, which results in iron retention. This may lead to bacteriostatic effects, but also represents the cellular basis for anemia in chronic diseases. M2 macrophages are characterized by high levels of CD163, SLC40A1, and HMOX1 that support iron donation to the microenvironment. This may contribute to tissue repair by providing iron to proliferating parenchymal cells and to fibroblasts for collagen synthesis. Outcome effects: The levels of iron and iron-related metabolites in macrophages influence their function during activation. The activation of HMOX1 at the resolution phase of inflammation protects tissues from microbial-initiated inflammatory damage and switches macrophages from a proinflammatory state M1 to M2 macrophages. Carbon monoxide can inhibit LPS-induced production of IL1B, IL6, CSF2, TNF, and NO in macrophages and monocyte-derived dendritic cells, possibly by preventing CHUK degradation. Biliverdin exhibits anti-oxidant and anti-inflammatory activities. Iron loading of macrophages inhibits IFNG-mediated secretion of proinflammatory cytokines and reduces microbicidal action of macrophages. The inhibitory effect of iron on CEBPB and HIF1A, which mediate NOS2 inducibility by cytokines, further contributes to the diminished microbicidal activity of iron-loaded macrophages. Furthermore, since NO contributes to the inhibition of ferritin translation, iron further contributes to increased iron accumulation through a feedback loop. Lastly, iron regulatory proteins including ACO1 and IREB2 post-transcriptionally regulate mRNA modification of several iron genes. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36c97d7a-dcdb-4c60-b8dd-1b8e452ccf4d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-36c97d7a-dcdb-4c60-b8dd-1b8e452ccf4d EGF -> NCOR2 Expression Target uuid-36c97d7a-dcdb-4c60-b8dd-1b8e452ccf4d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36c97d7a-dcdb-4c60-b8dd-1b8e452ccf4d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Source PS:Tissue CellType: endothelial cell CellType: neutrophil Description: Neutrophils in gout are attracted to the synovium and cause an inflammatory response. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36df596e-0ccb-409a-a037-5c4cf267b322 NodeType: Pathway Notes: Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. Neutrophils play an important role in gout. They are attracted to the synovium and induce an inflammatory response. Signaling description: Monocyte-derived cytokines including IL8, IL6, TNF, and IL1B promote endothelial cell activation. These cytokines bind to their receptors and through the NF-kB pathway lead to the protein synthesis which results in neutrophil recruitment. CXCL1 and CXCL2 cause neutrophil mobilization while VCAM1, ICAM1, and SELE are responsible for neutrophil adhesion on the endothelial cell surface. In addition, MSU may initiate complement activation by binding to the C5 component which also promotes neutrophil recruitment in the synovium. Outcome effects: Activated neutrophils produce inflammatory cytokines and promote ROS generation, and elastase on the cell which causes osteoclast retraction that opens access to bone resorption by osteoclasts (not shown). Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ_System: lymphatic system PMID: 23344781 PathwayType: signaling Source: Diseases Tissue: blood urn:agi-pathway:uuid-36df596e-0ccb-409a-a037-5c4cf267b322 Neutrophil Recruitment in Sinovium in Gout uuid-36df596e-0ccb-409a-a037-5c4cf267b322 PS:CellType endothelial cell PS:CellType neutrophil PS:Description Neutrophils in gout are attracted to the synovium and cause an inflammatory response. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-36df596e-0ccb-409a-a037-5c4cf267b322 PS:NodeType Pathway PS:Notes Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. Neutrophils play an important role in gout. They are attracted to the synovium and induce an inflammatory response. Signaling description: Monocyte-derived cytokines including IL8, IL6, TNF, and IL1B promote endothelial cell activation. These cytokines bind to their receptors and through the NF-kB pathway lead to the protein synthesis which results in neutrophil recruitment. CXCL1 and CXCL2 cause neutrophil mobilization while VCAM1, ICAM1, and SELE are responsible for neutrophil adhesion on the endothelial cell surface. In addition, MSU may initiate complement activation by binding to the C5 component which also promotes neutrophil recruitment in the synovium. Outcome effects: Activated neutrophils produce inflammatory cytokines and promote ROS generation, and elastase on the cell which causes osteoclast retraction that opens access to bone resorption by osteoclasts (not shown). Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ_System lymphatic system PS:PMID 23344781 PS:PathwayType signaling PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3704f930-fd61-4f66-8d45-9848d6b3c350 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-3704f930-fd61-4f66-8d45-9848d6b3c350 EPCAM signaling in CECs uuid-3704f930-fd61-4f66-8d45-9848d6b3c350 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3704f930-fd61-4f66-8d45-9848d6b3c350 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-370505a4-5f2a-4a39-94d7-09d0ca17d00e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-370505a4-5f2a-4a39-94d7-09d0ca17d00e ADRA1A -> IL6 Production uuid-370505a4-5f2a-4a39-94d7-09d0ca17d00e PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-370505a4-5f2a-4a39-94d7-09d0ca17d00e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3714d3f4-8b9c-46a0-9509-f6fbcab1e2b7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3714d3f4-8b9c-46a0-9509-f6fbcab1e2b7 FLT3LG -> AP-1/CREB/CREBBP Expression Targets uuid-3714d3f4-8b9c-46a0-9509-f6fbcab1e2b7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3714d3f4-8b9c-46a0-9509-f6fbcab1e2b7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage Description: Dectin-1 (CLEC7A) is a recognition receptor for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37349c45-7009-4fc4-9392-166325ba4057 NodeType: Pathway Notes: Headnote: Dectin-1 (CLEC7A) is a recognition receptor for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. Signaling description: CLEC7A recognizes 1,3-beta-glucan expressed by fungal pathogens and leads to the activation of NF-kB through both SYK-dependent and SYK-independent pathways. Outcome effects: The main result of the SYK-dependent pathway is the activation of calcineurin and promotion of the activation of NFATC2, leading to the expression of cytokines IL2, IL10, and COX2 (PTGS2). In the SYK-independent CLEC7A-related pathway, the activation of RAF1 or CARD9 leads to the phosphorylation and acetylation of NF-kB p65 subunit (RELA). The binding of acetylated p65 to the IL10 enhancer increases the transcription of the gene. Organ: generic Organ_System: generic PMID: 21803640 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-37349c45-7009-4fc4-9392-166325ba4057 Dectin-1 (CLEC7A) Signaling uuid-37349c45-7009-4fc4-9392-166325ba4057 PS:CellType dendritic cell PS:CellType macrophage PS:Description Dectin-1 (CLEC7A) is a recognition receptor for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37349c45-7009-4fc4-9392-166325ba4057 PS:NodeType Pathway PS:Notes Headnote: Dectin-1 (CLEC7A) is a recognition receptor for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. Signaling description: CLEC7A recognizes 1,3-beta-glucan expressed by fungal pathogens and leads to the activation of NF-kB through both SYK-dependent and SYK-independent pathways. Outcome effects: The main result of the SYK-dependent pathway is the activation of calcineurin and promotion of the activation of NFATC2, leading to the expression of cytokines IL2, IL10, and COX2 (PTGS2). In the SYK-independent CLEC7A-related pathway, the activation of RAF1 or CARD9 leads to the phosphorylation and acetylation of NF-kB p65 subunit (RELA). The binding of acetylated p65 to the IL10 enhancer increases the transcription of the gene. PS:Organ generic PS:Organ_System generic PS:PMID 21803640 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3782e165-ce0d-4066-a9d5-f6141c293ce0 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3782e165-ce0d-4066-a9d5-f6141c293ce0 IAA biosynthesis template uuid-3782e165-ce0d-4066-a9d5-f6141c293ce0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3782e165-ce0d-4066-a9d5-f6141c293ce0 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3790262f-e8cd-4c56-950f-4fe2f574bdc4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3790262f-e8cd-4c56-950f-4fe2f574bdc4 IL8 Expression Targets uuid-3790262f-e8cd-4c56-950f-4fe2f574bdc4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3790262f-e8cd-4c56-950f-4fe2f574bdc4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuroglia Description: Microglia is a type of glial cell that acts as the first and main form of active immune defense in the central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3795aa88-befc-4721-bde5-df14ab8bd9a3 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). In AD, the newly formed Abeta plaques are thought to activate and recruit microglia, the glial cells which act as the first and main form of active immune defense in the central nervous system. Signaling description: Extracellular oligomers of Abeta activate microglia preferably through the Toll-like receptor (TLR4). The presence of CD14 and LY96 next to TLR4 on the cell surface is important for signal transduction. Abeta oligomers bind to TLR4 which interacts with MYD88. The signal is transduced to IRAK4 and then to IRAK1. Following activation by IRAK1, TRAF6 affects MAP3K7 which phosphorylates IKBK and provokes NF-kB release from its inhibitor, NFKBIA. Outcome effects: Free NF-kB promotes the expression of TNF, IL6, IL1, and PTGS2 genes. All of these proteins provoke inflammation in the brain, as well as the pathology progression. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 10858586 PMID: 20234358 PMID: 20303880 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-3795aa88-befc-4721-bde5-df14ab8bd9a3 Microglia Activation in Alzheimer's Disease uuid-3795aa88-befc-4721-bde5-df14ab8bd9a3 PS:CellType neuroglia PS:Description Microglia is a type of glial cell that acts as the first and main form of active immune defense in the central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3795aa88-befc-4721-bde5-df14ab8bd9a3 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). In AD, the newly formed Abeta plaques are thought to activate and recruit microglia, the glial cells which act as the first and main form of active immune defense in the central nervous system. Signaling description: Extracellular oligomers of Abeta activate microglia preferably through the Toll-like receptor (TLR4). The presence of CD14 and LY96 next to TLR4 on the cell surface is important for signal transduction. Abeta oligomers bind to TLR4 which interacts with MYD88. The signal is transduced to IRAK4 and then to IRAK1. Following activation by IRAK1, TRAF6 affects MAP3K7 which phosphorylates IKBK and provokes NF-kB release from its inhibitor, NFKBIA. Outcome effects: Free NF-kB promotes the expression of TNF, IL6, IL1, and PTGS2 genes. All of these proteins provoke inflammation in the brain, as well as the pathology progression. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 10858586 PS:PMID 20234358 PS:PMID 20303880 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Intermediate filaments, which are long molecules composed of many monomers, are a diverse group of cytoskeletal proteins that enable animal cells to withstand mechanical stress. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37a69415-d202-44b0-b226-8ccf517b246c NodeType: Pathway Notes: Headnote: Intermediate filaments, which are long molecules composed of many monomers, are a diverse group of cytoskeletal proteins that enable animal cells to withstand mechanical stress. Signaling description: There are five different types of intermediate filaments including Types I and II which contain acidic keratin and basic keratin and Type III which contains vimentin (VIM), desmin (DES), glial fibrillary acidic protein (GFAP), and peripherin (PRPH). Type IV contains neurofilament H (heavy), M (medium) and L (low) while Type V contains lamins which support inside the inner nuclear membrane. Two monomers twist around one another to form a dimer and two dimers align laterally to form a tetrameric protofilament. The protofilaments then associate in a staggered fashion to form a long protofilament. Outcome effects: Lastly, the protofilaments are arranged in parallel to form the intermediate filament. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-37a69415-d202-44b0-b226-8ccf517b246c Intermediate Filament Polymerization uuid-37a69415-d202-44b0-b226-8ccf517b246c PS:CellType generic PS:Description Intermediate filaments, which are long molecules composed of many monomers, are a diverse group of cytoskeletal proteins that enable animal cells to withstand mechanical stress. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37a69415-d202-44b0-b226-8ccf517b246c PS:NodeType Pathway PS:Notes Headnote: Intermediate filaments, which are long molecules composed of many monomers, are a diverse group of cytoskeletal proteins that enable animal cells to withstand mechanical stress. Signaling description: There are five different types of intermediate filaments including Types I and II which contain acidic keratin and basic keratin and Type III which contains vimentin (VIM), desmin (DES), glial fibrillary acidic protein (GFAP), and peripherin (PRPH). Type IV contains neurofilament H (heavy), M (medium) and L (low) while Type V contains lamins which support inside the inner nuclear membrane. Two monomers twist around one another to form a dimer and two dimers align laterally to form a tetrameric protofilament. The protofilaments then associate in a staggered fashion to form a long protofilament. Outcome effects: Lastly, the protofilaments are arranged in parallel to form the intermediate filament. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37b24169-aaca-412a-9c6a-f9c22216e25a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-37b24169-aaca-412a-9c6a-f9c22216e25a TCR -> STAT Expression Targets uuid-37b24169-aaca-412a-9c6a-f9c22216e25a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37b24169-aaca-412a-9c6a-f9c22216e25a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37b97729-5de8-4188-ae51-3d0e85430f7a NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-37b97729-5de8-4188-ae51-3d0e85430f7a TLR3 -> NF-kB Signaling uuid-37b97729-5de8-4188-ae51-3d0e85430f7a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37b97729-5de8-4188-ae51-3d0e85430f7a PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37e4c35b-3d5c-4e1e-8e15-35eeb2abac27 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-37e4c35b-3d5c-4e1e-8e15-35eeb2abac27 Similar immunological disorders - Proteins uuid-37e4c35b-3d5c-4e1e-8e15-35eeb2abac27 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37e4c35b-3d5c-4e1e-8e15-35eeb2abac27 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37feb42d-4713-4655-adc6-50d6d8c0eb9b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-37feb42d-4713-4655-adc6-50d6d8c0eb9b PDCD1 -> STAT Expression Targets uuid-37feb42d-4713-4655-adc6-50d6d8c0eb9b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-37feb42d-4713-4655-adc6-50d6d8c0eb9b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH that controls Ca2 and Pi metabolism through its effects on kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-380be76d-f3b0-45b6-978c-18d41f6e66f0 NodeType: Pathway Notes: Headnote: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of parathormone. PTH controls calcium and phosphorus metabolism through its effects on kidney. Signaling description: Hypersecretion of PTH is associated with hypercalcemia and hypophosphatemia. Precise mechanisms of the molecular signalings of these processes in kidney are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. CREB1 promotes VDR, which regulates expression of TRPV5/6 and SLC34A1/A2, involved in calcium and phosphorus reabsorption in kidney. Highlighted proteins: PTH with red highlight has increased expression. Pi with blue highlights has reduced level and Ca2+ with red highlight has increased level in blood serum. Organ: kidney Organ_System: urinary tract PMID: 23652552 PMID: 24985952 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-380be76d-f3b0-45b6-978c-18d41f6e66f0 Ca2+/Pi Reabsorption Decline in Kidney in Hyperparathyroidism uuid-380be76d-f3b0-45b6-978c-18d41f6e66f0 PS:CellType epithelial cell PS:Description Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH that controls Ca2 and Pi metabolism through its effects on kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-380be76d-f3b0-45b6-978c-18d41f6e66f0 PS:NodeType Pathway PS:Notes Headnote: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of parathormone. PTH controls calcium and phosphorus metabolism through its effects on kidney. Signaling description: Hypersecretion of PTH is associated with hypercalcemia and hypophosphatemia. Precise mechanisms of the molecular signalings of these processes in kidney are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. CREB1 promotes VDR, which regulates expression of TRPV5/6 and SLC34A1/A2, involved in calcium and phosphorus reabsorption in kidney. Highlighted proteins: PTH with red highlight has increased expression. Pi with blue highlights has reduced level and Ca2+ with red highlight has increased level in blood serum. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 23652552 PS:PMID 24985952 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-382461c2-ec93-4781-bf4c-74037c21ebaf NodeType: Pathway Notes: Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: The most profound sign of EC activation is the increase in nitric oxide (NO) release. NO production from ECs is stimulated by a variety of mechanical forces such as shear stress or vessel injury and soluble mediators including acetylcholine, VEGFA, bradykinin, sphingosine-1-P, H2O2, and AGT. These factors or vessel damage stimulate ECs to secrete mostly procoagulant or antifibrinolytic components such as VWF, TXA2, or SERPINE1 into the local environment, while the expression or secretion of components with anticoagulant and profibrinolytic properties is significantly reduced. In contrast to the specific activation of membrane receptors by soluble mediators, mechanical forces such as shear stress simultaneously activate many membrane proteins including receptors and mechanosensitive ion channels, via conformational changes or clustering, leading to the initiation of signal transduction. Outcome effects: However, the downstream signaling events remain to be elucidated. NOS3 is the primary enzyme in NO synthesis in epithelial cells. NOS3 is a peripheral membrane protein that is targeted to endothelial plasmalemmal caveolae through an interaction with CAV1. HSP90AA1 binds to NOS3 and facilitates the displacement of CAV1 by calmodulin. In addition to these protein interactions that modulate calmodulin binding, other cellular signaling cascades also regulate NOS3 activity. NO is the key endothelium-derived relaxing factor that plays a pivotal role in the regulation of vascular tone and vasomotor function. In addition to its vasodilatory effect, NO inhibits leukocyte adhesion to the endothelium, maintains vascular smooth muscle in a nonproliferative state, and limits platelet aggregation. The released NO targets cysteine groups in key regulator molecules such as NF-kB. NF-kB provides the expression of factors that promote thrombocyte activation and inhibit synthesis of coagulation factors in epithelial cells. Reactive oxygen species (ROS) also activate NF-kB. When ROS signaling predominates, it leads to the activation of ECs. Finally, the activation of NOS3 and increased synthesis of NO in epithelial cells cause vasodilation and activation of microcirculation at the site of injury. Nitrogen stimulates the secretion of inflammatory mediators such as histamine, which in turn increase vascular permeability and formation of edema at the injury location. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-382461c2-ec93-4781-bf4c-74037c21ebaf Vascular Endothelial Cell Activation by NO uuid-382461c2-ec93-4781-bf4c-74037c21ebaf PS:CellType endothelial cell PS:Description Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-382461c2-ec93-4781-bf4c-74037c21ebaf PS:NodeType Pathway PS:Notes Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: The most profound sign of EC activation is the increase in nitric oxide (NO) release. NO production from ECs is stimulated by a variety of mechanical forces such as shear stress or vessel injury and soluble mediators including acetylcholine, VEGFA, bradykinin, sphingosine-1-P, H2O2, and AGT. These factors or vessel damage stimulate ECs to secrete mostly procoagulant or antifibrinolytic components such as VWF, TXA2, or SERPINE1 into the local environment, while the expression or secretion of components with anticoagulant and profibrinolytic properties is significantly reduced. In contrast to the specific activation of membrane receptors by soluble mediators, mechanical forces such as shear stress simultaneously activate many membrane proteins including receptors and mechanosensitive ion channels, via conformational changes or clustering, leading to the initiation of signal transduction. Outcome effects: However, the downstream signaling events remain to be elucidated. NOS3 is the primary enzyme in NO synthesis in epithelial cells. NOS3 is a peripheral membrane protein that is targeted to endothelial plasmalemmal caveolae through an interaction with CAV1. HSP90AA1 binds to NOS3 and facilitates the displacement of CAV1 by calmodulin. In addition to these protein interactions that modulate calmodulin binding, other cellular signaling cascades also regulate NOS3 activity. NO is the key endothelium-derived relaxing factor that plays a pivotal role in the regulation of vascular tone and vasomotor function. In addition to its vasodilatory effect, NO inhibits leukocyte adhesion to the endothelium, maintains vascular smooth muscle in a nonproliferative state, and limits platelet aggregation. The released NO targets cysteine groups in key regulator molecules such as NF-kB. NF-kB provides the expression of factors that promote thrombocyte activation and inhibit synthesis of coagulation factors in epithelial cells. Reactive oxygen species (ROS) also activate NF-kB. When ROS signaling predominates, it leads to the activation of ECs. Finally, the activation of NOS3 and increased synthesis of NO in epithelial cells cause vasodilation and activation of microcirculation at the site of injury. Nitrogen stimulates the secretion of inflammatory mediators such as histamine, which in turn increase vascular permeability and formation of edema at the injury location. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38329c1d-d69a-4825-8883-dc8168e0bb28 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-38329c1d-d69a-4825-8883-dc8168e0bb28 Riboflavin Metabolism uuid-38329c1d-d69a-4825-8883-dc8168e0bb28 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38329c1d-d69a-4825-8883-dc8168e0bb28 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38602436-e66c-4f9b-9eb8-3677e248f1d8 NodeType: Pathway Notes: Resting memory CD4+ T cells and other cells with extended half-lives and cells resistant to viral-induced apoptosis maintain stores of provirus particles and host the production of virions episodically (blips) during the chronic phase of viral infection. Pathway 3. HIV latency and evasion of reservoir cell apoptosis in HIV chronic phase: Postintegration latency (Fig. 4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-38602436-e66c-4f9b-9eb8-3677e248f1d8 3_2_HIV postintegration latency uuid-38602436-e66c-4f9b-9eb8-3677e248f1d8 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38602436-e66c-4f9b-9eb8-3677e248f1d8 PS:NodeType Pathway PS:Notes Resting memory CD4+ T cells and other cells with extended half-lives and cells resistant to viral-induced apoptosis maintain stores of provirus particles and host the production of virions episodically (blips) during the chronic phase of viral infection. Pathway 3. HIV latency and evasion of reservoir cell apoptosis in HIV chronic phase: Postintegration latency (Fig. 4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38803590-b792-412f-80ce-601e9e9da999 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: nervous system PMID: 20602998 PMID: 22159035 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-38803590-b792-412f-80ce-601e9e9da999 LINE1 Retrotransposition in Neuron Development (Hypothesis) uuid-38803590-b792-412f-80ce-601e9e9da999 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38803590-b792-412f-80ce-601e9e9da999 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System nervous system PS:PMID 20602998 PS:PMID 22159035 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: Research in systemic scleroderma (SSc) centers on what enables SSc fibroblasts to remain persistently activated in the absence of exogenous stimuli. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38902d82-a31a-483b-be4a-77cc39ab920f NodeType: Pathway Notes: Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Signaling description: IL1A and IL1B are constitutively expressed in SSc fibroblasts. PDGF can induce IL1 in dermal fibroblasts from SSc patients, but not in normal fibroblasts. In turn, IL1 can induce PDGFA mRNA expression and PDGF-AA secretion in normal skin fibroblasts while endogenous IL1A is responsible for higher steady-state PDGFA mRNA levels in SSc compared to normal fibroblasts. In addition, IL1B upregulates PDGFRA and signaling through PDGFR is amplified in SSc fibroblasts. In addition to the direct effects on IL1 and IL1R1 expression, PDGF also increases CCL2 transcription and synthesis. CCL2 can also induce the production of TGFB1. Subsequently, TGFB1 selectively increases the expression of PDGFRA in SSc but not in normal fibroblasts while PDGF induces TGFBR1 and TGFBR2 transcripts enhancing only TGFBR1 surface expression on normal dermal fibroblasts. Outcome effects: SSc fibroblasts remain persistently activated in the absence of exogenous stimuli due to the constitutive production of endogenous cytokines such as IL1, TGFB1, PDGF, and CCL2 in addition to the upregulation of their receptors. This allows the development of several autocrine cytokine/chemokine loops in SSc fibroblasts that are only partially present in normal fibroblasts. The enhanced expression of TGFBR1 plays a central role in autocrine TGFB1 stimulation that augments SSc fibroblast collagen synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 18221988 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-38902d82-a31a-483b-be4a-77cc39ab920f Autocrine Cytokine/Chemokine Loops in Systemic Scleroderma uuid-38902d82-a31a-483b-be4a-77cc39ab920f PS:CellType fibroblast PS:Description Research in systemic scleroderma (SSc) centers on what enables SSc fibroblasts to remain persistently activated in the absence of exogenous stimuli. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38902d82-a31a-483b-be4a-77cc39ab920f PS:NodeType Pathway PS:Notes Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Signaling description: IL1A and IL1B are constitutively expressed in SSc fibroblasts. PDGF can induce IL1 in dermal fibroblasts from SSc patients, but not in normal fibroblasts. In turn, IL1 can induce PDGFA mRNA expression and PDGF-AA secretion in normal skin fibroblasts while endogenous IL1A is responsible for higher steady-state PDGFA mRNA levels in SSc compared to normal fibroblasts. In addition, IL1B upregulates PDGFRA and signaling through PDGFR is amplified in SSc fibroblasts. In addition to the direct effects on IL1 and IL1R1 expression, PDGF also increases CCL2 transcription and synthesis. CCL2 can also induce the production of TGFB1. Subsequently, TGFB1 selectively increases the expression of PDGFRA in SSc but not in normal fibroblasts while PDGF induces TGFBR1 and TGFBR2 transcripts enhancing only TGFBR1 surface expression on normal dermal fibroblasts. Outcome effects: SSc fibroblasts remain persistently activated in the absence of exogenous stimuli due to the constitutive production of endogenous cytokines such as IL1, TGFB1, PDGF, and CCL2 in addition to the upregulation of their receptors. This allows the development of several autocrine cytokine/chemokine loops in SSc fibroblasts that are only partially present in normal fibroblasts. The enhanced expression of TGFBR1 plays a central role in autocrine TGFB1 stimulation that augments SSc fibroblast collagen synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18221988 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3892ca7d-44a8-4719-9fe3-7478756383ba NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-3892ca7d-44a8-4719-9fe3-7478756383ba Genes with Mutations Associated with Melanoma uuid-3892ca7d-44a8-4719-9fe3-7478756383ba PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3892ca7d-44a8-4719-9fe3-7478756383ba PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-389ec8d3-4eb7-40a0-8f25-03e657cbc999 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-389ec8d3-4eb7-40a0-8f25-03e657cbc999 SST Expression Targets uuid-389ec8d3-4eb7-40a0-8f25-03e657cbc999 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-389ec8d3-4eb7-40a0-8f25-03e657cbc999 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38bc4ff5-06c9-4d7d-bad6-7c6d3b2d9892 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-38bc4ff5-06c9-4d7d-bad6-7c6d3b2d9892 Proteins Involved in Androgenetic Alopecia uuid-38bc4ff5-06c9-4d7d-bad6-7c6d3b2d9892 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38bc4ff5-06c9-4d7d-bad6-7c6d3b2d9892 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38cb4f42-4998-411a-ad66-297be00593b3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-38cb4f42-4998-411a-ad66-297be00593b3 S1P Expression Targets uuid-38cb4f42-4998-411a-ad66-297be00593b3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38cb4f42-4998-411a-ad66-297be00593b3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38cb7c48-6124-4849-b061-69695a56d73c NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-38cb7c48-6124-4849-b061-69695a56d73c Wilson's Disease Mutated Genes uuid-38cb7c48-6124-4849-b061-69695a56d73c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-38cb7c48-6124-4849-b061-69695a56d73c PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: It is generally accepted that phosphatidylinositol (3,4,5)-triphosphate (PIP3) binds to and activates serine/threonine kinase Akt. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39058384-034a-4138-9761-83c4407bbaed NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: It is generally accepted that phosphatidylinositol (3,4,5)-triphosphate (PIP3) binds to and activates serine/threonine kinase Akt also known as protein kinase B (AKT1), whereas tumor suppressor PTEN phosphatase dephosphorylates PIP3 (to phosphatidylinositol (4,5)-diphosphate, PIP2), thus decreasing activity of the AKT1 pathway. AKT1 can also be activated by phosphatidylinositol (3,4)-bisphosphate (PtdIns 3,4-P2), that in turn is dephosphorylated by PTEN. Another phosphatase dephosphorylating PtdIns 3,4-P2 is INPP4B (inositol polyphosphate-4-phosphatase), which is considered a tumor suppressor in epithelial carcinomas. It has been shown that androgen receptor (AR) induces the expression of INPP4B in prostate cancer cells, thus negatively regulating the AKT1 pathway. However, INPP4B depletion activates AKT1 and increases cellular proliferation. Outcome effects: Activated AKT1 promotes several anti-apoptotic pathways. AKT1 phosphorylates and activates cAMP responsive element binding protein 1 (CREB1), a mechanistic target of rapamycin (serine/threonine kinase (MTOR)) and inhibits tumor protein p53 (TP53). CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). Beta-catenin then translocates into the nucleus where it interacts with T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3) and mitogen-activated protein kinase kinase kinase 5 (MAP3K5, also referred to as ASK1), mediated by JNK -cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome C from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. Organ: prostate Organ_System: urinary tract PMID: 19275762 PMID: 21487159 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-39058384-034a-4138-9761-83c4407bbaed Androgen Receptor/Akt Signaling uuid-39058384-034a-4138-9761-83c4407bbaed PS:CellType cancer cell PS:Description It is generally accepted that phosphatidylinositol (3,4,5)-triphosphate (PIP3) binds to and activates serine/threonine kinase Akt. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39058384-034a-4138-9761-83c4407bbaed PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: It is generally accepted that phosphatidylinositol (3,4,5)-triphosphate (PIP3) binds to and activates serine/threonine kinase Akt also known as protein kinase B (AKT1), whereas tumor suppressor PTEN phosphatase dephosphorylates PIP3 (to phosphatidylinositol (4,5)-diphosphate, PIP2), thus decreasing activity of the AKT1 pathway. AKT1 can also be activated by phosphatidylinositol (3,4)-bisphosphate (PtdIns 3,4-P2), that in turn is dephosphorylated by PTEN. Another phosphatase dephosphorylating PtdIns 3,4-P2 is INPP4B (inositol polyphosphate-4-phosphatase), which is considered a tumor suppressor in epithelial carcinomas. It has been shown that androgen receptor (AR) induces the expression of INPP4B in prostate cancer cells, thus negatively regulating the AKT1 pathway. However, INPP4B depletion activates AKT1 and increases cellular proliferation. Outcome effects: Activated AKT1 promotes several anti-apoptotic pathways. AKT1 phosphorylates and activates cAMP responsive element binding protein 1 (CREB1), a mechanistic target of rapamycin (serine/threonine kinase (MTOR)) and inhibits tumor protein p53 (TP53). CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). Beta-catenin then translocates into the nucleus where it interacts with T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3) and mitogen-activated protein kinase kinase kinase 5 (MAP3K5, also referred to as ASK1), mediated by JNK -cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome C from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 19275762 PS:PMID 21487159 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3917feba-9a32-4110-a753-f114df7e2c07 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3917feba-9a32-4110-a753-f114df7e2c07 N-Glycan biosynthesis template uuid-3917feba-9a32-4110-a753-f114df7e2c07 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3917feba-9a32-4110-a753-f114df7e2c07 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The proximal tubule is responsible for approximately 80? of bicarbonate ion (HCO3-) reabsorption in the kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-392563b2-f137-426c-a142-6d721688af10 NodeType: Pathway Notes: Headnote: The proximal tubule is responsible for approximately 80% of bicarbonate ion (HCO3-) reabsorption in the kidney. Signaling description: The thick ascending limb of the loop of Henle, distal convoluted tubule, and cortical collecting duct are responsible for reabsorption of 10%, 6%, and 4% of HCO3-, respectively. In the tubular lumen, filtered HCO3- combines with H in a reaction catalyzed by CA4. The carbon dioxide (CO2) produced rapidly diffuses into the tubular cells and is combined with water (H2O) to produce intracellular H and HCO3-, which is catalyzed by soluble cytoplasmic CA2. Outcome effects: HCO3- is then co-transported with Na into the blood via SLC4A4. The intracellular H produced by CA2 is secreted into the tubular lumen primarily via SLC9A3. Basolaterally expressed CA4 and possibly CA12 facilitate reabsorption by dissipating bicarbonate at the basolateral surface. Organ: kidney Organ_System: urinary tract PMID: 17164835 PMID: 19948674 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-392563b2-f137-426c-a142-6d721688af10 Renal Proximal Tubule Acid-Base Homeostasis uuid-392563b2-f137-426c-a142-6d721688af10 PS:Description The proximal tubule is responsible for approximately 80? of bicarbonate ion (HCO3-) reabsorption in the kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-392563b2-f137-426c-a142-6d721688af10 PS:NodeType Pathway PS:Notes Headnote: The proximal tubule is responsible for approximately 80% of bicarbonate ion (HCO3-) reabsorption in the kidney. Signaling description: The thick ascending limb of the loop of Henle, distal convoluted tubule, and cortical collecting duct are responsible for reabsorption of 10%, 6%, and 4% of HCO3-, respectively. In the tubular lumen, filtered HCO3- combines with H in a reaction catalyzed by CA4. The carbon dioxide (CO2) produced rapidly diffuses into the tubular cells and is combined with water (H2O) to produce intracellular H and HCO3-, which is catalyzed by soluble cytoplasmic CA2. Outcome effects: HCO3- is then co-transported with Na into the blood via SLC4A4. The intracellular H produced by CA2 is secreted into the tubular lumen primarily via SLC9A3. Basolaterally expressed CA4 and possibly CA12 facilitate reabsorption by dissipating bicarbonate at the basolateral surface. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 17164835 PS:PMID 19948674 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-394b139c-3838-49c0-8669-c8abe999e446 NodeType: Pathway Notes: Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends of stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. Signaling description: A group of inhibitory receptors called killer-cell immunoglobulin-like receptors (KIRs) belong to the immunoglobulin superfamily (IgSF) proteins with either two (KIR2D) or three (KIR3D) extracellular immunoglobulin domains. NK cell inhibitory receptors via their PTPN11 and PTPN6 cytoplasmic adaptors block intracellular signaling, which is necessary for NK cell function. VAV signaling and actin remodeling are also blocked through dephosphorylation by PTPN11 and PTPN6. Outcome effects: If the activity of inhibitory receptors in NK cells is higher than the activity of stimulatory receptors, the production of cytotoxic perforins (PRF1), granzymes, and cytokines is diminished. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-394b139c-3838-49c0-8669-c8abe999e446 Natural Killer Cell Inhibitory Receptor Signaling uuid-394b139c-3838-49c0-8669-c8abe999e446 PS:CellType natural killer cell PS:Description Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-394b139c-3838-49c0-8669-c8abe999e446 PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends of stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. Signaling description: A group of inhibitory receptors called killer-cell immunoglobulin-like receptors (KIRs) belong to the immunoglobulin superfamily (IgSF) proteins with either two (KIR2D) or three (KIR3D) extracellular immunoglobulin domains. NK cell inhibitory receptors via their PTPN11 and PTPN6 cytoplasmic adaptors block intracellular signaling, which is necessary for NK cell function. VAV signaling and actin remodeling are also blocked through dephosphorylation by PTPN11 and PTPN6. Outcome effects: If the activity of inhibitory receptors in NK cells is higher than the activity of stimulatory receptors, the production of cytotoxic perforins (PRF1), granzymes, and cytokines is diminished. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3956c916-8806-484b-a512-d7e53fd92cbc NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3956c916-8806-484b-a512-d7e53fd92cbc Biosynthesis of flavonoids and anthocyanins template uuid-3956c916-8806-484b-a512-d7e53fd92cbc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3956c916-8806-484b-a512-d7e53fd92cbc PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-396adb16-a9a7-4233-9051-201879ebdfbb NodeType: Pathway Organ: generic Organ_System: generic PMID: 23328704 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-396adb16-a9a7-4233-9051-201879ebdfbb WNT/Calcium non-Canonical Signaling uuid-396adb16-a9a7-4233-9051-201879ebdfbb PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-396adb16-a9a7-4233-9051-201879ebdfbb PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 23328704 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-397c0af0-b8b2-4641-87a9-c8bd7f62ab79 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-397c0af0-b8b2-4641-87a9-c8bd7f62ab79 Ascorbate biosynthesis template uuid-397c0af0-b8b2-4641-87a9-c8bd7f62ab79 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-397c0af0-b8b2-4641-87a9-c8bd7f62ab79 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39acb1d8-e3ac-48ec-b91c-609bcab9c71b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-39acb1d8-e3ac-48ec-b91c-609bcab9c71b S protein interactions uuid-39acb1d8-e3ac-48ec-b91c-609bcab9c71b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39acb1d8-e3ac-48ec-b91c-609bcab9c71b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39b30d42-aa92-4a15-a434-b0d9f7c0d30f NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-39b30d42-aa92-4a15-a434-b0d9f7c0d30f Proteins Involved in Werner Syndrome (Adult Progeria) uuid-39b30d42-aa92-4a15-a434-b0d9f7c0d30f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39b30d42-aa92-4a15-a434-b0d9f7c0d30f PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Among the components of biological systems, proteins are the most susceptible to oxidative and nitrosative stress. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39d295b9-a7d2-485d-ac18-8714a7859ba0 NodeType: Pathway Notes: Headnote: Among other biomolecules, proteins are the most susceptible to oxidative and nitrosative stress. Signaling description: An exposure to various free radicals and non-radical oxygen and nitrogen derivatives leads to the modification of amino acid residue side chains, formation of protein-protein cross-links, and oxidation of the protein backbone, which result in protein fragmentation. Protein amino acid residue side chains are oxidized by the hydroxyl radical, which can be produced by Fenton's reagent (H2O2 in the presence of Fe2+ or Cu+). The nitrosative action of non-radical peroxynitrite is mediated by the formation of bicarbonate (CO3-) and nitrogen dioxide (NO2) free radicals in the presence of carbon dioxide (CO2). Free radical-induced protein amino acid side chain modifications are as markers of protein damage induced by oxidative/nitrosative stress. Outcome effects: The accumulation of oxidized proteins indicates a mismatch between ROS and RNS generation/scavenging and damaged protein utilization capacity. This mismatch is characteristic of a wide range of diseases associated with oxidative and nitrosative stress including atherosclerosis, diabetic complications, various cardiovascular disorders, inflammation and senescence related diseases, as well as neuropathies such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-39d295b9-a7d2-485d-ac18-8714a7859ba0 Protein Oxidation and Nitration Products as Disease Biomarkers uuid-39d295b9-a7d2-485d-ac18-8714a7859ba0 PS:CellType generic PS:Description Among the components of biological systems, proteins are the most susceptible to oxidative and nitrosative stress. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39d295b9-a7d2-485d-ac18-8714a7859ba0 PS:NodeType Pathway PS:Notes Headnote: Among other biomolecules, proteins are the most susceptible to oxidative and nitrosative stress. Signaling description: An exposure to various free radicals and non-radical oxygen and nitrogen derivatives leads to the modification of amino acid residue side chains, formation of protein-protein cross-links, and oxidation of the protein backbone, which result in protein fragmentation. Protein amino acid residue side chains are oxidized by the hydroxyl radical, which can be produced by Fenton's reagent (H2O2 in the presence of Fe2+ or Cu+). The nitrosative action of non-radical peroxynitrite is mediated by the formation of bicarbonate (CO3-) and nitrogen dioxide (NO2) free radicals in the presence of carbon dioxide (CO2). Free radical-induced protein amino acid side chain modifications are as markers of protein damage induced by oxidative/nitrosative stress. Outcome effects: The accumulation of oxidized proteins indicates a mismatch between ROS and RNS generation/scavenging and damaged protein utilization capacity. This mismatch is characteristic of a wide range of diseases associated with oxidative and nitrosative stress including atherosclerosis, diabetic complications, various cardiovascular disorders, inflammation and senescence related diseases, as well as neuropathies such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39ecf8f8-bdaa-457a-bf28-e9aa71b3d158 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-39ecf8f8-bdaa-457a-bf28-e9aa71b3d158 SMN1->mRNA transport uuid-39ecf8f8-bdaa-457a-bf28-e9aa71b3d158 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-39ecf8f8-bdaa-457a-bf28-e9aa71b3d158 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a04e054-4b4a-4ef4-b597-24fdd51aa146 NodeType: Pathway Notes: Thrombopoietin (TPO) regulates of megakaryocyte and platelet production. The receptor for thrombopoietin (TPOR; also known as MPL) associates with Janus kinases and initiates downstream STAT signaling. Organ: generic Organ_System: generic PMID: 28408900 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-3a04e054-4b4a-4ef4-b597-24fdd51aa146 Thrombopoietin Receptors Signaling in Platelet Maturation uuid-3a04e054-4b4a-4ef4-b597-24fdd51aa146 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a04e054-4b4a-4ef4-b597-24fdd51aa146 PS:NodeType Pathway PS:Notes Thrombopoietin (TPO) regulates of megakaryocyte and platelet production. The receptor for thrombopoietin (TPOR; also known as MPL) associates with Janus kinases and initiates downstream STAT signaling. PS:Organ generic PS:Organ_System generic PS:PMID 28408900 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a1c879a-2230-4806-aacb-160d77d949de NodeType: Pathway Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-3a1c879a-2230-4806-aacb-160d77d949de Proteins Involved in Breast Cancer Related to IGF1R/Akt Signaling Pathway uuid-3a1c879a-2230-4806-aacb-160d77d949de PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a1c879a-2230-4806-aacb-160d77d949de PS:NodeType Pathway PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Congenital Generalized Lipodystrophy (CGL) is a group of rare insulin resistance syndromes characterized by a generalized lipodystrophy and acromegaloid features. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a547e74-b468-44dc-988f-c0bc0b54802f NodeType: Pathway Notes: Headnote: Congenital generalized lipodystrophy type 2 (CGL2, also known as Berardinelli-Seip syndrome) is a rare autosomal recessive condition. CGL2 belongs to a group of extreme insulin resistance syndromes characterized by generalized lipodystrophy, hepatomegaly, acromegaloid features, severe low levels of leptin and adiponectin, and hypertriglyceridemia from birth or early infancy. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, abnormal accumulation of fat in internal organs, hirsutism, mental retardation, bone cysts with spontaneous fractures, and precocious puberty. Signaling description: Different forms of congenital generalized lipodystrophy may be caused by the disruption of different pathways. CGL type1 is caused by a mutation in the AGPAT2 gene, encoding a key enzyme in triglyceride biosynthesis (1-acyl-glycerol-3-phosphate-O-acyltransferase-2). CGL type 2 is caused by a mutation in the BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 (seipin)). Patients with BSCL2 mutations have lower serum leptin levels, an earlier onset of diabetes, and a higher prevalence of mild mental retardation and cardiomyopathy compared with other subtypes. CGL type 3 is caused by a mutation in the CAV1 gene encoding the caveolin 1 protein. CGL type 4 is caused by a mutation in the PTRF gene which encodes the cavin protein (polymerase I and transcript release factor). Patients with BSCL2 mutations have a higher prevalence of cardiomyopathy and muscular dystrophy compared with other subtypes.The mechanisms of this disease are not fully understood. Studies suggest that BSCL2 may play a critical role in the early development of adipocytes. Normally, BSCL2 binds to LPIN1 and induces PPARG and SREBF1. LPIN1 catalyzes the ultimate step in triglyceride synthesis. The expression of LPIN1 is required for adipocyte differentiation and also functions as a nuclear transcriptional coactivator with nuclear receptor PPARG to modulate expression of other genes involved in lipid metabolism. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4 thus increasing glucose uptake. SREBF1 promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. CAV1 plays an important role in caveolae formation and organization. PTRF is essential for normal oligomerization of caveolin 1. Changes in the function of CAV1 leads to the disruption of lipid transport, formation of lipid droplets, and adipocytes differentiation. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Mutated genes: Mutated genes are shown in white-out style. Organ_System: endocrine system Organ_System: integumentary system PMID: 20551664 PMID: 23475416 PMID: 25195639 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-3a547e74-b468-44dc-988f-c0bc0b54802f Berardinelli-Seip Syndrome Progression (Hypothesis) uuid-3a547e74-b468-44dc-988f-c0bc0b54802f PS:CellType adipocyte PS:Description Congenital Generalized Lipodystrophy (CGL) is a group of rare insulin resistance syndromes characterized by a generalized lipodystrophy and acromegaloid features. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a547e74-b468-44dc-988f-c0bc0b54802f PS:NodeType Pathway PS:Notes Headnote: Congenital generalized lipodystrophy type 2 (CGL2, also known as Berardinelli-Seip syndrome) is a rare autosomal recessive condition. CGL2 belongs to a group of extreme insulin resistance syndromes characterized by generalized lipodystrophy, hepatomegaly, acromegaloid features, severe low levels of leptin and adiponectin, and hypertriglyceridemia from birth or early infancy. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, abnormal accumulation of fat in internal organs, hirsutism, mental retardation, bone cysts with spontaneous fractures, and precocious puberty. Signaling description: Different forms of congenital generalized lipodystrophy may be caused by the disruption of different pathways. CGL type1 is caused by a mutation in the AGPAT2 gene, encoding a key enzyme in triglyceride biosynthesis (1-acyl-glycerol-3-phosphate-O-acyltransferase-2). CGL type 2 is caused by a mutation in the BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 (seipin)). Patients with BSCL2 mutations have lower serum leptin levels, an earlier onset of diabetes, and a higher prevalence of mild mental retardation and cardiomyopathy compared with other subtypes. CGL type 3 is caused by a mutation in the CAV1 gene encoding the caveolin 1 protein. CGL type 4 is caused by a mutation in the PTRF gene which encodes the cavin protein (polymerase I and transcript release factor). Patients with BSCL2 mutations have a higher prevalence of cardiomyopathy and muscular dystrophy compared with other subtypes.The mechanisms of this disease are not fully understood. Studies suggest that BSCL2 may play a critical role in the early development of adipocytes. Normally, BSCL2 binds to LPIN1 and induces PPARG and SREBF1. LPIN1 catalyzes the ultimate step in triglyceride synthesis. The expression of LPIN1 is required for adipocyte differentiation and also functions as a nuclear transcriptional coactivator with nuclear receptor PPARG to modulate expression of other genes involved in lipid metabolism. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4 thus increasing glucose uptake. SREBF1 promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. CAV1 plays an important role in caveolae formation and organization. PTRF is essential for normal oligomerization of caveolin 1. Changes in the function of CAV1 leads to the disruption of lipid transport, formation of lipid droplets, and adipocytes differentiation. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System endocrine system PS:Organ_System integumentary system PS:PMID 20551664 PS:PMID 23475416 PS:PMID 25195639 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a70beba-c014-4936-a388-e566e174df7a NodeType: Pathway Notes: The excessive mechanical loading of cartilage is a proven trigger of osteoarthritis. The mechanical stress initiates the release of proinflammatory cytokines, which alter the normal function of chondrocytes and lead to cartilage damage. The cartilage ECM is made of water, collagens (type II), proteoglycans, and hydrophilic macromolecules. Overexpressed in OA, aggrecanases, metalloproteinases, and collagenases break down components of the cartilage ECM. The progressive inflammation in OA leads to cartilage degradation and a breakdown of all joint tissues (bone, synovium, and ligaments). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3a70beba-c014-4936-a388-e566e174df7a 1_TNF and IL1B provoke ECM degradation in osteoarthritis uuid-3a70beba-c014-4936-a388-e566e174df7a PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a70beba-c014-4936-a388-e566e174df7a PS:NodeType Pathway PS:Notes The excessive mechanical loading of cartilage is a proven trigger of osteoarthritis. The mechanical stress initiates the release of proinflammatory cytokines, which alter the normal function of chondrocytes and lead to cartilage damage. The cartilage ECM is made of water, collagens (type II), proteoglycans, and hydrophilic macromolecules. Overexpressed in OA, aggrecanases, metalloproteinases, and collagenases break down components of the cartilage ECM. The progressive inflammation in OA leads to cartilage degradation and a breakdown of all joint tissues (bone, synovium, and ligaments). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a777afe-d7f7-4925-b3ae-8fa1de9902e4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-3a777afe-d7f7-4925-b3ae-8fa1de9902e4 PPARGC1A Repression in Huntington Disease uuid-3a777afe-d7f7-4925-b3ae-8fa1de9902e4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a777afe-d7f7-4925-b3ae-8fa1de9902e4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Reed Sternberg cell CellType: cancer cell Description: Classical Hodgkin lymphoma (HL) is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a8c4ddf-049a-4b54-837f-9e7086794b72 NodeType: Pathway Notes: Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). Signaling description: Classical Hodgkin lymphoma (HL) is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. They have lost expression of most B cell-typical genes (B cell receptor (BCR), immunoglobulins, and many B-cell specific CDs) and acquired expression of multiple genes typical for different immune system cells. With a few exceptions, Hodgkin and Reed-Sternberg (HRS) cells retain only B-cell features associated with antigen-presenting functions and interaction with TH cells, such as the expression of MHC II, CD40, and CD80. This suggests that communication with CD4 TH cells is important for HRS cells tumorigenesis. Furthermore, HRS cells express markers of T-cells (CD3, CD4, and GATA3), granulocytes and monocytes (CD15 and granzyme B (GZMB)), dendritic cells (fascin, TARC, and CCL17), myeloid cells (CSF1R and a1-antitrypsin), and plasma cells (MUM-1 and CD138). In conclusion, the biological relevance of these phenomena remains unclear. Most likely, the reprogramming helps HRS cells escape an immune system attack. Outcome effects: The down-regulation of B-cell commitment genes such as PAX-5, EBF-1, and TCF-3 is responsible for the loss of expression of most B-cell markers. In addition, the down-regulation of POU2AF1, POU2F2, and SPI1 genes is responsible for the block of immunoglobulins synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 11280769 PMID: 19078975 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3a8c4ddf-049a-4b54-837f-9e7086794b72 Hodgkin and Reed-Sternberg Cells Reprogramming uuid-3a8c4ddf-049a-4b54-837f-9e7086794b72 PS:CellType Reed Sternberg cell PS:CellType cancer cell PS:Description Classical Hodgkin lymphoma (HL) is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3a8c4ddf-049a-4b54-837f-9e7086794b72 PS:NodeType Pathway PS:Notes Headnote: Hodgkin lymphoma (HL) is one of the most frequent types of lymphoma in the Western world. The main clinical presentation is lymph node enlargement. It is subdivided into classical HL and nodular lymphocyte-predominant HL (NLPHL which accounts for only 5% of cases). Signaling description: Classical Hodgkin lymphoma (HL) is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. They have lost expression of most B cell-typical genes (B cell receptor (BCR), immunoglobulins, and many B-cell specific CDs) and acquired expression of multiple genes typical for different immune system cells. With a few exceptions, Hodgkin and Reed-Sternberg (HRS) cells retain only B-cell features associated with antigen-presenting functions and interaction with TH cells, such as the expression of MHC II, CD40, and CD80. This suggests that communication with CD4 TH cells is important for HRS cells tumorigenesis. Furthermore, HRS cells express markers of T-cells (CD3, CD4, and GATA3), granulocytes and monocytes (CD15 and granzyme B (GZMB)), dendritic cells (fascin, TARC, and CCL17), myeloid cells (CSF1R and a1-antitrypsin), and plasma cells (MUM-1 and CD138). In conclusion, the biological relevance of these phenomena remains unclear. Most likely, the reprogramming helps HRS cells escape an immune system attack. Outcome effects: The down-regulation of B-cell commitment genes such as PAX-5, EBF-1, and TCF-3 is responsible for the loss of expression of most B-cell markers. In addition, the down-regulation of POU2AF1, POU2F2, and SPI1 genes is responsible for the block of immunoglobulins synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 11280769 PS:PMID 19078975 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aba55ed-fbb2-445f-8bb4-afcd0f4636c0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-3aba55ed-fbb2-445f-8bb4-afcd0f4636c0 Modification of mHTT Toxicity uuid-3aba55ed-fbb2-445f-8bb4-afcd0f4636c0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aba55ed-fbb2-445f-8bb4-afcd0f4636c0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ac493ca-ae2e-4f95-b7fb-f4a3c4dbf49d NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3ac493ca-ae2e-4f95-b7fb-f4a3c4dbf49d TLR -> AP-1 Signaling uuid-3ac493ca-ae2e-4f95-b7fb-f4a3c4dbf49d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ac493ca-ae2e-4f95-b7fb-f4a3c4dbf49d PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: cancer cell CellType: cancer stem cell Description: Kynurenine and it's metabolites play important role in cancer-associated immunosuppression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aca3317-4147-4bb3-b102-7bb0c8b0d055 NodeType: Pathway Notes: Headnote: Kynurenine and it's metabolites are essential for cancer-associated immunosuppression. Signaling description: Kynurenine pathway (KP) is responsible for tryptophan turnover generating multiple intermediate metabolites. Among them, kynurenine (KYN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QUIN) were found to be immunosuppressive: in micromolar concentrations they were found to inhibit T-cell proliferation in vitro. The same substances induced selective apoptosis of thymocytes and of antigen-specific CD4 T-helper 1 cells. Another notable effect 3-HAA has on T-cells is its ability to cause a reduction in the fraction of CD4 TH17 cells and a reciprocal increase in the fraction of Tregs. IDO1 and TDO2, responsible for kynurenine production are often overexpressed in cancers. Outcome effects: Kynurenine and it's metabolites induce inhibition of proliferation and induction of apoptosis in the effector T-cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 20972599 PMID: 21744051 PMID: 23103127 PMID: 25400638 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-3aca3317-4147-4bb3-b102-7bb0c8b0d055 Kynurenine Metabolites Supress T-Cells in Cancer Immune Escape uuid-3aca3317-4147-4bb3-b102-7bb0c8b0d055 PS:CellType T-cell PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Kynurenine and it's metabolites play important role in cancer-associated immunosuppression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aca3317-4147-4bb3-b102-7bb0c8b0d055 PS:NodeType Pathway PS:Notes Headnote: Kynurenine and it's metabolites are essential for cancer-associated immunosuppression. Signaling description: Kynurenine pathway (KP) is responsible for tryptophan turnover generating multiple intermediate metabolites. Among them, kynurenine (KYN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QUIN) were found to be immunosuppressive: in micromolar concentrations they were found to inhibit T-cell proliferation in vitro. The same substances induced selective apoptosis of thymocytes and of antigen-specific CD4 T-helper 1 cells. Another notable effect 3-HAA has on T-cells is its ability to cause a reduction in the fraction of CD4 TH17 cells and a reciprocal increase in the fraction of Tregs. IDO1 and TDO2, responsible for kynurenine production are often overexpressed in cancers. Outcome effects: Kynurenine and it's metabolites induce inhibition of proliferation and induction of apoptosis in the effector T-cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 20972599 PS:PMID 21744051 PS:PMID 23103127 PS:PMID 25400638 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aee304c-ab37-4786-8716-740a44fb3ee6 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3aee304c-ab37-4786-8716-740a44fb3ee6 Proteins Involved in Prolactinoma uuid-3aee304c-ab37-4786-8716-740a44fb3ee6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3aee304c-ab37-4786-8716-740a44fb3ee6 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b070a03-c952-43a4-b070-aa5b3f5a74c2 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3b070a03-c952-43a4-b070-aa5b3f5a74c2 Overview. Diseases of the nervous system (chapter 5) uuid-3b070a03-c952-43a4-b070-aa5b3f5a74c2 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b070a03-c952-43a4-b070-aa5b3f5a74c2 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b0dec59-bb03-4d68-953e-826b4571cb4e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-3b0dec59-bb03-4d68-953e-826b4571cb4e M protein interactions uuid-3b0dec59-bb03-4d68-953e-826b4571cb4e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b0dec59-bb03-4d68-953e-826b4571cb4e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b2de982-5704-4d04-bbec-12a6015668a9 NodeType: Pathway Notes: Class III and class IV mutations cause reductions in transmembrane Cl- conductance. Class III mutations, in a manner similar to class II mutations, usually lead to a classic CF phenotype with pancreatic insufficiency. One of the major functions of CFTR is to regulate the movement of chloride (Cl-) and sodium (Na+) ions across epithelial cell membranes, such as the alveolar epithelia located in the lungs. Class III CFTR mutations disturb the protein’s chloride-transporting function. Mutated CFTR does not respond to cAMP stimulation even though it is located in the cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3b2de982-5704-4d04-bbec-12a6015668a9 2_Ion channel CFTR failure in cystic fibrosis airway epithelium (class III-IV mutations) uuid-3b2de982-5704-4d04-bbec-12a6015668a9 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b2de982-5704-4d04-bbec-12a6015668a9 PS:NodeType Pathway PS:Notes Class III and class IV mutations cause reductions in transmembrane Cl- conductance. Class III mutations, in a manner similar to class II mutations, usually lead to a classic CF phenotype with pancreatic insufficiency. One of the major functions of CFTR is to regulate the movement of chloride (Cl-) and sodium (Na+) ions across epithelial cell membranes, such as the alveolar epithelia located in the lungs. Class III CFTR mutations disturb the protein’s chloride-transporting function. Mutated CFTR does not respond to cAMP stimulation even though it is located in the cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The modulation of cytosolic Ca2 concentration constitutes a fundamental mechanism of signal transduction in excitable cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b4ddff2-7fdb-4ae6-80d8-271f607ca25f NodeType: Pathway Notes: Headnote: The modulation of cytosolic Ca2+ concentration constitutes a fundamental mechanism of signal transduction in excitable cells. Signaling description: Ca2+ oscillations are controlled by the release of Ca2+ from ER stores through inositol triphosphate receptor channels (IP3R) and by Ca2+ uptake into the ER lumen by sarco(endo)plasmic reticulum Ca2+-ATPases. In addition, mitochondria efficiently take up and release Ca2+. Outcome effects: Mitochondrial Ca2+ overload is responsible for increased ROS production mediated by the respiratory chain. Moreover, the increase of free Ca2+ concentration in the mitochondrial matrix above a certain level activates permeability transition pore(s) (mPTP) and triggers cascades of cellular processes leading to cell death. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-3b4ddff2-7fdb-4ae6-80d8-271f607ca25f Ca2+ Cytosolic Overload uuid-3b4ddff2-7fdb-4ae6-80d8-271f607ca25f PS:CellType generic PS:Description The modulation of cytosolic Ca2 concentration constitutes a fundamental mechanism of signal transduction in excitable cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b4ddff2-7fdb-4ae6-80d8-271f607ca25f PS:NodeType Pathway PS:Notes Headnote: The modulation of cytosolic Ca2+ concentration constitutes a fundamental mechanism of signal transduction in excitable cells. Signaling description: Ca2+ oscillations are controlled by the release of Ca2+ from ER stores through inositol triphosphate receptor channels (IP3R) and by Ca2+ uptake into the ER lumen by sarco(endo)plasmic reticulum Ca2+-ATPases. In addition, mitochondria efficiently take up and release Ca2+. Outcome effects: Mitochondrial Ca2+ overload is responsible for increased ROS production mediated by the respiratory chain. Moreover, the increase of free Ca2+ concentration in the mitochondrial matrix above a certain level activates permeability transition pore(s) (mPTP) and triggers cascades of cellular processes leading to cell death. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Anterograde transport is movement of molecules from the cell body to the tip of cilium for the formation and maintenance of eukaryotic cilia and flagella. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b6377b3-8980-4ec0-bfef-2a05b2085b20 NodeType: Pathway Notes: Headnote: Intraflagellar transport (IFT) is a specialized intracellular process essential for the formation and maintenance of eukaryotic cilia and flagella. IFT is a bidirectional transport (anterograde or orthograde and retrograde transport) along axonemal microtubules. Anterograde activities deliver IFT particles (IFT subcomplexes, IFT trains) to the tip of cilium and retrograde activities return them back to the cell body. Both motilities are tightly regulated to keep cilia intact and maintain them at their specified lengths. Signaling description: The anterograde transport of individual cargoes along the doublet microtubules of the flagellar axoneme is mediated by heterotrimeric kinesin-2 (KIF3A/KIF3B/KIFAP3) and OSM-3 kinesin (KIF17) motors. Kinesin motors move IFT-associated proteins and cargo, BBSome and IFT-B/A subcomplexes. In cooperation with these motors, IFT-B subcomplex binds to protein cargo through protein interaction domains. For many cargoes it is not yet understood how they interact with the IFT machinery. IFT-B subcomplex contains IFT-B1 core subunits (IFT88, IFT81, IFT74, IFT70 (TTC30B), IFT56 (TTC26), IFT52, IFT46, IFT27, IFT25 (HSPB11), and IFT22) and IFT-B2 peripheral subunits (IFT172, IFT80, IFT57, IFT54 (TRAF3IP1), IFT38 (CLUAP1) and IFT20), both of which are capable of assembly into stable complexes. IFT70 and IFT20 are required for the association of IFT-B subcomplex with OSM-3 and kinesin-2 motors respectively. BBSome may have a role in holding IFT-A and IFT-B together. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: Kinesin-2 and OSM-3 kinesin motors, IFT-B subcomplex and BBSome provide anterograde transport. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 22683354 PMID: 23945166 PMID: 28342295 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-3b6377b3-8980-4ec0-bfef-2a05b2085b20 Intraflagellar Transport: Anterograde Transport uuid-3b6377b3-8980-4ec0-bfef-2a05b2085b20 PS:CellType generic PS:Description Anterograde transport is movement of molecules from the cell body to the tip of cilium for the formation and maintenance of eukaryotic cilia and flagella. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b6377b3-8980-4ec0-bfef-2a05b2085b20 PS:NodeType Pathway PS:Notes Headnote: Intraflagellar transport (IFT) is a specialized intracellular process essential for the formation and maintenance of eukaryotic cilia and flagella. IFT is a bidirectional transport (anterograde or orthograde and retrograde transport) along axonemal microtubules. Anterograde activities deliver IFT particles (IFT subcomplexes, IFT trains) to the tip of cilium and retrograde activities return them back to the cell body. Both motilities are tightly regulated to keep cilia intact and maintain them at their specified lengths. Signaling description: The anterograde transport of individual cargoes along the doublet microtubules of the flagellar axoneme is mediated by heterotrimeric kinesin-2 (KIF3A/KIF3B/KIFAP3) and OSM-3 kinesin (KIF17) motors. Kinesin motors move IFT-associated proteins and cargo, BBSome and IFT-B/A subcomplexes. In cooperation with these motors, IFT-B subcomplex binds to protein cargo through protein interaction domains. For many cargoes it is not yet understood how they interact with the IFT machinery. IFT-B subcomplex contains IFT-B1 core subunits (IFT88, IFT81, IFT74, IFT70 (TTC30B), IFT56 (TTC26), IFT52, IFT46, IFT27, IFT25 (HSPB11), and IFT22) and IFT-B2 peripheral subunits (IFT172, IFT80, IFT57, IFT54 (TRAF3IP1), IFT38 (CLUAP1) and IFT20), both of which are capable of assembly into stable complexes. IFT70 and IFT20 are required for the association of IFT-B subcomplex with OSM-3 and kinesin-2 motors respectively. BBSome may have a role in holding IFT-A and IFT-B together. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: Kinesin-2 and OSM-3 kinesin motors, IFT-B subcomplex and BBSome provide anterograde transport. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22683354 PS:PMID 23945166 PS:PMID 28342295 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b6a13ae-e0e0-409f-b732-45a103cee522 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3b6a13ae-e0e0-409f-b732-45a103cee522 FIGF -> AP-1 Expression Target uuid-3b6a13ae-e0e0-409f-b732-45a103cee522 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b6a13ae-e0e0-409f-b732-45a103cee522 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b916726-068f-4493-9ce9-dccc0c9f0cd7 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3b916726-068f-4493-9ce9-dccc0c9f0cd7 Sphingolipid Metabolism uuid-3b916726-068f-4493-9ce9-dccc0c9f0cd7 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3b916726-068f-4493-9ce9-dccc0c9f0cd7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bc7ed66-e58d-49db-b6c6-b39a9a5b6477 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3bc7ed66-e58d-49db-b6c6-b39a9a5b6477 GPI-anchor biosynthesis template uuid-3bc7ed66-e58d-49db-b6c6-b39a9a5b6477 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bc7ed66-e58d-49db-b6c6-b39a9a5b6477 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bdc7e6c-6a42-4cc9-9b80-84b319cc5dd9 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3bdc7e6c-6a42-4cc9-9b80-84b319cc5dd9 Overview. Diseases of the respiratory (chapter 9) uuid-3bdc7e6c-6a42-4cc9-9b80-84b319cc5dd9 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bdc7e6c-6a42-4cc9-9b80-84b319cc5dd9 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: lactotroph Description: Prolactin (PRL) is a protein enabling female mammals to produce milk. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bf9f657-8bb2-4a21-8e68-1f997b8988aa NodeType: Pathway Notes: Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: PRL is secreted from the pituitary gland in response to different stimuli including nursing. Sucking by the baby on the nipple promotes PRL release. The sucking activates mechanoreceptors, and these signals are transferred by nerve fibers throughout the spinal cord to the hypothalamus and regulate PRL secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk ejection.There are several factors that inhibit or activate PRL production and release. Dopamine and leukemia inhibitory factor (LIF) have inhibitory effect; thyrotropin-releasing hormone (TRH), oxytocin (OXT), vasoactive intestinal peptide (VIP) and estrogens have stimulatory effects. Also some local pituitary factors, such as epidermal growth factor (EGF), fibroblast growth factor-2 (FGF2), endothelin-1 (EDN1) and pituitary adenylate cyclase activating peptide (ADCYAP1) stimulate the release of PRL. The classical dopaminergic inhibition of PRL release from the anterior pituitary is mediated through DRD2 receptor, G-proteins and adenylate cyclase (ADCY). Outcome effects: Action of dopamine induces a rapid change in cytosolic Ca2+ concentration, due o the fact that DRD2 receptor is coupled to voltage-gated calcium channels or via indirect action on GIRK and resulting in a marked decline in intracellular calcium. Estrogens stimulate PRL expression via ESR1. Estrogen effects on lactotroph cell growth are mediated through estrogen-induced stimulatory or inhibitory action of TGFs and other growth factors. Increasing estrogens concentrations reduce the intrapituitary production of TGFB1 and stimulate the synthesis of TGFB3. These two factors have opposite effects on lactotroph cell growth, since TGFB1 inhibits and TGFB3 stimulates the proliferation of these cells. Interestingly, these estradiol-induced changes are dependent on the presence of folliculostellate cell (FS). In particular, in FS cells, estradiol-induced TGFB3 stimulates the production of FGF2, which is a potent stimulator of PRL production and lactotroph cell proliferation. Alternatively, estrogens may affect lactotroph growth and function through altering the dopaminergic control. It is well known that estradiol downregulates hypothalamic DA production and suppresses the activity of DRD2 in lactotrophs by uncoupling the receptors from G proteins. Whereas estrogens predominantly stimulate PRL synthesis and release, this hormone was shown to differently affect lactotroph cell growth by acting either proliferative or apoptotically. Regarding apoptosis, it has been demonstrated that estrogens upregulate the Fas/FasL apoptotic pathway in lactotrophs and induces the intrapituitary production of TNF, which acts apoptotic through the TNF receptor 1 (TNFR1) expressed on lactotrophs. Whether lactotrophs undergo proliferation or apoptosis will then depend on the actual dominance of the different factors during the cycle. PRL not only stimulates lactation but also plays role in many processes and regulates fertility. It was shown that PRL suppresses gonadotropin-releasing hormones (FSH and LH) secretion by pituitary gonadotroph cells thereby suppressing ovulation in women and spermatogenesis in men. References: 1). Oner G (2013). Prolactin and Infertility, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/55557. Available from: http://www.intechopen.com/books/prolactin/prolactin-and-infertility 2). Reinhoffer V, Ola?h M, Vecsernye?s M, To?th EB, Nagy GM (2013 The Regulation of Pituitary Prolactin Secretion: Hypothalamic, Intrapituitary and Intracellular Factors and Signaling Mechanisms, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/5557 Organ: pituitary gland Organ_System: endocrine system PMID: 17307904 PMID: 20371569 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-3bf9f657-8bb2-4a21-8e68-1f997b8988aa Prolactin Production uuid-3bf9f657-8bb2-4a21-8e68-1f997b8988aa PS:CellType lactotroph PS:Description Prolactin (PRL) is a protein enabling female mammals to produce milk. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3bf9f657-8bb2-4a21-8e68-1f997b8988aa PS:NodeType Pathway PS:Notes Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: PRL is secreted from the pituitary gland in response to different stimuli including nursing. Sucking by the baby on the nipple promotes PRL release. The sucking activates mechanoreceptors, and these signals are transferred by nerve fibers throughout the spinal cord to the hypothalamus and regulate PRL secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk ejection.There are several factors that inhibit or activate PRL production and release. Dopamine and leukemia inhibitory factor (LIF) have inhibitory effect; thyrotropin-releasing hormone (TRH), oxytocin (OXT), vasoactive intestinal peptide (VIP) and estrogens have stimulatory effects. Also some local pituitary factors, such as epidermal growth factor (EGF), fibroblast growth factor-2 (FGF2), endothelin-1 (EDN1) and pituitary adenylate cyclase activating peptide (ADCYAP1) stimulate the release of PRL. The classical dopaminergic inhibition of PRL release from the anterior pituitary is mediated through DRD2 receptor, G-proteins and adenylate cyclase (ADCY). Outcome effects: Action of dopamine induces a rapid change in cytosolic Ca2+ concentration, due o the fact that DRD2 receptor is coupled to voltage-gated calcium channels or via indirect action on GIRK and resulting in a marked decline in intracellular calcium. Estrogens stimulate PRL expression via ESR1. Estrogen effects on lactotroph cell growth are mediated through estrogen-induced stimulatory or inhibitory action of TGFs and other growth factors. Increasing estrogens concentrations reduce the intrapituitary production of TGFB1 and stimulate the synthesis of TGFB3. These two factors have opposite effects on lactotroph cell growth, since TGFB1 inhibits and TGFB3 stimulates the proliferation of these cells. Interestingly, these estradiol-induced changes are dependent on the presence of folliculostellate cell (FS). In particular, in FS cells, estradiol-induced TGFB3 stimulates the production of FGF2, which is a potent stimulator of PRL production and lactotroph cell proliferation. Alternatively, estrogens may affect lactotroph growth and function through altering the dopaminergic control. It is well known that estradiol downregulates hypothalamic DA production and suppresses the activity of DRD2 in lactotrophs by uncoupling the receptors from G proteins. Whereas estrogens predominantly stimulate PRL synthesis and release, this hormone was shown to differently affect lactotroph cell growth by acting either proliferative or apoptotically. Regarding apoptosis, it has been demonstrated that estrogens upregulate the Fas/FasL apoptotic pathway in lactotrophs and induces the intrapituitary production of TNF, which acts apoptotic through the TNF receptor 1 (TNFR1) expressed on lactotrophs. Whether lactotrophs undergo proliferation or apoptosis will then depend on the actual dominance of the different factors during the cycle. PRL not only stimulates lactation but also plays role in many processes and regulates fertility. It was shown that PRL suppresses gonadotropin-releasing hormones (FSH and LH) secretion by pituitary gonadotroph cells thereby suppressing ovulation in women and spermatogenesis in men. References: 1). Oner G (2013). Prolactin and Infertility, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/55557. Available from: http://www.intechopen.com/books/prolactin/prolactin-and-infertility 2). Reinhoffer V, Ola?h M, Vecsernye?s M, To?th EB, Nagy GM (2013 The Regulation of Pituitary Prolactin Secretion: Hypothalamic, Intrapituitary and Intracellular Factors and Signaling Mechanisms, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/5557 PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 17307904 PS:PMID 20371569 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c0d0c21-5a1e-4772-9ad2-c446009a95ba NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-3c0d0c21-5a1e-4772-9ad2-c446009a95ba Genes with Mutations Associated with Rheumatoid Arthritis uuid-3c0d0c21-5a1e-4772-9ad2-c446009a95ba PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c0d0c21-5a1e-4772-9ad2-c446009a95ba PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c2068d9-56c3-4aa5-8dbe-9d1b22a338b7 NodeType: Pathway Organ: generic Organ_System: generic PMID: 28513565 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-3c2068d9-56c3-4aa5-8dbe-9d1b22a338b7 EGFR Signaling uuid-3c2068d9-56c3-4aa5-8dbe-9d1b22a338b7 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c2068d9-56c3-4aa5-8dbe-9d1b22a338b7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 28513565 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c557bbe-5fbf-4dd5-bd6f-e59277d6bf5d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3c557bbe-5fbf-4dd5-bd6f-e59277d6bf5d scopolin and esculin biosynthesis template uuid-3c557bbe-5fbf-4dd5-bd6f-e59277d6bf5d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c557bbe-5fbf-4dd5-bd6f-e59277d6bf5d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: When CD4 CD8 T cells bind to antigen, they enter the next stage of differentiation which is the process of positive selection of T cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c5aa6e5-d045-4656-b8ab-98e9a9dcee59 NodeType: Pathway Notes: Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Signaling description: When CD4 CD8 T-cells bind to antigen, they enter the next stage of differentiation which is the process of positive selection of T- cells. In some cases, T-cell receptors (TCRs) in T-cells remain non-functional or non-activated by antigen-MHC protein complex. The unoccupied TCR complex fails to transmit the survival signal through ATK1 signaling, thereby inducing death by neglect. EGR1 is one of the earliest transcription factors expressed after TCR stimulation on double positive (DP) CD4 CD8 thymocytes. EGR1 enhances the expression of negative regulators of differentiation pathways such as ID3 and the anti-apoptosis molecule, BCL2. BCL11B is the second most important transcription factor in the control of both positive selection and survival of DP thymocytes. Other transcription factors such as RORC, HNF1A, and more recently MYB, have also been implicated in positive selection. Outcome effects: It has been proposed that glucocorticoids (GCs) induce apoptosis and death by neglect, acting as regulators of the differentiation and selection of developing thymocytes at this stage of maturation. GCs control the selection of DP thymocytes by modifying their TCR-related signaling. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-3c5aa6e5-d045-4656-b8ab-98e9a9dcee59 T-Cell Positive Selection and Neglect Induced Death uuid-3c5aa6e5-d045-4656-b8ab-98e9a9dcee59 PS:CellType T-cell PS:Description When CD4 CD8 T cells bind to antigen, they enter the next stage of differentiation which is the process of positive selection of T cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c5aa6e5-d045-4656-b8ab-98e9a9dcee59 PS:NodeType Pathway PS:Notes Headnote: T-cells originate from hematopoietic stem cells in the bone marrow and go through positive or negative selection in the thymus to mature. Signaling description: When CD4 CD8 T-cells bind to antigen, they enter the next stage of differentiation which is the process of positive selection of T- cells. In some cases, T-cell receptors (TCRs) in T-cells remain non-functional or non-activated by antigen-MHC protein complex. The unoccupied TCR complex fails to transmit the survival signal through ATK1 signaling, thereby inducing death by neglect. EGR1 is one of the earliest transcription factors expressed after TCR stimulation on double positive (DP) CD4 CD8 thymocytes. EGR1 enhances the expression of negative regulators of differentiation pathways such as ID3 and the anti-apoptosis molecule, BCL2. BCL11B is the second most important transcription factor in the control of both positive selection and survival of DP thymocytes. Other transcription factors such as RORC, HNF1A, and more recently MYB, have also been implicated in positive selection. Outcome effects: It has been proposed that glucocorticoids (GCs) induce apoptosis and death by neglect, acting as regulators of the differentiation and selection of developing thymocytes at this stage of maturation. GCs control the selection of DP thymocytes by modifying their TCR-related signaling. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: granulosa cell Description: Anovulation or block of ovulation in polycystic ovary syndrome (PCOS) is due to the disruption of the two stages of follicular development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c5d18ac-c221-48a8-8763-0ee1611199c8 NodeType: Pathway Notes: Headnote: Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Anovulation or block of ovulation in polycystic ovary syndrome (PCOS) is due to the disruption of the two stages of follicular development. The first is excessive follicular growth and the second is violation of the selection of one of the follicles from the increased pool and its further maturation into a dominant follicle. Signaling description: Normally, FSH promotes folliculogenesis by means of granulosa cell proliferation and differentiation, which surround the oocyte. In the pathology, signaling is blocked by AMH, estrogens, FST, and inhibin complex. The arrested signaling includes the PI3K, PKC, and PKA routes, which normally lead to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 pathway. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. The impaired FSH signaling prevents AKT1 activation, which normally inhibits FOXO1, a negative regulator of cell proliferation and differentiation. The excess of androgens bind to their intracellular receptor (AR) and trigger IGF1R appearance on granulosa cell surfaces. Elevated IGF1 binds to its receptor, which induces PI3K activation. PI3K promotes AKT1 phosphorylation of CDKN1B, BAD, and GSK3B resulting in their inhibition. These proteins normally promote granulosa cell proliferation. Outcome effects: Granulosa cells are necessary for appropriate follicle development, thus the arrest of their proliferation and differentiation stops follicle growth with this being one of the major causes of anovulation in PCOS. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Organ: ovary Organ_System: reproductive system PMID: 12017544 PMID: 19078868 PMID: 20591140 PMID: 21606667 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-3c5d18ac-c221-48a8-8763-0ee1611199c8 Ovulation Block uuid-3c5d18ac-c221-48a8-8763-0ee1611199c8 PS:CellType granulosa cell PS:Description Anovulation or block of ovulation in polycystic ovary syndrome (PCOS) is due to the disruption of the two stages of follicular development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c5d18ac-c221-48a8-8763-0ee1611199c8 PS:NodeType Pathway PS:Notes Headnote: Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Anovulation or block of ovulation in polycystic ovary syndrome (PCOS) is due to the disruption of the two stages of follicular development. The first is excessive follicular growth and the second is violation of the selection of one of the follicles from the increased pool and its further maturation into a dominant follicle. Signaling description: Normally, FSH promotes folliculogenesis by means of granulosa cell proliferation and differentiation, which surround the oocyte. In the pathology, signaling is blocked by AMH, estrogens, FST, and inhibin complex. The arrested signaling includes the PI3K, PKC, and PKA routes, which normally lead to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 pathway. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. The impaired FSH signaling prevents AKT1 activation, which normally inhibits FOXO1, a negative regulator of cell proliferation and differentiation. The excess of androgens bind to their intracellular receptor (AR) and trigger IGF1R appearance on granulosa cell surfaces. Elevated IGF1 binds to its receptor, which induces PI3K activation. PI3K promotes AKT1 phosphorylation of CDKN1B, BAD, and GSK3B resulting in their inhibition. These proteins normally promote granulosa cell proliferation. Outcome effects: Granulosa cells are necessary for appropriate follicle development, thus the arrest of their proliferation and differentiation stops follicle growth with this being one of the major causes of anovulation in PCOS. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 12017544 PS:PMID 19078868 PS:PMID 20591140 PS:PMID 21606667 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c6cf7c4-53b4-42d8-9311-1b1301a45750 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3c6cf7c4-53b4-42d8-9311-1b1301a45750 Omega-6-Fatty Acid Metabolism uuid-3c6cf7c4-53b4-42d8-9311-1b1301a45750 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c6cf7c4-53b4-42d8-9311-1b1301a45750 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c6f57ff-58e2-42ca-890d-7e10d4310121 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3c6f57ff-58e2-42ca-890d-7e10d4310121 ICAM2 -> CTNNB/FOXO/STAT3 Signaling uuid-3c6f57ff-58e2-42ca-890d-7e10d4310121 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c6f57ff-58e2-42ca-890d-7e10d4310121 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: Thrombospondin-1 (THBS1) is a potent angiogenesis inhibitor, and down-regulation of THBS1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c886087-7382-405c-bc75-a0a34a7990cd NodeType: Pathway Notes: Headnote: Thrombospondin-1 (THBS1) is a potent endogenous inhibitor of both physiologic and pathologic angiogenesis. THBS1 and THBS2 exert their direct effects through CD36, CD47, and integrins. The pathology of THBS1 signaling in cancers is characterized by down-regulation of THBS1 leading to enhanced angiogenesis. Signaling description: The activation of MYC and ID1 and inactivation of TP53 in tumors causes down-regulation of THBS1 which results in impairment of pro-apoptotic THBS/CD36/MAPK/CASP signaling, re-activation of proangiogenic KDR/PI3K/AKT1/NO signaling, activation of MMP2/9 and the absence of direct inhibitory effect of THBS1 on VEGFA, FGF2, HGF. Outcome effects: The re-activation of KDR signaling leads to induction of angiogenesis, and the impairment of CASP activation causes inhibition of apoptosis and endothelial cell survival. Further, activation of MMPs leads to extracellular matrix degradation and invasiveness. VEGFA, FGF2, HGF activation stimulates angiogenesis. Animal data: The role of integrins in THBS was established mainly in animal (mice) experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 14699013 PMID: 16406676 PMID: 22553494 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-3c886087-7382-405c-bc75-a0a34a7990cd Inhibition of THBS1 Activates Angiogenesis in Cancer uuid-3c886087-7382-405c-bc75-a0a34a7990cd PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description Thrombospondin-1 (THBS1) is a potent angiogenesis inhibitor, and down-regulation of THBS1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c886087-7382-405c-bc75-a0a34a7990cd PS:NodeType Pathway PS:Notes Headnote: Thrombospondin-1 (THBS1) is a potent endogenous inhibitor of both physiologic and pathologic angiogenesis. THBS1 and THBS2 exert their direct effects through CD36, CD47, and integrins. The pathology of THBS1 signaling in cancers is characterized by down-regulation of THBS1 leading to enhanced angiogenesis. Signaling description: The activation of MYC and ID1 and inactivation of TP53 in tumors causes down-regulation of THBS1 which results in impairment of pro-apoptotic THBS/CD36/MAPK/CASP signaling, re-activation of proangiogenic KDR/PI3K/AKT1/NO signaling, activation of MMP2/9 and the absence of direct inhibitory effect of THBS1 on VEGFA, FGF2, HGF. Outcome effects: The re-activation of KDR signaling leads to induction of angiogenesis, and the impairment of CASP activation causes inhibition of apoptosis and endothelial cell survival. Further, activation of MMPs leads to extracellular matrix degradation and invasiveness. VEGFA, FGF2, HGF activation stimulates angiogenesis. Animal data: The role of integrins in THBS was established mainly in animal (mice) experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 14699013 PS:PMID 16406676 PS:PMID 22553494 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Germline mutations in BRCA1/2, MLH1 and PALB2 genes and somatic mutation in ARID1A and ATRX genes have been detected in a large number of known cases of familial pancreatic cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c9580bf-c6f2-4f1b-a935-c79d4daed857 NodeType: Pathway Notes: Headnote: Pancreatic cancer refers to malignant transformation of the pancreas. BRCA1, BRCA2, and PALB2 are important components of DNA repair pathways. Germline mutations in BRCA2 and PALB2 genes have been detected in a large number of known cases of familial pancreatic cancer. At the same time, the risk of pancreatic cancer in carriers of BRCA1 germline mutations is less established. It has been demonstrated that somatic mutations in ATRX and ARID1A genes, somatic and germline mutations in mismatch repair genes including MLH1, MSH2, and MSH6, high levels of microsatellite instability, and loss of MSH2 and MSH6 expression are all characteristic of pancreatic cancer.Mutations of these genes result in an overall increase in genomic instability and catastrophic DNA damage Signaling description: Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and the genes that participate in homologous recombination and double-strand break repair including BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2. RAD51 binds to ATRX which is involved in chromatin remodeling. In addition, BRCA1 interacts with SMARCA4, an essential component of the chromatin remodeling complex SWI/SNF. SMARCA4 interacts with ARID1A which is a member of the SWI/SNF family. Lastly, BRCA2 participates in the formation of KAT2B/MYSM1 and KAT2A/TADA2A/TADA3 chromatin remodeling complexes. Outcome effects: Mutations in these genes lead to block of DNA repair and disruption of response to DNA damage. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 22806689 PMID: 23135763 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-3c9580bf-c6f2-4f1b-a935-c79d4daed857 DNA Repair and Chromatin Remodeling Block in Pancreatic Neoplasms uuid-3c9580bf-c6f2-4f1b-a935-c79d4daed857 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Germline mutations in BRCA1/2, MLH1 and PALB2 genes and somatic mutation in ARID1A and ATRX genes have been detected in a large number of known cases of familial pancreatic cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c9580bf-c6f2-4f1b-a935-c79d4daed857 PS:NodeType Pathway PS:Notes Headnote: Pancreatic cancer refers to malignant transformation of the pancreas. BRCA1, BRCA2, and PALB2 are important components of DNA repair pathways. Germline mutations in BRCA2 and PALB2 genes have been detected in a large number of known cases of familial pancreatic cancer. At the same time, the risk of pancreatic cancer in carriers of BRCA1 germline mutations is less established. It has been demonstrated that somatic mutations in ATRX and ARID1A genes, somatic and germline mutations in mismatch repair genes including MLH1, MSH2, and MSH6, high levels of microsatellite instability, and loss of MSH2 and MSH6 expression are all characteristic of pancreatic cancer.Mutations of these genes result in an overall increase in genomic instability and catastrophic DNA damage Signaling description: Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and the genes that participate in homologous recombination and double-strand break repair including BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2. RAD51 binds to ATRX which is involved in chromatin remodeling. In addition, BRCA1 interacts with SMARCA4, an essential component of the chromatin remodeling complex SWI/SNF. SMARCA4 interacts with ARID1A which is a member of the SWI/SNF family. Lastly, BRCA2 participates in the formation of KAT2B/MYSM1 and KAT2A/TADA2A/TADA3 chromatin remodeling complexes. Outcome effects: Mutations in these genes lead to block of DNA repair and disruption of response to DNA damage. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 22806689 PS:PMID 23135763 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c980c4f-f7c5-426c-8466-6d0875a6014e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3c980c4f-f7c5-426c-8466-6d0875a6014e Isoleucine degradation template uuid-3c980c4f-f7c5-426c-8466-6d0875a6014e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3c980c4f-f7c5-426c-8466-6d0875a6014e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ca56743-90d7-422e-bf86-fe5d1ba98ecf NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. Signaling description: Mast cells are activated by several causes including external factors such as cold, injury, and radiation. Mast cell activation, through the aggregation of FCeR receptors with IgE, is the main path of activation in allergic reactions. The synthesis of mediators involved in inflammation in mast cells is triggered by alternative FCeR receptors. Determining the number of participating ligands and patterns of intersection between relevant signaling pathways is an important research task. The signaling pathways link mast cell activation with known major triggers. Anaphylatoxins, including C5a and C3, are peptides that are formed upon activation of the complement system by antigens, products of necrosis or apoptosis, antibodies, and pathogens. In addition, thrombin, kallikrein, and house dust mite protease have anaphylatoxin-like activity. TPSAB1, which is released during mast cell activation, leads to the additional production of C3 and C5a. C5a and C3 receptors (C5AR1 and C3AR1) trigger mast cell degranulation as well as chemokine synthesis. The signaling cascade is initiated by a G-protein-dependent mechanism. C5a induces degranulation in mast cells via signaling pathways that require PLCB1 but not PI3K or MAPK1. In contrast, C3 promotes cytokine gene expression in mast cells via signaling pathways that require PLCB1, PI3K, and MAPK1/2. The neuropeptides, NGF and NTF3, activate the functions of mast cells. NGF is the peptide that stimulates growth of several neural cells. Under inflammatory conditions such as allergy and arthritis, NGF is produced, stored, and released by mast cells, as well as other cells. The causes of enhanced NGF concentration are far from being fully understood. The binding interaction between NGF and NTRK1 receptor facilitates the activation of PI3K, AKT1, and RAF1 (MAPK cascade). Neuropeptides stimulate mast cell degranulation and the release of histamine. NGF has recently been shown to stimulate the expression of IL6 in bone marrow-derived mast cells. NGF accumulates in the focus of an allergic reaction or inflammation and stimulates directed motion of mast cells. The increased concentration of NGF causes pain associated with inflammation. NTF3 activates mast cells via NTRK2 and NTRK3 receptors. Anandamide is another neuropeptide that participates in mast cell activation. It is a cannabinoid neurotransmitter that affects behavior and perception. Presumably, lipopolysaccharides, which are inflammatory agents, stimulate the synthesis of anandamide in lymphocytes. Cannabinoid receptors (CNR2) are present in mast cells, but their action regarding mast cell function is poorly understood. It has been suggested that CNR2 can either inhibit or stimulate the release of histamine. Serotonin, which is released upon activation of thrombocytes in inflammation or injury, is capable of activating mast cell degranulation. Mast cells in humans express HTR1A subtype. However, the details of serotonin receptor signaling in mast cells are unknown. It is hypothesized that HTR1A promotes inflammation by increasing mast cells at the site of tissue injury. In addition, lysophosphatidic acid (LPA) is a prominent lipid component of serum that has pleiotropic effects in inflammation. In response to inflammation, LPA diffuses into the extravascular space where it is a potent mast cell activator, which unlike other triggers favors the release of tryptase. In mast cells, LPA acts through LPAR5, which is involved in LPA-induced calcium flux, particularly at low ligand concentrations and crucial for the generation of CCL4 response to LPA. CCL4 is a potent chemoatt Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-3ca56743-90d7-422e-bf86-fe5d1ba98ecf Mast-Cells De Novo Synthesized Mediators via IgE Independent Signaling uuid-3ca56743-90d7-422e-bf86-fe5d1ba98ecf PS:CellType mast cell PS:Description Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ca56743-90d7-422e-bf86-fe5d1ba98ecf PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. Signaling description: Mast cells are activated by several causes including external factors such as cold, injury, and radiation. Mast cell activation, through the aggregation of FCeR receptors with IgE, is the main path of activation in allergic reactions. The synthesis of mediators involved in inflammation in mast cells is triggered by alternative FCeR receptors. Determining the number of participating ligands and patterns of intersection between relevant signaling pathways is an important research task. The signaling pathways link mast cell activation with known major triggers. Anaphylatoxins, including C5a and C3, are peptides that are formed upon activation of the complement system by antigens, products of necrosis or apoptosis, antibodies, and pathogens. In addition, thrombin, kallikrein, and house dust mite protease have anaphylatoxin-like activity. TPSAB1, which is released during mast cell activation, leads to the additional production of C3 and C5a. C5a and C3 receptors (C5AR1 and C3AR1) trigger mast cell degranulation as well as chemokine synthesis. The signaling cascade is initiated by a G-protein-dependent mechanism. C5a induces degranulation in mast cells via signaling pathways that require PLCB1 but not PI3K or MAPK1. In contrast, C3 promotes cytokine gene expression in mast cells via signaling pathways that require PLCB1, PI3K, and MAPK1/2. The neuropeptides, NGF and NTF3, activate the functions of mast cells. NGF is the peptide that stimulates growth of several neural cells. Under inflammatory conditions such as allergy and arthritis, NGF is produced, stored, and released by mast cells, as well as other cells. The causes of enhanced NGF concentration are far from being fully understood. The binding interaction between NGF and NTRK1 receptor facilitates the activation of PI3K, AKT1, and RAF1 (MAPK cascade). Neuropeptides stimulate mast cell degranulation and the release of histamine. NGF has recently been shown to stimulate the expression of IL6 in bone marrow-derived mast cells. NGF accumulates in the focus of an allergic reaction or inflammation and stimulates directed motion of mast cells. The increased concentration of NGF causes pain associated with inflammation. NTF3 activates mast cells via NTRK2 and NTRK3 receptors. Anandamide is another neuropeptide that participates in mast cell activation. It is a cannabinoid neurotransmitter that affects behavior and perception. Presumably, lipopolysaccharides, which are inflammatory agents, stimulate the synthesis of anandamide in lymphocytes. Cannabinoid receptors (CNR2) are present in mast cells, but their action regarding mast cell function is poorly understood. It has been suggested that CNR2 can either inhibit or stimulate the release of histamine. Serotonin, which is released upon activation of thrombocytes in inflammation or injury, is capable of activating mast cell degranulation. Mast cells in humans express HTR1A subtype. However, the details of serotonin receptor signaling in mast cells are unknown. It is hypothesized that HTR1A promotes inflammation by increasing mast cells at the site of tissue injury. In addition, lysophosphatidic acid (LPA) is a prominent lipid component of serum that has pleiotropic effects in inflammation. In response to inflammation, LPA diffuses into the extravascular space where it is a potent mast cell activator, which unlike other triggers favors the release of tryptase. In mast cells, LPA acts through LPAR5, which is involved in LPA-induced calcium flux, particularly at low ligand concentrations and crucial for the generation of CCL4 response to LPA. CCL4 is a potent chemoatt PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cb64620-9829-405d-a57d-fcbd302ebeed NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3cb64620-9829-405d-a57d-fcbd302ebeed CSF2 -> NF-kB Expression Targets uuid-3cb64620-9829-405d-a57d-fcbd302ebeed PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cb64620-9829-405d-a57d-fcbd302ebeed PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cc6182d-ff68-44ce-932c-6043ca5ae10f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3cc6182d-ff68-44ce-932c-6043ca5ae10f Sensory neuron activation in Itch (Pruritis) uuid-3cc6182d-ff68-44ce-932c-6043ca5ae10f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cc6182d-ff68-44ce-932c-6043ca5ae10f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cc6c85a-812a-4ec7-8528-e43faa9fc09c NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3cc6c85a-812a-4ec7-8528-e43faa9fc09c AngiopoietinR -> STAT Signaling uuid-3cc6c85a-812a-4ec7-8528-e43faa9fc09c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cc6c85a-812a-4ec7-8528-e43faa9fc09c PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cd5c63f-16d9-49cd-a2db-9b3ca33af7c7 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-3cd5c63f-16d9-49cd-a2db-9b3ca33af7c7 GR-| muscle cell differentiation uuid-3cd5c63f-16d9-49cd-a2db-9b3ca33af7c7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cd5c63f-16d9-49cd-a2db-9b3ca33af7c7 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The inactive, cytosolic AHR is part of a protein complex that includes the 90-kDa heat shock protein (HSP90), the SRC protein kinase, and the AHR-interacting protein AIP. Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cdbb90e-b9f0-4e7d-97be-f8dfb724bc29 NodeType: Pathway Notes: Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: The inactive, cytosolic Aryl Hydrocarbon Receptor (AHR) is part of a protein complex that includes the 90-kDa heat shock protein (HSP90), the SRC protein kinase, and the AHR-interacting protein AIP. Ligand binding triggers conformational changes, dissociation of the AhR/HSP90/SRC complex and translocation of the AHR to the nucleus. Outcome effects: Once in the nucleus, the AHR establishes protein-protein interactions with the AHR nuclear translocator (ARNT) and with additional coactivators and transcription factors, such as NCOA and GTF2B. AHR interacts with transcription factors with well-characterized functions in the immune system and in other organ systems e.g., MAF, ESR1/2, AR, E2F, RB1, RELB, STAT and others (genomic action). In addition to its direct transcriptional regulation of target genes, the AHR also has been shown to control cellular processes through nongenomic signaling pathways. One of these pathways results from the release of SRC from the AHR/HSP90/SRC complex, enabling SRC to then target multiple cellular targets via interaction with EGFR and downstream MAPK signaling. Transcription of AHR repressor AHRR is controlled by AHR. PMID: 23908379 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-3cdbb90e-b9f0-4e7d-97be-f8dfb724bc29 Aryl Hydrocarbon Receptor Genomic and non-Genomic Signaling uuid-3cdbb90e-b9f0-4e7d-97be-f8dfb724bc29 PS:Description The inactive, cytosolic AHR is part of a protein complex that includes the 90-kDa heat shock protein (HSP90), the SRC protein kinase, and the AHR-interacting protein AIP. Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cdbb90e-b9f0-4e7d-97be-f8dfb724bc29 PS:NodeType Pathway PS:Notes Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: The inactive, cytosolic Aryl Hydrocarbon Receptor (AHR) is part of a protein complex that includes the 90-kDa heat shock protein (HSP90), the SRC protein kinase, and the AHR-interacting protein AIP. Ligand binding triggers conformational changes, dissociation of the AhR/HSP90/SRC complex and translocation of the AHR to the nucleus. Outcome effects: Once in the nucleus, the AHR establishes protein-protein interactions with the AHR nuclear translocator (ARNT) and with additional coactivators and transcription factors, such as NCOA and GTF2B. AHR interacts with transcription factors with well-characterized functions in the immune system and in other organ systems e.g., MAF, ESR1/2, AR, E2F, RB1, RELB, STAT and others (genomic action). In addition to its direct transcriptional regulation of target genes, the AHR also has been shown to control cellular processes through nongenomic signaling pathways. One of these pathways results from the release of SRC from the AHR/HSP90/SRC complex, enabling SRC to then target multiple cellular targets via interaction with EGFR and downstream MAPK signaling. Transcription of AHR repressor AHRR is controlled by AHR. PS:PMID 23908379 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cef2fbd-90b5-4cdd-b28d-7b2341f8159a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3cef2fbd-90b5-4cdd-b28d-7b2341f8159a MRGX2+>Mast Cell Degranulation uuid-3cef2fbd-90b5-4cdd-b28d-7b2341f8159a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3cef2fbd-90b5-4cdd-b28d-7b2341f8159a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d2707d0-6920-43eb-bf03-6542d943f75a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-3d2707d0-6920-43eb-bf03-6542d943f75a GUCYC2 Signaling uuid-3d2707d0-6920-43eb-bf03-6542d943f75a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d2707d0-6920-43eb-bf03-6542d943f75a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: mesenchymal stem cell Description: Lamellipodia and filopodia are cytoskeletal actin protrusions on the leading edge of the cell found primarily in mobile cells and implicated in cancer cell metastatic progression. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d3fc1df-835b-4bf7-b8ee-2b7118498342 NodeType: Pathway Notes: Headnote: Lamellipodia are cytoskeletal actin projections on the leading edge of the cell found mostly in mobile cells. Filopodia are slim cytoplasmic protrusions that extend from the leading edge of lamellipodia in migrating cells. Both lamellipodia and filopodia are implicated in cancer cell metastatic progression. Signaling description: It is not completely clear what triggers the formation of these cytoskeletal projections. Most probably, the activation of receptor tyrosine kinases leads to PI3K signaling activation and triggers the process. The lamellipodia formation is regulated mostly through the RAC1/ WAVE complex/actin related protein 2/3 complex, RAC1/DIAPH and RAC1/PAK1/LIMK/CFL1 pathways. All these signaling routes eventually lead to actin polymerization. The filopodia formation is regulated mainly through the CDC42/WAS/actin related protein 2/3 complex and CDC42/ DIAPH, CDC42/ BAIAP2, CDC42/ PAK1/LIMK/CFL1 pathways which similarly lead to actin polymerization. Outcome effects: Actin polymerization promotes lamellipodia/filopodia formation and cancer cell migration. Organ: oncogenic Organ_System: oncogenic PMID: 18719708 PMID: 21697900 PMID: 26186729 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-3d3fc1df-835b-4bf7-b8ee-2b7118498342 Lamellipodia and Filopodia Formation in Cancer uuid-3d3fc1df-835b-4bf7-b8ee-2b7118498342 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType mesenchymal stem cell PS:Description Lamellipodia and filopodia are cytoskeletal actin protrusions on the leading edge of the cell found primarily in mobile cells and implicated in cancer cell metastatic progression. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d3fc1df-835b-4bf7-b8ee-2b7118498342 PS:NodeType Pathway PS:Notes Headnote: Lamellipodia are cytoskeletal actin projections on the leading edge of the cell found mostly in mobile cells. Filopodia are slim cytoplasmic protrusions that extend from the leading edge of lamellipodia in migrating cells. Both lamellipodia and filopodia are implicated in cancer cell metastatic progression. Signaling description: It is not completely clear what triggers the formation of these cytoskeletal projections. Most probably, the activation of receptor tyrosine kinases leads to PI3K signaling activation and triggers the process. The lamellipodia formation is regulated mostly through the RAC1/ WAVE complex/actin related protein 2/3 complex, RAC1/DIAPH and RAC1/PAK1/LIMK/CFL1 pathways. All these signaling routes eventually lead to actin polymerization. The filopodia formation is regulated mainly through the CDC42/WAS/actin related protein 2/3 complex and CDC42/ DIAPH, CDC42/ BAIAP2, CDC42/ PAK1/LIMK/CFL1 pathways which similarly lead to actin polymerization. Outcome effects: Actin polymerization promotes lamellipodia/filopodia formation and cancer cell migration. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18719708 PS:PMID 21697900 PS:PMID 26186729 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d465265-0b79-49b7-a735-1395dde23969 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3d465265-0b79-49b7-a735-1395dde23969 Caffeine Metabolism uuid-3d465265-0b79-49b7-a735-1395dde23969 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d465265-0b79-49b7-a735-1395dde23969 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: podocyte Description: Glomerulonephritis is a nephritis characterized by inflamed glomeruli and blood vessels in kidneys. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d4ac1a1-afa3-41cf-b54f-163919b9075a NodeType: Pathway Notes: Glomerulonephritis is a nephritis characterized by inflamed glomeruli and blood vessels in kidneys. Podocytes play a key role in renal filtration barrier. Overexpression of TNF and TGFB1 in renal cells due to inflammation can leads to podocyte injury. Organ: kidney Organ_System: urinary tract PMID: 11912180 PMID: 16688120 PMID: 17410103 PMID: 21782129 PMID: 22806900 PMID: 22958490 PMID: 24107418 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-3d4ac1a1-afa3-41cf-b54f-163919b9075a Podocyte Dysfunction in Glomerulonephritis uuid-3d4ac1a1-afa3-41cf-b54f-163919b9075a PS:CellType podocyte PS:Description Glomerulonephritis is a nephritis characterized by inflamed glomeruli and blood vessels in kidneys. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d4ac1a1-afa3-41cf-b54f-163919b9075a PS:NodeType Pathway PS:Notes Glomerulonephritis is a nephritis characterized by inflamed glomeruli and blood vessels in kidneys. Podocytes play a key role in renal filtration barrier. Overexpression of TNF and TGFB1 in renal cells due to inflammation can leads to podocyte injury. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 11912180 PS:PMID 16688120 PS:PMID 17410103 PS:PMID 21782129 PS:PMID 22806900 PS:PMID 22958490 PS:PMID 24107418 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d502d15-75cf-41a0-86c0-1a97c27cf2fc NodeType: Pathway Notes: Headnote: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Signaling description: One of the first signs of APR is synthesis of acute phase proteins (APPs) in the liver. The release of proinflammatory cytokines, nitric oxide, and glucocorticoids, initiates the synthesis of APPs. IL6 is the key mediator for hepatocytic secretion of most APPs. Kupffer cells, which are specialized macrophages located in the liver, may be an additional source of proinflammatory cytokines. The physiological role of highly expressed (positive) APPs is to reduce the systemic effects of tissue damage by enhancing clot formation, reducing proteolysis, and facilitating the clearance of toxic metabolites. During APR, plasma viscosity increases as a result of changes in total blood protein concentration including the increase of fibrinogen, which influences the erythrocyte sedimentation rate (ESR). Systemic APR is profound in bacterial infections, while generally milder in viral infections. Among APPs, CP and C3 expressions are increased by approximately 50% in APR. Further, HP, fibrinogen, A2M, and LBP are increased by 2-3-fold, while CRP and SAA1 are rapidly increased up to 5-1000-fold. This pathway describes the most common signaling that leads to the expression of APPs in the liver. The transcription factors that induce the expression of APPs include CEBPB, STAT1, STAT3, STAT5, NF-kB, HNF4A, SP1, and Jun/Fos. CEBPA is down-regulated in APR, while glucocorticoids are positive effectors of APP expression. Outcome effects: SERPINE2 is an important component of hepatic APR and a major physiological inhibitor of plasminogen (PLG) activation and inducer of blood coagulation. Furthermore, FN1, fibrinogen, F8, and VWF, cause clot formation. LBP, which is an opsonin, transfers LPS to CD14 on macrophages. CRP acts as an opsonin as well and activates complement by the classical C1q pathway. CRP is a member of the pentraxin family, which function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. IL6 induction is mediated by STAT3 and CEBPB, which leads to CRP expression. In addition, SERPINA1 is a serine protease inhibitor with targets that include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. A2M has many diversified and complex functions, but is primarily known for its ability to inhibit a broad spectrum of proteases. It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. A2M acts as a carrier protein because it also binds to numerous growth factors and cytokines. In addition, the physiological function of CP includes copper transport, coagulation, angiogenesis, defense against oxidant stress, and iron homeostasis. HP binds free hemoglobin in blood plasma released from erythrocytes with high affinity and thereby inhibits its oxidative activity. SAA1 is thought to influence high density lipoprotein-cholesterol transport. In tissues, it attracts inflammatory cells and inhibits the respiratory burst of leukocytes. Following secretion into the circulation, it associates with high-density lipoprotein (HDL) particles. During acute inflammation, serum SAA1 levels may rise up to 1000-fold. SAA1 exhibits significant immunological activity by being chemotactic for neutrophils and mast cells. ORM1 is one of the major APPs in humans and regulates injury-induced angiogenesis by promoting the downstream stimulation of the angiogenic process by VEGF. SERPINA3 is a plasma protease inhibitor and has a suppressive effect on neutrophil chemotaxis. Lastly, SERPING1 is a serine protease inhibitor (serpin) and major inhibitor of the contact coagulation system. It is also an important regulator of complement activation inhibiting the first component of complement C1. Another important biological role of SERPING1 is the regulation of vascular pe Organ: liver Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-3d502d15-75cf-41a0-86c0-1a97c27cf2fc Positive Acute Phase Proteins Synthesis uuid-3d502d15-75cf-41a0-86c0-1a97c27cf2fc PS:CellType hepatocyte PS:Description The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d502d15-75cf-41a0-86c0-1a97c27cf2fc PS:NodeType Pathway PS:Notes Headnote: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Signaling description: One of the first signs of APR is synthesis of acute phase proteins (APPs) in the liver. The release of proinflammatory cytokines, nitric oxide, and glucocorticoids, initiates the synthesis of APPs. IL6 is the key mediator for hepatocytic secretion of most APPs. Kupffer cells, which are specialized macrophages located in the liver, may be an additional source of proinflammatory cytokines. The physiological role of highly expressed (positive) APPs is to reduce the systemic effects of tissue damage by enhancing clot formation, reducing proteolysis, and facilitating the clearance of toxic metabolites. During APR, plasma viscosity increases as a result of changes in total blood protein concentration including the increase of fibrinogen, which influences the erythrocyte sedimentation rate (ESR). Systemic APR is profound in bacterial infections, while generally milder in viral infections. Among APPs, CP and C3 expressions are increased by approximately 50% in APR. Further, HP, fibrinogen, A2M, and LBP are increased by 2-3-fold, while CRP and SAA1 are rapidly increased up to 5-1000-fold. This pathway describes the most common signaling that leads to the expression of APPs in the liver. The transcription factors that induce the expression of APPs include CEBPB, STAT1, STAT3, STAT5, NF-kB, HNF4A, SP1, and Jun/Fos. CEBPA is down-regulated in APR, while glucocorticoids are positive effectors of APP expression. Outcome effects: SERPINE2 is an important component of hepatic APR and a major physiological inhibitor of plasminogen (PLG) activation and inducer of blood coagulation. Furthermore, FN1, fibrinogen, F8, and VWF, cause clot formation. LBP, which is an opsonin, transfers LPS to CD14 on macrophages. CRP acts as an opsonin as well and activates complement by the classical C1q pathway. CRP is a member of the pentraxin family, which function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. IL6 induction is mediated by STAT3 and CEBPB, which leads to CRP expression. In addition, SERPINA1 is a serine protease inhibitor with targets that include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. A2M has many diversified and complex functions, but is primarily known for its ability to inhibit a broad spectrum of proteases. It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. A2M acts as a carrier protein because it also binds to numerous growth factors and cytokines. In addition, the physiological function of CP includes copper transport, coagulation, angiogenesis, defense against oxidant stress, and iron homeostasis. HP binds free hemoglobin in blood plasma released from erythrocytes with high affinity and thereby inhibits its oxidative activity. SAA1 is thought to influence high density lipoprotein-cholesterol transport. In tissues, it attracts inflammatory cells and inhibits the respiratory burst of leukocytes. Following secretion into the circulation, it associates with high-density lipoprotein (HDL) particles. During acute inflammation, serum SAA1 levels may rise up to 1000-fold. SAA1 exhibits significant immunological activity by being chemotactic for neutrophils and mast cells. ORM1 is one of the major APPs in humans and regulates injury-induced angiogenesis by promoting the downstream stimulation of the angiogenic process by VEGF. SERPINA3 is a plasma protease inhibitor and has a suppressive effect on neutrophil chemotaxis. Lastly, SERPING1 is a serine protease inhibitor (serpin) and major inhibitor of the contact coagulation system. It is also an important regulator of complement activation inhibiting the first component of complement C1. Another important biological role of SERPING1 is the regulation of vascular pe PS:Organ liver PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d5e68ce-c35b-477b-a5e4-a5291f524e96 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3d5e68ce-c35b-477b-a5e4-a5291f524e96 Wilson's Disease Drugs uuid-3d5e68ce-c35b-477b-a5e4-a5291f524e96 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3d5e68ce-c35b-477b-a5e4-a5291f524e96 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dbb180e-c6da-473f-8f2f-3e2c8f57dd06 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-3dbb180e-c6da-473f-8f2f-3e2c8f57dd06 H2AK119 Deubiqitination uuid-3dbb180e-c6da-473f-8f2f-3e2c8f57dd06 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dbb180e-c6da-473f-8f2f-3e2c8f57dd06 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: MYCN amplification is found in about 22 percent of neuroblastoma (NB) cases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dcb6f5b-7325-4f07-a321-f94cf3af4922 NodeType: Pathway Notes: Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. MYCN amplification is found in about 22% of NB cases. Signaling description: MYCN forms a heterodimer with MAX and the protein complex functions as a transcriptional activator. MYCN expression targets are ODC1, MCM7, PTMA, TERT, PAX3, ID2, MDM2, and others. MYCN activation also leads to the overexpression of ABCB1 and ABCC1 and is responsible for drug resistance. The amplification of MDM2, DDX1, and MYCL1 are found in a small subset of NB cases. The loss of the short arm of chromosome 1 occurs in about 25-35% of NB tumors. Tumor suppressors including CHD5, MIR34A, and KIF1B are localized in chromosome 1 and they all affect cell growth. In addition, TP53 or CDKN2A may be mutated in rare cases of NB. Although TP53 is a transcriptional target of MYCN, MYCN also inhibits its function through increased levels of TP53 negative regulators such as MDM2 and TWIST1. Outcome effects: The genetic rearrangements result in the inhibition of apoptosis and activation of proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: nervous system PMID: 12438307 PMID: 12612655 PMID: 21295685 PMID: 22430387 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-3dcb6f5b-7325-4f07-a321-f94cf3af4922 non-Hereditary Genetic Rearrangements in Neuroblastoma uuid-3dcb6f5b-7325-4f07-a321-f94cf3af4922 PS:CellType cancer cell PS:CellType neural stem cell PS:Description MYCN amplification is found in about 22 percent of neuroblastoma (NB) cases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dcb6f5b-7325-4f07-a321-f94cf3af4922 PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. MYCN amplification is found in about 22% of NB cases. Signaling description: MYCN forms a heterodimer with MAX and the protein complex functions as a transcriptional activator. MYCN expression targets are ODC1, MCM7, PTMA, TERT, PAX3, ID2, MDM2, and others. MYCN activation also leads to the overexpression of ABCB1 and ABCC1 and is responsible for drug resistance. The amplification of MDM2, DDX1, and MYCL1 are found in a small subset of NB cases. The loss of the short arm of chromosome 1 occurs in about 25-35% of NB tumors. Tumor suppressors including CHD5, MIR34A, and KIF1B are localized in chromosome 1 and they all affect cell growth. In addition, TP53 or CDKN2A may be mutated in rare cases of NB. Although TP53 is a transcriptional target of MYCN, MYCN also inhibits its function through increased levels of TP53 negative regulators such as MDM2 and TWIST1. Outcome effects: The genetic rearrangements result in the inhibition of apoptosis and activation of proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System nervous system PS:PMID 12438307 PS:PMID 12612655 PS:PMID 21295685 PS:PMID 22430387 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: endothelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dd93878-507e-4419-827a-b6cc7841901d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-3dd93878-507e-4419-827a-b6cc7841901d Infection->TLRs in corneal ulcer uuid-3dd93878-507e-4419-827a-b6cc7841901d PS:CellType endothelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3dd93878-507e-4419-827a-b6cc7841901d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ddedb10-b1ba-4614-bd7a-c1bf0bf719c4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-3ddedb10-b1ba-4614-bd7a-c1bf0bf719c4 UDP-sugars interconversion template uuid-3ddedb10-b1ba-4614-bd7a-c1bf0bf719c4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ddedb10-b1ba-4614-bd7a-c1bf0bf719c4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:Organ PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de09a70-f3ef-4b78-90a7-e7a4ba0ca4d2 NodeType: Pathway Organ: skin PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-3de09a70-f3ef-4b78-90a7-e7a4ba0ca4d2 Differentiation of psoriatic T cells uuid-3de09a70-f3ef-4b78-90a7-e7a4ba0ca4d2 PS:CellType T-cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de09a70-f3ef-4b78-90a7-e7a4ba0ca4d2 PS:NodeType Pathway PS:Organ skin PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de71997-ecf6-4d0d-949f-640d14a44e91 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-3de71997-ecf6-4d0d-949f-640d14a44e91 VEGFR -> AP-1/CREB/MYC Signaling uuid-3de71997-ecf6-4d0d-949f-640d14a44e91 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de71997-ecf6-4d0d-949f-640d14a44e91 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Proteins traffic between the trans-Golgi network (TGN) and endosomes in a multi-step process consisting of membrane-bound vesicle formation (budding), targeting, tethering, and membrane fusion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de8ca6d-a44a-4514-afbb-561e57b1014e NodeType: Pathway Notes: Headnote: Proteins traffic between the trans-Golgi network (TGN) and endosomes in a multi-step process consisting of membrane-bound vesicle formation (budding), targeting, tethering, and membrane fusion. Signaling description: Cargo proteins are concentrated at a specialized region on the donor membrane and packed into a nascent vesicle. Vesicles with a clathrin coat from the plasma membrane and the TGN move to late endosomes. The receptors that use clathrin-coated vesicle endocytosis have a unique peptide signal, Phe-Arg-X-Tyr. This signal mediates clathrin adaptors AP-1, AP-2, AP-3, AP-4, GGA1, and GGA2 thus providing cargo selectivity in the transport vesicle from TGN to the endosome. CLINT1, PICALM, and calmodulin also contain binding motifs for clathrin allowing them to participate in clathrin-mediated budding at the TGN, endosome, or the plasma membrane. Vesicle-membrane SNAREs (SNAP receptors) are a set of proteins that cycle between the TGN and endosomes that mediate membrane fusion. There are over 30 SNAP receptors in humans, each associated with a particular membrane-enclosed organelle involved in the endocytic pathway. These transmembrane proteins exist as complementary sets of vesicle membrane SNAP receptors (v-SNAREs) and target membrane SNAP receptors (t-SNAREs). The complex formed brings the two membranes in close proximity allowing fusion of the lipid bilayers. The combination of SNAP receptors and tethering factors such as Golgi transport complex, TRAPP complex, GOLGA1, and GOLGA4 is largely responsible for the specificity of organelle-fusion events. Tethering factors are recruited from the cytosol to the TGN by small GTPases including RAB9A, RAB5A, or ARFRP1. Intracellular sorting receptors, M6PR and IGF2R, play an essential role in retrograde endosome-Golgi transport. Other important proteins in retrograde transport from endosomes to the TGN include transmembrane peptidases such as FURIN, CPD, and vacuolar sorting proteins. Vacuolar sorting proteins form a retromer protein complex which consists of two discrete complexes, a core assembly containing VPS35, VPS26A, and VPS29 and an associated dimer of proteins from the sorting nexin (SNX) protein family, SNX1 and SNX2. In addition to acid-hydrolase receptors, some bacterial and plant toxins internalized from the extracellular space also undergo retrograde transport. In human cells, two SNAP receptor complexes have been implicated in the transport of Shiga toxin from early and/or recycling endosomes to the TGN. The first includes BET1L, STX5, GOSR1, and YKT6 proteins, while the second consists of STX16, STX6, VTI1A, and VAMP4 proteins. Organ: generic Organ_System: generic PMID: 12757749 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-3de8ca6d-a44a-4514-afbb-561e57b1014e Golgi to Endosome Transport uuid-3de8ca6d-a44a-4514-afbb-561e57b1014e PS:CellType generic PS:Description Proteins traffic between the trans-Golgi network (TGN) and endosomes in a multi-step process consisting of membrane-bound vesicle formation (budding), targeting, tethering, and membrane fusion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3de8ca6d-a44a-4514-afbb-561e57b1014e PS:NodeType Pathway PS:Notes Headnote: Proteins traffic between the trans-Golgi network (TGN) and endosomes in a multi-step process consisting of membrane-bound vesicle formation (budding), targeting, tethering, and membrane fusion. Signaling description: Cargo proteins are concentrated at a specialized region on the donor membrane and packed into a nascent vesicle. Vesicles with a clathrin coat from the plasma membrane and the TGN move to late endosomes. The receptors that use clathrin-coated vesicle endocytosis have a unique peptide signal, Phe-Arg-X-Tyr. This signal mediates clathrin adaptors AP-1, AP-2, AP-3, AP-4, GGA1, and GGA2 thus providing cargo selectivity in the transport vesicle from TGN to the endosome. CLINT1, PICALM, and calmodulin also contain binding motifs for clathrin allowing them to participate in clathrin-mediated budding at the TGN, endosome, or the plasma membrane. Vesicle-membrane SNAREs (SNAP receptors) are a set of proteins that cycle between the TGN and endosomes that mediate membrane fusion. There are over 30 SNAP receptors in humans, each associated with a particular membrane-enclosed organelle involved in the endocytic pathway. These transmembrane proteins exist as complementary sets of vesicle membrane SNAP receptors (v-SNAREs) and target membrane SNAP receptors (t-SNAREs). The complex formed brings the two membranes in close proximity allowing fusion of the lipid bilayers. The combination of SNAP receptors and tethering factors such as Golgi transport complex, TRAPP complex, GOLGA1, and GOLGA4 is largely responsible for the specificity of organelle-fusion events. Tethering factors are recruited from the cytosol to the TGN by small GTPases including RAB9A, RAB5A, or ARFRP1. Intracellular sorting receptors, M6PR and IGF2R, play an essential role in retrograde endosome-Golgi transport. Other important proteins in retrograde transport from endosomes to the TGN include transmembrane peptidases such as FURIN, CPD, and vacuolar sorting proteins. Vacuolar sorting proteins form a retromer protein complex which consists of two discrete complexes, a core assembly containing VPS35, VPS26A, and VPS29 and an associated dimer of proteins from the sorting nexin (SNX) protein family, SNX1 and SNX2. In addition to acid-hydrolase receptors, some bacterial and plant toxins internalized from the extracellular space also undergo retrograde transport. In human cells, two SNAP receptor complexes have been implicated in the transport of Shiga toxin from early and/or recycling endosomes to the TGN. The first includes BET1L, STX5, GOSR1, and YKT6 proteins, while the second consists of STX16, STX6, VTI1A, and VAMP4 proteins. PS:Organ generic PS:Organ_System generic PS:PMID 12757749 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Cytokine-mediated destruction of beta cells is central to the development of type 1 diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3deac240-a392-473e-aaa9-090415ae8e4a NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: Pro-inflammatory factors such as IL1B, IFNG, and likely TNF induce NOS2 overexpression in beta-cells, leading to the overproduction of NO (nitric oxide) which induces cytotoxicity. The transcription of NOS2 in response to cytokine exposure is regulated by NF-kB (in case of exposure to IL1B) and STAT1 (in case of IFNG). IL1 by itself is sufficient to induce NOS2 expression in rat islets, whereas human and mouse tissues require IL1 and IFNG. IFNG synergizes with IL1B for the induction of beta-cell apoptosis. In human islets and rat beta cells, cytokines induce apoptosis via the canonical intrinsic mitochondrial pathway. IL1B also induces calcineurin-dependent dephosphorylation of BAD/BAX and leads to cytochrome c (CYCS) release and activation of CASP9 and CASP3. In beta-cells, TNF, but not IL1B induces the activation of CASP8, indicating that TNF is able to activate the extrinsic pathway. Outcome effects: NF-kB functions as a "master switch" which controls the effector genes important for maintaining beta-cell homeostasis or apoptosis. Cytokines and hyperglycemia induce NF-kB-related beta-cell apoptosis but simultaneously defend against it. For example, NF-kb induces TNFAIP3 and HMOX1 expression in beta cells leading to an anti-apoptotic effect. Excessive activation of NF-kB by cytokines in beta-cells results in the up-regulated expression of CCL2. Glucose and IL1B can activate TNF expression in pancreatic beta- and alpha-cells in mice and humans. In murine beta-cells, TNF expression is dependent on calcineurin/NFAT/MAPK signaling. NFAT activates TNF expression in cooperation with ATF2 and JUN transcription factors. MAFA/CEBPB interaction could repress NFAT-mediated TNF expression. Organ: pancreas Organ_System: endocrine system PMID: 19470609 PMID: 21059644 PMID: 24559923 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-3deac240-a392-473e-aaa9-090415ae8e4a beta-Cell Destruction through Cytokines in Diabetes Mellitus uuid-3deac240-a392-473e-aaa9-090415ae8e4a PS:CellType insulin-secreting cell PS:Description Cytokine-mediated destruction of beta cells is central to the development of type 1 diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3deac240-a392-473e-aaa9-090415ae8e4a PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: Pro-inflammatory factors such as IL1B, IFNG, and likely TNF induce NOS2 overexpression in beta-cells, leading to the overproduction of NO (nitric oxide) which induces cytotoxicity. The transcription of NOS2 in response to cytokine exposure is regulated by NF-kB (in case of exposure to IL1B) and STAT1 (in case of IFNG). IL1 by itself is sufficient to induce NOS2 expression in rat islets, whereas human and mouse tissues require IL1 and IFNG. IFNG synergizes with IL1B for the induction of beta-cell apoptosis. In human islets and rat beta cells, cytokines induce apoptosis via the canonical intrinsic mitochondrial pathway. IL1B also induces calcineurin-dependent dephosphorylation of BAD/BAX and leads to cytochrome c (CYCS) release and activation of CASP9 and CASP3. In beta-cells, TNF, but not IL1B induces the activation of CASP8, indicating that TNF is able to activate the extrinsic pathway. Outcome effects: NF-kB functions as a "master switch" which controls the effector genes important for maintaining beta-cell homeostasis or apoptosis. Cytokines and hyperglycemia induce NF-kB-related beta-cell apoptosis but simultaneously defend against it. For example, NF-kb induces TNFAIP3 and HMOX1 expression in beta cells leading to an anti-apoptotic effect. Excessive activation of NF-kB by cytokines in beta-cells results in the up-regulated expression of CCL2. Glucose and IL1B can activate TNF expression in pancreatic beta- and alpha-cells in mice and humans. In murine beta-cells, TNF expression is dependent on calcineurin/NFAT/MAPK signaling. NFAT activates TNF expression in cooperation with ATF2 and JUN transcription factors. MAFA/CEBPB interaction could repress NFAT-mediated TNF expression. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19470609 PS:PMID 21059644 PS:PMID 24559923 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3df0cc36-1ad0-45ef-80f2-3a17f4fe9c8e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3df0cc36-1ad0-45ef-80f2-3a17f4fe9c8e DLL3 Expression Targets uuid-3df0cc36-1ad0-45ef-80f2-3a17f4fe9c8e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3df0cc36-1ad0-45ef-80f2-3a17f4fe9c8e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e04a7f0-ae52-41e6-a68b-107cfeb078a8 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-3e04a7f0-ae52-41e6-a68b-107cfeb078a8 AMPA Receptors -> Calcium Influx uuid-3e04a7f0-ae52-41e6-a68b-107cfeb078a8 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e04a7f0-ae52-41e6-a68b-107cfeb078a8 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e117f7e-511f-4fa0-8882-432085b44501 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-3e117f7e-511f-4fa0-8882-432085b44501 Role of N2 Neutrophils in Tumor-Promoting Inflammation and Tumor Progression uuid-3e117f7e-511f-4fa0-8882-432085b44501 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e117f7e-511f-4fa0-8882-432085b44501 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e28cc8d-57bf-4b2c-a446-f885a3d0c143 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3e28cc8d-57bf-4b2c-a446-f885a3d0c143 CXCL5 Expression Targets uuid-3e28cc8d-57bf-4b2c-a446-f885a3d0c143 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e28cc8d-57bf-4b2c-a446-f885a3d0c143 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e2be759-1a06-42c1-92df-73db52d9416c NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3e2be759-1a06-42c1-92df-73db52d9416c Metabolism of Glycerophospholipids and Ether Lipids uuid-3e2be759-1a06-42c1-92df-73db52d9416c PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e2be759-1a06-42c1-92df-73db52d9416c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle consists of four discrete phases including S phase, M phase, and two Gap phases, G1 and G2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e2cf9f1-72f6-4b94-bf9b-fd771ff235ec NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle includes four discrete phases including the S phase in which DNA is replicated, M phase when the chromosomes are separated in the process of mitosis, and two Gap phases, G1 and G2 in which the cell prepares for mitosis. Signaling description: In mammalian cells, CCND and CDK4/6 are needed for G1 progression, CCNE and CDK2 for G1-S transition, CCNA and CDK2 for S phase progression, and CCNB and CDK1 for entry of the cell into M phase. The disruption of cyclin action leads to either cell cycle arrest or to uncontrolled cell proliferation. The G1 phase is marked by the synthesis of enzymes required for the S phase. During G1/S transition, phosphorylation of RB1 by CDK4/6 and CDK2 disrupts the RB1-repressor complex, permitting transcription of the S phase genes which are required for further DNA replication. Many diverse stimuli exert G1/S checkpoint control and most of them act by inducing members of the INK4 family of cyclin-dependent kinase inhibitors including CDKN2D, CDKN2C, CDKN2A, and CDKN2B or CIP/KIP family of cyclin-dependent kinase inhibitors such as CDKN1A and CDKN1B. The S phase begins when DNA synthesis commences, and when it is complete all of the chromosomes have been replicated. In the S phase, CCNA and CCNE are required to induce DNA replication and synthesis. The G2 phase continues until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production of microtubules for mitosis. The G2/M checkpoint is determined by a threshold level of the active CCNB1-CDK1 complex. CDK1 activity is modulated primarily through the regulation of its inhibitory phosphorylation sites by WEE1 and MYT1. Multiple feedback loops function in parallel to enhance CCNB-CDK1 activation. The G2/M checkpoint prevents the cell from entering mitosis if the genome is damaged. The M phase (mitosis) promoting factor activates the anaphase-promoting complex (APC/C) which allows its sister chromatids to move to the poles (anaphase), completing mitosis. Outcome effects: The anaphase begins when APC/C destroys PTTG1. APC/C activity maintains low CCNB levels through G1 phase until silencing of APC/C in the S phase through direct inactivation by CCNA-CDK2. The spindle assembly checkpoint (SAC) stops the cell cycle in the M phase. The proteins responsible for the SAC signal make up the mitotic checkpoint complex (MCC). The proteolysis of CCNB and inactivation of the CCNB-CDK1 kinase can inhibit SAC activity. Organ: generic Organ_System: generic PMID: 11259164 PMID: 23861057 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-3e2cf9f1-72f6-4b94-bf9b-fd771ff235ec Cell Cycle Overiew uuid-3e2cf9f1-72f6-4b94-bf9b-fd771ff235ec PS:CellType generic PS:Description The mammalian cell cycle consists of four discrete phases including S phase, M phase, and two Gap phases, G1 and G2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e2cf9f1-72f6-4b94-bf9b-fd771ff235ec PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle includes four discrete phases including the S phase in which DNA is replicated, M phase when the chromosomes are separated in the process of mitosis, and two Gap phases, G1 and G2 in which the cell prepares for mitosis. Signaling description: In mammalian cells, CCND and CDK4/6 are needed for G1 progression, CCNE and CDK2 for G1-S transition, CCNA and CDK2 for S phase progression, and CCNB and CDK1 for entry of the cell into M phase. The disruption of cyclin action leads to either cell cycle arrest or to uncontrolled cell proliferation. The G1 phase is marked by the synthesis of enzymes required for the S phase. During G1/S transition, phosphorylation of RB1 by CDK4/6 and CDK2 disrupts the RB1-repressor complex, permitting transcription of the S phase genes which are required for further DNA replication. Many diverse stimuli exert G1/S checkpoint control and most of them act by inducing members of the INK4 family of cyclin-dependent kinase inhibitors including CDKN2D, CDKN2C, CDKN2A, and CDKN2B or CIP/KIP family of cyclin-dependent kinase inhibitors such as CDKN1A and CDKN1B. The S phase begins when DNA synthesis commences, and when it is complete all of the chromosomes have been replicated. In the S phase, CCNA and CCNE are required to induce DNA replication and synthesis. The G2 phase continues until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production of microtubules for mitosis. The G2/M checkpoint is determined by a threshold level of the active CCNB1-CDK1 complex. CDK1 activity is modulated primarily through the regulation of its inhibitory phosphorylation sites by WEE1 and MYT1. Multiple feedback loops function in parallel to enhance CCNB-CDK1 activation. The G2/M checkpoint prevents the cell from entering mitosis if the genome is damaged. The M phase (mitosis) promoting factor activates the anaphase-promoting complex (APC/C) which allows its sister chromatids to move to the poles (anaphase), completing mitosis. Outcome effects: The anaphase begins when APC/C destroys PTTG1. APC/C activity maintains low CCNB levels through G1 phase until silencing of APC/C in the S phase through direct inactivation by CCNA-CDK2. The spindle assembly checkpoint (SAC) stops the cell cycle in the M phase. The proteins responsible for the SAC signal make up the mitotic checkpoint complex (MCC). The proteolysis of CCNB and inactivation of the CCNB-CDK1 kinase can inhibit SAC activity. PS:Organ generic PS:Organ_System generic PS:PMID 11259164 PS:PMID 23861057 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e5c4aad-3284-4ed9-b2ed-cc4c808e2435 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3e5c4aad-3284-4ed9-b2ed-cc4c808e2435 PDGFB -> STAT Expression Target uuid-3e5c4aad-3284-4ed9-b2ed-cc4c808e2435 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e5c4aad-3284-4ed9-b2ed-cc4c808e2435 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e6ceb78-5b21-4ec1-9481-6bb79ba79219 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3e6ceb78-5b21-4ec1-9481-6bb79ba79219 Vitamin A (Retinol) Metabolism and Visual Cycle uuid-3e6ceb78-5b21-4ec1-9481-6bb79ba79219 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e6ceb78-5b21-4ec1-9481-6bb79ba79219 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e7da42a-2162-4a90-bd85-51534676fa3f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3e7da42a-2162-4a90-bd85-51534676fa3f VIP Expression Targets uuid-3e7da42a-2162-4a90-bd85-51534676fa3f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3e7da42a-2162-4a90-bd85-51534676fa3f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3eaf1840-3b83-4f34-973a-ea80dd553a25 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3eaf1840-3b83-4f34-973a-ea80dd553a25 PARP1-+>myofibroblast differentiation uuid-3eaf1840-3b83-4f34-973a-ea80dd553a25 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3eaf1840-3b83-4f34-973a-ea80dd553a25 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source CellType: stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ebd5936-74b2-4ec0-95e8-c71d05b590d8 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-3ebd5936-74b2-4ec0-95e8-c71d05b590d8 Proteins Involved in Stem Cell Exhaustion in Aging uuid-3ebd5936-74b2-4ec0-95e8-c71d05b590d8 PS:CellType stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ebd5936-74b2-4ec0-95e8-c71d05b590d8 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ec19baf-18ad-496b-8955-eee458dac411 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-3ec19baf-18ad-496b-8955-eee458dac411 MolSynthesis for Histones Modification Sites uuid-3ec19baf-18ad-496b-8955-eee458dac411 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ec19baf-18ad-496b-8955-eee458dac411 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Protein kinase C (PKC) activation occurs in diabetic microangiopathy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ec6da8d-f527-4686-a039-35efdea5976c NodeType: Pathway Notes: Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. In diabetes, hyperglycemia is the major underlying cause of diabetic microangiopathy. Signaling description: Protein kinase C (PKC) activation by diacylglycerol is implicated in diabetic microangiopathy. The major source of diacylglycerol, which is elevated in diabetes, is intracellular hyperglycemia which induces de novo synthesis of diacylglycerol which is formed from the glycolytic intermediate, dihydroxyacetone phosphate, through the reduction of the latter to glycerol-3-phosphate and stepwise acylation (not shown). PKC beta-II (PRKCB) is an essential isozyme among the PKC isoforms, which is activated in vascular tissues during hyperglycemia. Due to the PRKCB activation, NF-kB is released from its inhibitor, NFKBIA and binds to the promoter regions of TGFB1 and EDN1 genes. Elevated EDN1 levels are observed in diabetic patients. TGFB1 triggers FN1, collagen IV, and collagen VI expression. Diacylglycerol similarly primarily affects PRKCD in diabetic edotheliocytes, and via MAPK-cascades, activates JUN which is a transcription factor for FN1. Outcome effects: Elevation of extracellular FN1, collagen IV, and collagen VI proteins leads to the thickening of capillary basement membranes which is the result of exchange diffusion impairment (metabolites and oxygen) in tissue. The expression of EDN1, which is a powerful vasoconstrictor, contributes to the elevation of blood pressure. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system Organ_System: endocrine system PMID: 17574431 PMID: 18230954 PMID: 18793542 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-3ec6da8d-f527-4686-a039-35efdea5976c Protein Kinase C in Diabetic Microangiopathy uuid-3ec6da8d-f527-4686-a039-35efdea5976c PS:CellType vascular smooth muscle cell PS:Description Protein kinase C (PKC) activation occurs in diabetic microangiopathy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3ec6da8d-f527-4686-a039-35efdea5976c PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. In diabetes, hyperglycemia is the major underlying cause of diabetic microangiopathy. Signaling description: Protein kinase C (PKC) activation by diacylglycerol is implicated in diabetic microangiopathy. The major source of diacylglycerol, which is elevated in diabetes, is intracellular hyperglycemia which induces de novo synthesis of diacylglycerol which is formed from the glycolytic intermediate, dihydroxyacetone phosphate, through the reduction of the latter to glycerol-3-phosphate and stepwise acylation (not shown). PKC beta-II (PRKCB) is an essential isozyme among the PKC isoforms, which is activated in vascular tissues during hyperglycemia. Due to the PRKCB activation, NF-kB is released from its inhibitor, NFKBIA and binds to the promoter regions of TGFB1 and EDN1 genes. Elevated EDN1 levels are observed in diabetic patients. TGFB1 triggers FN1, collagen IV, and collagen VI expression. Diacylglycerol similarly primarily affects PRKCD in diabetic edotheliocytes, and via MAPK-cascades, activates JUN which is a transcription factor for FN1. Outcome effects: Elevation of extracellular FN1, collagen IV, and collagen VI proteins leads to the thickening of capillary basement membranes which is the result of exchange diffusion impairment (metabolites and oxygen) in tissue. The expression of EDN1, which is a powerful vasoconstrictor, contributes to the elevation of blood pressure. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:Organ_System endocrine system PS:PMID 17574431 PS:PMID 18230954 PS:PMID 18793542 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f18f37d-1f33-4836-adb1-a6584c2d7aa5 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-3f18f37d-1f33-4836-adb1-a6584c2d7aa5 ADRA2A -> Hyperpolarization uuid-3f18f37d-1f33-4836-adb1-a6584c2d7aa5 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f18f37d-1f33-4836-adb1-a6584c2d7aa5 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f5788ff-bc88-4931-83a5-961f4f286224 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3f5788ff-bc88-4931-83a5-961f4f286224 IGF2 -> STAT Expression Targets uuid-3f5788ff-bc88-4931-83a5-961f4f286224 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f5788ff-bc88-4931-83a5-961f4f286224 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f6b440f-0455-4ae8-abf1-83b2c0263dc2 NodeType: Pathway Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3f6b440f-0455-4ae8-abf1-83b2c0263dc2 Proteins Involved in Female Infertility uuid-3f6b440f-0455-4ae8-abf1-83b2c0263dc2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f6b440f-0455-4ae8-abf1-83b2c0263dc2 PS:NodeType Pathway PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Hypertrophic cardiomyopathy is the most common monogenically inherited form of heart disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f7252e1-4b73-486c-b8e6-fd46b1a44a4d NodeType: Pathway Notes: Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Mutations in more than 20 genes may induce hypertrophic cardiomyopathy (HCM). Most of these genes encode sarcomeric proteins; however genes of non-sarcomeric proteins may also be mutated. Signaling description: Beta-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) are the three most common causal genes for HCM and collectively account for approximately 75% of all HCM cases. The mutated sarcomeric protein genes are cardiac troponin I (TNNI3), cardiac troponin C (TNNC1), cardiac alpha-actin (ACTC1), alpha-tropomyosin (TPM1), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), and alpha-myosin heavy chain (MYH6). In addition, HCM-causing mutations have been identified in several genes encoding Z disk proteins including telethonin (TCAP), myozenin 2 (MYOZ2), cardiac muscle LIM protein (CSRP3), and ankyrin repeat and KH domain-containing protein 1 (ANKRD1) as well as in proteins connecting the plasma membrane and sarcomere such as vinculin (VCL), junctophilin 2 (JPH2), and caveolin 3 (CAV3). Titin (TTN) spreading from Z- to M-disk may also be mutated. Calcium (Ca2+) also has an important role in the pathogenesis of HCM. Normally during action potential, Ca2+ enters the cardiomyocyte through the voltage-gated L-type Ca2+ channels (CACNA1C) which are responsible for Ca2+ influx and to a lesser extent via the Na+/Ca2+ exchanger (SLC8A1), thereby triggering Ca2+-induced Ca2+ release through cardiac ryanodine receptor (RYR2) from the sarcoplasmic reticulum (SR). This Ca2+ binds TNNC1 and activates the myofilaments during systole leading to contraction. Outcome effects: During diastole, Ca2+ is taken back up into the SR by cardiac muscle Ca2+ transporting ATPase (ATP2A2) and is pumped out of the cells by SLC8A1 which results in relaxation. The increase in intracellular Ca2+ in HCM is the result of two different mechanisms. The mutated sarcomeric proteins use more adenosine triphosphate (ATP) to produce the same force of contraction. Therefore, it compromises Ca2+ reuptake by the ATP2A2 transporter into the SR and more Ca2+ becomes available inside the cells. Finally, mutations in sarcomeric and non-sarcomeric proteins lead to impaired sarcomere assembly and impaired myofibrillar contractile function. This, in addition to intracellular Ca2+ overload, leads to compensatory cardiomyocyte hypertrophy. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: heart Organ_System: cardiovascular system PMID: 21415408 PMID: 21700950 PMID: 21825071 PMID: 22027658 PMID: 22796258 PMID: 22874472 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-3f7252e1-4b73-486c-b8e6-fd46b1a44a4d Sarcomere Disorganization and Intracellular Calcium Overload uuid-3f7252e1-4b73-486c-b8e6-fd46b1a44a4d PS:CellType cardiac myocyte PS:Description Hypertrophic cardiomyopathy is the most common monogenically inherited form of heart disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f7252e1-4b73-486c-b8e6-fd46b1a44a4d PS:NodeType Pathway PS:Notes Headnote: Hypertrophic cardiomyopathy (HCM) is the most common monogenically inherited form of heart disease characterized by the thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. Mutations in more than 20 genes may induce hypertrophic cardiomyopathy (HCM). Most of these genes encode sarcomeric proteins; however genes of non-sarcomeric proteins may also be mutated. Signaling description: Beta-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) are the three most common causal genes for HCM and collectively account for approximately 75% of all HCM cases. The mutated sarcomeric protein genes are cardiac troponin I (TNNI3), cardiac troponin C (TNNC1), cardiac alpha-actin (ACTC1), alpha-tropomyosin (TPM1), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), and alpha-myosin heavy chain (MYH6). In addition, HCM-causing mutations have been identified in several genes encoding Z disk proteins including telethonin (TCAP), myozenin 2 (MYOZ2), cardiac muscle LIM protein (CSRP3), and ankyrin repeat and KH domain-containing protein 1 (ANKRD1) as well as in proteins connecting the plasma membrane and sarcomere such as vinculin (VCL), junctophilin 2 (JPH2), and caveolin 3 (CAV3). Titin (TTN) spreading from Z- to M-disk may also be mutated. Calcium (Ca2+) also has an important role in the pathogenesis of HCM. Normally during action potential, Ca2+ enters the cardiomyocyte through the voltage-gated L-type Ca2+ channels (CACNA1C) which are responsible for Ca2+ influx and to a lesser extent via the Na+/Ca2+ exchanger (SLC8A1), thereby triggering Ca2+-induced Ca2+ release through cardiac ryanodine receptor (RYR2) from the sarcoplasmic reticulum (SR). This Ca2+ binds TNNC1 and activates the myofilaments during systole leading to contraction. Outcome effects: During diastole, Ca2+ is taken back up into the SR by cardiac muscle Ca2+ transporting ATPase (ATP2A2) and is pumped out of the cells by SLC8A1 which results in relaxation. The increase in intracellular Ca2+ in HCM is the result of two different mechanisms. The mutated sarcomeric proteins use more adenosine triphosphate (ATP) to produce the same force of contraction. Therefore, it compromises Ca2+ reuptake by the ATP2A2 transporter into the SR and more Ca2+ becomes available inside the cells. Finally, mutations in sarcomeric and non-sarcomeric proteins lead to impaired sarcomere assembly and impaired myofibrillar contractile function. This, in addition to intracellular Ca2+ overload, leads to compensatory cardiomyocyte hypertrophy. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 21415408 PS:PMID 21700950 PS:PMID 21825071 PS:PMID 22027658 PS:PMID 22796258 PS:PMID 22874472 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue myocardium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f76a685-ea9a-4215-9585-dc4f0aa8a4a5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3f76a685-ea9a-4215-9585-dc4f0aa8a4a5 Glutamate/Gq Expression Targets uuid-3f76a685-ea9a-4215-9585-dc4f0aa8a4a5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f76a685-ea9a-4215-9585-dc4f0aa8a4a5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f94ece9-11de-4c8a-9f22-43034d3a67ae NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3f94ece9-11de-4c8a-9f22-43034d3a67ae SPP1-+>IR uuid-3f94ece9-11de-4c8a-9f22-43034d3a67ae PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3f94ece9-11de-4c8a-9f22-43034d3a67ae PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fa592ee-799a-485f-beaf-0fe3b1bb1e30 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-3fa592ee-799a-485f-beaf-0fe3b1bb1e30 EGF -> FOXO3A Expression Targets uuid-3fa592ee-799a-485f-beaf-0fe3b1bb1e30 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fa592ee-799a-485f-beaf-0fe3b1bb1e30 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fafc4e0-de30-43bd-8d8f-b6612f5279a4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-3fafc4e0-de30-43bd-8d8f-b6612f5279a4 Proteins Involved in Sleep Disorders uuid-3fafc4e0-de30-43bd-8d8f-b6612f5279a4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fafc4e0-de30-43bd-8d8f-b6612f5279a4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fcc991c-0564-462f-ac7a-d74a381ae573 NodeType: Pathway Notes: Studies have described more than 100 variations associated with ulcerative colitis. However, much more additional work is needed to confirm the associations and the disease-specific manifestations for many of declared variations. Sometimes, it is impossible to separate ulcerative colitis from Crohn’s disease and other manifestations of inflammatory bowel diseases in data analysis and in diagnosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-3fcc991c-0564-462f-ac7a-d74a381ae573 4_1_Polymorphisms associated with inflammatory bowel diseases uuid-3fcc991c-0564-462f-ac7a-d74a381ae573 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fcc991c-0564-462f-ac7a-d74a381ae573 PS:NodeType Pathway PS:Notes Studies have described more than 100 variations associated with ulcerative colitis. However, much more additional work is needed to confirm the associations and the disease-specific manifestations for many of declared variations. Sometimes, it is impossible to separate ulcerative colitis from Crohn’s disease and other manifestations of inflammatory bowel diseases in data analysis and in diagnosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fce2849-d3c4-4adc-852d-b2b95ecb3fa3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-3fce2849-d3c4-4adc-852d-b2b95ecb3fa3 SPARC+>fibroblastic foci in IPF uuid-3fce2849-d3c4-4adc-852d-b2b95ecb3fa3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fce2849-d3c4-4adc-852d-b2b95ecb3fa3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Mantle Cell Lymphoma (MCL) is one of the B-cell malignancies with the highest degree of genomic instability. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fd0b118-f392-4561-9085-5e89ad6d9366 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and the aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. The role of CCND1 in promoting MCL lymphomagenesis is related to its function in the cell cycle regulating cyclin-dependent kinases, CDK4 and CDK6. Several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL is one of the B-cell malignancies with the highest degree of genomic instability, and a large number of secondary chromosomal alterations have been described in MCL including losses, gains, and amplifications of chromosomal regions that contain genes involved in cell-cycle regulation. TP53, RB1, ATM, CDKN2A, CDKN2C, HIC1, CHEK2, and MIR29A genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplification events deregulate genes such as CDK4, BMI1, and MDM2. Outcome effects: The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promotes cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In conclusion, all of the described genetic events lead to uncontrolled tumor proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 18410453 PMID: 20940415 PMID: 23023712 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-3fd0b118-f392-4561-9085-5e89ad6d9366 Cell Cycle Dysregulation in Mantle Cell Lymphoma uuid-3fd0b118-f392-4561-9085-5e89ad6d9366 PS:CellType B-cell PS:CellType cancer cell PS:Description Mantle Cell Lymphoma (MCL) is one of the B-cell malignancies with the highest degree of genomic instability. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fd0b118-f392-4561-9085-5e89ad6d9366 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and the aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. The role of CCND1 in promoting MCL lymphomagenesis is related to its function in the cell cycle regulating cyclin-dependent kinases, CDK4 and CDK6. Several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL is one of the B-cell malignancies with the highest degree of genomic instability, and a large number of secondary chromosomal alterations have been described in MCL including losses, gains, and amplifications of chromosomal regions that contain genes involved in cell-cycle regulation. TP53, RB1, ATM, CDKN2A, CDKN2C, HIC1, CHEK2, and MIR29A genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplification events deregulate genes such as CDK4, BMI1, and MDM2. Outcome effects: The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promotes cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In conclusion, all of the described genetic events lead to uncontrolled tumor proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 18410453 PS:PMID 20940415 PS:PMID 23023712 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fd3b98c-5efe-4b61-ad5e-22aba646d3fb NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: colon Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-3fd3b98c-5efe-4b61-ad5e-22aba646d3fb EGFR -> Expression Targets in Colon uuid-3fd3b98c-5efe-4b61-ad5e-22aba646d3fb PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3fd3b98c-5efe-4b61-ad5e-22aba646d3fb PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ colon PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3feb295e-9222-4a5c-a7b4-111ecf51c1a3 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-3feb295e-9222-4a5c-a7b4-111ecf51c1a3 D-Amino Acid Metabolism uuid-3feb295e-9222-4a5c-a7b4-111ecf51c1a3 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-3feb295e-9222-4a5c-a7b4-111ecf51c1a3 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4009e7fe-11fd-4ce6-9624-efa03518f1e8 NodeType: Pathway urn:agi-pathway:uuid-4009e7fe-11fd-4ce6-9624-efa03518f1e8 Focal Junction Assembly uuid-4009e7fe-11fd-4ce6-9624-efa03518f1e8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4009e7fe-11fd-4ce6-9624-efa03518f1e8 PS:NodeType Pathway PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4024a3d0-11be-4cf9-b204-f80b02fa5c80 NodeType: Pathway Notes: Endothelium is a monolayer tissue that regulates interactions between the arterial wall and many cells and factors coming from circulating blood such as immune cells, hormones, and mediators of cellular function. Disturbance of endothelium-dependent vasodilation leads to endothelial dysfunction and disruption of the targeted action of vasoactive molecules on the vascular muscle tone. NO production can be stimulated by bradykinin, histamine, and other substances. A bradykinin deficiency and a lack of constitutional activation of nitric oxide synthase (NOS3) lead to a shortage of NO and prostaglandin and therefore impaired vasodilation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: Blood Vessels Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: endothelium urn:agi-pathway:uuid-4024a3d0-11be-4cf9-b204-f80b02fa5c80 4_Endothelial cells repress vasoconstriction in hypertension uuid-4024a3d0-11be-4cf9-b204-f80b02fa5c80 PS:CellType endothelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4024a3d0-11be-4cf9-b204-f80b02fa5c80 PS:NodeType Pathway PS:Notes Endothelium is a monolayer tissue that regulates interactions between the arterial wall and many cells and factors coming from circulating blood such as immune cells, hormones, and mediators of cellular function. Disturbance of endothelium-dependent vasodilation leads to endothelial dysfunction and disruption of the targeted action of vasoactive molecules on the vascular muscle tone. NO production can be stimulated by bradykinin, histamine, and other substances. A bradykinin deficiency and a lack of constitutional activation of nitric oxide synthase (NOS3) lead to a shortage of NO and prostaglandin and therefore impaired vasodilation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ Blood Vessels PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue endothelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Genetic studies have identified a missense mutation in GABRB3 in a patient with chronic insomnia who had a family history of sleep problems. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4047d635-2f32-4fda-9253-5d9eb43daff3 NodeType: Pathway Notes: Headnote: A missense mutation in the gene encoding the beta-3 subunit of the GABAA receptor (GABRB3) was detected in a patient with chronic insomnia who had a family history of sleep problems. Signaling description: The Cl- conductance evoked by GABA decays faster in GABRB3 mutated channels than in wild-type channels. These results indicate that mutations in the GABAA-receptors may be involved in the pathogenesis of insomnia. Furthermore, sleep disorders including insomnia have been effectively treated with the therapeutic agents that stimulate GABAA-receptor Cl- channel activity. GABRB3 mutations / polymorphisms are also associated with development of epilepsy and autism.Also, adenosine was shown to play important role in sleep control. Adenosine deaminase (ADA) is an enzyme that catalyzes the hydrolysis of adenosine to inosine. ADA polymorphism was shown to modulate the duration of slow-wave sleep as well as the intensity of sleep. ADA polymorphism was shown to modulate the duration of slow-wave sleep as well as the intensity of sleep. Organ: brain Organ_System: nervous system PMID: 12189488 PMID: 16221767 PMID: 16457993 PMID: 19660984 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-4047d635-2f32-4fda-9253-5d9eb43daff3 GABRB3 Mutation and Adenosine Deaminase Polymorphism uuid-4047d635-2f32-4fda-9253-5d9eb43daff3 PS:CellType neuron PS:Description Genetic studies have identified a missense mutation in GABRB3 in a patient with chronic insomnia who had a family history of sleep problems. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4047d635-2f32-4fda-9253-5d9eb43daff3 PS:NodeType Pathway PS:Notes Headnote: A missense mutation in the gene encoding the beta-3 subunit of the GABAA receptor (GABRB3) was detected in a patient with chronic insomnia who had a family history of sleep problems. Signaling description: The Cl- conductance evoked by GABA decays faster in GABRB3 mutated channels than in wild-type channels. These results indicate that mutations in the GABAA-receptors may be involved in the pathogenesis of insomnia. Furthermore, sleep disorders including insomnia have been effectively treated with the therapeutic agents that stimulate GABAA-receptor Cl- channel activity. GABRB3 mutations / polymorphisms are also associated with development of epilepsy and autism.Also, adenosine was shown to play important role in sleep control. Adenosine deaminase (ADA) is an enzyme that catalyzes the hydrolysis of adenosine to inosine. ADA polymorphism was shown to modulate the duration of slow-wave sleep as well as the intensity of sleep. ADA polymorphism was shown to modulate the duration of slow-wave sleep as well as the intensity of sleep. PS:Organ brain PS:Organ_System nervous system PS:PMID 12189488 PS:PMID 16221767 PS:PMID 16457993 PS:PMID 19660984 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4048f287-bec2-4d30-849f-ea402cb93b7a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-4048f287-bec2-4d30-849f-ea402cb93b7a Tryptophan degradation template uuid-4048f287-bec2-4d30-849f-ea402cb93b7a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4048f287-bec2-4d30-849f-ea402cb93b7a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4055dfcc-3fbb-47f6-9fd8-756c51bb9bb6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4055dfcc-3fbb-47f6-9fd8-756c51bb9bb6 Insulin -> ELK/SRF/HIF1A/MYC/SREBF Expression Targets uuid-4055dfcc-3fbb-47f6-9fd8-756c51bb9bb6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4055dfcc-3fbb-47f6-9fd8-756c51bb9bb6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4061e4ee-60db-4e73-a4a1-9a03adc875e5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4061e4ee-60db-4e73-a4a1-9a03adc875e5 Myelin sphingolipids biosynthesis uuid-4061e4ee-60db-4e73-a4a1-9a03adc875e5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4061e4ee-60db-4e73-a4a1-9a03adc875e5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Brain Dysfunction in Phenylketonuria In phenylketonuria (PKU) occurs due to high levels of phenylalanine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40793df2-1986-4d7c-983d-610158ac0feb NodeType: Pathway Notes: Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. Signaling description: Phenylalanine enters the brain using the L-type amino acid transporter SLC7A5 in competition with eight other L-type amino acids (i.e. tyrosine, tryptophan, valine, isoleucine, leucine, threonine, methionine, and histidine). Among thse amino acids, tyrosine and tryptophan are listed on the pathway since their deficiencies severely affect the pathology manifestation and progress. The SLC7A5 transporter has a high affinity for phenylalanine, resulting in a high transport velocity even if blood phenylalanine level is only slightly elevated. Outcome effects: Increased brain phenylalanine inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH2) leading to decreased dopamine and serotonin biosynthesis. The lack of dopamine and serotonin disrupts synaptic plasticity and transmission of nerve impulse. In the neuron, phenylalanine is converted to phenylpyruvate by aromatic-amino-acid-glyoxylate transaminase. Phenylpyruvate downregulates pyruvate carboxylase (PC) causing decreased L-aspartate and L-glutamate formation which are important for the listed processes. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 11043156 PMID: 20123477 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-40793df2-1986-4d7c-983d-610158ac0feb Brain Dysfunction in Phenylketonuria uuid-40793df2-1986-4d7c-983d-610158ac0feb PS:CellType neuron PS:Description Brain Dysfunction in Phenylketonuria In phenylketonuria (PKU) occurs due to high levels of phenylalanine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40793df2-1986-4d7c-983d-610158ac0feb PS:NodeType Pathway PS:Notes Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. Signaling description: Phenylalanine enters the brain using the L-type amino acid transporter SLC7A5 in competition with eight other L-type amino acids (i.e. tyrosine, tryptophan, valine, isoleucine, leucine, threonine, methionine, and histidine). Among thse amino acids, tyrosine and tryptophan are listed on the pathway since their deficiencies severely affect the pathology manifestation and progress. The SLC7A5 transporter has a high affinity for phenylalanine, resulting in a high transport velocity even if blood phenylalanine level is only slightly elevated. Outcome effects: Increased brain phenylalanine inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH2) leading to decreased dopamine and serotonin biosynthesis. The lack of dopamine and serotonin disrupts synaptic plasticity and transmission of nerve impulse. In the neuron, phenylalanine is converted to phenylpyruvate by aromatic-amino-acid-glyoxylate transaminase. Phenylpyruvate downregulates pyruvate carboxylase (PC) causing decreased L-aspartate and L-glutamate formation which are important for the listed processes. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 11043156 PS:PMID 20123477 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: MITF is a master regulator of melanocyte development and differentiation and also functions as an oncogene in melanoma cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4089e1dd-18f9-488b-8176-63cd0e988332 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. MITF is a key regulator of melanocyte development and differentiation and also functions as an oncogene in melanoma cells. Signaling description: Ultraviolet (UV) radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor MC1R resulting in the expression of MITF. WNT3A/CTNNB1 signaling also induces MITF expression. PAX3, SOX10, CREB1, and TCF4/LEF1 bind directly to the MITF promoter. These proteins along with MITF are tightly involved in the melanocyte development and melanomagenesis. Firstly, MITF regulates the expression of genes responsible for melanin production and transportation to keratinocytes such as TYR, TYRP1, DCT, MLANA, PMEL, RAB27A, and others. Melanin is an important chromophore in the skin and is able to absorb UV radiation and visible light. It is also able to scavenge molecular oxygen and hydroxyl radicals thereby protecting DNA from UV damage. In addition, MITF plays both cancer-promoting and cancer-inhibiting roles in melanoma. Most likely, a low level of MITF expression promotes proliferation in melanoma, whereas a high level of MITF expression promotes differentiation through the induction of cellular senescence and melanin production. MITF also has an ability to up-regulate the transcription of both melanoma-promoting genes (CCND1, BCL2, and MET) and melanoma-repressing genes (CDKN2A, CDKN1A, and DIAPH1). APEX1 is regulated by MITF and is involved in DNA repair. SNAI1 and SNAI2 are the key players in epithelial-mesenchymal transition, which is a crucial phenomenon during invasion and metastasis of melanoma. SNAI1 and SNAI2 are directly activated by MITF and represses E-cadherin (CDH1) transcription. Finally, MITF may be overexpressed due to a mutation or gene amplification in about 10% of melanoma cases. Outcome effects: Following exposure to UV radiation, multiple molecular alterations of the MITF related signaling lead to dysregulation of melanocyte differentiation and proliferation and melanomagenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 19056669 PMID: 19708915 PMID: 20067521 PMID: 20201954 PMID: 22046555 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4089e1dd-18f9-488b-8176-63cd0e988332 MITF as a Regulator of Melanoma Cell Development uuid-4089e1dd-18f9-488b-8176-63cd0e988332 PS:CellType cancer cell PS:CellType melanocyte PS:Description MITF is a master regulator of melanocyte development and differentiation and also functions as an oncogene in melanoma cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4089e1dd-18f9-488b-8176-63cd0e988332 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. MITF is a key regulator of melanocyte development and differentiation and also functions as an oncogene in melanoma cells. Signaling description: Ultraviolet (UV) radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor MC1R resulting in the expression of MITF. WNT3A/CTNNB1 signaling also induces MITF expression. PAX3, SOX10, CREB1, and TCF4/LEF1 bind directly to the MITF promoter. These proteins along with MITF are tightly involved in the melanocyte development and melanomagenesis. Firstly, MITF regulates the expression of genes responsible for melanin production and transportation to keratinocytes such as TYR, TYRP1, DCT, MLANA, PMEL, RAB27A, and others. Melanin is an important chromophore in the skin and is able to absorb UV radiation and visible light. It is also able to scavenge molecular oxygen and hydroxyl radicals thereby protecting DNA from UV damage. In addition, MITF plays both cancer-promoting and cancer-inhibiting roles in melanoma. Most likely, a low level of MITF expression promotes proliferation in melanoma, whereas a high level of MITF expression promotes differentiation through the induction of cellular senescence and melanin production. MITF also has an ability to up-regulate the transcription of both melanoma-promoting genes (CCND1, BCL2, and MET) and melanoma-repressing genes (CDKN2A, CDKN1A, and DIAPH1). APEX1 is regulated by MITF and is involved in DNA repair. SNAI1 and SNAI2 are the key players in epithelial-mesenchymal transition, which is a crucial phenomenon during invasion and metastasis of melanoma. SNAI1 and SNAI2 are directly activated by MITF and represses E-cadherin (CDH1) transcription. Finally, MITF may be overexpressed due to a mutation or gene amplification in about 10% of melanoma cases. Outcome effects: Following exposure to UV radiation, multiple molecular alterations of the MITF related signaling lead to dysregulation of melanocyte differentiation and proliferation and melanomagenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 19056669 PS:PMID 19708915 PS:PMID 20067521 PS:PMID 20201954 PS:PMID 22046555 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40aa3fe3-5104-4eef-90fb-de7133d2cdb0 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-40aa3fe3-5104-4eef-90fb-de7133d2cdb0 P2RY1/2/4/6 -> Potassium Channels uuid-40aa3fe3-5104-4eef-90fb-de7133d2cdb0 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40aa3fe3-5104-4eef-90fb-de7133d2cdb0 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40c3be29-9d08-4660-9d4f-0c7ca4dbc935 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-40c3be29-9d08-4660-9d4f-0c7ca4dbc935 KITLG -> STAT Expression Targets uuid-40c3be29-9d08-4660-9d4f-0c7ca4dbc935 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40c3be29-9d08-4660-9d4f-0c7ca4dbc935 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: melanocyte Description: The progression of melanoma to an invasive and metastatic phase is associated with the loss of normal intercellular connections, increased motility, and dedifferentiation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40d722bf-6070-4398-a646-7545764de628 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. The metastatic melanoma is the most fatal stage of disease. Signaling description: The molecular changes that lead to the metastatic progression of melanoma include loss of E-cadherin (CDH1), as well as an increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). Normally, CDH1 is expressed in melanocytes and keratinocytes where it positively regulates the association of the two cell types. CDH2 is responsible for interacting with other CDH2-expressing cells such as dermal fibroblasts and vascular endothelium and enables the metastatic spread. Vitronectin receptor (integrin) induces the expression of MMP2 which is an enzyme that degrades collagen in basement membranes, increases BCL2 expression and stimulates the motility of melanoma cells through reorganization of cytoskeleton. In addition, the activation of NODAL has a role in melanocyte dedifferentiation and is regulated by NOTCH4 signaling. POU5F1 driven by EPAS1 is also involved in dedifferentiation. Furthermore, WNT5A is over-expressed in melanoma. It downregulates CDH1, while, KISS, which is a metastasis suppressor, up-regulates VIM and tumor homing and metastasis antigen (CD44). Finally, overexpressed SNAI1 and SNAI2 are the key players in epithelial-mesenchymal transition which is a crucial phenomenon during invasion and metastasis of melanoma. Outcome effects: The progression of melanoma to an invasive and metastatic phase is associated with the loss of normal intercellular connections, increased motility, and dedifferentiation caused by a number of molecular alterations including loss of E-cadherin (CDH1) and an increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). The over-expression of SNAI1 and SNAI2 proteins in melanoma activates the epithelial-mesenchymal transition and metastatis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes mutated in melanoma are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 12778131 PMID: 17557303 PMID: 20079807 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-40d722bf-6070-4398-a646-7545764de628 Dedifferentiation and Metastatic Progression in Melanoma uuid-40d722bf-6070-4398-a646-7545764de628 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType melanocyte PS:Description The progression of melanoma to an invasive and metastatic phase is associated with the loss of normal intercellular connections, increased motility, and dedifferentiation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40d722bf-6070-4398-a646-7545764de628 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. The metastatic melanoma is the most fatal stage of disease. Signaling description: The molecular changes that lead to the metastatic progression of melanoma include loss of E-cadherin (CDH1), as well as an increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). Normally, CDH1 is expressed in melanocytes and keratinocytes where it positively regulates the association of the two cell types. CDH2 is responsible for interacting with other CDH2-expressing cells such as dermal fibroblasts and vascular endothelium and enables the metastatic spread. Vitronectin receptor (integrin) induces the expression of MMP2 which is an enzyme that degrades collagen in basement membranes, increases BCL2 expression and stimulates the motility of melanoma cells through reorganization of cytoskeleton. In addition, the activation of NODAL has a role in melanocyte dedifferentiation and is regulated by NOTCH4 signaling. POU5F1 driven by EPAS1 is also involved in dedifferentiation. Furthermore, WNT5A is over-expressed in melanoma. It downregulates CDH1, while, KISS, which is a metastasis suppressor, up-regulates VIM and tumor homing and metastasis antigen (CD44). Finally, overexpressed SNAI1 and SNAI2 are the key players in epithelial-mesenchymal transition which is a crucial phenomenon during invasion and metastasis of melanoma. Outcome effects: The progression of melanoma to an invasive and metastatic phase is associated with the loss of normal intercellular connections, increased motility, and dedifferentiation caused by a number of molecular alterations including loss of E-cadherin (CDH1) and an increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). The over-expression of SNAI1 and SNAI2 proteins in melanoma activates the epithelial-mesenchymal transition and metastatis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes mutated in melanoma are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 12778131 PS:PMID 17557303 PS:PMID 20079807 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40e8f04a-c4a2-49ab-9eb0-10be8ea438ff NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-40e8f04a-c4a2-49ab-9eb0-10be8ea438ff NTRK -> FOXO/MYCN Signaling uuid-40e8f04a-c4a2-49ab-9eb0-10be8ea438ff PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40e8f04a-c4a2-49ab-9eb0-10be8ea438ff PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40fe9c66-b69c-4e61-ad18-a67cb9de3b8e NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: thymus gland Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-40fe9c66-b69c-4e61-ad18-a67cb9de3b8e CD40 -> Expression Targets in Thymus uuid-40fe9c66-b69c-4e61-ad18-a67cb9de3b8e PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-40fe9c66-b69c-4e61-ad18-a67cb9de3b8e PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ thymus gland PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4124c5eb-ef88-4dce-a1ce-c6f25ee385d3 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-4124c5eb-ef88-4dce-a1ce-c6f25ee385d3 Angelman Syndrome: Mechanism of Repression of Paternal UBE3A Gene in Brain uuid-4124c5eb-ef88-4dce-a1ce-c6f25ee385d3 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4124c5eb-ef88-4dce-a1ce-c6f25ee385d3 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Hyper IgM syndrome (HIGM1) is a family of genetic disorders in which the level of immunoglobulin M (IgM) antibodies is relatively high. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41450dd1-fe4d-439c-ac54-513dca7d520e NodeType: Pathway Notes: Headnote: Hyper IgM syndrome (HIGM1) is a family of genetic disorders characterized by an abnormally level of immunoglobulin M (IgM) antibodies decreased levels or absence of other antibodies. It is a rare primary immunodeficiency disorder usually inherited in an X-linked recessive manner. Signaling description: All B-cells initially produce IgM antibodies prior to undergoing class switching due to exposure to a recognized antigen. Healthy B-cells efficiently switch to other types of antibodies necessary to attack invading bacteria, viruses, and other pathogens. In the majority of individuals with HIGM1, B-cells keep producing IgM antibodies as they are unable to switch to a different type of antibody. This results in an overproduction of IgM antibodies and an underproduction of all other immunoglobulin types including IgA, IgG, and IgE. The disorder causes immunodeficiencies including a higher susceptibility to various types of infections. Individuals with HIGM1 also typically have a lowered number of neutrophils and platelets. Conservative treatment consists of prophylactic intravenous immunoglobulin infusions at doses of 400-600 mg/kg per month.There are five identified genes with mutations that lead to HIGM1: 1) CD40 ligand (CD40LG) gene (in this case, which is the most common T-cells cannot induce immunoglobulin class switching in B-cells), 2) CD40 gene (B-cells cannot receive the signal from T-cells to switch classes), 3) Activation-induced cytidine deaminase (AICDA) gene (B-cells cannot switch classes), 4) Uracil-DNA glycosylase (UNG) gene (B-cells cannot switch classes, but somatic hypermutation does not cause the effect), and 5) NEMO (IKBKG) gene which causes X-linked HIGM1 with ectodermal dysplasia. Outcome effects: Due to these mutations, B-cells can no longer recombine genetic material to change heavy chain production which is a required step in class switch recombination. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: lymphatic system PMID: 15319456 PMID: 15661021 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-41450dd1-fe4d-439c-ac54-513dca7d520e Hyper IgM Syndrome uuid-41450dd1-fe4d-439c-ac54-513dca7d520e PS:CellType B-cell PS:Description Hyper IgM syndrome (HIGM1) is a family of genetic disorders in which the level of immunoglobulin M (IgM) antibodies is relatively high. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41450dd1-fe4d-439c-ac54-513dca7d520e PS:NodeType Pathway PS:Notes Headnote: Hyper IgM syndrome (HIGM1) is a family of genetic disorders characterized by an abnormally level of immunoglobulin M (IgM) antibodies decreased levels or absence of other antibodies. It is a rare primary immunodeficiency disorder usually inherited in an X-linked recessive manner. Signaling description: All B-cells initially produce IgM antibodies prior to undergoing class switching due to exposure to a recognized antigen. Healthy B-cells efficiently switch to other types of antibodies necessary to attack invading bacteria, viruses, and other pathogens. In the majority of individuals with HIGM1, B-cells keep producing IgM antibodies as they are unable to switch to a different type of antibody. This results in an overproduction of IgM antibodies and an underproduction of all other immunoglobulin types including IgA, IgG, and IgE. The disorder causes immunodeficiencies including a higher susceptibility to various types of infections. Individuals with HIGM1 also typically have a lowered number of neutrophils and platelets. Conservative treatment consists of prophylactic intravenous immunoglobulin infusions at doses of 400-600 mg/kg per month.There are five identified genes with mutations that lead to HIGM1: 1) CD40 ligand (CD40LG) gene (in this case, which is the most common T-cells cannot induce immunoglobulin class switching in B-cells), 2) CD40 gene (B-cells cannot receive the signal from T-cells to switch classes), 3) Activation-induced cytidine deaminase (AICDA) gene (B-cells cannot switch classes), 4) Uracil-DNA glycosylase (UNG) gene (B-cells cannot switch classes, but somatic hypermutation does not cause the effect), and 5) NEMO (IKBKG) gene which causes X-linked HIGM1 with ectodermal dysplasia. Outcome effects: Due to these mutations, B-cells can no longer recombine genetic material to change heavy chain production which is a required step in class switch recombination. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 15319456 PS:PMID 15661021 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41641562-a74f-41f8-807b-d374dc21d27c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-41641562-a74f-41f8-807b-d374dc21d27c rs11385942 genes uuid-41641562-a74f-41f8-807b-d374dc21d27c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41641562-a74f-41f8-807b-d374dc21d27c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-416c2314-8a9a-4071-9e59-28c8a6c6b084 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-416c2314-8a9a-4071-9e59-28c8a6c6b084 CCL5 Expression Targets uuid-416c2314-8a9a-4071-9e59-28c8a6c6b084 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-416c2314-8a9a-4071-9e59-28c8a6c6b084 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: keratinocyte Description: Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4175f597-f6f9-4602-9c06-4e5f0089fee9 NodeType: Pathway Notes: Headnote: Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications by destruction of nearby bony structures. In general, squamous epithelial cells of cholesteatoma are characterized by uncoordinated proliferation, migration, aggressiveness, and recurrence. Clinically, acquired cholesteatoma is usually related to chronic suppurative inflammation of the middle ear, which plays an important role in the etiopathogenesis of cholesteatoma. Signaling description: Cytokines and mediators which are released in the inflammatory responses may promote the formation and progression of cholesteatoma by stimulating migration and proliferation of keratinocytes in the tympanic membrane and deep part of external auditory canal. Epidermal growth factor (EGF) is one of the most important cytokines which to play a critical role in cholesteatoma. Increased EGF expression has been demonstrated in cholesteatoma epithelium, and high EGF levels have also been shown in cholesteatoma debris and subepithelial tissue. Recently, some downstream targets of EGF have been identified, and among them phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most important kinase cascades that mediates a wide range of cellular functions such as survival, proliferation, migration, and differentiation. The binding of EGF to the extracellular domain of EGFR promotes the activation of EGFR through autophosphorylation of their intracellular domains, which subsequently triggers the PI3K/Akt signaling pathway. Activation of the PI3K/Akt signaling pathway can lead to cell proliferation and growth by regulating cyclinD1 expression. It was shown that the EGFR/PI3K/Akt/cyclinD1 pathway is active in cholesteatoma and may be involved in the cellular hyperplasia mechanism in acquired cholesteatoma epithelium. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 23463347 PMID: 24311896 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-4175f597-f6f9-4602-9c06-4e5f0089fee9 EGF/cyclinD1 Signaling in Acquired Middle Ear Cholesteatoma uuid-4175f597-f6f9-4602-9c06-4e5f0089fee9 PS:CellType cancer cell PS:CellType keratinocyte PS:Description Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4175f597-f6f9-4602-9c06-4e5f0089fee9 PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications by destruction of nearby bony structures. In general, squamous epithelial cells of cholesteatoma are characterized by uncoordinated proliferation, migration, aggressiveness, and recurrence. Clinically, acquired cholesteatoma is usually related to chronic suppurative inflammation of the middle ear, which plays an important role in the etiopathogenesis of cholesteatoma. Signaling description: Cytokines and mediators which are released in the inflammatory responses may promote the formation and progression of cholesteatoma by stimulating migration and proliferation of keratinocytes in the tympanic membrane and deep part of external auditory canal. Epidermal growth factor (EGF) is one of the most important cytokines which to play a critical role in cholesteatoma. Increased EGF expression has been demonstrated in cholesteatoma epithelium, and high EGF levels have also been shown in cholesteatoma debris and subepithelial tissue. Recently, some downstream targets of EGF have been identified, and among them phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most important kinase cascades that mediates a wide range of cellular functions such as survival, proliferation, migration, and differentiation. The binding of EGF to the extracellular domain of EGFR promotes the activation of EGFR through autophosphorylation of their intracellular domains, which subsequently triggers the PI3K/Akt signaling pathway. Activation of the PI3K/Akt signaling pathway can lead to cell proliferation and growth by regulating cyclinD1 expression. It was shown that the EGFR/PI3K/Akt/cyclinD1 pathway is active in cholesteatoma and may be involved in the cellular hyperplasia mechanism in acquired cholesteatoma epithelium. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 23463347 PS:PMID 24311896 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: intestinal cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41ad8dbc-e31f-4407-a7e2-2f60cdf6d758 NodeType: Pathway Notes: Innate lymphoid cells (ILCs) expressing the nuclear receptor RORC play vital roles in defense against intestinal pathogens, epithelial homeostasis, and development of intestinal lymphoid follicles. Organ: colon Organ: intestine Organ_System: digestive system PMID: 21336274 PMID: 21681197 PMID: 22101730 PMID: 22177117 PMID: 22666222 PMID: 22865043 PMID: 23975386 PMID: 24527450 PMID: 25256754 PMID: 25741338 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-41ad8dbc-e31f-4407-a7e2-2f60cdf6d758 AHR in Intestinal Cell Antimicrobial Barrier Maintenance uuid-41ad8dbc-e31f-4407-a7e2-2f60cdf6d758 PS:CellType intestinal cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41ad8dbc-e31f-4407-a7e2-2f60cdf6d758 PS:NodeType Pathway PS:Notes Innate lymphoid cells (ILCs) expressing the nuclear receptor RORC play vital roles in defense against intestinal pathogens, epithelial homeostasis, and development of intestinal lymphoid follicles. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 21336274 PS:PMID 21681197 PS:PMID 22101730 PS:PMID 22177117 PS:PMID 22666222 PS:PMID 22865043 PS:PMID 23975386 PS:PMID 24527450 PS:PMID 25256754 PS:PMID 25741338 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41b02648-7c47-443b-b24b-b0e278c80674 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-41b02648-7c47-443b-b24b-b0e278c80674 Erythropoietin -> AP-1/MYC/CREB Expression Targets uuid-41b02648-7c47-443b-b24b-b0e278c80674 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41b02648-7c47-443b-b24b-b0e278c80674 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41c19762-f62e-4ace-98fc-84104824e274 NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-41c19762-f62e-4ace-98fc-84104824e274 Proteins with Altered Expression in Chronic Obstructive Pulmonary Disease uuid-41c19762-f62e-4ace-98fc-84104824e274 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41c19762-f62e-4ace-98fc-84104824e274 PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41d6f5a4-aa96-4fbc-b70e-71fdde0e7f2b NodeType: Pathway Organ: pancreas Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-41d6f5a4-aa96-4fbc-b70e-71fdde0e7f2b Proteins Involved in Pancreatic Cancer uuid-41d6f5a4-aa96-4fbc-b70e-71fdde0e7f2b PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41d6f5a4-aa96-4fbc-b70e-71fdde0e7f2b PS:NodeType Pathway PS:Organ pancreas PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41eb4d3c-be5e-4daf-bd4f-7b9e694c46e3 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-41eb4d3c-be5e-4daf-bd4f-7b9e694c46e3 Proteins Involved in Hutchinson-Gilford Progeria Sindrome uuid-41eb4d3c-be5e-4daf-bd4f-7b9e694c46e3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41eb4d3c-be5e-4daf-bd4f-7b9e694c46e3 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41f44752-a19d-47d1-a355-5baa629b5f06 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-41f44752-a19d-47d1-a355-5baa629b5f06 Glycolitic reprogramming in myofibroblats uuid-41f44752-a19d-47d1-a355-5baa629b5f06 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-41f44752-a19d-47d1-a355-5baa629b5f06 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42055ab0-dea0-49b5-a665-c239c3ddb8b1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-42055ab0-dea0-49b5-a665-c239c3ddb8b1 MEP pathway template uuid-42055ab0-dea0-49b5-a665-c239c3ddb8b1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42055ab0-dea0-49b5-a665-c239c3ddb8b1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42156bce-b37c-4cb9-bada-82cedffc264d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-42156bce-b37c-4cb9-bada-82cedffc264d Fungicide biosyntesis template uuid-42156bce-b37c-4cb9-bada-82cedffc264d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42156bce-b37c-4cb9-bada-82cedffc264d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4222dc84-c76c-44fd-a013-a57bacb9be4d NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-4222dc84-c76c-44fd-a013-a57bacb9be4d IL9R -> STAT Signaling uuid-4222dc84-c76c-44fd-a013-a57bacb9be4d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4222dc84-c76c-44fd-a013-a57bacb9be4d PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Cyclosporine is an immunosuppressant drug used to reduce the activity of a patient's immune system after an organ transplant to lower the risk of organ rejection. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-424354f0-8ae7-4a64-8d93-beea8bd12d4c NodeType: Pathway Notes: Headnote: Cyclosporine is an immunosuppressant drug used to reduce the activity of a patient's immune system after an organ transplant to lower the risk of organ rejection. Signaling description: Cyclosporine therapy is associated with several forms of nephrotoxicity with the most significant being the reversible impairment of glomerular filtration and irreversible interstitial fibrosis. The molecular mechanism underlying chronic cyclosporine nephropathy is multifactorial. Cyclosporine initially binds to a specific family of receptors known as cyclophilins. This drug-receptor complex inhibits activation of the phosphatase calcineurin. Outcome effects: Subsequently, cyclosporine decreases basolateral Na+/K+-exchanging ATPase and apical Na+-K+-Cl- cotransporter activities, which leads to an enhanced intrarenal renin-angiotensin (REN-AGT) system activity. This, in turn, causes the activation of NF-kB and Jun/Fos transcription factors, resulting in the increased production of EDN1, TGFB1, and the proinflammatory cytokine CCL2. Organ: kidney Organ: nephron Organ_System: urinary tract PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-424354f0-8ae7-4a64-8d93-beea8bd12d4c Cyclosporine Induced Nephrotoxicity uuid-424354f0-8ae7-4a64-8d93-beea8bd12d4c PS:Description Cyclosporine is an immunosuppressant drug used to reduce the activity of a patient's immune system after an organ transplant to lower the risk of organ rejection. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-424354f0-8ae7-4a64-8d93-beea8bd12d4c PS:NodeType Pathway PS:Notes Headnote: Cyclosporine is an immunosuppressant drug used to reduce the activity of a patient's immune system after an organ transplant to lower the risk of organ rejection. Signaling description: Cyclosporine therapy is associated with several forms of nephrotoxicity with the most significant being the reversible impairment of glomerular filtration and irreversible interstitial fibrosis. The molecular mechanism underlying chronic cyclosporine nephropathy is multifactorial. Cyclosporine initially binds to a specific family of receptors known as cyclophilins. This drug-receptor complex inhibits activation of the phosphatase calcineurin. Outcome effects: Subsequently, cyclosporine decreases basolateral Na+/K+-exchanging ATPase and apical Na+-K+-Cl- cotransporter activities, which leads to an enhanced intrarenal renin-angiotensin (REN-AGT) system activity. This, in turn, causes the activation of NF-kB and Jun/Fos transcription factors, resulting in the increased production of EDN1, TGFB1, and the proinflammatory cytokine CCL2. PS:Organ kidney PS:Organ nephron PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4257a803-41db-41c5-9a17-4362923f961d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4257a803-41db-41c5-9a17-4362923f961d cornea surface layer uuid-4257a803-41db-41c5-9a17-4362923f961d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4257a803-41db-41c5-9a17-4362923f961d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells recognize and attack damaged or infected cells in an organism in the absence of antibodies. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42833ecd-7b80-469d-9713-cab46994011c NodeType: Pathway Notes: Headnote: Natural killer (NK) cells recognize and attack damaged or infected cells in an organism in the absence of antibodies. NK cells provide rapid responses to virally infected cells and cancer cells. NK cells can recognize stressed cells in the absence of antigen-MHC complex, allowing for a much faster immune reaction. Signaling description: The activation of NK cells depends on the strong activation of stimulatory NK cell receptors. ITGAL and ITGB2 can rapidly induce signals for activation by promoting adhesion between NK cells and a target cell. FCGR3A and FCER1G provide antibody-dependent T-cell-mediated cytotoxicity (ADCC). FCGR3A and FCER1G recognize and bind to the Fc region of IgG which has bound to the surface of a target cell. KLRK1 binds to non-classical (also non-polymorphic) MHC1 molecules such as MICA. Engaged KLRK1 and other stimulatory receptors on the NK cell surface induces the phosphorylation of VAV1, resulting in the actin-dependent clustering of stimulatory receptors and their recruitment to lipid rafts. This leads to more VAV1 phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. Outcome effects: The stimulatory receptors of NK cells cause the release of calcium and activate JUN/FOS transcriptional complex. This leads to key NK cell-mediated responses including the transcription of cytokines and FASLG in addition to the formation of immunological synapses with granules of perforins (PRF1) and granzymes (GZMA/GZMB). FASLG, PRF1, and GZMA/GZMB all result in the death of target cells. Finally, cytokine-mediated STAT5 and STAT1 activation also results in the production of PRF1 and GZMA/GZMB. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-42833ecd-7b80-469d-9713-cab46994011c Natural Killer Cell Activation uuid-42833ecd-7b80-469d-9713-cab46994011c PS:CellType natural killer cell PS:Description Natural killer (NK) cells recognize and attack damaged or infected cells in an organism in the absence of antibodies. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42833ecd-7b80-469d-9713-cab46994011c PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells recognize and attack damaged or infected cells in an organism in the absence of antibodies. NK cells provide rapid responses to virally infected cells and cancer cells. NK cells can recognize stressed cells in the absence of antigen-MHC complex, allowing for a much faster immune reaction. Signaling description: The activation of NK cells depends on the strong activation of stimulatory NK cell receptors. ITGAL and ITGB2 can rapidly induce signals for activation by promoting adhesion between NK cells and a target cell. FCGR3A and FCER1G provide antibody-dependent T-cell-mediated cytotoxicity (ADCC). FCGR3A and FCER1G recognize and bind to the Fc region of IgG which has bound to the surface of a target cell. KLRK1 binds to non-classical (also non-polymorphic) MHC1 molecules such as MICA. Engaged KLRK1 and other stimulatory receptors on the NK cell surface induces the phosphorylation of VAV1, resulting in the actin-dependent clustering of stimulatory receptors and their recruitment to lipid rafts. This leads to more VAV1 phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. Outcome effects: The stimulatory receptors of NK cells cause the release of calcium and activate JUN/FOS transcriptional complex. This leads to key NK cell-mediated responses including the transcription of cytokines and FASLG in addition to the formation of immunological synapses with granules of perforins (PRF1) and granzymes (GZMA/GZMB). FASLG, PRF1, and GZMA/GZMB all result in the death of target cells. Finally, cytokine-mediated STAT5 and STAT1 activation also results in the production of PRF1 and GZMA/GZMB. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-428c687f-c18b-405d-b224-6badd0be8b41 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-428c687f-c18b-405d-b224-6badd0be8b41 Heme oxidation template uuid-428c687f-c18b-405d-b224-6badd0be8b41 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-428c687f-c18b-405d-b224-6badd0be8b41 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42d9f98a-9626-4bf6-8b5a-5bfa17163d95 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-42d9f98a-9626-4bf6-8b5a-5bfa17163d95 TCR -> NF-kB Expression Targets uuid-42d9f98a-9626-4bf6-8b5a-5bfa17163d95 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42d9f98a-9626-4bf6-8b5a-5bfa17163d95 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42db764e-ccb0-4c9f-984a-77a966e8bbe2 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-42db764e-ccb0-4c9f-984a-77a966e8bbe2 Cholesterol Catabolism uuid-42db764e-ccb0-4c9f-984a-77a966e8bbe2 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42db764e-ccb0-4c9f-984a-77a966e8bbe2 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42ec7263-a803-4c45-9531-2a9639dc0f01 NodeType: Pathway Notes: The HTLVs can enter the cell in the form of an intact virion. The viral envelope proteins interact with cellular membrane proteins leading to viral entry. Alternatively, viral genomic RNA can be transmitted from one cell to another through a virological synapse. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-42ec7263-a803-4c45-9531-2a9639dc0f01 1_HTLV-1 enters the cell uuid-42ec7263-a803-4c45-9531-2a9639dc0f01 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42ec7263-a803-4c45-9531-2a9639dc0f01 PS:NodeType Pathway PS:Notes The HTLVs can enter the cell in the form of an intact virion. The viral envelope proteins interact with cellular membrane proteins leading to viral entry. Alternatively, viral genomic RNA can be transmitted from one cell to another through a virological synapse. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42f87daa-e7f4-46a7-bd0d-ae4a939b771d NodeType: Pathway Organ: prostate Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-42f87daa-e7f4-46a7-bd0d-ae4a939b771d Proteins with Altered Expression in Prostate Cancer uuid-42f87daa-e7f4-46a7-bd0d-ae4a939b771d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-42f87daa-e7f4-46a7-bd0d-ae4a939b771d PS:NodeType Pathway PS:Organ prostate PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-433e1b60-2085-415d-aa92-2582d588c326 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-433e1b60-2085-415d-aa92-2582d588c326 Chorismate biosynthesis template uuid-433e1b60-2085-415d-aa92-2582d588c326 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-433e1b60-2085-415d-aa92-2582d588c326 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-436fe544-7998-4ae6-9e2c-c70977743f21 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: mouth Organ_System: digestive system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-436fe544-7998-4ae6-9e2c-c70977743f21 Estrogen Effects on Pregnancy Gingivitis uuid-436fe544-7998-4ae6-9e2c-c70977743f21 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-436fe544-7998-4ae6-9e2c-c70977743f21 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell CellType: smooth muscle myocyte Description: Vasoconstriction and vasodilation are regulated by vascular smooth muscle cell (VSMC) contractility. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4373d159-a59a-499a-8f28-c7fa7ff1702e NodeType: Pathway Notes: Headnote: Vasoconstriction and vasodilation are regulated by vascular smooth muscle cell (VSMC) contractility. The phosphorylation of myosin light chain (MYL9) by myosin light chain kinase (MYLK) and its dephosphorylation by myosin light chain phosphatase (MLCP) induces VSMC constriction or relaxation, respectively. Signaling description: Reactive oxygen species (ROS) such as superoxide radical and hydrogen peroxide (H2O2) as well as reactive nitrogen species (RNS) such as nitric oxide (NO) and peroxynitrite have an central role in balancing MYLK and MLCP activity, thus regulating VSMC contractility. NO is a vasodilating agent produced in the endothelium by endothelial nitric oxide synthase 3 (NOS3). NO diffuses to VSMCs where it induces cGMP production by the direct activation of soluble guanylate cyclase (sGC). cGMP activates cGMP-dependent protein kinase (PKG), which in turn phosphorylates and activates MLCP. cGMP also causes vasodilation by lowering cytosolic Ca2+ by activating K channels and via PKG-mediated activation of Ca2+ uptake by Ca2+-transporting ATPase. Conversely, NO inhibits MYLK through ADCY/cAMP/PKA pathway. NO mediates ADCY activation through the upregulation of PTGS1/2 and upstream enzymes that convert PGH2 to PGI2, PGE2, and PGD2. NO also reduces the production of TXA2, TXB2, and 20-HETE through inhibiting thromboxane-A synthase and alkane 1-monooxygenase, respectively. In contrast, the inhibition of ALOX15 by NO reduces the production of dilating agents such as 11,12-EET and 12(S)-HPETE. In general, H2O2 acts in an opposite manner as NO. It activates the production of constricting agents such as 12(R)-hydroxyeicosatetraenoic acid (12(R)-HETE), TXA2, TXB2, PGH2, and PGF2alpha and inhibits the production of a dilating agent 11,12-EET. Outcome effects: H2O2 activates phospholipase A2, thus enhancing the production of arachidonic acid, which serves as a precursor for the biosynthesis of prostaglandins, thromboxanes, and tri- and tetraenoic acids. Conversely, arachidonic acid itself acts as a vasoconstrictor through MLCP inhibition. H2O2 induces the inhibitive phosphorylation of MLCP by ROCK1 through the downregulation of upstream PTPN11. In addition, the upregulation of arginase by H2O2 reduces the availability of arginine which is a substrate for NO production by NOS3. Another ROS that interferes with NO production is superoxide radical which reacts with NO to produce the highly reactive peroxynitrite. The oxidation of tetrahydrobiopterin, an essential NOS3 cofactor, by peroxynitrite results in the uncoupling of NOS3 and the production of superoxide radical rather than NO. Highlighted proteins: Entities with elevated level are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-4373d159-a59a-499a-8f28-c7fa7ff1702e ROS and RNS in Vasoconstriction and Vasodilation Regulation uuid-4373d159-a59a-499a-8f28-c7fa7ff1702e PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Vasoconstriction and vasodilation are regulated by vascular smooth muscle cell (VSMC) contractility. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4373d159-a59a-499a-8f28-c7fa7ff1702e PS:NodeType Pathway PS:Notes Headnote: Vasoconstriction and vasodilation are regulated by vascular smooth muscle cell (VSMC) contractility. The phosphorylation of myosin light chain (MYL9) by myosin light chain kinase (MYLK) and its dephosphorylation by myosin light chain phosphatase (MLCP) induces VSMC constriction or relaxation, respectively. Signaling description: Reactive oxygen species (ROS) such as superoxide radical and hydrogen peroxide (H2O2) as well as reactive nitrogen species (RNS) such as nitric oxide (NO) and peroxynitrite have an central role in balancing MYLK and MLCP activity, thus regulating VSMC contractility. NO is a vasodilating agent produced in the endothelium by endothelial nitric oxide synthase 3 (NOS3). NO diffuses to VSMCs where it induces cGMP production by the direct activation of soluble guanylate cyclase (sGC). cGMP activates cGMP-dependent protein kinase (PKG), which in turn phosphorylates and activates MLCP. cGMP also causes vasodilation by lowering cytosolic Ca2+ by activating K channels and via PKG-mediated activation of Ca2+ uptake by Ca2+-transporting ATPase. Conversely, NO inhibits MYLK through ADCY/cAMP/PKA pathway. NO mediates ADCY activation through the upregulation of PTGS1/2 and upstream enzymes that convert PGH2 to PGI2, PGE2, and PGD2. NO also reduces the production of TXA2, TXB2, and 20-HETE through inhibiting thromboxane-A synthase and alkane 1-monooxygenase, respectively. In contrast, the inhibition of ALOX15 by NO reduces the production of dilating agents such as 11,12-EET and 12(S)-HPETE. In general, H2O2 acts in an opposite manner as NO. It activates the production of constricting agents such as 12(R)-hydroxyeicosatetraenoic acid (12(R)-HETE), TXA2, TXB2, PGH2, and PGF2alpha and inhibits the production of a dilating agent 11,12-EET. Outcome effects: H2O2 activates phospholipase A2, thus enhancing the production of arachidonic acid, which serves as a precursor for the biosynthesis of prostaglandins, thromboxanes, and tri- and tetraenoic acids. Conversely, arachidonic acid itself acts as a vasoconstrictor through MLCP inhibition. H2O2 induces the inhibitive phosphorylation of MLCP by ROCK1 through the downregulation of upstream PTPN11. In addition, the upregulation of arginase by H2O2 reduces the availability of arginine which is a substrate for NO production by NOS3. Another ROS that interferes with NO production is superoxide radical which reacts with NO to produce the highly reactive peroxynitrite. The oxidation of tetrahydrobiopterin, an essential NOS3 cofactor, by peroxynitrite results in the uncoupling of NOS3 and the production of superoxide radical rather than NO. Highlighted proteins: Entities with elevated level are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43781af0-4905-4b17-9ee2-ddc55c185646 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-43781af0-4905-4b17-9ee2-ddc55c185646 FrizzledR -> JUN/PAX2 Signaling uuid-43781af0-4905-4b17-9ee2-ddc55c185646 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43781af0-4905-4b17-9ee2-ddc55c185646 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source Description: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43b0c256-acf8-4d08-b756-0e0dabefd1a3 NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Glutamate excitotoxicity is one of the pathological processes leading to cell death in PD. The persistent presence of glutamate in the interneuron space occurs due to microglia activation. Glutamate stimulation of NMDA receptors triggers calcium (Ca2+) influx into the cell. Further, Ca2+ activates the NF-kB dependent nitric oxide synthase 1 (NOS1) transcription via the calmodulin/PI3K/Akt pathway. In addition, Ca2+ influx promotes the release of cytochrome c (CYCS) from mitochondria via calpain and calcineurin, Outcome effects: S-nitrosylation with excessive nitric oxide (NO) generated by NOS1 contributes to protein misfolding. The increased formation of misfolded proteins and release of CYCS commit the neurons to apoptosis. Organ: brain Organ_System: nervous system PMID: 10991662 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-43b0c256-acf8-4d08-b756-0e0dabefd1a3 Glutamate Role in Parkinson's Disease uuid-43b0c256-acf8-4d08-b756-0e0dabefd1a3 PS:Description Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43b0c256-acf8-4d08-b756-0e0dabefd1a3 PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Glutamate excitotoxicity is one of the pathological processes leading to cell death in PD. The persistent presence of glutamate in the interneuron space occurs due to microglia activation. Glutamate stimulation of NMDA receptors triggers calcium (Ca2+) influx into the cell. Further, Ca2+ activates the NF-kB dependent nitric oxide synthase 1 (NOS1) transcription via the calmodulin/PI3K/Akt pathway. In addition, Ca2+ influx promotes the release of cytochrome c (CYCS) from mitochondria via calpain and calcineurin, Outcome effects: S-nitrosylation with excessive nitric oxide (NO) generated by NOS1 contributes to protein misfolding. The increased formation of misfolded proteins and release of CYCS commit the neurons to apoptosis. PS:Organ brain PS:Organ_System nervous system PS:PMID 10991662 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43c8e5d2-c2b4-41b7-82b7-e07ce29d6184 NodeType: Pathway Notes: Headnote: Osteopetrosis (known as marble bone disease) is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs and is caused by the failure of osteoclast development or function. Signaling description: Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which is involved in WNT signaling. Outcome effects: Impairment of WNT signaling causes osteopetrosis. PORCN mutations are associated with osteopathia striata in Goltz Syndrome, while FAM123B gene mutations are linked to osteopathia striata with cranial stenosis. OSTM1 regulates CTNNB1/LEF1 interaction and causes rare forms of osteopetrosis. LRP1 mutations also lead to rare forms of the disorder. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 17936098 PMID: 18296023 PMID: 19232111 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-43c8e5d2-c2b4-41b7-82b7-e07ce29d6184 WNT Signaling Dysregulation in Osteoblast uuid-43c8e5d2-c2b4-41b7-82b7-e07ce29d6184 PS:CellType osteoblast PS:Description Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43c8e5d2-c2b4-41b7-82b7-e07ce29d6184 PS:NodeType Pathway PS:Notes Headnote: Osteopetrosis (known as marble bone disease) is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs and is caused by the failure of osteoclast development or function. Signaling description: Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which is involved in WNT signaling. Outcome effects: Impairment of WNT signaling causes osteopetrosis. PORCN mutations are associated with osteopathia striata in Goltz Syndrome, while FAM123B gene mutations are linked to osteopathia striata with cranial stenosis. OSTM1 regulates CTNNB1/LEF1 interaction and causes rare forms of osteopetrosis. LRP1 mutations also lead to rare forms of the disorder. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 17936098 PS:PMID 18296023 PS:PMID 19232111 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/CCNF regulates DNA repair, centrosome duplication and spindle assembly. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43dce78e-eb90-47d9-b023-1809d94c7197 NodeType: Pathway Notes: Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/CCNF complex, CCNF (FBXO1) acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/CCNF related signaling leads to regulation of DNA repair, centrosome duplication and spindle assembly. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: During G2 phase, SCF/CCNF targets and degrades the CP110 to limit centrosome duplication to once per cell cycle. SCF/CCNF promotes the degradation of NUSAP1, a protein involved in mitotic spindle organization. Also, SCF/CCNF mediates the degradation of RRM2 in G2 phase prevents genome instability. Animal data: Role of SCF/CCNF in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 22632967 PMID: 23182110 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-43dce78e-eb90-47d9-b023-1809d94c7197 SCF/CCNF Complex uuid-43dce78e-eb90-47d9-b023-1809d94c7197 PS:CellType generic PS:Description SCF/CCNF regulates DNA repair, centrosome duplication and spindle assembly. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43dce78e-eb90-47d9-b023-1809d94c7197 PS:NodeType Pathway PS:Notes Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/CCNF complex, CCNF (FBXO1) acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/CCNF related signaling leads to regulation of DNA repair, centrosome duplication and spindle assembly. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: During G2 phase, SCF/CCNF targets and degrades the CP110 to limit centrosome duplication to once per cell cycle. SCF/CCNF promotes the degradation of NUSAP1, a protein involved in mitotic spindle organization. Also, SCF/CCNF mediates the degradation of RRM2 in G2 phase prevents genome instability. Animal data: Role of SCF/CCNF in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22632967 PS:PMID 23182110 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: osteoclast Description: The main reason for abnormal osteoclast activation in gout is the impaired ratio of TNFSF11 and its soluble receptor TNFRSF11B. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43e8adb4-9ece-4263-93f4-eb36ddb2cf4e NodeType: Pathway Notes: Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, renal functional impairment, tophi and bone erosion. Signaling description: Impaired ratio of TNFSF11 and its soluble receptor TNFRSF11B leads to abnormal osteoclast activation in gout. Both proteins are produced by osteoblasts and are designed to maintain bone homeostasis by triggering osteoclast activation (bone resorption) and preventing excessive bone destruction. TNFSF11 also is known as RANKL, initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. This signaling involves TRAF6, TRAF2, and TRAF5 proteins and affects the NF-kB and MAPK pathways. Also, PGE2 synthesized by monocytes increases TNFSF11 signaling through MAP3K7 activation. Outcome effects: The resulting signaling promotes osteoclast differentiation and cell survival. At the same time, TNFSF11 signaling promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. Also, MSU crystals impair TNFSF11/TNFRSF11B ratio by promoting constant activation of osteoclasts by TNFSF11 leading to pathological bone resorption and bone erosion. Cytokines such as IL1B (through NF-kB pathway) and IL6 (through JAK-STAT pathway) also contribute to osteoclast activation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: bone Organ_System: skeletal system PMID: 22231231 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-43e8adb4-9ece-4263-93f4-eb36ddb2cf4e Osteoclast Activation in Gout uuid-43e8adb4-9ece-4263-93f4-eb36ddb2cf4e PS:CellType osteoclast PS:Description The main reason for abnormal osteoclast activation in gout is the impaired ratio of TNFSF11 and its soluble receptor TNFRSF11B. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43e8adb4-9ece-4263-93f4-eb36ddb2cf4e PS:NodeType Pathway PS:Notes Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, renal functional impairment, tophi and bone erosion. Signaling description: Impaired ratio of TNFSF11 and its soluble receptor TNFRSF11B leads to abnormal osteoclast activation in gout. Both proteins are produced by osteoblasts and are designed to maintain bone homeostasis by triggering osteoclast activation (bone resorption) and preventing excessive bone destruction. TNFSF11 also is known as RANKL, initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. This signaling involves TRAF6, TRAF2, and TRAF5 proteins and affects the NF-kB and MAPK pathways. Also, PGE2 synthesized by monocytes increases TNFSF11 signaling through MAP3K7 activation. Outcome effects: The resulting signaling promotes osteoclast differentiation and cell survival. At the same time, TNFSF11 signaling promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. Also, MSU crystals impair TNFSF11/TNFRSF11B ratio by promoting constant activation of osteoclasts by TNFSF11 leading to pathological bone resorption and bone erosion. Cytokines such as IL1B (through NF-kB pathway) and IL6 (through JAK-STAT pathway) also contribute to osteoclast activation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ bone PS:Organ_System skeletal system PS:PMID 22231231 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43ed03b5-e572-408f-927b-c256c20fb1f2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-43ed03b5-e572-408f-927b-c256c20fb1f2 teichoic acid (poly-glycerol) biosynthesis template uuid-43ed03b5-e572-408f-927b-c256c20fb1f2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43ed03b5-e572-408f-927b-c256c20fb1f2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: sebocyte Description: Acne is regarded as an androgen-dependent disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43f3231d-cda6-4a44-ac15-383f05395bc2 NodeType: Pathway Notes: Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. One of the major pathologic processes in the formation of acne lesions is androgen-induced sebocyte hyperfunction. Signaling description: In the sebocyte, the circulating androgenic pro-hormone, dehydroepiandrosterone (DHEA) is converted to dihydrotestosterone. Both testosterone and dihydrotestosterone are able to bind the androgen receptor (AR). However, dihydrotestosterone has a ten-fold higher affinity to AR compared to testosterone. Dihydrotestosterone exerts its effect on sebaceous glands by increasing sebocyte proliferation, and elevating lipid production via SREBF1. The increased conversion of DHEA to dihydrotestosterone is mediated by the IGF1-induced SRD5A1 hyperactivity. IGF1 plays an important role in the pathologic process. It induces AR trans-activation and SREBF1 activation. In the nucleus, AR and SREBF1 bind to the repressive protein, FOXO1. IGF1 activates PI3K and causes the AKT1-mediated FOXO1 phosphorylation. Phosphorylated FOXO1 leaves AR and SREBF1, which induces sebocyte hyperfunction. Outcome effects: Following binding to the AR, dihydrotestosterone initiates transcription of androgen-responsive genes, and thus promotes increased cell proliferation and fatty acid biosynthesis which leads to comedogenesis and hyperseborrhea, respectively. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 15556719 PMID: 19555434 PMID: 19588637 PMID: 20082943 PMID: 24575836 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-43f3231d-cda6-4a44-ac15-383f05395bc2 Androgen Induced Sebocyte Hyperfunction uuid-43f3231d-cda6-4a44-ac15-383f05395bc2 PS:CellType sebocyte PS:Description Acne is regarded as an androgen-dependent disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-43f3231d-cda6-4a44-ac15-383f05395bc2 PS:NodeType Pathway PS:Notes Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. One of the major pathologic processes in the formation of acne lesions is androgen-induced sebocyte hyperfunction. Signaling description: In the sebocyte, the circulating androgenic pro-hormone, dehydroepiandrosterone (DHEA) is converted to dihydrotestosterone. Both testosterone and dihydrotestosterone are able to bind the androgen receptor (AR). However, dihydrotestosterone has a ten-fold higher affinity to AR compared to testosterone. Dihydrotestosterone exerts its effect on sebaceous glands by increasing sebocyte proliferation, and elevating lipid production via SREBF1. The increased conversion of DHEA to dihydrotestosterone is mediated by the IGF1-induced SRD5A1 hyperactivity. IGF1 plays an important role in the pathologic process. It induces AR trans-activation and SREBF1 activation. In the nucleus, AR and SREBF1 bind to the repressive protein, FOXO1. IGF1 activates PI3K and causes the AKT1-mediated FOXO1 phosphorylation. Phosphorylated FOXO1 leaves AR and SREBF1, which induces sebocyte hyperfunction. Outcome effects: Following binding to the AR, dihydrotestosterone initiates transcription of androgen-responsive genes, and thus promotes increased cell proliferation and fatty acid biosynthesis which leads to comedogenesis and hyperseborrhea, respectively. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15556719 PS:PMID 19555434 PS:PMID 19588637 PS:PMID 20082943 PS:PMID 24575836 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4403e008-4918-4e0d-88f2-2e2a7358c815 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-4403e008-4918-4e0d-88f2-2e2a7358c815 Rhamnose degradation template uuid-4403e008-4918-4e0d-88f2-2e2a7358c815 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4403e008-4918-4e0d-88f2-2e2a7358c815 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-441b49d0-7688-42e6-b9fc-bef14712642e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-441b49d0-7688-42e6-b9fc-bef14712642e Glucose Metabolism uuid-441b49d0-7688-42e6-b9fc-bef14712642e PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-441b49d0-7688-42e6-b9fc-bef14712642e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4421d966-6e65-40f1-bc8d-e3d4b57ccec1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4421d966-6e65-40f1-bc8d-e3d4b57ccec1 TNFSF13 Expression Targets uuid-4421d966-6e65-40f1-bc8d-e3d4b57ccec1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4421d966-6e65-40f1-bc8d-e3d4b57ccec1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4429f4d9-0e36-4477-b210-2efa9519d0fb NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-4429f4d9-0e36-4477-b210-2efa9519d0fb Proteins Involved in Atherosclerosis uuid-4429f4d9-0e36-4477-b210-2efa9519d0fb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4429f4d9-0e36-4477-b210-2efa9519d0fb PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Transient (TNDM) and permanent (PNDM) neonatal diabetes mellitus are rare conditions occurring in 1:300,000-400,000 live births. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-442b7360-e78d-49f1-b14b-10806dc8ed81 NodeType: Pathway Notes: Headnote: Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions which occur in 1:300,000 to 400,000 live births. TNDM infants develop diabetes in the first few weeks of life, then go into remission in a few months, with possible relapse to a permanent diabetes state usually around adolescence or adulthood. The pancreatic dysfunction in this condition may be maintained throughout life, with a relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early post-natal period and does not go into remission. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances. Signaling description: One third to one half of all PNDM cases involve mutations in KCNJ11 and ABCC8 genes responsible for pancreatic ATP-sensitive potassium (K ) channels (KATP) involved in the regulation of insulin secretion. Normally, glucose is transported into the beta cell by SLC2A2. GCK phosphorylates glucose to glucose-6-phosphate as the rate-limiting step in glucose metabolism. Glycolysis increases the ATP/ADP ratio which is sensed by the KATP channels. The increase of the ATP/ADP ratio leads to KATP channel closure, followed by membrane depolarization which results in the opening of voltage-gated Ca2 channels. The influx of Ca2 triggers the exocytosis of insulin. Outcome effects: The activating mutations in genes encoding the two subunits of the pancreatic KATP channel (namely KCNJ11 and ABCC8) lead to the channel opening. Increased K outflow leads to hyperpolarization and stabilization of membrane potential, thus blocking insulin exocytosis. SLC2A2 and GCK may also be mutated in rare cases of neonatal diabetes. Mutations in genes encoding transcription factors including PDX1, PTF1A, RFX6, GLIS3, PAX6, NEUROD1, NEUROG3, HNF1B, and GATA6 cause abnormal development of the pancreatic endocrine cells. PDX1 mutation is associated with pancreas agenesis; while PTF1A mutation is associated with pancreatic hypoplasia, neonatal diabetes, and cerebellar hypoplasia. In addition, GLIS3 mutation is associated with neonatal diabetes, hypothyroidism, congenital glaucoma, kidney cysts, and hepatic fibrosis. FOXP3 mutation is associated with immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. Furthermore, EIF2AK3 mutation is associated with Wolcott-Rallison syndrome, an autosomal recessive disorder characterized by infancy onset diabetes associated with a spondyloepiphyseal dysplasia. EIF2AK3 mutation leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) causing increased stress on ER folding machinery. Mutations in the INS gene cause abnormal proinsulin processing within the ER which leads to beta cell toxicity. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: pancreas Organ_System: endocrine system PMID: 18436707 PMID: 22124439 PMID: 24843477 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-442b7360-e78d-49f1-b14b-10806dc8ed81 Neonatal Diabetes Mellitus uuid-442b7360-e78d-49f1-b14b-10806dc8ed81 PS:CellType insulin-secreting cell PS:Description Transient (TNDM) and permanent (PNDM) neonatal diabetes mellitus are rare conditions occurring in 1:300,000-400,000 live births. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-442b7360-e78d-49f1-b14b-10806dc8ed81 PS:NodeType Pathway PS:Notes Headnote: Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions which occur in 1:300,000 to 400,000 live births. TNDM infants develop diabetes in the first few weeks of life, then go into remission in a few months, with possible relapse to a permanent diabetes state usually around adolescence or adulthood. The pancreatic dysfunction in this condition may be maintained throughout life, with a relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early post-natal period and does not go into remission. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances. Signaling description: One third to one half of all PNDM cases involve mutations in KCNJ11 and ABCC8 genes responsible for pancreatic ATP-sensitive potassium (K ) channels (KATP) involved in the regulation of insulin secretion. Normally, glucose is transported into the beta cell by SLC2A2. GCK phosphorylates glucose to glucose-6-phosphate as the rate-limiting step in glucose metabolism. Glycolysis increases the ATP/ADP ratio which is sensed by the KATP channels. The increase of the ATP/ADP ratio leads to KATP channel closure, followed by membrane depolarization which results in the opening of voltage-gated Ca2 channels. The influx of Ca2 triggers the exocytosis of insulin. Outcome effects: The activating mutations in genes encoding the two subunits of the pancreatic KATP channel (namely KCNJ11 and ABCC8) lead to the channel opening. Increased K outflow leads to hyperpolarization and stabilization of membrane potential, thus blocking insulin exocytosis. SLC2A2 and GCK may also be mutated in rare cases of neonatal diabetes. Mutations in genes encoding transcription factors including PDX1, PTF1A, RFX6, GLIS3, PAX6, NEUROD1, NEUROG3, HNF1B, and GATA6 cause abnormal development of the pancreatic endocrine cells. PDX1 mutation is associated with pancreas agenesis; while PTF1A mutation is associated with pancreatic hypoplasia, neonatal diabetes, and cerebellar hypoplasia. In addition, GLIS3 mutation is associated with neonatal diabetes, hypothyroidism, congenital glaucoma, kidney cysts, and hepatic fibrosis. FOXP3 mutation is associated with immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. Furthermore, EIF2AK3 mutation is associated with Wolcott-Rallison syndrome, an autosomal recessive disorder characterized by infancy onset diabetes associated with a spondyloepiphyseal dysplasia. EIF2AK3 mutation leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) causing increased stress on ER folding machinery. Mutations in the INS gene cause abnormal proinsulin processing within the ER which leads to beta cell toxicity. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 18436707 PS:PMID 22124439 PS:PMID 24843477 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-442de31c-7ecc-4f8b-b5fe-cc3ba39819ac NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-442de31c-7ecc-4f8b-b5fe-cc3ba39819ac EctodysplasinR -> LEF1 Signaling uuid-442de31c-7ecc-4f8b-b5fe-cc3ba39819ac PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-442de31c-7ecc-4f8b-b5fe-cc3ba39819ac PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44325c07-80d0-4e55-a0ad-b3fda0407f51 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-44325c07-80d0-4e55-a0ad-b3fda0407f51 IGF2 -> HIF1A/MYC Expression Targets uuid-44325c07-80d0-4e55-a0ad-b3fda0407f51 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44325c07-80d0-4e55-a0ad-b3fda0407f51 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44438213-005f-4016-85fc-ee7d96b606f6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-44438213-005f-4016-85fc-ee7d96b606f6 TGFB3-TGFBR2 Expression Targets uuid-44438213-005f-4016-85fc-ee7d96b606f6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44438213-005f-4016-85fc-ee7d96b606f6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-444c5903-58e6-410e-8abb-3d5d924568ab NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: colon Organ: small intestine Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-444c5903-58e6-410e-8abb-3d5d924568ab Elevated Receptors -> Expression Targets in Small Intestine uuid-444c5903-58e6-410e-8abb-3d5d924568ab PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-444c5903-58e6-410e-8abb-3d5d924568ab PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4452e5fe-5570-4bb7-8936-5695420682e8 NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G1/S transition determines the whether the cell should divide or not. Signaling description: At the G1/S checkpoint, the cell cycle arrest is induced by DNA damage and is p53-dependent. Namely, ATM and ATR 'recognize' DNA damage. These kinases phosphorylate p53, which stimulates the induction of CDKN1A, causes CDKs inhibition and cell cycle arrest, preventing the replication of damaged DNA. MDM2 inhibits p53 transcriptional activity and contributes to the proteolytic degradation of p53. CDKN2A binds to MDM2 and this prevents p53 proteolysis. Outcome effects: In the case of severely damaged cells, p53 induces cell death by activating genes (e.g. Bax, Fas and genes involved in oxidative stress pathways) involved in apoptotic signaling. DNA protein kinase (PRKDC), a DNA double-strand break repair enzyme is related to ATM and ATR, but it is unknown whether it also has a role at the G1/S checkpoint. TGF-Beta, DNA damage, contact inhibition, replicative senescence and growth factors are all stimuli for the G1/S DNA damage checkpoint. TGF-Beta additionally inhibits the transcription of CDC25A, a phosphatase that activates the cell cycle kinases. ATM-mediated phosphorylation of NBN may be required to induce S phase arrest during the S phase checkpoint. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-4452e5fe-5570-4bb7-8936-5695420682e8 G1/S Phase Transition uuid-4452e5fe-5570-4bb7-8936-5695420682e8 PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4452e5fe-5570-4bb7-8936-5695420682e8 PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G1/S transition determines the whether the cell should divide or not. Signaling description: At the G1/S checkpoint, the cell cycle arrest is induced by DNA damage and is p53-dependent. Namely, ATM and ATR 'recognize' DNA damage. These kinases phosphorylate p53, which stimulates the induction of CDKN1A, causes CDKs inhibition and cell cycle arrest, preventing the replication of damaged DNA. MDM2 inhibits p53 transcriptional activity and contributes to the proteolytic degradation of p53. CDKN2A binds to MDM2 and this prevents p53 proteolysis. Outcome effects: In the case of severely damaged cells, p53 induces cell death by activating genes (e.g. Bax, Fas and genes involved in oxidative stress pathways) involved in apoptotic signaling. DNA protein kinase (PRKDC), a DNA double-strand break repair enzyme is related to ATM and ATR, but it is unknown whether it also has a role at the G1/S checkpoint. TGF-Beta, DNA damage, contact inhibition, replicative senescence and growth factors are all stimuli for the G1/S DNA damage checkpoint. TGF-Beta additionally inhibits the transcription of CDC25A, a phosphatase that activates the cell cycle kinases. ATM-mediated phosphorylation of NBN may be required to induce S phase arrest during the S phase checkpoint. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-445e8e0b-1471-488c-a9a5-ecf22ef67948 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-445e8e0b-1471-488c-a9a5-ecf22ef67948 AGT -> TP53 Expression Targets uuid-445e8e0b-1471-488c-a9a5-ecf22ef67948 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-445e8e0b-1471-488c-a9a5-ecf22ef67948 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44615d31-0e9f-4e35-8169-2b43d682f04b NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In Asia, HCC is commonly related to hepatitis B or C virus (HBV and HCV) infection, while in Africa it is linked to chronic hepatitis B. The incidence is on the rise in some developed countries including Japan, UK, France, and U.S. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. Less common causes of HCC are exposure to dietary hepatocarcinogen like aflatoxin, insulin resistance syndrome, several genetic disorders, and drug-induced (e.g. anabolic steroids). HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: HCC is characterized by mutations in TP53 gene, CCND1 overexpression, and the silencing of CDKN1A, CDKN1B, CDKN2A, and RB1 proteins. Epidemiologically, TP53 mutation was frequently found in aflatoxin-induced HCC (50%). Mutations of RB1 were found only in 15% of HCC cases; however, silencing of RB1 in HCC occurs more frequently (25-48%). Normally, TP53 stimulates CDKN1A, CDKN2A, and CDKN1B which inhibit the activity of CDK2, CDK4, and CDK6. CCND1/2/3, CCNE1, CCNA1, and catalytic partners CDK2/4/6 phosphorylate RB1 resulting in the release of E2F1 transcription factor which is required for the activation of S phase-specific genes, regulation of cell cycle and differentiation, and progression of cell proliferation. TP53 also promotes BAX resulting in the activation of apoptotic caspase cascade. Outcome effects: In HCC, the genetic changes in TP53 and RB1 lead to redundant proliferation, block of apoptosis, and disruption of cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 20175032 PMID: 21115898 PMID: 23426905 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-44615d31-0e9f-4e35-8169-2b43d682f04b TP53 Signaling in Hepatocellular Carcinoma uuid-44615d31-0e9f-4e35-8169-2b43d682f04b PS:CellType cancer cell PS:CellType hepatocyte PS:Description Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44615d31-0e9f-4e35-8169-2b43d682f04b PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In Asia, HCC is commonly related to hepatitis B or C virus (HBV and HCV) infection, while in Africa it is linked to chronic hepatitis B. The incidence is on the rise in some developed countries including Japan, UK, France, and U.S. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. Less common causes of HCC are exposure to dietary hepatocarcinogen like aflatoxin, insulin resistance syndrome, several genetic disorders, and drug-induced (e.g. anabolic steroids). HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: HCC is characterized by mutations in TP53 gene, CCND1 overexpression, and the silencing of CDKN1A, CDKN1B, CDKN2A, and RB1 proteins. Epidemiologically, TP53 mutation was frequently found in aflatoxin-induced HCC (50%). Mutations of RB1 were found only in 15% of HCC cases; however, silencing of RB1 in HCC occurs more frequently (25-48%). Normally, TP53 stimulates CDKN1A, CDKN2A, and CDKN1B which inhibit the activity of CDK2, CDK4, and CDK6. CCND1/2/3, CCNE1, CCNA1, and catalytic partners CDK2/4/6 phosphorylate RB1 resulting in the release of E2F1 transcription factor which is required for the activation of S phase-specific genes, regulation of cell cycle and differentiation, and progression of cell proliferation. TP53 also promotes BAX resulting in the activation of apoptotic caspase cascade. Outcome effects: In HCC, the genetic changes in TP53 and RB1 lead to redundant proliferation, block of apoptosis, and disruption of cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 20175032 PS:PMID 21115898 PS:PMID 23426905 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44d97d9e-ebf6-47ab-abc2-c9beb9dac4cb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-44d97d9e-ebf6-47ab-abc2-c9beb9dac4cb Cannabinoid biosynthesis template uuid-44d97d9e-ebf6-47ab-abc2-c9beb9dac4cb PS:Source Metabolic Pathways PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44d97d9e-ebf6-47ab-abc2-c9beb9dac4cb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44eb5b73-1240-4603-89fa-024dfede03cc NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-44eb5b73-1240-4603-89fa-024dfede03cc Fibronectin Expression Targets uuid-44eb5b73-1240-4603-89fa-024dfede03cc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44eb5b73-1240-4603-89fa-024dfede03cc PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44fac1ca-2b6f-4f22-a84a-23d3135c9772 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Source: Diseases urn:agi-pathway:uuid-44fac1ca-2b6f-4f22-a84a-23d3135c9772 Proteins Involved in Cataract uuid-44fac1ca-2b6f-4f22-a84a-23d3135c9772 PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-44fac1ca-2b6f-4f22-a84a-23d3135c9772 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45012c70-5733-4900-bba5-8cfc121b4b96 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-45012c70-5733-4900-bba5-8cfc121b4b96 PRL/PRLR Expression Targets uuid-45012c70-5733-4900-bba5-8cfc121b4b96 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45012c70-5733-4900-bba5-8cfc121b4b96 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-450244a6-ff2a-4af9-a5e5-f0801ed4d2c6 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-450244a6-ff2a-4af9-a5e5-f0801ed4d2c6 IL6 Expression Targets -> Nociception uuid-450244a6-ff2a-4af9-a5e5-f0801ed4d2c6 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-450244a6-ff2a-4af9-a5e5-f0801ed4d2c6 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-451afe4e-e7a3-4a43-9c28-22335b0bac3a NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-451afe4e-e7a3-4a43-9c28-22335b0bac3a Ethanol Metabolism uuid-451afe4e-e7a3-4a43-9c28-22335b0bac3a PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-451afe4e-e7a3-4a43-9c28-22335b0bac3a PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45346e5f-b9d2-4f2f-8fc5-dc215a18383c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-45346e5f-b9d2-4f2f-8fc5-dc215a18383c WNT9B Expression Targets uuid-45346e5f-b9d2-4f2f-8fc5-dc215a18383c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45346e5f-b9d2-4f2f-8fc5-dc215a18383c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45402048-3da8-4557-abf2-6240c6dcb444 NodeType: Pathway Notes: General of mechanisms that occur under basal conditions in non-active dendritic spine is presented on the pathway. Organ: brain Organ_System: nervous system PMID: 21119699 PMID: 22986281 PMID: 24042850 PMID: 27426863 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-45402048-3da8-4557-abf2-6240c6dcb444 Synaptic Potentiation by PKMZ in LTP Maintenance - Basal State uuid-45402048-3da8-4557-abf2-6240c6dcb444 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45402048-3da8-4557-abf2-6240c6dcb444 PS:NodeType Pathway PS:Notes General of mechanisms that occur under basal conditions in non-active dendritic spine is presented on the pathway. PS:Organ brain PS:Organ_System nervous system PS:PMID 21119699 PS:PMID 22986281 PS:PMID 24042850 PS:PMID 27426863 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte CellType: striated muscle cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4595f76c-9e70-4708-a77d-8abe9364abfa NodeType: Pathway Notes: Calcium (Ca2 ) plays an important role in the pathogenesis of Dilated cardiomyopathy (DCM). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 12649072 PMID: 23900355 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-4595f76c-9e70-4708-a77d-8abe9364abfa Ca2+ Signaling in Dilated Cardiomyopathy uuid-4595f76c-9e70-4708-a77d-8abe9364abfa PS:CellType cardiac myocyte PS:CellType striated muscle cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4595f76c-9e70-4708-a77d-8abe9364abfa PS:NodeType Pathway PS:Notes Calcium (Ca2 ) plays an important role in the pathogenesis of Dilated cardiomyopathy (DCM). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 12649072 PS:PMID 23900355 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Regulation of synthesis and release of growth hormone via ghrelin, GHRH and SST in hypothalamic neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45abfb8b-090f-4481-a6a9-0e7463d22385 NodeType: Pathway Notes: Headnote: Ghrelin activates the release of GHRH, which in turn activates the release of somatostatin (SST). SST blocks the release of ghrelin and GHRH through a feedback loop mechanism. Ghrelin, GHRH and SST work together in the neurons of hypothalamus. Signaling description: Ghrelin interacts with the growth hormone secretagogue receptor (GHSR) leading to intracellular Ca2+ influx through the PLC/PKC pathway. Intracellular calcium activates the secretion of growth hormone (GH1). GHRH binds to GHRHR and activates the ADCY/cAMP/PKA pathway. PKA phosphorylates and activates the transcription factors POU1F1 and CREB1 which bind to GH1 promoter and activate its transcription. SST inhibits transcription of GH1 by blocking the ADCY signaling. Outcome effects: Ghrelin and GHRH are important for the stimulation of neurons in hypothalamus. Effects of ghrelin and GHRH can be inhibited by SST. Animal data: The effects of ghrelin, GHRH and SST in hypothalamic neurons were revealed from animal model experiments. Organ: brain Organ: hypothalamus Organ_System: nervous system PMID: 12586774 PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-45abfb8b-090f-4481-a6a9-0e7463d22385 Ghrelin and SST Regulate GH1 Release in Hypothalamus uuid-45abfb8b-090f-4481-a6a9-0e7463d22385 PS:CellType neuron PS:Description Regulation of synthesis and release of growth hormone via ghrelin, GHRH and SST in hypothalamic neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45abfb8b-090f-4481-a6a9-0e7463d22385 PS:NodeType Pathway PS:Notes Headnote: Ghrelin activates the release of GHRH, which in turn activates the release of somatostatin (SST). SST blocks the release of ghrelin and GHRH through a feedback loop mechanism. Ghrelin, GHRH and SST work together in the neurons of hypothalamus. Signaling description: Ghrelin interacts with the growth hormone secretagogue receptor (GHSR) leading to intracellular Ca2+ influx through the PLC/PKC pathway. Intracellular calcium activates the secretion of growth hormone (GH1). GHRH binds to GHRHR and activates the ADCY/cAMP/PKA pathway. PKA phosphorylates and activates the transcription factors POU1F1 and CREB1 which bind to GH1 promoter and activate its transcription. SST inhibits transcription of GH1 by blocking the ADCY signaling. Outcome effects: Ghrelin and GHRH are important for the stimulation of neurons in hypothalamus. Effects of ghrelin and GHRH can be inhibited by SST. Animal data: The effects of ghrelin, GHRH and SST in hypothalamic neurons were revealed from animal model experiments. PS:Organ brain PS:Organ hypothalamus PS:Organ_System nervous system PS:PMID 12586774 PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45bcb1d6-9a5d-43b9-af3f-3ba8abe45dd3 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-45bcb1d6-9a5d-43b9-af3f-3ba8abe45dd3 Overview. Diseases of the ear (chapter 7) uuid-45bcb1d6-9a5d-43b9-af3f-3ba8abe45dd3 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45bcb1d6-9a5d-43b9-af3f-3ba8abe45dd3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45c1715c-6069-4665-83b1-f6c0c3bdde66 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-45c1715c-6069-4665-83b1-f6c0c3bdde66 Hemophilia Anatomy and Molecular Biomarkers uuid-45c1715c-6069-4665-83b1-f6c0c3bdde66 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45c1715c-6069-4665-83b1-f6c0c3bdde66 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45c8dc22-9c56-4152-867c-f04409f132d2 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-45c8dc22-9c56-4152-867c-f04409f132d2 TAAR1 -> Neurotransmitter Uptake uuid-45c8dc22-9c56-4152-867c-f04409f132d2 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45c8dc22-9c56-4152-867c-f04409f132d2 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell CellType: fibroblast CellType: macrophage Description: BSG is a cell surface glycoprotein that is highly up-regulated in malignant cancer cells and stimulates hyaluronic acid production, as well as several downstream signaling pathways. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45cc4997-c75c-4b87-b953-a50ae8ddb529 NodeType: Pathway Notes: Headnote: Basigin (BSG) also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is highly up-regulated in malignant cancer cells and stimulates hyaluronic acid production, as well as, several downstream signaling pathways. Signaling description: BSG is upregulated in cancer by multiple transcription factors including SP1/3, MYC, STAT3, HIF1A, EGR2, SNAI2 and others. BSG stimulates hyaluronic acid production and CD44 activation with subsequent activation of metastatic progression. BSG interacts with integrins VLA2/3/6. The integrin signaling leads to cell migration and activation of cell proliferation. BSG may block apoptosis/anoikis through MAPK1/3 - dependent inactivation of BCL2L11. The precise mechanism of MAPK1/3 activation by BSG is unknown. BSG may also regulate autophagy via BECN1 inactivation. In addition, BSG interacts with monocarboxylate transporters SLC16A1/3. Malignant cancer cells use the glycolytic pathway and require monocarboxylate transporters to efflux lactate that results from glycolysis. Glycolysis and lactate secretion contribute to malignant cell behaviors and drug resistance in tumor cells. BSG promote MMP1/2/3/9/11/13/14/15 production and secretion by fibroblasts, endothelial cells, macrophages and cancer cells, contributing to cell invasion. The precise mechanism of MMPs regulation by BSG is not clear. Outcome effects: BSG promotes cancer cell motility, invasion, proliferation, survival, drug resistance and cancer-specific metabolism. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15928045 PMID: 18490190 PMID: 19176383 PMID: 23888049 PMID: 25081536 PMID: 25268615 PMID: 26604323 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-45cc4997-c75c-4b87-b953-a50ae8ddb529 BSG (CD147) in Cancer Cells Motility, Invasion and Survival uuid-45cc4997-c75c-4b87-b953-a50ae8ddb529 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:CellType fibroblast PS:CellType macrophage PS:Description BSG is a cell surface glycoprotein that is highly up-regulated in malignant cancer cells and stimulates hyaluronic acid production, as well as several downstream signaling pathways. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45cc4997-c75c-4b87-b953-a50ae8ddb529 PS:NodeType Pathway PS:Notes Headnote: Basigin (BSG) also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is highly up-regulated in malignant cancer cells and stimulates hyaluronic acid production, as well as, several downstream signaling pathways. Signaling description: BSG is upregulated in cancer by multiple transcription factors including SP1/3, MYC, STAT3, HIF1A, EGR2, SNAI2 and others. BSG stimulates hyaluronic acid production and CD44 activation with subsequent activation of metastatic progression. BSG interacts with integrins VLA2/3/6. The integrin signaling leads to cell migration and activation of cell proliferation. BSG may block apoptosis/anoikis through MAPK1/3 - dependent inactivation of BCL2L11. The precise mechanism of MAPK1/3 activation by BSG is unknown. BSG may also regulate autophagy via BECN1 inactivation. In addition, BSG interacts with monocarboxylate transporters SLC16A1/3. Malignant cancer cells use the glycolytic pathway and require monocarboxylate transporters to efflux lactate that results from glycolysis. Glycolysis and lactate secretion contribute to malignant cell behaviors and drug resistance in tumor cells. BSG promote MMP1/2/3/9/11/13/14/15 production and secretion by fibroblasts, endothelial cells, macrophages and cancer cells, contributing to cell invasion. The precise mechanism of MMPs regulation by BSG is not clear. Outcome effects: BSG promotes cancer cell motility, invasion, proliferation, survival, drug resistance and cancer-specific metabolism. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15928045 PS:PMID 18490190 PS:PMID 19176383 PS:PMID 23888049 PS:PMID 25081536 PS:PMID 25268615 PS:PMID 26604323 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45ed175a-e30b-4fa3-b058-a367997398c3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-45ed175a-e30b-4fa3-b058-a367997398c3 Cholestasis overview model uuid-45ed175a-e30b-4fa3-b058-a367997398c3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45ed175a-e30b-4fa3-b058-a367997398c3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45fb1fc7-3e55-4052-83f5-cd0535d803c2 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-45fb1fc7-3e55-4052-83f5-cd0535d803c2 Lipids Enhance Apoptotic Cell Engulfment and Reduce Inflammation uuid-45fb1fc7-3e55-4052-83f5-cd0535d803c2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-45fb1fc7-3e55-4052-83f5-cd0535d803c2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-460964a1-fd8a-45f0-bb47-925c39379b50 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-460964a1-fd8a-45f0-bb47-925c39379b50 Cys degradation template uuid-460964a1-fd8a-45f0-bb47-925c39379b50 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-460964a1-fd8a-45f0-bb47-925c39379b50 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4638c0f8-cdd8-46fb-86d0-cda70bb65ed7 NodeType: Pathway Notes: Headnote: Embryos are gonadally identical, regardless of genetic sex, until a certain point in development when the testis-determining factor causes male sex organs to develop.The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY, the sex-determining region of the Y chromosome. Signaling description: When complexed with the SF1 (NR5A1) protein, SRY acts as a transcription factor that can upregulate other transcription factors, most importantly SOX9, which then activates and forms a feedforward loop with FGF9. Sertoli cell proliferation and differentiation is mainly activated by FGF9. SOX9 expression causes the development of primary sex cords, which later develop into seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now induced Leydig cells of the testis then start secreting testosterone while the Sertoli cells produce anti-Müllerian hormone (AMH) to inhibit the creation of a female reproductive system.Besides NR5A1, other transcription factors such as SP1, WT1, GATA4, FOG2 (ZFPM2), SIX1/4 control expression of SRY. DAX1 (NR0B1) is an antagonist of male development. There is evidence from work on suppression of male development that DAX1 can interfere with function of NR5A1, and in turn transcription of SRY by recruiting corepressors.Gonadal target genes of SOX9 include AMH, FGF9, desert hedgehog (DHH), prostaglandin D synthase (PTGDS), and VANIN1 (VNN1).Prostaglandin D2 (PGD2) is necessary and sufficient to recruit cells that do not express SRY to express SOX9 and differentiate into Sertoli cells. Outcome effects: During testis differentiation, SRY, SOX9 and FGF9 act to downregulate the ovarian pathway by suppressing RSPO1 and WNT4, which promote the development of the gonad as an ovary. Highlighted proteins: Key players of male sex determination are highlighted in red. Key players of female sex determination (repressed) are highlighted in blue. Organ: testis Organ_System: reproductive system PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-4638c0f8-cdd8-46fb-86d0-cda70bb65ed7 Male Sex Determination uuid-4638c0f8-cdd8-46fb-86d0-cda70bb65ed7 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4638c0f8-cdd8-46fb-86d0-cda70bb65ed7 PS:NodeType Pathway PS:Notes Headnote: Embryos are gonadally identical, regardless of genetic sex, until a certain point in development when the testis-determining factor causes male sex organs to develop.The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY, the sex-determining region of the Y chromosome. Signaling description: When complexed with the SF1 (NR5A1) protein, SRY acts as a transcription factor that can upregulate other transcription factors, most importantly SOX9, which then activates and forms a feedforward loop with FGF9. Sertoli cell proliferation and differentiation is mainly activated by FGF9. SOX9 expression causes the development of primary sex cords, which later develop into seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now induced Leydig cells of the testis then start secreting testosterone while the Sertoli cells produce anti-Müllerian hormone (AMH) to inhibit the creation of a female reproductive system.Besides NR5A1, other transcription factors such as SP1, WT1, GATA4, FOG2 (ZFPM2), SIX1/4 control expression of SRY. DAX1 (NR0B1) is an antagonist of male development. There is evidence from work on suppression of male development that DAX1 can interfere with function of NR5A1, and in turn transcription of SRY by recruiting corepressors.Gonadal target genes of SOX9 include AMH, FGF9, desert hedgehog (DHH), prostaglandin D synthase (PTGDS), and VANIN1 (VNN1).Prostaglandin D2 (PGD2) is necessary and sufficient to recruit cells that do not express SRY to express SOX9 and differentiate into Sertoli cells. Outcome effects: During testis differentiation, SRY, SOX9 and FGF9 act to downregulate the ovarian pathway by suppressing RSPO1 and WNT4, which promote the development of the gonad as an ovary. Highlighted proteins: Key players of male sex determination are highlighted in red. Key players of female sex determination (repressed) are highlighted in blue. PS:Organ testis PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: CD8 cells and NK cells kill damaged or infected cells in an organism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-463ea690-1c95-492d-9b04-a20c97abe920 NodeType: Pathway Notes: Headnote: CD8 cells and NK cells kill damaged or infected cells. CD8 T-cells (cytotoxic T-lymphocytes) attack and kill cells that are infected particularly by viruses or cells that are damaged in other ways such as cancer cells. Signaling description: Most CD8 T cells express T-cell receptors (TCRs) that can recognize a specific antigen and stimulate CD8 cell differentiation. The binding between TCR complex coactivator, CD8A and the MHC class I protein complex keeps CD8 T-cells and the target cell bound closely together during antigen-specific activation. CD8 cell activation occurs following antigen recognition by the TCR complex and CD8A coactivator. CD28 receptor signaling also contributes to CD8 cell activation. Once activated, CD8 cells undergo proliferation with the help of growth factors for T-cells such as IL2 or IL12. These cytokines increase the number of CD8 cells specific for the target antigen. Outcome effects: Lastly, the expression of FAS receptor ligand (FASLG) and production of granzyme B (GZMB) and perforin (PRF1) are the main mechanisms of CD8 T-cell cytotoxicity. Cytotoxicity may be mediated indirectly by the release of cytokines such as TNF-beta (LTA) and IFNG from cytotoxic cells. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-463ea690-1c95-492d-9b04-a20c97abe920 CD8+ T-Cell Activation uuid-463ea690-1c95-492d-9b04-a20c97abe920 PS:CellType T-cell PS:Description CD8 cells and NK cells kill damaged or infected cells in an organism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-463ea690-1c95-492d-9b04-a20c97abe920 PS:NodeType Pathway PS:Notes Headnote: CD8 cells and NK cells kill damaged or infected cells. CD8 T-cells (cytotoxic T-lymphocytes) attack and kill cells that are infected particularly by viruses or cells that are damaged in other ways such as cancer cells. Signaling description: Most CD8 T cells express T-cell receptors (TCRs) that can recognize a specific antigen and stimulate CD8 cell differentiation. The binding between TCR complex coactivator, CD8A and the MHC class I protein complex keeps CD8 T-cells and the target cell bound closely together during antigen-specific activation. CD8 cell activation occurs following antigen recognition by the TCR complex and CD8A coactivator. CD28 receptor signaling also contributes to CD8 cell activation. Once activated, CD8 cells undergo proliferation with the help of growth factors for T-cells such as IL2 or IL12. These cytokines increase the number of CD8 cells specific for the target antigen. Outcome effects: Lastly, the expression of FAS receptor ligand (FASLG) and production of granzyme B (GZMB) and perforin (PRF1) are the main mechanisms of CD8 T-cell cytotoxicity. Cytotoxicity may be mediated indirectly by the release of cytokines such as TNF-beta (LTA) and IFNG from cytotoxic cells. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-464e8669-0e23-47f2-b334-86011131f9ce NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-464e8669-0e23-47f2-b334-86011131f9ce CD22 -> STAT Expression Targets uuid-464e8669-0e23-47f2-b334-86011131f9ce PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-464e8669-0e23-47f2-b334-86011131f9ce PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-467e5796-215b-4c1e-b175-678150eba841 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-467e5796-215b-4c1e-b175-678150eba841 PDGFC -> CREB Expression Target uuid-467e5796-215b-4c1e-b175-678150eba841 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-467e5796-215b-4c1e-b175-678150eba841 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Cetuximab, a monoclonal antibody against EGFR, is used to treat metastatic colorectal cancer and head and neck cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4685196d-6bf9-4e45-b257-1c15c9c589a4 NodeType: Pathway Notes: Headnote: Cetuximab, a partially humanized monoclonal antibody against epidermal growth factor receptor (EGFR) is used to treat metastatic colorectal cancer and head and neck cancer. At the same time, only 10-20% of patients with metastatic colorectal cancer will benefit from anti-EGFR therapy. Understanding the reasons of underlying cetuximab resistance and discovering the biomarkers of response will help to predict which patients should receive anti-EGFR therapy. A patient's response to anti-EGFR therapy depends on the importance of the EGFR signal for cancer progression in the given case. EGFR mediates its action through PI3K/AKT1 and Ras/Raf/MAPK pathways. Outcome effects: Mutations in genes coding for members of the PI3K/AKT1 and Ras/Raf/MAPK pathways may cause their constant activation independent of the EGF/EGFR binding. EGFR is a member of ERBB family of receptors. Changes in expression and mutation status of other ERBB proteins and their ligands affect cetuximab sensitivity through activation of its downstream pathways independent of EGF/EGFR binding. Protein tyrosine kinases, other than ERBB family members, can also activate PI3K/AKT1 and Ras/Raf/MAPK pathways. This contributes to resistance and the inhibition of EGFR which is unable to block pathways leading to cell proliferation. EGFR promotes cell proliferation, not only as a receptor, but can be transported to the nucleus and act on several transcription factors and other nuclear proteins. Cetuximab can also cause antibody-dependent cellular cytotoxicity (ADCC). Mutations in FC gamma receptors that are involved in ADCC influence cetuximab sensitivity. Another important mechanism of resistance to anti-EGFR therapies is epithelial-to-mesenchymal transition (EMT). The activation of EMT program decreases the cell's dependence on EGF/EGFR signaling and therefore sensitivity to cetuximab. Highlighted proteins: Proteins highlighted in blue are known to increase sensitivity to cetuximab, and proteins highlighted in red are known to decrease sensitivity to cetuximab. Organ: colon Organ: intestine Organ_System: integumentary system PMID: 21139621 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4685196d-6bf9-4e45-b257-1c15c9c589a4 Cetuximab Resistance in Colorectal Cancer uuid-4685196d-6bf9-4e45-b257-1c15c9c589a4 PS:CellType cancer cell PS:Description Cetuximab, a monoclonal antibody against EGFR, is used to treat metastatic colorectal cancer and head and neck cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4685196d-6bf9-4e45-b257-1c15c9c589a4 PS:NodeType Pathway PS:Notes Headnote: Cetuximab, a partially humanized monoclonal antibody against epidermal growth factor receptor (EGFR) is used to treat metastatic colorectal cancer and head and neck cancer. At the same time, only 10-20% of patients with metastatic colorectal cancer will benefit from anti-EGFR therapy. Understanding the reasons of underlying cetuximab resistance and discovering the biomarkers of response will help to predict which patients should receive anti-EGFR therapy. A patient's response to anti-EGFR therapy depends on the importance of the EGFR signal for cancer progression in the given case. EGFR mediates its action through PI3K/AKT1 and Ras/Raf/MAPK pathways. Outcome effects: Mutations in genes coding for members of the PI3K/AKT1 and Ras/Raf/MAPK pathways may cause their constant activation independent of the EGF/EGFR binding. EGFR is a member of ERBB family of receptors. Changes in expression and mutation status of other ERBB proteins and their ligands affect cetuximab sensitivity through activation of its downstream pathways independent of EGF/EGFR binding. Protein tyrosine kinases, other than ERBB family members, can also activate PI3K/AKT1 and Ras/Raf/MAPK pathways. This contributes to resistance and the inhibition of EGFR which is unable to block pathways leading to cell proliferation. EGFR promotes cell proliferation, not only as a receptor, but can be transported to the nucleus and act on several transcription factors and other nuclear proteins. Cetuximab can also cause antibody-dependent cellular cytotoxicity (ADCC). Mutations in FC gamma receptors that are involved in ADCC influence cetuximab sensitivity. Another important mechanism of resistance to anti-EGFR therapies is epithelial-to-mesenchymal transition (EMT). The activation of EMT program decreases the cell's dependence on EGF/EGFR signaling and therefore sensitivity to cetuximab. Highlighted proteins: Proteins highlighted in blue are known to increase sensitivity to cetuximab, and proteins highlighted in red are known to decrease sensitivity to cetuximab. PS:Organ colon PS:Organ intestine PS:Organ_System integumentary system PS:PMID 21139621 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-469a3717-7be0-49e4-af92-f78bd39c6d73 NodeType: Pathway Notes: Headnote: Ichthyosis is a family of mostly genetic disorders with dry, scaly and thickened skin. Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Skin development is altered in utero. Hyperkeratosis of the hair canal occurs in the second trimester and characteristic ultrastructural abnormalities including abnormal lamellar granules are present in the affected fetal epidermis. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis. Signaling description: Ceramide activates PPAR delta, leading to stimulation of the transmembrane transporter ABCA12 production. ABCA12 is important for the transport of lipids, as well as regulation of protein synthesis in the developing skin layer. In the stratum corneum, ABCA12 transports glucosylceramides into epidermal lamellar bodies. In keratinizing keratinocytes of the upper epidermis, ABCA12 is responsible for the lamellar granule lipid transport. The role of ABCA12 defects in the pathogenesis of harlequin ichthyosis is depicted on the pathway. Outcome effects: Deficient ABCA12 function causes lipid transport disruption in lamellar bodies, and therefore leads to a decrease in intercellular lipid levels in the stratum corneum. ABCA12 mutations have been associated with defects in the distribution and transport of glycosylceramide, as well as decreased levels of hydroxyceramides, one of the main components in the lipid barrier in the intercellular spaces. The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier. It might also be due to the lack of desquamation of the corneocytes, which could be caused by defects in the transport of certain proteases, such as kallikrein 5 and cathepsin D. Increased amounts of cellular glucosylceramide and gangliosides induce apoptosis in keratinocytes. Animal data: CTSD, KLK5 and glucosylceramide are highlighted in blue illustrating the protective skin barrier disruption in the stratum corneum. Gangliosides and glucosylceramide with red highlights have increased accumulation in harlequin ichthyosis. Animal data: not shown Mutated proteins: ABCA12 gene mutated in harlequin ichthyosis is in white-out style. Organ: skin Organ_System: integumentary system PMID: 18957418 PMID: 23562412 PMID: 23954554 PMID: 24055887 PMID: 26945532 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-469a3717-7be0-49e4-af92-f78bd39c6d73 Harlequin Ichthyosis uuid-469a3717-7be0-49e4-af92-f78bd39c6d73 PS:CellType keratinocyte PS:Description Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-469a3717-7be0-49e4-af92-f78bd39c6d73 PS:NodeType Pathway PS:Notes Headnote: Ichthyosis is a family of mostly genetic disorders with dry, scaly and thickened skin. Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Skin development is altered in utero. Hyperkeratosis of the hair canal occurs in the second trimester and characteristic ultrastructural abnormalities including abnormal lamellar granules are present in the affected fetal epidermis. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis. Signaling description: Ceramide activates PPAR delta, leading to stimulation of the transmembrane transporter ABCA12 production. ABCA12 is important for the transport of lipids, as well as regulation of protein synthesis in the developing skin layer. In the stratum corneum, ABCA12 transports glucosylceramides into epidermal lamellar bodies. In keratinizing keratinocytes of the upper epidermis, ABCA12 is responsible for the lamellar granule lipid transport. The role of ABCA12 defects in the pathogenesis of harlequin ichthyosis is depicted on the pathway. Outcome effects: Deficient ABCA12 function causes lipid transport disruption in lamellar bodies, and therefore leads to a decrease in intercellular lipid levels in the stratum corneum. ABCA12 mutations have been associated with defects in the distribution and transport of glycosylceramide, as well as decreased levels of hydroxyceramides, one of the main components in the lipid barrier in the intercellular spaces. The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier. It might also be due to the lack of desquamation of the corneocytes, which could be caused by defects in the transport of certain proteases, such as kallikrein 5 and cathepsin D. Increased amounts of cellular glucosylceramide and gangliosides induce apoptosis in keratinocytes. Animal data: CTSD, KLK5 and glucosylceramide are highlighted in blue illustrating the protective skin barrier disruption in the stratum corneum. Gangliosides and glucosylceramide with red highlights have increased accumulation in harlequin ichthyosis. Animal data: not shown Mutated proteins: ABCA12 gene mutated in harlequin ichthyosis is in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18957418 PS:PMID 23562412 PS:PMID 23954554 PS:PMID 24055887 PS:PMID 26945532 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-469dc0cf-23fd-4819-bbb0-6d2c47e2c1f2 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-469dc0cf-23fd-4819-bbb0-6d2c47e2c1f2 Genes with Mutation in Cancer-Associated Dysregulated DNA Repair uuid-469dc0cf-23fd-4819-bbb0-6d2c47e2c1f2 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-469dc0cf-23fd-4819-bbb0-6d2c47e2c1f2 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46a28564-5d46-4716-ae09-19905ef67628 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-46a28564-5d46-4716-ae09-19905ef67628 Lipotoxicity through TLRs uuid-46a28564-5d46-4716-ae09-19905ef67628 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46a28564-5d46-4716-ae09-19905ef67628 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of WNT signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46b24474-0e78-442b-af3c-c067267cd4e7 NodeType: Pathway Notes: Headnote: The canonical WNT pathway causes an accumulation of CTNNB1 in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional co-activator of transcription factors that belong to the TCF/LEF family. The conserved WNT/CTNNB1 pathway regulates stem cell pluripotency and cell fate decisions during development and is often deregulated in cancer. Signaling description: WNT ligands bind to FZD receptors, leading to the formation of a larger cell surface complex with LRP5/6. Activation of the WNT receptor complex triggers displacement of the multifunctional kinase GSK3B from a regulatory APC/AXIN1/GSK3B-complex. In the absence of WNT-signal (off-state), CTNNB, undergoes coordinated phosphorylation by CSNK1A1 and the APC/AXIN1/GSK3B-complex leading to its ubiquitination and proteasomal degradation. In the presence of WNT ligand (on-state), the co-receptor LRP5/6 is complexed with WNT-bound FZD. This leads to activation of DLV by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK3B from APC/AXIN1 through an undetermined mechanism that may involve substrate trapping and/or endosome sequestration. Stabilized CTNNB1 is translocated to the nucleus, where it binds to LEF1/TCF4 transcription factors, displacing co-repressors and recruiting additional co-activators to WNT target genes. Activating mutations in CTNNB1, LEF1, CREBBP genes and hyperexpression of WNT ligands, LRP5/6, FRAT1, FOXM1, BCL9 lead to constant WNT signaling activation. Outcome effects: WNT pathway is kept in on-state leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18432252 PMID: 22438566 PMID: 22617421 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-46b24474-0e78-442b-af3c-c067267cd4e7 WNT Canonical Signaling Activation in Cancer uuid-46b24474-0e78-442b-af3c-c067267cd4e7 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of WNT signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46b24474-0e78-442b-af3c-c067267cd4e7 PS:NodeType Pathway PS:Notes Headnote: The canonical WNT pathway causes an accumulation of CTNNB1 in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional co-activator of transcription factors that belong to the TCF/LEF family. The conserved WNT/CTNNB1 pathway regulates stem cell pluripotency and cell fate decisions during development and is often deregulated in cancer. Signaling description: WNT ligands bind to FZD receptors, leading to the formation of a larger cell surface complex with LRP5/6. Activation of the WNT receptor complex triggers displacement of the multifunctional kinase GSK3B from a regulatory APC/AXIN1/GSK3B-complex. In the absence of WNT-signal (off-state), CTNNB, undergoes coordinated phosphorylation by CSNK1A1 and the APC/AXIN1/GSK3B-complex leading to its ubiquitination and proteasomal degradation. In the presence of WNT ligand (on-state), the co-receptor LRP5/6 is complexed with WNT-bound FZD. This leads to activation of DLV by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK3B from APC/AXIN1 through an undetermined mechanism that may involve substrate trapping and/or endosome sequestration. Stabilized CTNNB1 is translocated to the nucleus, where it binds to LEF1/TCF4 transcription factors, displacing co-repressors and recruiting additional co-activators to WNT target genes. Activating mutations in CTNNB1, LEF1, CREBBP genes and hyperexpression of WNT ligands, LRP5/6, FRAT1, FOXM1, BCL9 lead to constant WNT signaling activation. Outcome effects: WNT pathway is kept in on-state leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18432252 PS:PMID 22438566 PS:PMID 22617421 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: alveolar macrophage CellType: cancer cell CellType: cancer stem cell Description: Silicosis and asbestosis result from occupational hazards and are characterized by lung fibrosis and high risk of lung cancer or mesothelioma development due to chronic inflammatory process. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46c6dd4b-dee5-4cb0-a6b4-6c8374996588 NodeType: Pathway Notes: Headnote: Silicosis and asbestosis are two forms of fibrotic lung disease resulting from the inhalation of inert materials indigestible by pulmonary alveolar macrophages - crystalline silica and asbestos respectively. This pathology is predictable among people overexposed to dusts in various industries and occupations such as mining, construction, manufacturing, and building maintenance. Asbestos and silica accumulation in the lung tissue leads to inflammatory response and may cause not only pulmonary fibrosis but also lung cancer or mesothelioma development as a result of chronic inflammation. Signaling description: Silica and asbestos captured by macrophages activate ROS production by NAD(P)H oxidase. H2O2 may activate both NFkB and MAPK1/JUN-FOS and induce TNF and IL1B production. ROS also activate inflammasome formation. As a result CASP1 promotes the maturation and secretion of pro-inflammatory cytokines IL1B and IL18. Outcome effects: During long-standing chronic inflammation, TNF, IL1B and IL18 can make a significant impact into the development of pulmonary fibrosis, lung cancer and mesothelioma. According to current knowledge, chronic inflammation is regarded as the main underlying mechanism for cancer development in asbestosis and silicosis. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ: lung Organ_System: respiratory system PMID: 17476347 PMID: 20303878 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-46c6dd4b-dee5-4cb0-a6b4-6c8374996588 Asbestosis- and Silicosis-Associated Inflammation Provokes Cancer Development uuid-46c6dd4b-dee5-4cb0-a6b4-6c8374996588 PS:CellType alveolar macrophage PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Silicosis and asbestosis result from occupational hazards and are characterized by lung fibrosis and high risk of lung cancer or mesothelioma development due to chronic inflammatory process. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46c6dd4b-dee5-4cb0-a6b4-6c8374996588 PS:NodeType Pathway PS:Notes Headnote: Silicosis and asbestosis are two forms of fibrotic lung disease resulting from the inhalation of inert materials indigestible by pulmonary alveolar macrophages - crystalline silica and asbestos respectively. This pathology is predictable among people overexposed to dusts in various industries and occupations such as mining, construction, manufacturing, and building maintenance. Asbestos and silica accumulation in the lung tissue leads to inflammatory response and may cause not only pulmonary fibrosis but also lung cancer or mesothelioma development as a result of chronic inflammation. Signaling description: Silica and asbestos captured by macrophages activate ROS production by NAD(P)H oxidase. H2O2 may activate both NFkB and MAPK1/JUN-FOS and induce TNF and IL1B production. ROS also activate inflammasome formation. As a result CASP1 promotes the maturation and secretion of pro-inflammatory cytokines IL1B and IL18. Outcome effects: During long-standing chronic inflammation, TNF, IL1B and IL18 can make a significant impact into the development of pulmonary fibrosis, lung cancer and mesothelioma. According to current knowledge, chronic inflammation is regarded as the main underlying mechanism for cancer development in asbestosis and silicosis. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17476347 PS:PMID 20303878 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46c7a66b-7971-48aa-a631-18272cce90d4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-46c7a66b-7971-48aa-a631-18272cce90d4 ROS metabolism template uuid-46c7a66b-7971-48aa-a631-18272cce90d4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46c7a66b-7971-48aa-a631-18272cce90d4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46cb7234-0924-4212-a85f-b96c6ac9ba55 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-46cb7234-0924-4212-a85f-b96c6ac9ba55 MMP11 promotes tumor invasion uuid-46cb7234-0924-4212-a85f-b96c6ac9ba55 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46cb7234-0924-4212-a85f-b96c6ac9ba55 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: smooth muscle myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46e9a292-6141-4ff9-a3ae-503cbce292b4 NodeType: Pathway Notes: Vasoconstrictors and other signals from endothelial cells induce contraction and the proliferation of pulmonary artery smooth muscle cells (PASMCs). Growth factors including epidermal growth factor (EGF), platelet-derived growth factor subunits A and B (PDGFA and PDGFB), and insulin-like growth factor 1 (IGF1) are all overexpressed in PAH, and they play a role in the stimulation of PASMCs in PAH. Enhanced PASMC proliferation and contractility result in artery wall thickening and lumen narrowing, which are the primary factors leading to increased pulmonary vascular resistance and the development of pulmonary hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-46e9a292-6141-4ff9-a3ae-503cbce292b4 2_The intense proliferation and contractile activity of smooth muscle cells in pulmonary hypertension uuid-46e9a292-6141-4ff9-a3ae-503cbce292b4 PS:CellType smooth muscle myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-46e9a292-6141-4ff9-a3ae-503cbce292b4 PS:NodeType Pathway PS:Notes Vasoconstrictors and other signals from endothelial cells induce contraction and the proliferation of pulmonary artery smooth muscle cells (PASMCs). Growth factors including epidermal growth factor (EGF), platelet-derived growth factor subunits A and B (PDGFA and PDGFB), and insulin-like growth factor 1 (IGF1) are all overexpressed in PAH, and they play a role in the stimulation of PASMCs in PAH. Enhanced PASMC proliferation and contractility result in artery wall thickening and lumen narrowing, which are the primary factors leading to increased pulmonary vascular resistance and the development of pulmonary hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Link PS:NodeType PS:Pathway_Author PS:Source CellType: neutrophil Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47002453-b3a1-4f78-8fc5-c9c893bd3150 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-47002453-b3a1-4f78-8fc5-c9c893bd3150 Neutrophil Chemotaxis in cornea uuid-47002453-b3a1-4f78-8fc5-c9c893bd3150 PS:CellType neutrophil PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47002453-b3a1-4f78-8fc5-c9c893bd3150 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-470ea415-4c7d-4711-acf4-8a49b84713e2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-470ea415-4c7d-4711-acf4-8a49b84713e2 Volatile benzenoid ester biosynthesis template uuid-470ea415-4c7d-4711-acf4-8a49b84713e2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-470ea415-4c7d-4711-acf4-8a49b84713e2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4727421c-d8a6-4411-97a0-2260df42a302 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4727421c-d8a6-4411-97a0-2260df42a302 NSP4 interactions uuid-4727421c-d8a6-4411-97a0-2260df42a302 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4727421c-d8a6-4411-97a0-2260df42a302 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47384986-38b5-4554-93f2-9b034f2bdcab NodeType: Pathway Organ: mouth Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-47384986-38b5-4554-93f2-9b034f2bdcab Proteins Involved in Periodontitis uuid-47384986-38b5-4554-93f2-9b034f2bdcab PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47384986-38b5-4554-93f2-9b034f2bdcab PS:NodeType Pathway PS:Organ mouth PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47514cf1-549c-42c1-8124-0e1e4bbda99e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-47514cf1-549c-42c1-8124-0e1e4bbda99e FSHR Expression Targets uuid-47514cf1-549c-42c1-8124-0e1e4bbda99e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47514cf1-549c-42c1-8124-0e1e4bbda99e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4755caa3-86dc-4499-81cc-b3b4b6a78d50 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4755caa3-86dc-4499-81cc-b3b4b6a78d50 HBEGF -> STAT Expression Targets uuid-4755caa3-86dc-4499-81cc-b3b4b6a78d50 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4755caa3-86dc-4499-81cc-b3b4b6a78d50 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4768d123-4d73-4c6e-8c3f-615e3b7c5f34 NodeType: Pathway Organ: Retina Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4768d123-4d73-4c6e-8c3f-615e3b7c5f34 Proteins Involved in Retinitis Pigmentosa uuid-4768d123-4d73-4c6e-8c3f-615e3b7c5f34 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4768d123-4d73-4c6e-8c3f-615e3b7c5f34 PS:NodeType Pathway PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Prostate-specific antigen (PSA), also known as kallikrein-3 protein (KLK3), is a secreted peptidase expressed predominantly in the prostatic epithelial cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-476a8453-3df2-40f8-beeb-d4e4b8117907 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Prostate-specific antigen (PSA), also known as kallikrein-3 protein (KLK3), is a secreted peptidase expressed predominantly in the prostatic epithelial cells. The promoter region of the KLK3 gene has an androgen-responsive element and the expression of KLK3 is regulated by the androgen receptor (AR). In the normal prostate, kallikreins are activated in secretory epithelial cells, but are inhibited by Zn2+ in a reversible manner. They become active due to the Zn2+ ion loss promoting proteolysis of the extracellular matrix components, semenogelins (SEMG1/2) and fibronectin (FN1), thus enabling spermatozoa to ""swim"" freely. This is possible due to the prostate's ability to accumulate cellular levels of zinc that are much higher than in other mammalian cells. However, it has been shown that zinc-accumulating apparatus is often downregulated in prostate cancer cells. This can lead to the decline of Zn2 levels in the cell and as a result increase KLK3 activity. Outcome effects: Elevated KLK3 activity may result in increased proteolysis of insulin-like growth factor binding protein 3 (IGFBP3) and components of the extracellular matrix contributing to cancer progression and metastatic behavior of prostate cancer cells. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Organ: prostate Organ_System: urinary tract PMID: 17253191 PMID: 18687738 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-476a8453-3df2-40f8-beeb-d4e4b8117907 Androgen Receptor/Prostate Specific Antigen Signaling in Prostate Cancer uuid-476a8453-3df2-40f8-beeb-d4e4b8117907 PS:CellType cancer cell PS:Description Prostate-specific antigen (PSA), also known as kallikrein-3 protein (KLK3), is a secreted peptidase expressed predominantly in the prostatic epithelial cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-476a8453-3df2-40f8-beeb-d4e4b8117907 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Prostate-specific antigen (PSA), also known as kallikrein-3 protein (KLK3), is a secreted peptidase expressed predominantly in the prostatic epithelial cells. The promoter region of the KLK3 gene has an androgen-responsive element and the expression of KLK3 is regulated by the androgen receptor (AR). In the normal prostate, kallikreins are activated in secretory epithelial cells, but are inhibited by Zn2+ in a reversible manner. They become active due to the Zn2+ ion loss promoting proteolysis of the extracellular matrix components, semenogelins (SEMG1/2) and fibronectin (FN1), thus enabling spermatozoa to ""swim"" freely. This is possible due to the prostate's ability to accumulate cellular levels of zinc that are much higher than in other mammalian cells. However, it has been shown that zinc-accumulating apparatus is often downregulated in prostate cancer cells. This can lead to the decline of Zn2 levels in the cell and as a result increase KLK3 activity. Outcome effects: Elevated KLK3 activity may result in increased proteolysis of insulin-like growth factor binding protein 3 (IGFBP3) and components of the extracellular matrix contributing to cancer progression and metastatic behavior of prostate cancer cells. Highlighted proteins: Protein with increased expression or activity is highlighted in red. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 17253191 PS:PMID 18687738 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-476cfe9d-3e71-414d-a983-c652c2b26ad8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-476cfe9d-3e71-414d-a983-c652c2b26ad8 menaquinone-7 biosynthesis template uuid-476cfe9d-3e71-414d-a983-c652c2b26ad8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-476cfe9d-3e71-414d-a983-c652c2b26ad8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4772630e-87f1-4751-8d30-9e4bc862e361 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-4772630e-87f1-4751-8d30-9e4bc862e361 Genes with Mutations in Cancer-Associated Enabling of Replicative Immortality uuid-4772630e-87f1-4751-8d30-9e4bc862e361 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4772630e-87f1-4751-8d30-9e4bc862e361 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47875bfa-dc2c-46b9-9a28-fc86833e0500 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-47875bfa-dc2c-46b9-9a28-fc86833e0500 Frizzled Receptors -> ARRB1/ARRB2 Canonical Signaling uuid-47875bfa-dc2c-46b9-9a28-fc86833e0500 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47875bfa-dc2c-46b9-9a28-fc86833e0500 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47a00d57-a8d3-4386-9e16-bd67e445a50c NodeType: Pathway Organ: breast Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-47a00d57-a8d3-4386-9e16-bd67e445a50c Proteins with Altered Expression in Breast Cancer uuid-47a00d57-a8d3-4386-9e16-bd67e445a50c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47a00d57-a8d3-4386-9e16-bd67e445a50c PS:NodeType Pathway PS:Organ breast PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47a73fe1-7a63-469b-9f01-d76a39c46c7d NodeType: Pathway Organ: generic Organ_System: generic PMID: 18267068 PMID: 20685151 PMID: 2391518 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-47a73fe1-7a63-469b-9f01-d76a39c46c7d NF-kB Canonical Signaling uuid-47a73fe1-7a63-469b-9f01-d76a39c46c7d PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47a73fe1-7a63-469b-9f01-d76a39c46c7d PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 18267068 PS:PMID 20685151 PS:PMID 2391518 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47d48dbb-3ab4-496d-b64c-8755b4863a6f NodeType: Pathway Notes: Patients with Crohn’s disease–associated NOD2 and autophagy-related 16 like 1 (ATG16L1) mutations have decreased autophagic responses to infection and ineffective elimination of ingested pathogenic bacteria and therefore exhibit free bacterial expansion. In healthy dendritic cell, macrophages and other intestine cells, NOD2, and ATG16L1 are involved in autophagy and consequently in the trafficking of ingested organisms to lysosomes where they are eliminated. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-47d48dbb-3ab4-496d-b64c-8755b4863a6f 3_Autophagy dysfunction in Crohn's disease uuid-47d48dbb-3ab4-496d-b64c-8755b4863a6f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47d48dbb-3ab4-496d-b64c-8755b4863a6f PS:NodeType Pathway PS:Notes Patients with Crohn’s disease–associated NOD2 and autophagy-related 16 like 1 (ATG16L1) mutations have decreased autophagic responses to infection and ineffective elimination of ingested pathogenic bacteria and therefore exhibit free bacterial expansion. In healthy dendritic cell, macrophages and other intestine cells, NOD2, and ATG16L1 are involved in autophagy and consequently in the trafficking of ingested organisms to lysosomes where they are eliminated. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47f924fe-7a09-430c-8c63-d605937780cb NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-47f924fe-7a09-430c-8c63-d605937780cb ICAM1 -> AP-1/CREB/ELK/SRF Signaling uuid-47f924fe-7a09-430c-8c63-d605937780cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-47f924fe-7a09-430c-8c63-d605937780cb PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48031df6-b45e-4cd8-8dca-34e44611807a NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-48031df6-b45e-4cd8-8dca-34e44611807a Proteins with Altered Expression in Asthma uuid-48031df6-b45e-4cd8-8dca-34e44611807a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48031df6-b45e-4cd8-8dca-34e44611807a PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Clara cell Description: Club cells are cell type of bronchiolar epithelia which express SCGB1A1 to protect the bronchiole lining. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48475357-c7e9-44d6-a507-8bdff7733bd6 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Club cells are a cell type of bronchiolar epithelia which express SCGB1A1 to protect the bronchiole lining. LGALS3 is another club cell specific secreted protein. The role of club cells in asthma is still controversial. Club cells are involved in allergen-induced mucus production, but seem to exert protective effects against asthma. In addition, club cells are the major progenitors for goblet cells. Club cells give rise to goblet cells following an allergen challenge, a process called mucus metaplasia. NGF promotes the proliferation of lung epithelium in vitro and the renewal of club cells following lung injury in vivo. Serum levels of NGF have been shown to be enhanced in asthmatics. Club cell's own mucin expression is limited specifically to a subset of club cells (generations 2-4) that continue to express SCGB1A1. There is a (Hypothesis) that allergen-induced mucus production depends upon IL4R signaling in club cells. In mice, IL13 can induce mucus metaplasia via STAT6. Probably, Notch may silence the ciliated program in the cells that will continue to expand and differentiate into secretory cells in the developing airways. SPDEF is required for goblet cell differentiation induced by allergens. SPDEF regulates a group of genes associated with mucin biosynthesis and secretion, suppressing of TTF1 and FOXA2 and inducting of FOXA3. SPDEF is induced following pulmonary allergen and IL-13 exposure. Expression of Sox2 in club cells is required also for the differentiation of ciliated and goblet cells in the postnatal lung. Outcome effects: Club cells drive eosinophil accumulation in allergic asthma through CCL11 production. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 19502490 PMID: 21472689 PMID: 21828027 PMID: 23940685 PMID: 25504013 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-48475357-c7e9-44d6-a507-8bdff7733bd6 Club-Cell Role in Asthma uuid-48475357-c7e9-44d6-a507-8bdff7733bd6 PS:CellType Clara cell PS:Description Club cells are cell type of bronchiolar epithelia which express SCGB1A1 to protect the bronchiole lining. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48475357-c7e9-44d6-a507-8bdff7733bd6 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Club cells are a cell type of bronchiolar epithelia which express SCGB1A1 to protect the bronchiole lining. LGALS3 is another club cell specific secreted protein. The role of club cells in asthma is still controversial. Club cells are involved in allergen-induced mucus production, but seem to exert protective effects against asthma. In addition, club cells are the major progenitors for goblet cells. Club cells give rise to goblet cells following an allergen challenge, a process called mucus metaplasia. NGF promotes the proliferation of lung epithelium in vitro and the renewal of club cells following lung injury in vivo. Serum levels of NGF have been shown to be enhanced in asthmatics. Club cell's own mucin expression is limited specifically to a subset of club cells (generations 2-4) that continue to express SCGB1A1. There is a (Hypothesis) that allergen-induced mucus production depends upon IL4R signaling in club cells. In mice, IL13 can induce mucus metaplasia via STAT6. Probably, Notch may silence the ciliated program in the cells that will continue to expand and differentiate into secretory cells in the developing airways. SPDEF is required for goblet cell differentiation induced by allergens. SPDEF regulates a group of genes associated with mucin biosynthesis and secretion, suppressing of TTF1 and FOXA2 and inducting of FOXA3. SPDEF is induced following pulmonary allergen and IL-13 exposure. Expression of Sox2 in club cells is required also for the differentiation of ciliated and goblet cells in the postnatal lung. Outcome effects: Club cells drive eosinophil accumulation in allergic asthma through CCL11 production. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 19502490 PS:PMID 21472689 PS:PMID 21828027 PS:PMID 23940685 PS:PMID 25504013 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4888bc1a-2383-4952-b0bb-c61a632f98e5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4888bc1a-2383-4952-b0bb-c61a632f98e5 GNRH2 Expression Targets uuid-4888bc1a-2383-4952-b0bb-c61a632f98e5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4888bc1a-2383-4952-b0bb-c61a632f98e5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48cae632-64ba-4a43-88d8-15a11fca2354 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-48cae632-64ba-4a43-88d8-15a11fca2354 microRNAs -| Snail1/2, CTNNB1, TCFs uuid-48cae632-64ba-4a43-88d8-15a11fca2354 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48cae632-64ba-4a43-88d8-15a11fca2354 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48d2f443-eadc-44dc-829b-b8afbfe43133 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-48d2f443-eadc-44dc-829b-b8afbfe43133 Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors uuid-48d2f443-eadc-44dc-829b-b8afbfe43133 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-48d2f443-eadc-44dc-829b-b8afbfe43133 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: N-cell Description: Fatty acids activate secretion of neurotensin from N-cells in small and medium intestine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49039250-50dd-4dc3-b02f-fe0237689dc9 NodeType: Pathway Notes: Headnote: N-cells are located in the small and large intestine and secrete tridecapeptide neurotensin (processed from NTS) released in response to short and medium chain fatty acid signal. Signaling description: Short and medium chain fatty acids interact with fatty acid receptors. The exact type of fatty acid receptor in the N-cells is not identified (the most common receptors are shown on the pathway). Fatty acid receptors increase cAMP synthesis, PKA and PKC activation via G-proteins. In turn, PKA and PKC phosphorylate and activate STAT3 and JUN/FOS transcription factors and lead to the expression of NTS gene. The processing of NTS propeptide leads to formation of two neuropeptides: neurotensin (13 a.a.) and neuromedin N. The neurotensin peptide blocks intestine motility by inhibition of muscle contraction._ Outcome effects: Short and medium chain fatty acids dependent expression of neurotensin inactivates gastric motility. Organ: jejunum Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-49039250-50dd-4dc3-b02f-fe0237689dc9 N-cell: Neurotensin Production uuid-49039250-50dd-4dc3-b02f-fe0237689dc9 PS:CellType N-cell PS:Description Fatty acids activate secretion of neurotensin from N-cells in small and medium intestine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49039250-50dd-4dc3-b02f-fe0237689dc9 PS:NodeType Pathway PS:Notes Headnote: N-cells are located in the small and large intestine and secrete tridecapeptide neurotensin (processed from NTS) released in response to short and medium chain fatty acid signal. Signaling description: Short and medium chain fatty acids interact with fatty acid receptors. The exact type of fatty acid receptor in the N-cells is not identified (the most common receptors are shown on the pathway). Fatty acid receptors increase cAMP synthesis, PKA and PKC activation via G-proteins. In turn, PKA and PKC phosphorylate and activate STAT3 and JUN/FOS transcription factors and lead to the expression of NTS gene. The processing of NTS propeptide leads to formation of two neuropeptides: neurotensin (13 a.a.) and neuromedin N. The neurotensin peptide blocks intestine motility by inhibition of muscle contraction._ Outcome effects: Short and medium chain fatty acids dependent expression of neurotensin inactivates gastric motility. PS:Organ jejunum PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4908a93e-58bd-4978-babd-550f82652eb9 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PMID: 21884931 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-4908a93e-58bd-4978-babd-550f82652eb9 Macroautophagy Decline uuid-4908a93e-58bd-4978-babd-550f82652eb9 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4908a93e-58bd-4978-babd-550f82652eb9 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 21884931 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49118b9f-5e09-4dc4-ae7a-2d7166cbcbb1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-49118b9f-5e09-4dc4-ae7a-2d7166cbcbb1 PDGFC -> STAT Expression Target uuid-49118b9f-5e09-4dc4-ae7a-2d7166cbcbb1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49118b9f-5e09-4dc4-ae7a-2d7166cbcbb1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Apoptosis of endothelial cells (ECs) is a key event in the pathogenesis of systemic scleroderma, also known as systemic sclerosis (SSc). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-491d0e1b-b1f6-4b1f-816c-4185fc06221e NodeType: Pathway Notes: Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Apoptosis of endothelial cells (ECs) is a key event in the pathogenesis SSc. Signaling description: FAS-mediated apoptosis of ECs may represent a primary pathogenic event in the skin. FAS induces apoptosis of activated FAS-positive inflammatory and mesenchymal cells after injury and inflammation, thereby limiting the immune response and promoting tissue repair. Prolonged inflammation without apoptosis results in tissue injury as can excessive apoptosis. Outcome effects: EC apoptosis, possibly mediated by ADCC (antibody-dependent cell-mediated cytotoxicity), is a key pathogenic event in human SSc. Apoptotic ECs are present in skin biopsies of patients in the early inflammatory stage of SSc and with localized scleroderma but not in those with fibrotic changes or in healthy controls. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 18221988 PMID: 8698871 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-491d0e1b-b1f6-4b1f-816c-4185fc06221e FAS Mediated Apoptosis in Systemic Scleroderma uuid-491d0e1b-b1f6-4b1f-816c-4185fc06221e PS:CellType endothelial cell PS:Description Apoptosis of endothelial cells (ECs) is a key event in the pathogenesis of systemic scleroderma, also known as systemic sclerosis (SSc). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-491d0e1b-b1f6-4b1f-816c-4185fc06221e PS:NodeType Pathway PS:Notes Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Apoptosis of endothelial cells (ECs) is a key event in the pathogenesis SSc. Signaling description: FAS-mediated apoptosis of ECs may represent a primary pathogenic event in the skin. FAS induces apoptosis of activated FAS-positive inflammatory and mesenchymal cells after injury and inflammation, thereby limiting the immune response and promoting tissue repair. Prolonged inflammation without apoptosis results in tissue injury as can excessive apoptosis. Outcome effects: EC apoptosis, possibly mediated by ADCC (antibody-dependent cell-mediated cytotoxicity), is a key pathogenic event in human SSc. Apoptotic ECs are present in skin biopsies of patients in the early inflammatory stage of SSc and with localized scleroderma but not in those with fibrotic changes or in healthy controls. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18221988 PS:PMID 8698871 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-491ef023-d185-4d69-a701-b5e2f640dadd NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-491ef023-d185-4d69-a701-b5e2f640dadd Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality uuid-491ef023-d185-4d69-a701-b5e2f640dadd PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-491ef023-d185-4d69-a701-b5e2f640dadd PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49257292-09a6-4d91-8837-bb95456e5ffb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-49257292-09a6-4d91-8837-bb95456e5ffb FLT1 mediates survival in post-EMT cancer cells uuid-49257292-09a6-4d91-8837-bb95456e5ffb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49257292-09a6-4d91-8837-bb95456e5ffb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: thyroid cell Description: Apoptosis or programmed cell death appears to play a major role in the final stage of Hashimoto's thyroiditis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49263761-4096-4121-ada2-22f8e5cd9f55 NodeType: Pathway Notes: Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. HT is considered to be a Th1-mediated disease resulting in the aberrant infiltration of lymphoid cells and destruction of thyroid follicles. Apoptosis or programmed cell death appears to play a major role in the final stage of HT. Signaling description: An increased number of apoptotic cells is observed in patients with HT; however, the mechanism and regulation of apoptosis in the thyroid gland in HT remains unclear. The interaction with autoantigen leads to the production of different cytokines inducing T-helper type 1 (Th1)-mediated cell immune response. The stimulation of the Fas/Fas ligand apoptotic pathway by pro-inflammatory cytokines is the most important mechanism of T lymphocyte mediated apoptosis. Apoptotic molecules such as FAS and Fas ligand (FASLG) are expressed at low levels by normal thyroid cells compared to patients with HT. Outcome effects: FAS can facilitate apoptosis in thyroid cells via DAXX and RIPK1 leading to hypothyroidism. In addition, polymorphisms in ENO1, which is involved in triggering apoptosis in thyroid cells, are associated with HT. As a (Hypothesis), single nucleotide polymorphisms (SNPs) in ENO1 associated with HT may be related to fibrosis and hypothyroidism. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: thyroid gland Organ_System: endocrine system PMID: 12114310 PMID: 9626160 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-49263761-4096-4121-ada2-22f8e5cd9f55 Apoptosis of Thyroid Cell in Hashimoto's Thyroiditis uuid-49263761-4096-4121-ada2-22f8e5cd9f55 PS:CellType T-cell PS:CellType thyroid cell PS:Description Apoptosis or programmed cell death appears to play a major role in the final stage of Hashimoto's thyroiditis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49263761-4096-4121-ada2-22f8e5cd9f55 PS:NodeType Pathway PS:Notes Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. HT results from a complex combination of genetic, environmental, and endogenous factors which interplay to initiate thyroid autoimmunity. HT is considered to be a Th1-mediated disease resulting in the aberrant infiltration of lymphoid cells and destruction of thyroid follicles. Apoptosis or programmed cell death appears to play a major role in the final stage of HT. Signaling description: An increased number of apoptotic cells is observed in patients with HT; however, the mechanism and regulation of apoptosis in the thyroid gland in HT remains unclear. The interaction with autoantigen leads to the production of different cytokines inducing T-helper type 1 (Th1)-mediated cell immune response. The stimulation of the Fas/Fas ligand apoptotic pathway by pro-inflammatory cytokines is the most important mechanism of T lymphocyte mediated apoptosis. Apoptotic molecules such as FAS and Fas ligand (FASLG) are expressed at low levels by normal thyroid cells compared to patients with HT. Outcome effects: FAS can facilitate apoptosis in thyroid cells via DAXX and RIPK1 leading to hypothyroidism. In addition, polymorphisms in ENO1, which is involved in triggering apoptosis in thyroid cells, are associated with HT. As a (Hypothesis), single nucleotide polymorphisms (SNPs) in ENO1 associated with HT may be related to fibrosis and hypothyroidism. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 12114310 PS:PMID 9626160 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: CD8 cells and NK cells kill damaged or infected cells in an organism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-493908b7-dd04-4504-94cf-0360921ebda6 NodeType: Pathway Notes: Headnote: CD8 cells and NK cells kill damaged or infected cells in an organism. Most CD8 T-cells express T-cell receptors (TCRs) that can recognize a specific antigen. NK cells can recognize a pathogen and/or damaged cell in the absence of antibodies. FAS-like death receptors and the action of granzyme B (GZMB) and perforin (PRF1) on the cell membrane are the main mechanisms of CD8 T-cell and NK-cell cytotoxicity. Signaling description: Cytotoxicity may be mediated by the release of cytokines such as IFNG from cytotoxic cells. GZMB and PRF1 production can induce apoptosis in target cells by forming transmembrane pores and through the cleavage and activation of caspases. DNase (DFFB) is activated through the cleavage of its associated inhibitor, DFFA by caspase-3 (CASP3). DFFB is then able to interact with topoisomerase II (TOP2B) to condense chromatin, leading to DNA fragmentation and target cell apoptosis. When CD8 cells and NK cells are activated, they begin to express the surface protein, FASLG which can bind to FAS expressed on the target cell and trigger apoptosis. The engagement of FAS with FASLG allows for the recruitment of procaspases CASP8 and CASP10. These caspases then activate the effector caspases CASP3, CASP6, and CASP7, leading to the cleavage of death substrates such as LMNB1, PARP1, and PRKDC. Outcome effects: The final result is apoptosis of the cell that expresses FAS. However, FAS-FASLG interaction is thought to be more important to T-lymphocyte development rather than to the cytolytic activity of CD8 cells and NK cells. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-493908b7-dd04-4504-94cf-0360921ebda6 T-Cell Cytotoxic Mediated Cell Death uuid-493908b7-dd04-4504-94cf-0360921ebda6 PS:CellType T-cell PS:Description CD8 cells and NK cells kill damaged or infected cells in an organism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-493908b7-dd04-4504-94cf-0360921ebda6 PS:NodeType Pathway PS:Notes Headnote: CD8 cells and NK cells kill damaged or infected cells in an organism. Most CD8 T-cells express T-cell receptors (TCRs) that can recognize a specific antigen. NK cells can recognize a pathogen and/or damaged cell in the absence of antibodies. FAS-like death receptors and the action of granzyme B (GZMB) and perforin (PRF1) on the cell membrane are the main mechanisms of CD8 T-cell and NK-cell cytotoxicity. Signaling description: Cytotoxicity may be mediated by the release of cytokines such as IFNG from cytotoxic cells. GZMB and PRF1 production can induce apoptosis in target cells by forming transmembrane pores and through the cleavage and activation of caspases. DNase (DFFB) is activated through the cleavage of its associated inhibitor, DFFA by caspase-3 (CASP3). DFFB is then able to interact with topoisomerase II (TOP2B) to condense chromatin, leading to DNA fragmentation and target cell apoptosis. When CD8 cells and NK cells are activated, they begin to express the surface protein, FASLG which can bind to FAS expressed on the target cell and trigger apoptosis. The engagement of FAS with FASLG allows for the recruitment of procaspases CASP8 and CASP10. These caspases then activate the effector caspases CASP3, CASP6, and CASP7, leading to the cleavage of death substrates such as LMNB1, PARP1, and PRKDC. Outcome effects: The final result is apoptosis of the cell that expresses FAS. However, FAS-FASLG interaction is thought to be more important to T-lymphocyte development rather than to the cytolytic activity of CD8 cells and NK cells. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49393bc3-5587-4eae-ad68-9d60fd209dc7 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-49393bc3-5587-4eae-ad68-9d60fd209dc7 AngiopoietinR -> FOXO Signaling uuid-49393bc3-5587-4eae-ad68-9d60fd209dc7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49393bc3-5587-4eae-ad68-9d60fd209dc7 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49446557-8cfd-4a91-a474-d489b06314ff NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-49446557-8cfd-4a91-a474-d489b06314ff Carotenoid cleavage template uuid-49446557-8cfd-4a91-a474-d489b06314ff PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49446557-8cfd-4a91-a474-d489b06314ff PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neutrophil Description: Neutrophils have been implicated in the development of bronchial hyperresponsiveness as the first cells recruited to the site of an allergic reaction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4990a24e-08a4-4dbc-94a2-6e316c4c6e2f NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Neutrophils have been implicated in the development of bronchial hyperresponsiveness as the primary cells recruited to the site of an allergic reaction. Neutrophils are the major antibacterial cellular agents in inflammation since they combine functions of granulocytes and phagocytes. Neutrophils have a role in the development of severe chronic asthma and the onset of sudden severe attacks. Activation of neutrophils through adherence on endothelial cell depends on integrins and selectins expressed on the surface of both neutrophils and endothelial cells. PSGL-1 protein on the surface of neutrophils is the ligand for E-selectin. It is important for neutrophil rolling and integrin-dependent activation of adhesion of neutrophils on cells of blood vessel. Upon binding of PSGL-1 to E-selectin, SYK is activated through LYN/DAP12, which results in activation of complex ITGAL/ITGB2 by MAPK1 kinase (this part of the pathway is truncated here for a better layout). Receptors IRGAL, ITGB2, ITGB1/ITGA9 on the surface of neutrophils facilitate high levels of adhesion between neutrophils and endothelial cells, mostly through their association with ICAM-1. Activation of integrins on neutrophil surface leads to its adhesion to endothelial cells, and at the same time activates signaling pathways in in the neutrophil. Outcome effects: The major event is the cytoskeleton reorganization which forces neutrophil secretory vesicles to move towards the external membrane. Moreover, integrins trigger intracellular signaling cascades that lead to ROS production through the PI3K/RAC1 related signaling. IL-8 is a principal factor in neutrophil delivery. Other chemokines that are specific for neutrophils include epithelial cell derived neutrophil activating peptide, PPBP, CXCL5, CXCL2, and CXCL6. Neutrophil chemoattractants can increase integrin-dependent adhesion of neutrophils by stimulating integrin synthesis or change the cell shape by directly modulating actin cytoskeleton. IL8 binding to CXCR2 causes the release of MMP9 from tertiary granules. Elevated levels of MMP-9 have been found in patients with asthma. Further, MMP9 might promote eosinophil movement. CR1 and CD11b expression was higher on resting peripheral blood neutrophils in severe steroid-dependent asthmatics compared to normal and mild asthmatics. Surface molecules CR1 and CD11b neutrophil surface mediate binding and phagocytosis of C3b-coated particles and immune complexes. Neutrophil proteases (elastase, cathepsin G, and proteinase-3) may enhance airway inflammation in asthma through the activation of eosinophils to produce superoxide and neutrophilic cytokines and chemokines. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 10764310 PMID: 16600024 PMID: 19862934 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4990a24e-08a4-4dbc-94a2-6e316c4c6e2f Neutrophil Degranulation via FPR1/IL8 uuid-4990a24e-08a4-4dbc-94a2-6e316c4c6e2f PS:CellType neutrophil PS:Description Neutrophils have been implicated in the development of bronchial hyperresponsiveness as the first cells recruited to the site of an allergic reaction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4990a24e-08a4-4dbc-94a2-6e316c4c6e2f PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Neutrophils have been implicated in the development of bronchial hyperresponsiveness as the primary cells recruited to the site of an allergic reaction. Neutrophils are the major antibacterial cellular agents in inflammation since they combine functions of granulocytes and phagocytes. Neutrophils have a role in the development of severe chronic asthma and the onset of sudden severe attacks. Activation of neutrophils through adherence on endothelial cell depends on integrins and selectins expressed on the surface of both neutrophils and endothelial cells. PSGL-1 protein on the surface of neutrophils is the ligand for E-selectin. It is important for neutrophil rolling and integrin-dependent activation of adhesion of neutrophils on cells of blood vessel. Upon binding of PSGL-1 to E-selectin, SYK is activated through LYN/DAP12, which results in activation of complex ITGAL/ITGB2 by MAPK1 kinase (this part of the pathway is truncated here for a better layout). Receptors IRGAL, ITGB2, ITGB1/ITGA9 on the surface of neutrophils facilitate high levels of adhesion between neutrophils and endothelial cells, mostly through their association with ICAM-1. Activation of integrins on neutrophil surface leads to its adhesion to endothelial cells, and at the same time activates signaling pathways in in the neutrophil. Outcome effects: The major event is the cytoskeleton reorganization which forces neutrophil secretory vesicles to move towards the external membrane. Moreover, integrins trigger intracellular signaling cascades that lead to ROS production through the PI3K/RAC1 related signaling. IL-8 is a principal factor in neutrophil delivery. Other chemokines that are specific for neutrophils include epithelial cell derived neutrophil activating peptide, PPBP, CXCL5, CXCL2, and CXCL6. Neutrophil chemoattractants can increase integrin-dependent adhesion of neutrophils by stimulating integrin synthesis or change the cell shape by directly modulating actin cytoskeleton. IL8 binding to CXCR2 causes the release of MMP9 from tertiary granules. Elevated levels of MMP-9 have been found in patients with asthma. Further, MMP9 might promote eosinophil movement. CR1 and CD11b expression was higher on resting peripheral blood neutrophils in severe steroid-dependent asthmatics compared to normal and mild asthmatics. Surface molecules CR1 and CD11b neutrophil surface mediate binding and phagocytosis of C3b-coated particles and immune complexes. Neutrophil proteases (elastase, cathepsin G, and proteinase-3) may enhance airway inflammation in asthma through the activation of eosinophils to produce superoxide and neutrophilic cytokines and chemokines. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 10764310 PS:PMID 16600024 PS:PMID 19862934 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49998e51-9b64-4dbe-a63e-ab97e185785c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-49998e51-9b64-4dbe-a63e-ab97e185785c Mitochondrial transport in axons uuid-49998e51-9b64-4dbe-a63e-ab97e185785c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49998e51-9b64-4dbe-a63e-ab97e185785c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Postmenopause is also frequently associated with arterial hypertension. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49d5074f-45ed-4cf6-9a6c-3aee6a4908f0 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Postmenopause is also frequently associated with arterial hypertension. Signaling description: The hypertension risk related to postmenopause is due to rapid reduction of estrogen levels, which has a direct effect on blood vessel functions. Estrogens influence the transcription of a number of genes. Once activated by estrogen, the ESR1 is translocated into the nucleus where it interacts with transcription factors including NCOA1/2/3 and EP300 to form a transcription complex to induce the expression of downstream target genes. In addition, rapid non-genomic effects are mediated by ESR1 and GPER. The loss of estrogens contributes to endothelial dysfunction and results in arterial hypertension. Endothelial dysfunction is typically characterized by a reduction in nitric oxide (NO) levels. Estradiol quickly stimulates NO production by increasing intracellular Ca2+ which activates NOS3 and in the long-term by upregulating the transcription of NOS3. Both acute and chronic effects of estradiol on NO promote vasodilation. CAV1 and CAV3 are the primary structural proteins of caveolae, which are vesicular invaginations of the plasma membrane that represent specialized membrane signaling organelles. They are the preferential site of ESR1 signaling complexes in endothelial cells. Activated ESR1 co-localizes with CAV1/3 and activates NOS3. Once activated by estradiol, membrane-bound ESR1 activates PIK3CA via PIK3R1. Outcome effects: PIK3CA, through PIP3 and PDPK1, activates AKT1, which phosphorylates and activates NOS3 and CREB1, which in turn bind the nuclear ESR1 transcription complex. In addition, GPER, via GNAQ, stimulates PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum. Ca2+ binds the multifunctional binding messenger protein, calmodulin, which activates NOS3. CAV3 inhibits ADCY, which activates NOS3 via PKA. Nuclear ESR1 transcription complex promotes the expression of PTGIS, PTGS2, and PTGS1, which catalyze the synthesis of prostaglandin involved in vasodilation and regulation of platelet function. In addition, nuclear ESR1 transcription complex promotes the expression of blood clotting regulators such as PROS1, THBD, and PROCR. Furthermore, ESR1 and GPER activate MAP kinases cascade via SRC/SHC1 and leads to the activation of IL6, IL8, CCL2, and VEGFA which are involved in the mediation of vascularization. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PMID: 19442151 PMID: 19549587 PMID: 22427070 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endothelium urn:agi-pathway:uuid-49d5074f-45ed-4cf6-9a6c-3aee6a4908f0 Arterial Hypertension uuid-49d5074f-45ed-4cf6-9a6c-3aee6a4908f0 PS:CellType endothelial cell PS:Description Postmenopause is also frequently associated with arterial hypertension. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49d5074f-45ed-4cf6-9a6c-3aee6a4908f0 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Postmenopause is also frequently associated with arterial hypertension. Signaling description: The hypertension risk related to postmenopause is due to rapid reduction of estrogen levels, which has a direct effect on blood vessel functions. Estrogens influence the transcription of a number of genes. Once activated by estrogen, the ESR1 is translocated into the nucleus where it interacts with transcription factors including NCOA1/2/3 and EP300 to form a transcription complex to induce the expression of downstream target genes. In addition, rapid non-genomic effects are mediated by ESR1 and GPER. The loss of estrogens contributes to endothelial dysfunction and results in arterial hypertension. Endothelial dysfunction is typically characterized by a reduction in nitric oxide (NO) levels. Estradiol quickly stimulates NO production by increasing intracellular Ca2+ which activates NOS3 and in the long-term by upregulating the transcription of NOS3. Both acute and chronic effects of estradiol on NO promote vasodilation. CAV1 and CAV3 are the primary structural proteins of caveolae, which are vesicular invaginations of the plasma membrane that represent specialized membrane signaling organelles. They are the preferential site of ESR1 signaling complexes in endothelial cells. Activated ESR1 co-localizes with CAV1/3 and activates NOS3. Once activated by estradiol, membrane-bound ESR1 activates PIK3CA via PIK3R1. Outcome effects: PIK3CA, through PIP3 and PDPK1, activates AKT1, which phosphorylates and activates NOS3 and CREB1, which in turn bind the nuclear ESR1 transcription complex. In addition, GPER, via GNAQ, stimulates PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum. Ca2+ binds the multifunctional binding messenger protein, calmodulin, which activates NOS3. CAV3 inhibits ADCY, which activates NOS3 via PKA. Nuclear ESR1 transcription complex promotes the expression of PTGIS, PTGS2, and PTGS1, which catalyze the synthesis of prostaglandin involved in vasodilation and regulation of platelet function. In addition, nuclear ESR1 transcription complex promotes the expression of blood clotting regulators such as PROS1, THBD, and PROCR. Furthermore, ESR1 and GPER activate MAP kinases cascade via SRC/SHC1 and leads to the activation of IL6, IL8, CCL2, and VEGFA which are involved in the mediation of vascularization. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 19442151 PS:PMID 19549587 PS:PMID 22427070 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endothelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49d6c708-f993-4355-9aea-27131049a3e2 NodeType: Pathway Notes: Thyroid hormones act through their nuclear receptors that are ubiquitously expressed in human tissues. The effects of thyroid hormones are cell-specific, and they regulate the metabolism in and other functions of tissues and organs. THR activates many specific cellular processes. The main target organ for thyroid hormones is the heart, and noticeable changes in cardiac function occur in patients with hypo- and hyperthyroidism. Also, thyroid hormones play a crucial role in cholesterol and lipid metabolism in the liver, in skeletal growth, and in the maintenance of bone mass. Pathway 2. Effects of thyroid hormone deficiency: General pathways of thyroid hormone signaling (Fig. 2). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ_System: endocrine system Organelle: nucleus PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-49d6c708-f993-4355-9aea-27131049a3e2 2_1_General pathways of thyroid hormone signaling uuid-49d6c708-f993-4355-9aea-27131049a3e2 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49d6c708-f993-4355-9aea-27131049a3e2 PS:NodeType Pathway PS:Notes Thyroid hormones act through their nuclear receptors that are ubiquitously expressed in human tissues. The effects of thyroid hormones are cell-specific, and they regulate the metabolism in and other functions of tissues and organs. THR activates many specific cellular processes. The main target organ for thyroid hormones is the heart, and noticeable changes in cardiac function occur in patients with hypo- and hyperthyroidism. Also, thyroid hormones play a crucial role in cholesterol and lipid metabolism in the liver, in skeletal growth, and in the maintenance of bone mass. Pathway 2. Effects of thyroid hormone deficiency: General pathways of thyroid hormone signaling (Fig. 2). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ_System endocrine system PS:Organelle nucleus PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: gastric parietal cell Description: Activation of P-cells by neuromediators leads to the stomach acid and leptin release. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49eca878-1866-476d-9d3b-7bd09595cdad NodeType: Pathway Notes: Headnote: P-cells (gastric parietal cells) are located in the stomach and secrete stomach acid and leptin in response to the neuromediators signals. Signaling description: Receptors for histamine, somatostatins, acetylcholine and gastrins are present on the basolateral membrane of P-cell. Histamine and somatostatins activate signaling via cAMP/PKC, whereas acetylcholine and gastrins act through PLCB1/diacylglycerol. PKC can mediate the activation of H+/K+-exchanging ATPases which along with Cl- channels produce stomach acid. The anion exchanger is necessary for the accumulation of Cl- anion in P-cells. It exchanges extracellular Cl- for HCO3- which is produced by carbonic anhydrase 1 (CA1) in cells. The HCO3- anion elevates blood pH. Also, gastrins can activate LEP expression via CCKAR/JAK2/STAT3 signaling. Leptin secretion is activated by intracellular calcium influx. cAMP and Ca2+ regulate the secretion of gastric intrinsic factor (GIF) which is necessary for stabilization of vitamin B12. GIF also binds to transcobalamin 1 (TCN1) and this complex transports vitamin B12 to the blood. Outcome effects: Activation of P-cells by neuromediators leads to the production of stomach acid and leptin expression. Organ: stomach Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-49eca878-1866-476d-9d3b-7bd09595cdad P-cell Activation uuid-49eca878-1866-476d-9d3b-7bd09595cdad PS:CellType gastric parietal cell PS:Description Activation of P-cells by neuromediators leads to the stomach acid and leptin release. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49eca878-1866-476d-9d3b-7bd09595cdad PS:NodeType Pathway PS:Notes Headnote: P-cells (gastric parietal cells) are located in the stomach and secrete stomach acid and leptin in response to the neuromediators signals. Signaling description: Receptors for histamine, somatostatins, acetylcholine and gastrins are present on the basolateral membrane of P-cell. Histamine and somatostatins activate signaling via cAMP/PKC, whereas acetylcholine and gastrins act through PLCB1/diacylglycerol. PKC can mediate the activation of H+/K+-exchanging ATPases which along with Cl- channels produce stomach acid. The anion exchanger is necessary for the accumulation of Cl- anion in P-cells. It exchanges extracellular Cl- for HCO3- which is produced by carbonic anhydrase 1 (CA1) in cells. The HCO3- anion elevates blood pH. Also, gastrins can activate LEP expression via CCKAR/JAK2/STAT3 signaling. Leptin secretion is activated by intracellular calcium influx. cAMP and Ca2+ regulate the secretion of gastric intrinsic factor (GIF) which is necessary for stabilization of vitamin B12. GIF also binds to transcobalamin 1 (TCN1) and this complex transports vitamin B12 to the blood. Outcome effects: Activation of P-cells by neuromediators leads to the production of stomach acid and leptin expression. PS:Organ stomach PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49fe7685-a953-43d7-acd8-17c3059b4e15 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-49fe7685-a953-43d7-acd8-17c3059b4e15 S100A Expression Targets uuid-49fe7685-a953-43d7-acd8-17c3059b4e15 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49fe7685-a953-43d7-acd8-17c3059b4e15 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49ff5595-4f3b-40e1-b53d-c6c7c011a08b NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-49ff5595-4f3b-40e1-b53d-c6c7c011a08b Heme Oxidation uuid-49ff5595-4f3b-40e1-b53d-c6c7c011a08b PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-49ff5595-4f3b-40e1-b53d-c6c7c011a08b PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a064926-30a6-4a44-9d35-642b68ad2349 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-4a064926-30a6-4a44-9d35-642b68ad2349 Proteins Involved in HIV Type 1 Infection uuid-4a064926-30a6-4a44-9d35-642b68ad2349 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a064926-30a6-4a44-9d35-642b68ad2349 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a10c427-1f27-4c36-8d20-f25c3471d081 NodeType: Pathway Notes: Interaction of viral and cellular proteins is needed for transcription and replication of the viral genome. As virion particles or viral RNA are engulfed by the host cell, structural proteins of the virus complete reverse transcription of the viral genome. The newly synthesized viral DNA then incorporates into the host genome. Expression of the virus regulatory proteins (tax, rex, p30II, p13II, and HBZ) is necessary for viral genome replication and for transcription of virus genes. However, the virus needs proteins of the host cell to complete these processes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4a10c427-1f27-4c36-8d20-f25c3471d081 2_Transcription and reproduction of the HTLV-1 genome uuid-4a10c427-1f27-4c36-8d20-f25c3471d081 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a10c427-1f27-4c36-8d20-f25c3471d081 PS:NodeType Pathway PS:Notes Interaction of viral and cellular proteins is needed for transcription and replication of the viral genome. As virion particles or viral RNA are engulfed by the host cell, structural proteins of the virus complete reverse transcription of the viral genome. The newly synthesized viral DNA then incorporates into the host genome. Expression of the virus regulatory proteins (tax, rex, p30II, p13II, and HBZ) is necessary for viral genome replication and for transcription of virus genes. However, the virus needs proteins of the host cell to complete these processes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: granulosa cell Description: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a1529c4-0dcc-457a-819d-affc9e488cb0 NodeType: Pathway Notes: Headnote: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Signaling description: Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB). Inhibins are structurally related to activins. Activin is a homodimer of two b subunits, which antagonizes the effect of inhibin. The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. The gene products of INHA, INHBA and INHBB are restricted to granulosa cells from the primordial follicle stage. If there is any mutation in the INHA gene, the association of a and b will be severely diminished, the homodimerization of two b subunits will take place dominantly. In other words, the concentration of inhibin will diminish and concentration of activins will rise. Outcome effects: In granulosa cells impairment of inhibin signaling may lead to CCND2 activation, cell proliferation and predispose to cancerogenesis.Protein with increased expression or activity is highlighted in red. Mutated gene is shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 19752047 PMID: 20382564 PMID: 20668067 PMID: 24696764 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4a1529c4-0dcc-457a-819d-affc9e488cb0 INHA Gene Mutations in Granulosa Cell Proliferation uuid-4a1529c4-0dcc-457a-819d-affc9e488cb0 PS:CellType granulosa cell PS:Description Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a1529c4-0dcc-457a-819d-affc9e488cb0 PS:NodeType Pathway PS:Notes Headnote: Inhibins plays important role in regulating ovarian function either as a negative modulators of pituitary FSH synthesis or as a paracrine factor. Signaling description: Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB). Inhibins are structurally related to activins. Activin is a homodimer of two b subunits, which antagonizes the effect of inhibin. The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. The gene products of INHA, INHBA and INHBB are restricted to granulosa cells from the primordial follicle stage. If there is any mutation in the INHA gene, the association of a and b will be severely diminished, the homodimerization of two b subunits will take place dominantly. In other words, the concentration of inhibin will diminish and concentration of activins will rise. Outcome effects: In granulosa cells impairment of inhibin signaling may lead to CCND2 activation, cell proliferation and predispose to cancerogenesis.Protein with increased expression or activity is highlighted in red. Mutated gene is shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 19752047 PS:PMID 20382564 PS:PMID 20668067 PS:PMID 24696764 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a1e913b-1b4f-4fbe-9a20-9e2493a969e6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4a1e913b-1b4f-4fbe-9a20-9e2493a969e6 COVID-19 Anatomy and molecular biomarkers uuid-4a1e913b-1b4f-4fbe-9a20-9e2493a969e6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a1e913b-1b4f-4fbe-9a20-9e2493a969e6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a3650aa-6b73-4e35-a2b4-1e76fb7c7e42 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-4a3650aa-6b73-4e35-a2b4-1e76fb7c7e42 Do not Eat me Signal: Viable Cells Inhibits Phagocytosis uuid-4a3650aa-6b73-4e35-a2b4-1e76fb7c7e42 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a3650aa-6b73-4e35-a2b4-1e76fb7c7e42 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a527fee-696b-4ec2-835d-c2797dff13f4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-4a527fee-696b-4ec2-835d-c2797dff13f4 NOTCH -> LEF1 Signaling uuid-4a527fee-696b-4ec2-835d-c2797dff13f4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a527fee-696b-4ec2-835d-c2797dff13f4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a548116-8b0f-453e-94e6-6b34969829b5 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-4a548116-8b0f-453e-94e6-6b34969829b5 ARRB1/ARRB2 and GPCRs Internalization uuid-4a548116-8b0f-453e-94e6-6b34969829b5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4a548116-8b0f-453e-94e6-6b34969829b5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ab6f4b6-9437-4d3f-b80b-9a863ded78fa NodeType: Pathway Notes: Psoriasis skin lesions contain increased amounts of T-helper 17 (Th17) cells. Genetic mutations and environmental factors together act to dysregulate the differentiation of the skin T cells and induce a shift to Th17 cell production. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-4ab6f4b6-9437-4d3f-b80b-9a863ded78fa 1_Differentiation of psoriatic T cells uuid-4ab6f4b6-9437-4d3f-b80b-9a863ded78fa PS:CellType T-cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ab6f4b6-9437-4d3f-b80b-9a863ded78fa PS:NodeType Pathway PS:Notes Psoriasis skin lesions contain increased amounts of T-helper 17 (Th17) cells. Genetic mutations and environmental factors together act to dysregulate the differentiation of the skin T cells and induce a shift to Th17 cell production. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: C-reactive protein (CRP) and amyloid P component, serum (APCS) belong to an ancient family of proteins known as pentraxins, which are serum proteins with a relatively uncommon pentameric structure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4acdbc5c-c5c0-453d-8394-3dd78f1b99c6 NodeType: Pathway Notes: Headnote: C-reactive protein (CRP) and amyloid P component, serum (APCS) belong to an ancient family of proteins known as pentraxins, which are serum proteins with a relatively uncommon pentameric structure. They are positive acute phase proteins (APPs) with elevated expression during inflammation. Signaling description: CRP levels of 10 mkg/mL-500 mkg/mL are observed in the acute phase response (APR). Although APCS is not an APP in humans, it is a very strong acute phase marker in mice. Pentraxins function as opsonins and recognize foreign antigens, phospholipids, or nuclear components released by damaged cells. CRP has a specific interaction with SNRPN, whereas APCS is a major recognition molecule for DNA. Similar to other APPs such as MBL2, CRP and APCS promote the clearance of pathogens following their association with phagocytes and trigger an immune response through the activation of the complement cascade. Outcome effects: CRP activates complement via the classical pathway at the level of C1QA, but inhibits the alternative pathway. CRP inhibits complement-mediated cytolysis via the lectin pathway by increasing CFH binding to C3. It is unclear how CRP enhances the binding of CFH to C3. Pentraxins also activate the innate immune system through its interaction with FCG receptors (FCGRs). It is well established that FCGR aggregation by immune complexes is necessary for receptor activation. FcgammaRII is the main receptor for pentraxins. In addition, APCS may stabilize amyloid fibrils against degradative enzymes. APCS may prevent the generation of fibrocytes and it has been suggested that this may contribute to the inhibition of fibrosis. Lastly, PTX3 is a long pentraxin produced locally in response to inflammatory stimuli such as TNF. Similar to the classical pentraxins, PTX3 activates complement and binds to FCGR3A. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-4acdbc5c-c5c0-453d-8394-3dd78f1b99c6 Complement Cascade Activation by Pentraxins uuid-4acdbc5c-c5c0-453d-8394-3dd78f1b99c6 PS:Description C-reactive protein (CRP) and amyloid P component, serum (APCS) belong to an ancient family of proteins known as pentraxins, which are serum proteins with a relatively uncommon pentameric structure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4acdbc5c-c5c0-453d-8394-3dd78f1b99c6 PS:NodeType Pathway PS:Notes Headnote: C-reactive protein (CRP) and amyloid P component, serum (APCS) belong to an ancient family of proteins known as pentraxins, which are serum proteins with a relatively uncommon pentameric structure. They are positive acute phase proteins (APPs) with elevated expression during inflammation. Signaling description: CRP levels of 10 mkg/mL-500 mkg/mL are observed in the acute phase response (APR). Although APCS is not an APP in humans, it is a very strong acute phase marker in mice. Pentraxins function as opsonins and recognize foreign antigens, phospholipids, or nuclear components released by damaged cells. CRP has a specific interaction with SNRPN, whereas APCS is a major recognition molecule for DNA. Similar to other APPs such as MBL2, CRP and APCS promote the clearance of pathogens following their association with phagocytes and trigger an immune response through the activation of the complement cascade. Outcome effects: CRP activates complement via the classical pathway at the level of C1QA, but inhibits the alternative pathway. CRP inhibits complement-mediated cytolysis via the lectin pathway by increasing CFH binding to C3. It is unclear how CRP enhances the binding of CFH to C3. Pentraxins also activate the innate immune system through its interaction with FCG receptors (FCGRs). It is well established that FCGR aggregation by immune complexes is necessary for receptor activation. FcgammaRII is the main receptor for pentraxins. In addition, APCS may stabilize amyloid fibrils against degradative enzymes. APCS may prevent the generation of fibrocytes and it has been suggested that this may contribute to the inhibition of fibrosis. Lastly, PTX3 is a long pentraxin produced locally in response to inflammatory stimuli such as TNF. Similar to the classical pentraxins, PTX3 activates complement and binds to FCGR3A. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4aee65c3-f0c1-40f7-a3a3-87369a749f16 NodeType: Pathway Notes: Desmosomes are major cell-cell junctions that are particularly abundant in epidermal cells and cardiomyocytes. ARVD may be caused by genetic defects of the structure of myocardial desmosomes. Desmosomes are multiprotein complexes that form intercellular contacts on the surface of heart muscle cells. Mutations in many proteins that comprise desmosomes can have harmful effects on cardiomyocyte function. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: heart Organ_System: cardiovascular system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: myocardium urn:agi-pathway:uuid-4aee65c3-f0c1-40f7-a3a3-87369a749f16 2_Desmosome dysfunction in cardiomyocytes in ARVD uuid-4aee65c3-f0c1-40f7-a3a3-87369a749f16 PS:CellType cardiac myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4aee65c3-f0c1-40f7-a3a3-87369a749f16 PS:NodeType Pathway PS:Notes Desmosomes are major cell-cell junctions that are particularly abundant in epidermal cells and cardiomyocytes. ARVD may be caused by genetic defects of the structure of myocardial desmosomes. Desmosomes are multiprotein complexes that form intercellular contacts on the surface of heart muscle cells. Mutations in many proteins that comprise desmosomes can have harmful effects on cardiomyocyte function. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ heart PS:Organ_System cardiovascular system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b1fe5fd-276a-4c6f-85ac-5ae2a9a906f5 NodeType: Pathway Notes: Headnote: Physiological responses to stressors, such as inflammation, are principally mediated by two neuroendocrine systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) system. Signaling description: The SNS is responsible for the acute stress response, which requires energy mobilization from the body stores and diverts the blood flow to skeletal muscles. The SNS effects occur due to the release of noradrenaline (also known as norepinephrine) from the sympathetic nerve terminals and the subsequent secretion of epinephrine (also known as adrenaline) and noradrenaline from chromaffin cells of the adrenal medulla. Chromaffin cells are similar to postsynaptic sympathetic neurons and release catecholamines (80% epinephrine and 20% noradrenaline) into the circulation. Acetylcholine, the key neurotransmitter in chromaffin cells, binds to postsynaptic nAChR and mAChR on chromaffin cells. nAChR and mAChR are differentially expressed in two separate populations of chromaffin cells (adrenergic and noradrenergic, respectively), which release different substances (epinephrine and noradrenaline). The cells with nAChR are more abundant. The activation of nAChR quickly leads to chromaffin cell depolarization, which in turn triggers electrical activity and calcium (Ca2+) influx from voltage-gated Ca2+ channels. Outcome effects: Increases in cytosolic Ca2+ lead to the fusion of secretory granules and exocytosis of epinephrine/noradrenaline into the bloodstream. mAChR causes a slow release of Ca2+ from the intracellular storage. ADCYAP1 causes persistent catecholamine release by the adrenal medulla. ADCYAP1 response includes PLC and PKC activation and Na+/Ca2+ exchange-mediated depolarization in chromaffin cells allowing LVACC Ca2+ channels to release catecholamine. In addition, angiotensin II is a potent regulator of catecholamine synthesis and release. Angiotensinogen (AGT), which is produced by the liver, does not appear to be an acute-phase protein. However, some forms of acute inflammation, such as an injection of lipopolysaccharide/cellulite or partial hepatectomy, increases the hepatic synthesis of AGT. AGT is converted to the active form, angiotensin II, by renin (REN) and ACE. The synthesis of catecholamine occurs in advance, and NGF serves as a mitogen for chromaffin cells which may be involved in this process. Catecholamines, such as noradrenaline and epinephrine, mediate adaptive cardiovascular and metabolic effects through interactions with adrenergic receptors. Alpha adrenergic receptors generally produce excitatory responses of smooth muscle in which they are located. Beta adrenergic receptors generally produce inhibitory responses of smooth muscle in response to bronchodilation, vasodilation, and uterine relaxation. ADRB1 produces cardiac positive responses and produces lipolysis in adipose tissue. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-4b1fe5fd-276a-4c6f-85ac-5ae2a9a906f5 Vitamin C Related Norepinephrine Synthesis uuid-4b1fe5fd-276a-4c6f-85ac-5ae2a9a906f5 PS:CellType neuron PS:Description Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b1fe5fd-276a-4c6f-85ac-5ae2a9a906f5 PS:NodeType Pathway PS:Notes Headnote: Physiological responses to stressors, such as inflammation, are principally mediated by two neuroendocrine systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) system. Signaling description: The SNS is responsible for the acute stress response, which requires energy mobilization from the body stores and diverts the blood flow to skeletal muscles. The SNS effects occur due to the release of noradrenaline (also known as norepinephrine) from the sympathetic nerve terminals and the subsequent secretion of epinephrine (also known as adrenaline) and noradrenaline from chromaffin cells of the adrenal medulla. Chromaffin cells are similar to postsynaptic sympathetic neurons and release catecholamines (80% epinephrine and 20% noradrenaline) into the circulation. Acetylcholine, the key neurotransmitter in chromaffin cells, binds to postsynaptic nAChR and mAChR on chromaffin cells. nAChR and mAChR are differentially expressed in two separate populations of chromaffin cells (adrenergic and noradrenergic, respectively), which release different substances (epinephrine and noradrenaline). The cells with nAChR are more abundant. The activation of nAChR quickly leads to chromaffin cell depolarization, which in turn triggers electrical activity and calcium (Ca2+) influx from voltage-gated Ca2+ channels. Outcome effects: Increases in cytosolic Ca2+ lead to the fusion of secretory granules and exocytosis of epinephrine/noradrenaline into the bloodstream. mAChR causes a slow release of Ca2+ from the intracellular storage. ADCYAP1 causes persistent catecholamine release by the adrenal medulla. ADCYAP1 response includes PLC and PKC activation and Na+/Ca2+ exchange-mediated depolarization in chromaffin cells allowing LVACC Ca2+ channels to release catecholamine. In addition, angiotensin II is a potent regulator of catecholamine synthesis and release. Angiotensinogen (AGT), which is produced by the liver, does not appear to be an acute-phase protein. However, some forms of acute inflammation, such as an injection of lipopolysaccharide/cellulite or partial hepatectomy, increases the hepatic synthesis of AGT. AGT is converted to the active form, angiotensin II, by renin (REN) and ACE. The synthesis of catecholamine occurs in advance, and NGF serves as a mitogen for chromaffin cells which may be involved in this process. Catecholamines, such as noradrenaline and epinephrine, mediate adaptive cardiovascular and metabolic effects through interactions with adrenergic receptors. Alpha adrenergic receptors generally produce excitatory responses of smooth muscle in which they are located. Beta adrenergic receptors generally produce inhibitory responses of smooth muscle in response to bronchodilation, vasodilation, and uterine relaxation. ADRB1 produces cardiac positive responses and produces lipolysis in adipose tissue. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b4f3328-0a35-4091-8245-447829735f19 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4b4f3328-0a35-4091-8245-447829735f19 PDCD1 -> AP-1 Expression Targets uuid-4b4f3328-0a35-4091-8245-447829735f19 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b4f3328-0a35-4091-8245-447829735f19 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b62d9fd-517d-4489-a81a-ffae17622cb8 NodeType: Pathway Notes: In order to be released into the blood after absorption, iron needs the transporter SLC40A1. HAMP can block the transport of iron by SLC40A1. Iron is required for erythropoiesis, oxygen transport, and a plethora of other biological functions. When HAMP blocks the release of iron from enterocytes, anemia gradually develops. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4b62d9fd-517d-4489-a81a-ffae17622cb8 2_High levels of hepcidin block iron absorption in the gut uuid-4b62d9fd-517d-4489-a81a-ffae17622cb8 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b62d9fd-517d-4489-a81a-ffae17622cb8 PS:NodeType Pathway PS:Notes In order to be released into the blood after absorption, iron needs the transporter SLC40A1. HAMP can block the transport of iron by SLC40A1. Iron is required for erythropoiesis, oxygen transport, and a plethora of other biological functions. When HAMP blocks the release of iron from enterocytes, anemia gradually develops. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b86b953-59cb-4cbe-8e88-1909daceb1c3 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-4b86b953-59cb-4cbe-8e88-1909daceb1c3 Proteins Involved in Lipodystrophy, Familial Partial uuid-4b86b953-59cb-4cbe-8e88-1909daceb1c3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b86b953-59cb-4cbe-8e88-1909daceb1c3 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b8d3fd1-52b9-4d99-839d-45c63813ae27 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4b8d3fd1-52b9-4d99-839d-45c63813ae27 TNF -> STAT Expression Targets uuid-4b8d3fd1-52b9-4d99-839d-45c63813ae27 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b8d3fd1-52b9-4d99-839d-45c63813ae27 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b8dc845-ccdf-4317-9eaf-c19ce4a8c84f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-4b8dc845-ccdf-4317-9eaf-c19ce4a8c84f TNFR -> NF-kB Signaling uuid-4b8dc845-ccdf-4317-9eaf-c19ce4a8c84f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b8dc845-ccdf-4317-9eaf-c19ce4a8c84f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b90445b-e2cb-4a58-bfb8-8d2b64a96d03 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-4b90445b-e2cb-4a58-bfb8-8d2b64a96d03 Hemapoietic Stem Cell -> Lymphoid Multipotent Progenitor Surface Expression Markers uuid-4b90445b-e2cb-4a58-bfb8-8d2b64a96d03 PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b90445b-e2cb-4a58-bfb8-8d2b64a96d03 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b9b03e7-7483-41d2-a6a6-95f8bc4062db NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4b9b03e7-7483-41d2-a6a6-95f8bc4062db microRNAs -| RUNX2 uuid-4b9b03e7-7483-41d2-a6a6-95f8bc4062db PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4b9b03e7-7483-41d2-a6a6-95f8bc4062db PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ba1066a-dfdc-42d2-a77e-2fa5dd16a85b NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: Normally, CD4 T-cell signaling includes T-cell receptor (TCR), CD4, CD28, and IL4 and provides B-cell involvement in the immune response to pathogens and contributes to Th17 differentiation which is important for immune defense in the intestine. At the core of signaling is TCR with its coreceptors (CD4 and CD28), which (through ERK (MAPK), JNK (MAPK8), and PI3K pathways) activate Jun/Fos, NF-kB, and NF-AT transcription factors and induce the expression of cytokines for Th17 differentiation and B-cell activation. T-cell activation is initiated by binding of TCR and its coreceptor, CD4 to the appropriate antigen presented by MHC class II protein complex molecules. Signals subsequently phosphorylate the immunoreceptor tyrosine-based activation motifs of the CD3 chains, followed by the recruitment and activation of ZAP70. Following phosphorylation by ZAP70, LAT interacts with PLCG1 which hydrolyzes phosphatidylinositol 4,5-bisphosphate (not shown) into secondary messengers, IP3 and diacylglycerol. The latter initiates calcium (Ca2) influx and the activation of PRKCQ and MAPK cascade which result in the activation of transcription through NF-kB and Jun/Fos. The released Ca2 interacts with calmodulin-calcineurin complex and activates NF-AT. CD28 is an important coreceptor for CD4 T-cells regulated by CD80 and CD86. The signal from CD28 is transduced to PI3K, which generates PIP3, which in turn initiates AKT1 activation through PDPK1. AKT1 provokes NF-kB release from its inhibitor, NFKBIA. In addition, IL2 and IL4, through JAK/STAT, promote GATA3 and MAF expression. CD247 (TCR zeta chain) may also activate JAK3 directly. Outcome effects: NF-AT, NF-kB, Jun/Fos, MAF, and GATA3 trigger the transcription of B-cell activating and Th17-differentiating cytokines. Viral Nef protein downregulates CD28 which blocks signal transduction to NF-AT. Finally, CD4 ligation with HIV envelope glycoprotein Gp120 (env) markedly inhibits TCR-induced activation and expression of JAK3, which transduces the signal to STAT and then to GATA3 and MAF for IL4, IL5, IL10, and IL13 transcription. The block of signaling in CD4 T-cells leads to the decline of the immune response. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival. HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 21994747 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-4ba1066a-dfdc-42d2-a77e-2fa5dd16a85b CD4+ T-Cell Function Decline in HIV uuid-4ba1066a-dfdc-42d2-a77e-2fa5dd16a85b PS:CellType T-cell PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ba1066a-dfdc-42d2-a77e-2fa5dd16a85b PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: Normally, CD4 T-cell signaling includes T-cell receptor (TCR), CD4, CD28, and IL4 and provides B-cell involvement in the immune response to pathogens and contributes to Th17 differentiation which is important for immune defense in the intestine. At the core of signaling is TCR with its coreceptors (CD4 and CD28), which (through ERK (MAPK), JNK (MAPK8), and PI3K pathways) activate Jun/Fos, NF-kB, and NF-AT transcription factors and induce the expression of cytokines for Th17 differentiation and B-cell activation. T-cell activation is initiated by binding of TCR and its coreceptor, CD4 to the appropriate antigen presented by MHC class II protein complex molecules. Signals subsequently phosphorylate the immunoreceptor tyrosine-based activation motifs of the CD3 chains, followed by the recruitment and activation of ZAP70. Following phosphorylation by ZAP70, LAT interacts with PLCG1 which hydrolyzes phosphatidylinositol 4,5-bisphosphate (not shown) into secondary messengers, IP3 and diacylglycerol. The latter initiates calcium (Ca2) influx and the activation of PRKCQ and MAPK cascade which result in the activation of transcription through NF-kB and Jun/Fos. The released Ca2 interacts with calmodulin-calcineurin complex and activates NF-AT. CD28 is an important coreceptor for CD4 T-cells regulated by CD80 and CD86. The signal from CD28 is transduced to PI3K, which generates PIP3, which in turn initiates AKT1 activation through PDPK1. AKT1 provokes NF-kB release from its inhibitor, NFKBIA. In addition, IL2 and IL4, through JAK/STAT, promote GATA3 and MAF expression. CD247 (TCR zeta chain) may also activate JAK3 directly. Outcome effects: NF-AT, NF-kB, Jun/Fos, MAF, and GATA3 trigger the transcription of B-cell activating and Th17-differentiating cytokines. Viral Nef protein downregulates CD28 which blocks signal transduction to NF-AT. Finally, CD4 ligation with HIV envelope glycoprotein Gp120 (env) markedly inhibits TCR-induced activation and expression of JAK3, which transduces the signal to STAT and then to GATA3 and MAF for IL4, IL5, IL10, and IL13 transcription. The block of signaling in CD4 T-cells leads to the decline of the immune response. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival. HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 21994747 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: The most common drugs for treatment of Autistic Disorder and their targets. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bace4c0-8f31-448c-9de3-45aae1a76df9 NodeType: Pathway Notes: The most common drugs for the treatment of autistic disorder and their targets. Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-4bace4c0-8f31-448c-9de3-45aae1a76df9 Drugs Targets in Autistic Disoreder (Hypothesis) uuid-4bace4c0-8f31-448c-9de3-45aae1a76df9 PS:Description The most common drugs for treatment of Autistic Disorder and their targets. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bace4c0-8f31-448c-9de3-45aae1a76df9 PS:NodeType Pathway PS:Notes The most common drugs for the treatment of autistic disorder and their targets. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bb6c9c1-759c-41e9-ae5d-a348a085a407 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-4bb6c9c1-759c-41e9-ae5d-a348a085a407 Enzymes-Erases of Histone Modifications uuid-4bb6c9c1-759c-41e9-ae5d-a348a085a407 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bb6c9c1-759c-41e9-ae5d-a348a085a407 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bcc6592-b119-4a22-a21b-a25fa687ccdd NodeType: Pathway Notes: Endogenous and exogenous erythropoietins inhibit HAMP expression and stimulate erythrocyte differentiation. Erythropoietin (EPO) production is reduced in AI/ACD. Erythropoietin substitutive drugs are actively used for the treatment of AI/ACD. Restored EPO functions to reactivate erythrocyte differentiation and facilitate the inhibition of HAMP. The inhibition of HAMP returns iron exported from enterocytes, splenic macrophages, and hepatocytes to the blood and thereby restores the systemic iron balance. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4bcc6592-b119-4a22-a21b-a25fa687ccdd 5_The rationale for the treatment of anemia of chronic disease with erythropoietin uuid-4bcc6592-b119-4a22-a21b-a25fa687ccdd PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bcc6592-b119-4a22-a21b-a25fa687ccdd PS:NodeType Pathway PS:Notes Endogenous and exogenous erythropoietins inhibit HAMP expression and stimulate erythrocyte differentiation. Erythropoietin (EPO) production is reduced in AI/ACD. Erythropoietin substitutive drugs are actively used for the treatment of AI/ACD. Restored EPO functions to reactivate erythrocyte differentiation and facilitate the inhibition of HAMP. The inhibition of HAMP returns iron exported from enterocytes, splenic macrophages, and hepatocytes to the blood and thereby restores the systemic iron balance. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bd96fb6-e901-422a-bd85-8f35f8df7cc8 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Crohn's disease is primarily a T-helper 1- (Th1) dominant condition; while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. Signaling description: It appears that divergent cytokine patterns are involved in the pathogenesis of Crohn's disease. The Th2-type immune response is characterized by the production of IL-4, IL-5, and IL-13. B-cell activation is especially important in Th2-cell mediated signaling. The detailed mechanisms of Th2-cell mediated molecular signaling in Crohn's disease are still poorly understood. The JAK2 gene provides instructions for making a protein that promotes the growth and proliferation of cells. This protein is part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. Outcome effects: JAK2 polymorphisms have been associated with Crohn's disease. It has also been shown that the expression of CD86 is higher in the intestinal epithelium of patients with Crohn's disease compared to normal controls. Additionally, elevated serum IL6, IL10, IL2 concentrations are found in active Crohn's disease. IL6 and IL10 are cytokines that are mostly important for the Th2-cell mediated immune response. Lastly, increased MAF expression was observed in sections from ulcerative colitis and Crohn's disease patients when compared to control patients. MAF is a transcriptional factor necessary for IL4 expression and for Th2-cell mediated immune response. Organ_System: lymphatic system PMID: 11994418 PMID: 15847059 PMID: 17392581 PMID: 22065112 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-4bd96fb6-e901-422a-bd85-8f35f8df7cc8 B-Cell Activation in Crohn's Disease uuid-4bd96fb6-e901-422a-bd85-8f35f8df7cc8 PS:CellType B-cell PS:Description Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bd96fb6-e901-422a-bd85-8f35f8df7cc8 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Crohn's disease is primarily a T-helper 1- (Th1) dominant condition; while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. Signaling description: It appears that divergent cytokine patterns are involved in the pathogenesis of Crohn's disease. The Th2-type immune response is characterized by the production of IL-4, IL-5, and IL-13. B-cell activation is especially important in Th2-cell mediated signaling. The detailed mechanisms of Th2-cell mediated molecular signaling in Crohn's disease are still poorly understood. The JAK2 gene provides instructions for making a protein that promotes the growth and proliferation of cells. This protein is part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. Outcome effects: JAK2 polymorphisms have been associated with Crohn's disease. It has also been shown that the expression of CD86 is higher in the intestinal epithelium of patients with Crohn's disease compared to normal controls. Additionally, elevated serum IL6, IL10, IL2 concentrations are found in active Crohn's disease. IL6 and IL10 are cytokines that are mostly important for the Th2-cell mediated immune response. Lastly, increased MAF expression was observed in sections from ulcerative colitis and Crohn's disease patients when compared to control patients. MAF is a transcriptional factor necessary for IL4 expression and for Th2-cell mediated immune response. PS:Organ_System lymphatic system PS:PMID 11994418 PS:PMID 15847059 PS:PMID 17392581 PS:PMID 22065112 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4be161eb-2f3f-4c18-ac6e-d201fb9a8df9 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: mouth Organ_System: digestive system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-4be161eb-2f3f-4c18-ac6e-d201fb9a8df9 Epithelial Cell in the Saliva Formation uuid-4be161eb-2f3f-4c18-ac6e-d201fb9a8df9 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4be161eb-2f3f-4c18-ac6e-d201fb9a8df9 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4be95e98-fb39-47f0-a256-948150406d48 NodeType: Pathway Notes: Headnote: Alström syndrome (AS) is among the rarest genetic disorders in the world, with only 266 reported cases in medical literature and over 501 known cases in 47 countries. AS is an autosomal recessive disease characterized by multi-organ dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence. Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed and systemic fibrosis develops with age. Signaling description: Mutations in ALMS1 gene have been found to be causative for AS. ALMS1 protein localizes intracellularly to the centrosome and may therefore influence microtubular function and impair the transport of SLC2A1-5 receptors to the cell surface. This may be the cause of diabetes development. Organ_System: endocrine system PMID: 17940554 PMID: 18154657 PMID: 19092165 PMID: 21135875 PMID: 22043170 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4be95e98-fb39-47f0-a256-948150406d48 Alstrom Syndrome Progression (Hypothesis) uuid-4be95e98-fb39-47f0-a256-948150406d48 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4be95e98-fb39-47f0-a256-948150406d48 PS:NodeType Pathway PS:Notes Headnote: Alström syndrome (AS) is among the rarest genetic disorders in the world, with only 266 reported cases in medical literature and over 501 known cases in 47 countries. AS is an autosomal recessive disease characterized by multi-organ dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence. Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed and systemic fibrosis develops with age. Signaling description: Mutations in ALMS1 gene have been found to be causative for AS. ALMS1 protein localizes intracellularly to the centrosome and may therefore influence microtubular function and impair the transport of SLC2A1-5 receptors to the cell surface. This may be the cause of diabetes development. PS:Organ_System endocrine system PS:PMID 17940554 PS:PMID 18154657 PS:PMID 19092165 PS:PMID 21135875 PS:PMID 22043170 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bf5cd74-954f-4c63-a161-606a106d7a26 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4bf5cd74-954f-4c63-a161-606a106d7a26 PPARG inhibits phenotypes associated with psoriasis uuid-4bf5cd74-954f-4c63-a161-606a106d7a26 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bf5cd74-954f-4c63-a161-606a106d7a26 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Ovarian cancer (OC) is the most common cause of cancer death. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bf6545c-9f11-4bf6-806b-b7edb940b1d2 NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Serous epithelial ovarian carcinoma is the most common type of ovarian cancer. High-grade and low-grade serous ovarian carcinomas are considered to have a different origin. The crucial pathogenic processes involved in the emergence of ovarian tumors, regardless of hyperestrogenism, are hormone-independent cell proliferation, block of apoptosis, cell invasion, dysfunction of DNA repair, and loss of cell differentiation. Signaling description: Different histotypes of ovarian cancer are formed by common mechanisms of malignization, but have different causes. According to genetic classification, there exist two groups of ovarian tumors. Tumors of the first type which include variable mucinous, endometrioid, clear cell carcinoma, and low-grade serous carcinoma are rather genetically stable and characterized by mutations in the KRAS, HRAS, BRAF, PTEN, and ARID1A genes. Tumors of the second type are biologically aggressive; their prototype is high-grade serous carcinoma which displays distinct genetic instability and mutations in TP53, BRCA1, and BRCA2 genes. Ovarian cancer is characterized by overexpressed EGFRs, VEGFRs, TGFBR1, PDGFRs, MET, IGF1R, LPAR2/3, NTRK2, WNT7A, and NOTCH3. Outcome effects: The overexpression of growth factor receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, the overexpression of TGFBR1 activates SMAD2/3/4 complex involved in cell proliferation. The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of ovarian epithelial cells. The overexpression of WNT triggers the constitutive activation of WNT/CTNNB1 signaling pathway resulting in loss of differentiation, redundant cell proliferation, and migration. Mutations in the BRCA1 and BRCA2 genes lead to block of DNA repair. Mutations in the BRAF, HRAS, and KRAS genes result in the activation of ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation and migration. Mutations in PTEN cause the activation of AKT1 signaling, and mutations in ARID1A result in the dysfunction of chromatin remodeling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 17204312 PMID: 18317228 PMID: 19221485 PMID: 19461510 PMID: 21347793 PMID: 22525820 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-4bf6545c-9f11-4bf6-806b-b7edb940b1d2 Ovarian Cancer uuid-4bf6545c-9f11-4bf6-806b-b7edb940b1d2 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Ovarian cancer (OC) is the most common cause of cancer death. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4bf6545c-9f11-4bf6-806b-b7edb940b1d2 PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Serous epithelial ovarian carcinoma is the most common type of ovarian cancer. High-grade and low-grade serous ovarian carcinomas are considered to have a different origin. The crucial pathogenic processes involved in the emergence of ovarian tumors, regardless of hyperestrogenism, are hormone-independent cell proliferation, block of apoptosis, cell invasion, dysfunction of DNA repair, and loss of cell differentiation. Signaling description: Different histotypes of ovarian cancer are formed by common mechanisms of malignization, but have different causes. According to genetic classification, there exist two groups of ovarian tumors. Tumors of the first type which include variable mucinous, endometrioid, clear cell carcinoma, and low-grade serous carcinoma are rather genetically stable and characterized by mutations in the KRAS, HRAS, BRAF, PTEN, and ARID1A genes. Tumors of the second type are biologically aggressive; their prototype is high-grade serous carcinoma which displays distinct genetic instability and mutations in TP53, BRCA1, and BRCA2 genes. Ovarian cancer is characterized by overexpressed EGFRs, VEGFRs, TGFBR1, PDGFRs, MET, IGF1R, LPAR2/3, NTRK2, WNT7A, and NOTCH3. Outcome effects: The overexpression of growth factor receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, the overexpression of TGFBR1 activates SMAD2/3/4 complex involved in cell proliferation. The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of ovarian epithelial cells. The overexpression of WNT triggers the constitutive activation of WNT/CTNNB1 signaling pathway resulting in loss of differentiation, redundant cell proliferation, and migration. Mutations in the BRCA1 and BRCA2 genes lead to block of DNA repair. Mutations in the BRAF, HRAS, and KRAS genes result in the activation of ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation and migration. Mutations in PTEN cause the activation of AKT1 signaling, and mutations in ARID1A result in the dysfunction of chromatin remodeling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 17204312 PS:PMID 18317228 PS:PMID 19221485 PS:PMID 19461510 PS:PMID 21347793 PS:PMID 22525820 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c07b50a-4ebf-4cdf-85a9-7da6c9af4277 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: network Source: Diseases urn:agi-pathway:uuid-4c07b50a-4ebf-4cdf-85a9-7da6c9af4277 Proteins with Altered Expression in Muscular Dystrophies uuid-4c07b50a-4ebf-4cdf-85a9-7da6c9af4277 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c07b50a-4ebf-4cdf-85a9-7da6c9af4277 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType network PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c0ec36b-81f3-4e13-a4dc-c157cca151fe NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4c0ec36b-81f3-4e13-a4dc-c157cca151fe GH1/GHR -> STAT Expression Targets uuid-4c0ec36b-81f3-4e13-a4dc-c157cca151fe PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c0ec36b-81f3-4e13-a4dc-c157cca151fe PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: A key component of the inflammatory reaction is the recruitment of neutrophils into the injured tissue. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c162fdd-0f29-434f-a776-74b058ed6c9a NodeType: Pathway Notes: Headnote: The recruitment of neutrophils into the injured tissue is a key component of the inflammatory response. Signaling description: The activated neutrophils generate large amounts of reactive oxygen species (ROS) and hypochlorous acid (HOCl). With the respiratory burst, ROS and HOCl are released from neutrophils to attack various pathogens. However, neutrophil-derived oxidants are also implicated in a range of injurious effects and are involved in the pathogenesis of chronic and acute inflammatory diseases. Outcome effects: Neutrophil-derived oxidants cause DNA base oxidation and damage to the plasma membrane by lipid peroxidation. Lipid peroxidation products such as crotonaldehyde, acrolein, 4-hydroxynonenal, and malondialdehyde damage DNA by forming exocyclic adducts, most of which are highly mutagenic. Highlighted proteins: Entities with increased level are highlighted in red. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-4c162fdd-0f29-434f-a776-74b058ed6c9a ROS in Neutrophil Mediated Cell Damage uuid-4c162fdd-0f29-434f-a776-74b058ed6c9a PS:CellType neutrophil PS:Description A key component of the inflammatory reaction is the recruitment of neutrophils into the injured tissue. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c162fdd-0f29-434f-a776-74b058ed6c9a PS:NodeType Pathway PS:Notes Headnote: The recruitment of neutrophils into the injured tissue is a key component of the inflammatory response. Signaling description: The activated neutrophils generate large amounts of reactive oxygen species (ROS) and hypochlorous acid (HOCl). With the respiratory burst, ROS and HOCl are released from neutrophils to attack various pathogens. However, neutrophil-derived oxidants are also implicated in a range of injurious effects and are involved in the pathogenesis of chronic and acute inflammatory diseases. Outcome effects: Neutrophil-derived oxidants cause DNA base oxidation and damage to the plasma membrane by lipid peroxidation. Lipid peroxidation products such as crotonaldehyde, acrolein, 4-hydroxynonenal, and malondialdehyde damage DNA by forming exocyclic adducts, most of which are highly mutagenic. Highlighted proteins: Entities with increased level are highlighted in red. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c3aa3bf-dd5a-469d-a4d7-9fd0614eb276 NodeType: Pathway Notes: Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which is involved in WNT signaling. Mutations in WNT pathway components cause skeletal abnormalities associated with a lack of TNFSF11. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4c3aa3bf-dd5a-469d-a4d7-9fd0614eb276 2_WNT signaling dysregulation in osteoblasts uuid-4c3aa3bf-dd5a-469d-a4d7-9fd0614eb276 PS:CellType osteoblast PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c3aa3bf-dd5a-469d-a4d7-9fd0614eb276 PS:NodeType Pathway PS:Notes Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which is involved in WNT signaling. Mutations in WNT pathway components cause skeletal abnormalities associated with a lack of TNFSF11. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c48433e-3de3-46ad-a338-4998644de82b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4c48433e-3de3-46ad-a338-4998644de82b Myofibroblast differentiation uuid-4c48433e-3de3-46ad-a338-4998644de82b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c48433e-3de3-46ad-a338-4998644de82b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neural crest cell Description: Mutations of PITX2, PAX6, LMX1B, and CYP1B1 cause dysgenesis of the anterior segment of the eye and are associated with glaucoma. PITX2, PAX6, and LMX1B control tyrosine hydroxylase activity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c53f49f-809a-46c3-a34e-07529e538075 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Mutations of PITX2, PAX6, LMX1B, and CYP1B1 cause dysgenesis of the anterior segment of the eye and are associated with glaucoma. Signaling description: PITX2, PAX6, and LMX1B control tyrosine hydroxylase (TH) activity. CYP1B1 catalyzes a rate limiting step in retinoic acid (RA) biosynthesis necessary for eye development, and activates TFAP2A, which can regulate TH. Outcome effects: TH converts L-tyrosine to L-DOPA, which affects exit from the cell cycle, and is a precursor of developmentally important catecholamines. Therefore, TH may contribute to angle development by producing L-DOPA. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 15558492 PMID: 20431268 PMID: 22173078 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4c53f49f-809a-46c3-a34e-07529e538075 Dysgenesis of the Anterior Segment of the Eye in Glaucoma uuid-4c53f49f-809a-46c3-a34e-07529e538075 PS:CellType neural crest cell PS:Description Mutations of PITX2, PAX6, LMX1B, and CYP1B1 cause dysgenesis of the anterior segment of the eye and are associated with glaucoma. PITX2, PAX6, and LMX1B control tyrosine hydroxylase activity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c53f49f-809a-46c3-a34e-07529e538075 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Mutations of PITX2, PAX6, LMX1B, and CYP1B1 cause dysgenesis of the anterior segment of the eye and are associated with glaucoma. Signaling description: PITX2, PAX6, and LMX1B control tyrosine hydroxylase (TH) activity. CYP1B1 catalyzes a rate limiting step in retinoic acid (RA) biosynthesis necessary for eye development, and activates TFAP2A, which can regulate TH. Outcome effects: TH converts L-tyrosine to L-DOPA, which affects exit from the cell cycle, and is a precursor of developmentally important catecholamines. Therefore, TH may contribute to angle development by producing L-DOPA. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 15558492 PS:PMID 20431268 PS:PMID 22173078 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c569ac4-6ac7-4657-b277-662921770d90 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-4c569ac4-6ac7-4657-b277-662921770d90 Biotin Metabolism uuid-4c569ac4-6ac7-4657-b277-662921770d90 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c569ac4-6ac7-4657-b277-662921770d90 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: A frequent event associated with pancreatic cancer progression is a mutation of SMAD4. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c753f37-9dee-4693-91fb-22c914e003f2 NodeType: Pathway Notes: Headnote: Pancreatic cancer refers to malignant transformation of the pancreas. A frequent event associated with pancreatic cancer progression is a mutation in the SMAD4 protein gene. In addition, pancreatic cancer is characterized by the overexpression of TGFB1 and mutations in TGFBR2, KRAS, and BRAF genes. Mutations in DAXX and ATRX are characteristic of neuroendocrine pancreatic cancer. Signaling description: SMAD2, 3, and 4 are the transcriptional regulators, coactivators, and mediators of signal transduction by TGFB proteins, which control proliferation, cellular differentiation,and other cellular functions. Normally, TGFB proteins bind to TGFBR2 which recruits and phosphorylates TGFBR1. TGFBR1 phosphorylates SMAD2 and SMAD3 which bind to and form a heterotrimeric complex with SMAD4. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in cell functions. Ligand-bound TGFBR1 activates KRAS and BRAF via SHC1/GRB2/SOS1. BRAF activates MAPK1/3 signaling pathway inducing genes involved in cell proliferation, differentiationand migration. TGFB proteins may also trigger apoptosis via DAXX. TGFBR2 binds to DAXX which activates MAP3K5 and JNK cascade (MAPK8, MAPK9, and MAPK10) resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. DAXX interacts with ATRX which binds to RAD51, which is involved in DNA repair while ATRX participates in chromatin remodeling. Outcome effects: These mutations lead to redundant proliferation, block of apoptosis and DNA repair, as well as disruption of the cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 21252315 PMID: 22806689 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-4c753f37-9dee-4693-91fb-22c914e003f2 TGFBR Signaling in Pancreatic Neoplasms uuid-4c753f37-9dee-4693-91fb-22c914e003f2 PS:CellType cancer cell PS:CellType epithelial cell PS:Description A frequent event associated with pancreatic cancer progression is a mutation of SMAD4. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c753f37-9dee-4693-91fb-22c914e003f2 PS:NodeType Pathway PS:Notes Headnote: Pancreatic cancer refers to malignant transformation of the pancreas. A frequent event associated with pancreatic cancer progression is a mutation in the SMAD4 protein gene. In addition, pancreatic cancer is characterized by the overexpression of TGFB1 and mutations in TGFBR2, KRAS, and BRAF genes. Mutations in DAXX and ATRX are characteristic of neuroendocrine pancreatic cancer. Signaling description: SMAD2, 3, and 4 are the transcriptional regulators, coactivators, and mediators of signal transduction by TGFB proteins, which control proliferation, cellular differentiation,and other cellular functions. Normally, TGFB proteins bind to TGFBR2 which recruits and phosphorylates TGFBR1. TGFBR1 phosphorylates SMAD2 and SMAD3 which bind to and form a heterotrimeric complex with SMAD4. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in cell functions. Ligand-bound TGFBR1 activates KRAS and BRAF via SHC1/GRB2/SOS1. BRAF activates MAPK1/3 signaling pathway inducing genes involved in cell proliferation, differentiationand migration. TGFB proteins may also trigger apoptosis via DAXX. TGFBR2 binds to DAXX which activates MAP3K5 and JNK cascade (MAPK8, MAPK9, and MAPK10) resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. DAXX interacts with ATRX which binds to RAD51, which is involved in DNA repair while ATRX participates in chromatin remodeling. Outcome effects: These mutations lead to redundant proliferation, block of apoptosis and DNA repair, as well as disruption of the cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 21252315 PS:PMID 22806689 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: mast cell Description: Mast cells infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c997acd-9baf-4f80-9609-56458030f6ea NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Mast cells infiltrate the airway mucous glands in subjects with asthma showing features of degranulation and a positive correlation with the degree of mucus obstruction. The major way of mast cell activation in allergic reactions is through the aggregation of FceRI receptors and IgE. Mast cells contain large amounts of cytoplasmic granules, including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release contents of their granules into surrounding tissue (degranulation). IgE - depended degranulation occurs rapidly, and mediators released into extracellular space produce an immediate effect. The content of the granules is pre-synthesized during maturation and proliferation of mast cells.Each FceRI receptor consists of 4 subunits: alpha-particle responsible for IgE binding, one intra-cellular beta-subunit, and two intra-cellular gamma subunits. For IgE-dependent activation, an antigen must bind at least two IgE molecules at the surface of a mast cell. Antigen binding to IgE cross-links two FceRI leading to Lyn phosphorylation. Multi-molecular complex, which includes Gads, SLP-76, PLCc, and Vav form on LAT. FceRI aggregation leads to PI3K, ERK, JNK, NF-?B, PLC and PKC activation. The activation of RAC1, CDC42, Ras lead to MAP kinase activation. Outcome effects: These pathways lead to degranulation, release of leukotrienes and cytok87 ine synthesis. KITLG is another important protein, which stimulates degranulation and the synthesis of pro-inflammatory cytokines in mast cells, and the intersection of signaling pathways initiated by KITL (SHC1) and FceRI (GRB2) eventually causes degranulation. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16750987 PMID: 24648846 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4c997acd-9baf-4f80-9609-56458030f6ea Mast-Cell Activation in Asthma uuid-4c997acd-9baf-4f80-9609-56458030f6ea PS:CellType mast cell PS:Description Mast cells infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4c997acd-9baf-4f80-9609-56458030f6ea PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Mast cells infiltrate the airway mucous glands in subjects with asthma showing features of degranulation and a positive correlation with the degree of mucus obstruction. The major way of mast cell activation in allergic reactions is through the aggregation of FceRI receptors and IgE. Mast cells contain large amounts of cytoplasmic granules, including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release contents of their granules into surrounding tissue (degranulation). IgE - depended degranulation occurs rapidly, and mediators released into extracellular space produce an immediate effect. The content of the granules is pre-synthesized during maturation and proliferation of mast cells.Each FceRI receptor consists of 4 subunits: alpha-particle responsible for IgE binding, one intra-cellular beta-subunit, and two intra-cellular gamma subunits. For IgE-dependent activation, an antigen must bind at least two IgE molecules at the surface of a mast cell. Antigen binding to IgE cross-links two FceRI leading to Lyn phosphorylation. Multi-molecular complex, which includes Gads, SLP-76, PLCc, and Vav form on LAT. FceRI aggregation leads to PI3K, ERK, JNK, NF-?B, PLC and PKC activation. The activation of RAC1, CDC42, Ras lead to MAP kinase activation. Outcome effects: These pathways lead to degranulation, release of leukotrienes and cytok87 ine synthesis. KITLG is another important protein, which stimulates degranulation and the synthesis of pro-inflammatory cytokines in mast cells, and the intersection of signaling pathways initiated by KITL (SHC1) and FceRI (GRB2) eventually causes degranulation. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16750987 PS:PMID 24648846 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca17a1a-6a3d-41b2-9433-be8b4fc7d51d NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4ca17a1a-6a3d-41b2-9433-be8b4fc7d51d TGFB+>SMADs in cornea uuid-4ca17a1a-6a3d-41b2-9433-be8b4fc7d51d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca17a1a-6a3d-41b2-9433-be8b4fc7d51d PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca40d28-028d-4841-a445-7b17e90a873a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-4ca40d28-028d-4841-a445-7b17e90a873a farnesylcysteine salvage template uuid-4ca40d28-028d-4841-a445-7b17e90a873a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca40d28-028d-4841-a445-7b17e90a873a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca9d5c6-f8a9-4540-b2cd-4fc6b37c5a60 NodeType: Pathway Notes: A number of studies noted of innate immune defects as a risk factor for otitis media in children. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ear Organ_System: sensory system PMID: 19586996 PMID: 19892042 PMID: 25888408 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: middle ear mucosa urn:agi-pathway:uuid-4ca9d5c6-f8a9-4540-b2cd-4fc6b37c5a60 Immune System Role in Otitis Media uuid-4ca9d5c6-f8a9-4540-b2cd-4fc6b37c5a60 PS:CellType dendritic cell PS:CellType macrophage PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ca9d5c6-f8a9-4540-b2cd-4fc6b37c5a60 PS:NodeType Pathway PS:Notes A number of studies noted of innate immune defects as a risk factor for otitis media in children. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ear PS:Organ_System sensory system PS:PMID 19586996 PS:PMID 19892042 PS:PMID 25888408 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue middle ear mucosa PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cd5192a-7e4e-487a-8304-5d2aa9f5675b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4cd5192a-7e4e-487a-8304-5d2aa9f5675b SARS Mpro (NSP5) inhibitors (Experimental) uuid-4cd5192a-7e4e-487a-8304-5d2aa9f5675b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cd5192a-7e4e-487a-8304-5d2aa9f5675b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cd97496-67a0-4df6-922e-dabcfde39a97 NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4cd97496-67a0-4df6-922e-dabcfde39a97 Proteins Involved in Myasthenia Gravis uuid-4cd97496-67a0-4df6-922e-dabcfde39a97 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cd97496-67a0-4df6-922e-dabcfde39a97 PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cfda38d-2f9a-47f1-b24d-f362a5735b45 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-4cfda38d-2f9a-47f1-b24d-f362a5735b45 Familial Mediterranean Fever Anatomy and Molecular Biomarkers uuid-4cfda38d-2f9a-47f1-b24d-f362a5735b45 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4cfda38d-2f9a-47f1-b24d-f362a5735b45 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d28736b-6264-4be4-bffb-23e32a5fedd6 NodeType: Pathway Notes: Headnote: Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis and congenital ichthyosiform erythroderma. Both forms of ARCI are associated with mutations in ALOXE3 and ALOX12B genes. Signaling description: 12-hydroperoxyeicosatetraenoic acid (12-HPETE) generated via the 12-LOX pathway is converted by eLOX-3 to hepoxilin A3 and hepoxilin B3, which are further metabolized to the corresponding trioxilins. The ALOXE3 and ALOX12B genes encode the epidermal LOXs eLOX-3 and 12R-LOX. The mechanisms for the involvement of 12-LOX and eLOX-3 in non syndromic forms of ichthyosis are described on the pathway. Outcome effects: The ALOXE3 and ALOX12B genes are predominantly expressed in the suprabasal layers of the epidermis, which supports their role in the advanced phases of epidermal differentiation, with participation in the processing of lamellar bodies. These enzymes act on adjacent steps in the hepoxilin pathway. 12R-LOX transforms arachidonic acid into 12R-hydroxyeicosatetraenoic acid, while eLOX-3 converts this product into an epoxyalcohol isomer of the hepoxilin A3 family. The hepoxilin product is unstable and is hydrolyzed in cells to a specific trihydroxy derivative (trioxilin). The products of the hepoxilin pathway may participate in the formation of intercellular lipids of the stratum corneum or act as signals for inducing keratinocyte differentiation. Patients with mutations in the ALOX12B gene show more limited, whitish desquamation compared with carriers of mutations in the ALOXE3 gene. The presence of erythema, palmoplantar hyperkeratosis, and accentuation of the palmoplantar folds are also associated with ALOX12B mutations. Highlighted proteins: Trioxilin A3 and trioxilin B3 are highlighted in blue in order to emphasize the protective skin barrier disruption in the stratum corneum. Mutated proteins: ALOX12B and ALOXE3 genes mutated in congenital ichthyosiform erythroderma and lamellar ichthyosis are in white-out style. Organ: skin Organ_System: integumentary system PMID: 18245815 PMID: 22832496 PMID: 23562412 PMID: 26945532 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-4d28736b-6264-4be4-bffb-23e32a5fedd6 ALOXE3 and ALOX12B Genes in Congenital Ichthyosiform Erythroderma and Lamellar Ichthyosis uuid-4d28736b-6264-4be4-bffb-23e32a5fedd6 PS:CellType keratinocyte PS:Description Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d28736b-6264-4be4-bffb-23e32a5fedd6 PS:NodeType Pathway PS:Notes Headnote: Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis and congenital ichthyosiform erythroderma. Both forms of ARCI are associated with mutations in ALOXE3 and ALOX12B genes. Signaling description: 12-hydroperoxyeicosatetraenoic acid (12-HPETE) generated via the 12-LOX pathway is converted by eLOX-3 to hepoxilin A3 and hepoxilin B3, which are further metabolized to the corresponding trioxilins. The ALOXE3 and ALOX12B genes encode the epidermal LOXs eLOX-3 and 12R-LOX. The mechanisms for the involvement of 12-LOX and eLOX-3 in non syndromic forms of ichthyosis are described on the pathway. Outcome effects: The ALOXE3 and ALOX12B genes are predominantly expressed in the suprabasal layers of the epidermis, which supports their role in the advanced phases of epidermal differentiation, with participation in the processing of lamellar bodies. These enzymes act on adjacent steps in the hepoxilin pathway. 12R-LOX transforms arachidonic acid into 12R-hydroxyeicosatetraenoic acid, while eLOX-3 converts this product into an epoxyalcohol isomer of the hepoxilin A3 family. The hepoxilin product is unstable and is hydrolyzed in cells to a specific trihydroxy derivative (trioxilin). The products of the hepoxilin pathway may participate in the formation of intercellular lipids of the stratum corneum or act as signals for inducing keratinocyte differentiation. Patients with mutations in the ALOX12B gene show more limited, whitish desquamation compared with carriers of mutations in the ALOXE3 gene. The presence of erythema, palmoplantar hyperkeratosis, and accentuation of the palmoplantar folds are also associated with ALOX12B mutations. Highlighted proteins: Trioxilin A3 and trioxilin B3 are highlighted in blue in order to emphasize the protective skin barrier disruption in the stratum corneum. Mutated proteins: ALOX12B and ALOXE3 genes mutated in congenital ichthyosiform erythroderma and lamellar ichthyosis are in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18245815 PS:PMID 22832496 PS:PMID 23562412 PS:PMID 26945532 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d4005cd-eef5-4c5e-b9b7-a29b77ba73be NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-4d4005cd-eef5-4c5e-b9b7-a29b77ba73be Alanine metabolism template uuid-4d4005cd-eef5-4c5e-b9b7-a29b77ba73be PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d4005cd-eef5-4c5e-b9b7-a29b77ba73be PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: TAM receptors is a subfamily of receptor protein tyrosine kinases (RTKs), including AXL, MERTK and TYRO3. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d49db6f-4d74-45ff-95d9-639349c6acb6 NodeType: Pathway Notes: Headnote: TAM receptors are a subfamily of receptor protein tyrosine kinases (RTKs), including AXL, MERTK and TYRO3. There are two well-known TAM receptors ligands - GAS6 and PROS1. TULP1 recently also has been described as AXL ligand. Signaling description: While the MAPK/ERK pathway typically results in AXL-mediated proliferation, AXL binding to and activation of PI3K has been linked to multiple downstream pathways converging on increased cell survival. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. Outcome effects: The downstream pathways of PI3K activation by AXL involve PI3K stimulation of AKT1, phosphorylation of NFKB, increased expression of antiapoptotic proteins such as BCL2 and BCL2L1, and inhibition of proapoptotic proteins such as CASP3. Another AXL-induced survival pathway may involve PI3K activation of the small GTPases Rac and Rho as well as the downstream JNK. Studies of GnRH neurons suggest that AXL directs migration of these cells via a signaling pathway involving PI3K, Ras, Rac1, MAPK14, MAPKAPK2, and HSPB1, which results in actin reorganization. AXL was shown to regulate natural killer cell development through interaction with FLT3. AXL also was shown to take part in angiogenesis through AXL - PTPN11 - KDR axis. Organ: generic Organ_System: generic PMID: 18421305 PMID: 18620092 PMID: 22187964 PMID: 25344858 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-4d49db6f-4d74-45ff-95d9-639349c6acb6 AXL Receptor Tyrosine Kinase Signaling uuid-4d49db6f-4d74-45ff-95d9-639349c6acb6 PS:CellType generic PS:Description TAM receptors is a subfamily of receptor protein tyrosine kinases (RTKs), including AXL, MERTK and TYRO3. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d49db6f-4d74-45ff-95d9-639349c6acb6 PS:NodeType Pathway PS:Notes Headnote: TAM receptors are a subfamily of receptor protein tyrosine kinases (RTKs), including AXL, MERTK and TYRO3. There are two well-known TAM receptors ligands - GAS6 and PROS1. TULP1 recently also has been described as AXL ligand. Signaling description: While the MAPK/ERK pathway typically results in AXL-mediated proliferation, AXL binding to and activation of PI3K has been linked to multiple downstream pathways converging on increased cell survival. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. Outcome effects: The downstream pathways of PI3K activation by AXL involve PI3K stimulation of AKT1, phosphorylation of NFKB, increased expression of antiapoptotic proteins such as BCL2 and BCL2L1, and inhibition of proapoptotic proteins such as CASP3. Another AXL-induced survival pathway may involve PI3K activation of the small GTPases Rac and Rho as well as the downstream JNK. Studies of GnRH neurons suggest that AXL directs migration of these cells via a signaling pathway involving PI3K, Ras, Rac1, MAPK14, MAPKAPK2, and HSPB1, which results in actin reorganization. AXL was shown to regulate natural killer cell development through interaction with FLT3. AXL also was shown to take part in angiogenesis through AXL - PTPN11 - KDR axis. PS:Organ generic PS:Organ_System generic PS:PMID 18421305 PS:PMID 18620092 PS:PMID 22187964 PS:PMID 25344858 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Protein kinase C delta (PRKCD) is a member of serine- and threonine-specific kinases involved in the regulation of various cell processes such as growth, apoptosis, and differentiation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d7b014e-dd17-45e3-8e1e-73f054ef78ae NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Protein kinase C delta (PRKCD) is a member of serine- and threonine-specific kinases involved in the regulation of various cell processes such as growth, apoptosis, and differentiation. It has been demonstrated that the PRKCD gene promoter has an androgen response element and is highly responsive to androgens. Outcome effects: Activated PRKCD can initiate proapoptotic program through the stimulation of tumor necrosis factor (TNF) expression and induction of p38 MAPK signaling cascade. There is also evidence that PRKCD can inhibit Akt survival pathway inducing Akt kinase dephosphorylation. Organ: prostate Organ_System: urinary tract PMID: 12824193 PMID: 17553165 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4d7b014e-dd17-45e3-8e1e-73f054ef78ae Androgen Receptor/Protein Kinase C-delta Signaling uuid-4d7b014e-dd17-45e3-8e1e-73f054ef78ae PS:CellType cancer cell PS:Description Protein kinase C delta (PRKCD) is a member of serine- and threonine-specific kinases involved in the regulation of various cell processes such as growth, apoptosis, and differentiation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d7b014e-dd17-45e3-8e1e-73f054ef78ae PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Protein kinase C delta (PRKCD) is a member of serine- and threonine-specific kinases involved in the regulation of various cell processes such as growth, apoptosis, and differentiation. It has been demonstrated that the PRKCD gene promoter has an androgen response element and is highly responsive to androgens. Outcome effects: Activated PRKCD can initiate proapoptotic program through the stimulation of tumor necrosis factor (TNF) expression and induction of p38 MAPK signaling cascade. There is also evidence that PRKCD can inhibit Akt survival pathway inducing Akt kinase dephosphorylation. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 12824193 PS:PMID 17553165 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d7b87b3-b518-43f3-857e-f2b95b31135b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4d7b87b3-b518-43f3-857e-f2b95b31135b Chenodeoxycholate biosynthesis uuid-4d7b87b3-b518-43f3-857e-f2b95b31135b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d7b87b3-b518-43f3-857e-f2b95b31135b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: The loss of NKX3-1 protein expression is often linked to prostate carcinogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d8b1201-31c8-4f98-a6dd-3e0d599ee489 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The transcription factor, NKX3-1 is a tumor suppressor with a prostate-specific and androgen-regulated pattern of expression. The loss of NKX3-1 protein expression is often linked to prostate carcinogenesis. One of the known roles of NKX3-1 is to modulate the activity of TP53 through the interaction with HDAC1 (histone deacetylase 1) and thereby removing it from the p53-MDM2-HDAC1 complex. As a result, TP53 is acetylated and activated to induce apoptosis. Another possible way in which the androgen receptor (AR) could regulate cellular processes such as proliferation and cell growth is to increase the expression via NKX3-1 of IGFBP3 (insulin-like growth factor binding protein 3) that is responsible for decreasing the bioavailability of IGF-1 (insulin-like growth factor 1). AR can also increase the bioavailability of IGF-1 by up-regulating the expression of KLK3 (kallikrein-related peptidase 3, also known as PSA or prostate-specific antigen) which cleaves IGFBP3. Furthermore, NKX3-1 may serve as a transcriptional repressor by decreasing the expression of QSOX1 (pro-oxidant enzyme quiescin Q6). Outcome effects: The loss of NKX3-1 function due to mutation can lead to an increased level of QSOX1 and tumor initiation. NKX3-1 itself can be regulated by phosphorylation and casein kinase II participates in this process by enhancing the stability of NKX3-1 and also changing its DNA binding affinity. There is also evidence that chronic inflammation may induce cancer initiation and progression due to inflammatory cytokines such as TNF (tumor necrosis factor) and IL1B (interleukin 1, beta), which can enhance NKX3-1 protein loss. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. Organ: prostate Organ_System: urinary tract PMID: 17202838 PMID: 19258508 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-4d8b1201-31c8-4f98-a6dd-3e0d599ee489 Androgen Receptor/NKX3-1 Signaling uuid-4d8b1201-31c8-4f98-a6dd-3e0d599ee489 PS:CellType cancer cell PS:Description The loss of NKX3-1 protein expression is often linked to prostate carcinogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d8b1201-31c8-4f98-a6dd-3e0d599ee489 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The transcription factor, NKX3-1 is a tumor suppressor with a prostate-specific and androgen-regulated pattern of expression. The loss of NKX3-1 protein expression is often linked to prostate carcinogenesis. One of the known roles of NKX3-1 is to modulate the activity of TP53 through the interaction with HDAC1 (histone deacetylase 1) and thereby removing it from the p53-MDM2-HDAC1 complex. As a result, TP53 is acetylated and activated to induce apoptosis. Another possible way in which the androgen receptor (AR) could regulate cellular processes such as proliferation and cell growth is to increase the expression via NKX3-1 of IGFBP3 (insulin-like growth factor binding protein 3) that is responsible for decreasing the bioavailability of IGF-1 (insulin-like growth factor 1). AR can also increase the bioavailability of IGF-1 by up-regulating the expression of KLK3 (kallikrein-related peptidase 3, also known as PSA or prostate-specific antigen) which cleaves IGFBP3. Furthermore, NKX3-1 may serve as a transcriptional repressor by decreasing the expression of QSOX1 (pro-oxidant enzyme quiescin Q6). Outcome effects: The loss of NKX3-1 function due to mutation can lead to an increased level of QSOX1 and tumor initiation. NKX3-1 itself can be regulated by phosphorylation and casein kinase II participates in this process by enhancing the stability of NKX3-1 and also changing its DNA binding affinity. There is also evidence that chronic inflammation may induce cancer initiation and progression due to inflammatory cytokines such as TNF (tumor necrosis factor) and IL1B (interleukin 1, beta), which can enhance NKX3-1 protein loss. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 17202838 PS:PMID 19258508 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d90a2af-41df-4d46-9001-5572f0bf9fad NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4d90a2af-41df-4d46-9001-5572f0bf9fad CCL16 Expression Targets uuid-4d90a2af-41df-4d46-9001-5572f0bf9fad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d90a2af-41df-4d46-9001-5572f0bf9fad PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d975fd5-84e6-4f8f-9aac-c66ae857e3bd NodeType: Pathway Notes: Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by a vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: VEGFA, EGF, and TGFB1 are general growth factors that activate epithelial cells in inflammation. TGFB1 stimulates the expression of endothelin, a potent blood flow control protein, in addition to the synthesis of cell adhesion molecules required for recruiting leukocytes into the site of injury. In addition, EGF and VEGFA stimulate the synthesis of nitrogen, adhesion molecules such as TXA2, and PGE2 through an increase in intracellular calcium (Ca2+), and activation of NF-kB and Jun/Fos transcription factors. Conversely, inflammation and the action of growth factors lead to downregulation of the expression of components with anticoagulant and profibrinolytic properties such as THBD, PROCR, and PGI2 in epithelial cells. SP1 and YBX1 most likely play an important role in this process. Adhesion molecules are synthesized by ECs and are subsequently stored in the Weibel-Palade bodies of ECs. Outcome effects: Upon stimulation of platelets or ECs, the granules may fuse with the plasma membrane allowing SELP and others to translocate to the cell surface. Both Ca2+ and H+ are able to induce the secretion of Weibel-Palade bodies. Lastly, tissue damage, free radicals, and various mediators including anti-inflammatory cytokines may lead to an increase in Ca2+ levels. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-4d975fd5-84e6-4f8f-9aac-c66ae857e3bd Vascular Endothelial Cell Activation by Growth Factors uuid-4d975fd5-84e6-4f8f-9aac-c66ae857e3bd PS:CellType endothelial cell PS:Description Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4d975fd5-84e6-4f8f-9aac-c66ae857e3bd PS:NodeType Pathway PS:Notes Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by a vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: VEGFA, EGF, and TGFB1 are general growth factors that activate epithelial cells in inflammation. TGFB1 stimulates the expression of endothelin, a potent blood flow control protein, in addition to the synthesis of cell adhesion molecules required for recruiting leukocytes into the site of injury. In addition, EGF and VEGFA stimulate the synthesis of nitrogen, adhesion molecules such as TXA2, and PGE2 through an increase in intracellular calcium (Ca2+), and activation of NF-kB and Jun/Fos transcription factors. Conversely, inflammation and the action of growth factors lead to downregulation of the expression of components with anticoagulant and profibrinolytic properties such as THBD, PROCR, and PGI2 in epithelial cells. SP1 and YBX1 most likely play an important role in this process. Adhesion molecules are synthesized by ECs and are subsequently stored in the Weibel-Palade bodies of ECs. Outcome effects: Upon stimulation of platelets or ECs, the granules may fuse with the plasma membrane allowing SELP and others to translocate to the cell surface. Both Ca2+ and H+ are able to induce the secretion of Weibel-Palade bodies. Lastly, tissue damage, free radicals, and various mediators including anti-inflammatory cytokines may lead to an increase in Ca2+ levels. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: The Familial Partial Lipodystrophies type 4 (FPL4) is resulted from an autosomal dominantly inherited mutation in the PLIN1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e097cb1-219d-48e0-8400-5b5b1f03a654 NodeType: Pathway Notes: Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. FPL type 4 is the result of an autosomal dominantly inherited mutation in perilipin 1 (PLIN1) gene. FPL4 is characterized by childhood or young adult onset of loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin-resistant diabetes mellitus, hypertriglyceridemia, and hypertension. Signaling description: PLIN1 is localized on the surface of lipid droplets which protects them until they can be broken down by hormone-sensitive lipase. PLIN1 regulates SREBF1, which promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. SREBF1 promotes PPARG, which promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4, thus increasing glucose uptake. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ_System: endocrine system Organ_System: integumentary system PMID: 20551664 PMID: 23272513 PMID: 24152769 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-4e097cb1-219d-48e0-8400-5b5b1f03a654 Familial Partial Lipodystrophy Type 4 Progression (Hypothesis) uuid-4e097cb1-219d-48e0-8400-5b5b1f03a654 PS:CellType adipocyte PS:Description The Familial Partial Lipodystrophies type 4 (FPL4) is resulted from an autosomal dominantly inherited mutation in the PLIN1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e097cb1-219d-48e0-8400-5b5b1f03a654 PS:NodeType Pathway PS:Notes Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. FPL type 4 is the result of an autosomal dominantly inherited mutation in perilipin 1 (PLIN1) gene. FPL4 is characterized by childhood or young adult onset of loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin-resistant diabetes mellitus, hypertriglyceridemia, and hypertension. Signaling description: PLIN1 is localized on the surface of lipid droplets which protects them until they can be broken down by hormone-sensitive lipase. PLIN1 regulates SREBF1, which promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. SREBF1 promotes PPARG, which promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4, thus increasing glucose uptake. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System endocrine system PS:Organ_System integumentary system PS:PMID 20551664 PS:PMID 23272513 PS:PMID 24152769 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e2b4668-8e36-4e45-a5fd-ff403308a92b NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-4e2b4668-8e36-4e45-a5fd-ff403308a92b CD38 -> cADPR/Calcium Signaling uuid-4e2b4668-8e36-4e45-a5fd-ff403308a92b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e2b4668-8e36-4e45-a5fd-ff403308a92b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e510d20-b912-4a55-84eb-7c6f75c1e8af NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4e510d20-b912-4a55-84eb-7c6f75c1e8af Proteins Involved in Graves Disease uuid-4e510d20-b912-4a55-84eb-7c6f75c1e8af PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e510d20-b912-4a55-84eb-7c6f75c1e8af PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e5ce532-000f-4c0f-a1b4-c21aa19f8334 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4e5ce532-000f-4c0f-a1b4-c21aa19f8334 AGT -> ELK/SRF Expression Targets uuid-4e5ce532-000f-4c0f-a1b4-c21aa19f8334 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e5ce532-000f-4c0f-a1b4-c21aa19f8334 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: Acute promyelocytic leukemia (AML-M3) is characterized by chromosomal translocations involving the retinoic acid receptor alpha (RARA). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e5d9300-2eca-4991-ac96-d993319a1769 NodeType: Pathway Notes: Headnote: Acute promyelocytic leukemia (AML-M3) is a form of acute myeloid leukemia with an abnormal accumulation of immature granulocytes called promyelocytes. It is characterized by chromosomal translocations involving the retinoic acid receptor alpha (RARA). Signaling description: The most common translocation is PML-RAR, which is found in more than 98% of AML-M3 cases. PLZF-RAR and NPM-RAR are more rare translocations. PML-RAR, NPM-RAR, and PLZF-RAR fusion proteins modulate retinoid-responsive gene expression by disrupting the retinoid acid signal pathway and inhibiting myeloid differentiation at the promyelocyte stage. Cell differentiation is also blocked through SPI1, NCOR1/2, and histone deacetylase. In addition, FLT3, a class III receptor tyrosine kinase may be mutated in up to 38% of AML-M3 cases. Outcome effects: In AML, cell proliferation is triggered through the activation of catenin-beta1 (CTNNB1) while CCND1, GATA4, CCNA1, and MYC play a role in cell cycle activation. Mutated genes: Mutated genes are shown in white-out style. Organ_System: hematological system PMID: 20096459 PMID: 20966922 PMID: 21245861 PMID: 22778276 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-4e5d9300-2eca-4991-ac96-d993319a1769 RARA Signaling in Acute Myeloid Leukemia (M3) uuid-4e5d9300-2eca-4991-ac96-d993319a1769 PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description Acute promyelocytic leukemia (AML-M3) is characterized by chromosomal translocations involving the retinoic acid receptor alpha (RARA). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e5d9300-2eca-4991-ac96-d993319a1769 PS:NodeType Pathway PS:Notes Headnote: Acute promyelocytic leukemia (AML-M3) is a form of acute myeloid leukemia with an abnormal accumulation of immature granulocytes called promyelocytes. It is characterized by chromosomal translocations involving the retinoic acid receptor alpha (RARA). Signaling description: The most common translocation is PML-RAR, which is found in more than 98% of AML-M3 cases. PLZF-RAR and NPM-RAR are more rare translocations. PML-RAR, NPM-RAR, and PLZF-RAR fusion proteins modulate retinoid-responsive gene expression by disrupting the retinoid acid signal pathway and inhibiting myeloid differentiation at the promyelocyte stage. Cell differentiation is also blocked through SPI1, NCOR1/2, and histone deacetylase. In addition, FLT3, a class III receptor tyrosine kinase may be mutated in up to 38% of AML-M3 cases. Outcome effects: In AML, cell proliferation is triggered through the activation of catenin-beta1 (CTNNB1) while CCND1, GATA4, CCNA1, and MYC play a role in cell cycle activation. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System hematological system PS:PMID 20096459 PS:PMID 20966922 PS:PMID 21245861 PS:PMID 22778276 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e771eea-0234-4806-bb19-931493787a82 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-4e771eea-0234-4806-bb19-931493787a82 Elevated Receptors -> Expression Targets in Heart uuid-4e771eea-0234-4806-bb19-931493787a82 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e771eea-0234-4806-bb19-931493787a82 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e7b12bf-0ad6-4449-b96f-6197e72cf0d9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4e7b12bf-0ad6-4449-b96f-6197e72cf0d9 PDGFB -> FOXO3A Expression Target uuid-4e7b12bf-0ad6-4449-b96f-6197e72cf0d9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e7b12bf-0ad6-4449-b96f-6197e72cf0d9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e854c54-855f-4ea4-963e-5df52b934423 NodeType: Pathway Notes: The main hypothesis explaining the origin of pain in hemiplegic migraine is associated with vasodilation. Glutamate can lead to vasodilation in a migraine by stimulating prostaglandin H2 (PGH2) and NO synthesis in neurons, astrocytes, endothelial, and smooth muscle cells of the dura mater leading to vasodilation and the consequent headache. It is believed that migraine pain is caused by the expansion of blood vessels. However, the exact mechanism underlying the development of pain in hemiplegic migraine is not completely understood. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: brain Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4e854c54-855f-4ea4-963e-5df52b934423 1_2_Glutamate overload and NO-mediated vasodilation uuid-4e854c54-855f-4ea4-963e-5df52b934423 PS:CellType endothelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e854c54-855f-4ea4-963e-5df52b934423 PS:NodeType Pathway PS:Notes The main hypothesis explaining the origin of pain in hemiplegic migraine is associated with vasodilation. Glutamate can lead to vasodilation in a migraine by stimulating prostaglandin H2 (PGH2) and NO synthesis in neurons, astrocytes, endothelial, and smooth muscle cells of the dura mater leading to vasodilation and the consequent headache. It is believed that migraine pain is caused by the expansion of blood vessels. However, the exact mechanism underlying the development of pain in hemiplegic migraine is not completely understood. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ brain PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e8cc03e-6327-417f-b69f-e33ebbb3ec90 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-4e8cc03e-6327-417f-b69f-e33ebbb3ec90 Organophosphorus Compounds Degradation uuid-4e8cc03e-6327-417f-b69f-e33ebbb3ec90 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e8cc03e-6327-417f-b69f-e33ebbb3ec90 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Macromolecules greater than 40kDa are transported across the nuclear pore complexes (NPCs) actively using soluble transport factors or carrier molecules that cycle between the nucleus and cytoplasm. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e8da80a-29dc-45d9-b6d7-c95c1fb98ddc NodeType: Pathway Notes: Headnote: Macromolecules greater than 40kDa are transported across the nuclear pore complexes (NPCs) actively using soluble transport factors or carrier molecules that cycle between the nucleus and cytoplasm. Signaling description: NPCs are large macromolecular assemblies with eight-fold rotational symmetry that allow the transport of RNA and ribosomes from the nucleus to the cytoplasm. NPCs also allow transport of proteins, carbohydrates, signal molecules, and lipids into the nucleus. They are built from 30 different proteins called nucleoporins. The nuclear protein import process involves cargo-carrier import complex assembly in the cytoplasm, its translocation through NPC, disassembly of this complex in the nucleus, and recycling of importins. Most nuclear transport pathways use a homologous family of carrier molecules collectively called karyopherins, with import carriers called importins and export carriers called exportins. Many proteins are imported using importin beta (KPNB1), often using importin alpha (KPNA2) as an adaptor while some are imported using other importins such as TNPO1. Cargo proteins are targeted for nuclear import by short NLS (nuclear localization signal) sequence motifs. In the cytoplasm, cargo proteins that contain a classic NLS form an import complex with KPNB1-KPNA2 heterodimer, which facilitates movement through NPCs. Outcome effects: In the nucleus, RAN binds to KPNB1 which dissociates and releases the cargo. Nucleoporins such as NUP50 catalyze cargo dissociation and are involved in importin recycling. RAN then binds to importins and is exported to the cytoplasm, where cytoplasmic RANGAP1 stimulates the dissociation of RAN from the importins and thereby releases them for another import cycle. Cytoplasmic RAN is imported into the nucleus by Gm10349. KPNA2 is recycled to the cytoplasm by its nuclear export factor, CSE1L. Many proteins are exported using XPO1; however pre-microRNA and tRNA are exported by XPO5 and XPOT. The nuclear export of mRNA is performed by NXF1/NXT1 heterodimer. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-4e8da80a-29dc-45d9-b6d7-c95c1fb98ddc Protein Nuclear Import and Export uuid-4e8da80a-29dc-45d9-b6d7-c95c1fb98ddc PS:CellType generic PS:Description Macromolecules greater than 40kDa are transported across the nuclear pore complexes (NPCs) actively using soluble transport factors or carrier molecules that cycle between the nucleus and cytoplasm. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4e8da80a-29dc-45d9-b6d7-c95c1fb98ddc PS:NodeType Pathway PS:Notes Headnote: Macromolecules greater than 40kDa are transported across the nuclear pore complexes (NPCs) actively using soluble transport factors or carrier molecules that cycle between the nucleus and cytoplasm. Signaling description: NPCs are large macromolecular assemblies with eight-fold rotational symmetry that allow the transport of RNA and ribosomes from the nucleus to the cytoplasm. NPCs also allow transport of proteins, carbohydrates, signal molecules, and lipids into the nucleus. They are built from 30 different proteins called nucleoporins. The nuclear protein import process involves cargo-carrier import complex assembly in the cytoplasm, its translocation through NPC, disassembly of this complex in the nucleus, and recycling of importins. Most nuclear transport pathways use a homologous family of carrier molecules collectively called karyopherins, with import carriers called importins and export carriers called exportins. Many proteins are imported using importin beta (KPNB1), often using importin alpha (KPNA2) as an adaptor while some are imported using other importins such as TNPO1. Cargo proteins are targeted for nuclear import by short NLS (nuclear localization signal) sequence motifs. In the cytoplasm, cargo proteins that contain a classic NLS form an import complex with KPNB1-KPNA2 heterodimer, which facilitates movement through NPCs. Outcome effects: In the nucleus, RAN binds to KPNB1 which dissociates and releases the cargo. Nucleoporins such as NUP50 catalyze cargo dissociation and are involved in importin recycling. RAN then binds to importins and is exported to the cytoplasm, where cytoplasmic RANGAP1 stimulates the dissociation of RAN from the importins and thereby releases them for another import cycle. Cytoplasmic RAN is imported into the nucleus by Gm10349. KPNA2 is recycled to the cytoplasm by its nuclear export factor, CSE1L. Many proteins are exported using XPO1; however pre-microRNA and tRNA are exported by XPO5 and XPOT. The nuclear export of mRNA is performed by NXF1/NXT1 heterodimer. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ea50b59-1d43-49ec-af18-dea34a0c8ab8 NodeType: Pathway Notes: Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway describes thyroid gland development in relation to a mutation in GLIS3. The proteins that are regulated by GLIS3 were added to the pathway following the analysis of existing neighbors of GLIS3 in Pathway Studio. Only those that are important for the development of thyroid cells were added. Although there is some evidence that cells have no more than 2-3 cascades of transcription factors, the path of GLIS3-RUNX2-SMAD3-NKX2-1 transcription factors is shown because it may be activated consistently in different cells during morphogenesis. Outcome effects: GLIS3 functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, thyroid, eye, liver and kidney. Mutations in GLIS3 can cause a recessive form of neonatal diabetes and congenital hypothyroidism. . Mutated gene: Mutated gene is shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 15665157 PMID: 16715098 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-4ea50b59-1d43-49ec-af18-dea34a0c8ab8 GLIS3 Targets in Thyroid Dysgenesis (Hypothesis) uuid-4ea50b59-1d43-49ec-af18-dea34a0c8ab8 PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ea50b59-1d43-49ec-af18-dea34a0c8ab8 PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway describes thyroid gland development in relation to a mutation in GLIS3. The proteins that are regulated by GLIS3 were added to the pathway following the analysis of existing neighbors of GLIS3 in Pathway Studio. Only those that are important for the development of thyroid cells were added. Although there is some evidence that cells have no more than 2-3 cascades of transcription factors, the path of GLIS3-RUNX2-SMAD3-NKX2-1 transcription factors is shown because it may be activated consistently in different cells during morphogenesis. Outcome effects: GLIS3 functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, thyroid, eye, liver and kidney. Mutations in GLIS3 can cause a recessive form of neonatal diabetes and congenital hypothyroidism. . Mutated gene: Mutated gene is shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15665157 PS:PMID 16715098 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4eba0452-c7e9-45f3-81da-cbf6c5608305 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-4eba0452-c7e9-45f3-81da-cbf6c5608305 PDCD1 -> NF-kB Expression Targets uuid-4eba0452-c7e9-45f3-81da-cbf6c5608305 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4eba0452-c7e9-45f3-81da-cbf6c5608305 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4eca8fba-45a1-4020-bc13-80f9acc8c8c1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4eca8fba-45a1-4020-bc13-80f9acc8c8c1 Renin-Angiotensin system uuid-4eca8fba-45a1-4020-bc13-80f9acc8c8c1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4eca8fba-45a1-4020-bc13-80f9acc8c8c1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ed6aa4a-7b2e-47db-9aff-7cdcdca652ff NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4ed6aa4a-7b2e-47db-9aff-7cdcdca652ff ADCY-PKA-|Myofibroblasts uuid-4ed6aa4a-7b2e-47db-9aff-7cdcdca652ff PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ed6aa4a-7b2e-47db-9aff-7cdcdca652ff PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: neuron Description: Early-onset Parkinson's disease (PD) is characterized by alpha-synuclein (SNCA) aggregation and Lewy body formation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f0bf992-462c-4ad7-8f39-8a1c079cf614 NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Early-onset Parkinson's disease (PD) is characterized by alpha-synuclein (SNCA) aggregation and Lewy body formation. Normally, SNCA is involved in vesicle trafficking, dopamine release, and chaperone-mediated autophagy. The protein is also a competitive inhibitor of tyrosine hydroxylase (TH), the rate-limiting enzyme in L-DOPA biosynthesis from L-tyrosine. Mutations in the SNCA gene produce incorrect protein folding and lead to its aggregation and disruption of dopamine release which can ultimately cause cell death. Two missense mutations (A30P and A53T) in the gene encoding SNCA have been found in cases of the autosomal dominant form of disease. A triplication of the wild-type SNCA locus was also discovered suggesting that overexpression of SNCA may be sufficient to trigger the disease. Outcome effects: Misfolded SNCA has an increased tendency to aggregate with calpain and tubulin with TGM2 proteins facilitating this process as well as 3,4-dihydroxyphenylacetaldehyde (DOPAL). An elevated concentration of DOPAL is found in the brains of PD patients with mutated SNCA. Aggregated protein with its interacting substances, mainly ubiquitin, forms Lewy bodies which are the pathological hallmarks of PD. Highlighted proteins: Entities with incresed level or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 19193223 PMID: 22024360 PMID: 22825468 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-4f0bf992-462c-4ad7-8f39-8a1c079cf614 SNCA in Young Onset Parkinson's Disease uuid-4f0bf992-462c-4ad7-8f39-8a1c079cf614 PS:CellType neuron PS:Description Early-onset Parkinson's disease (PD) is characterized by alpha-synuclein (SNCA) aggregation and Lewy body formation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f0bf992-462c-4ad7-8f39-8a1c079cf614 PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Early-onset Parkinson's disease (PD) is characterized by alpha-synuclein (SNCA) aggregation and Lewy body formation. Normally, SNCA is involved in vesicle trafficking, dopamine release, and chaperone-mediated autophagy. The protein is also a competitive inhibitor of tyrosine hydroxylase (TH), the rate-limiting enzyme in L-DOPA biosynthesis from L-tyrosine. Mutations in the SNCA gene produce incorrect protein folding and lead to its aggregation and disruption of dopamine release which can ultimately cause cell death. Two missense mutations (A30P and A53T) in the gene encoding SNCA have been found in cases of the autosomal dominant form of disease. A triplication of the wild-type SNCA locus was also discovered suggesting that overexpression of SNCA may be sufficient to trigger the disease. Outcome effects: Misfolded SNCA has an increased tendency to aggregate with calpain and tubulin with TGM2 proteins facilitating this process as well as 3,4-dihydroxyphenylacetaldehyde (DOPAL). An elevated concentration of DOPAL is found in the brains of PD patients with mutated SNCA. Aggregated protein with its interacting substances, mainly ubiquitin, forms Lewy bodies which are the pathological hallmarks of PD. Highlighted proteins: Entities with incresed level or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 19193223 PS:PMID 22024360 PS:PMID 22825468 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f10cf1a-b9ac-4296-a89b-8b730ea3c0ca NodeType: Pathway Notes: Headnote: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Signaling description: One of the first signs of APR is the synthesis of acute phase proteins (APPs) in the liver. The release of proinflammatory cytokines, nitric oxide, and glucocorticoids initiates the synthesis of APPs. IL6 is the key mediator for hepatocytic secretion of most APPs. An APP has been defined as one, whose plasma concentration increases (positive APP) or decreases (negative APP) by at least 25% during inflammatory disorders. Some examples of negative APPs include albumin (ALB), transferrin (TF), transthyretin (TTR), RBP1, antithrombin (SERPINC1), and transcortin (SERPINA6). The decrease of these proteins may be used as markers of inflammation. The physiological role of the reduced synthesis of these proteins is to reserve amino acids to produce positive APPs more efficiently. Some transcription factors that may be involved in regulating the synthesis of negative APPs in liver are described on the pathway. Outcome effects: It is recognized that CEBPA is downregulated in APR. ALB is an example of a negative APP and constitutes about half of blood serum protein. It transports hormones, fatty acids and other compounds, buffers pH, and maintains osmotic pressure. SERPINA6, RBP1, TTR, and TF are major transport proteins in the blood. SERPINA6, which is an alpha-globulin protein, has corticosteroid-binding properties and is a key transport protein for glucocorticoids and progestins in the blood. SERPINA6 binds to corticosteroid, glucocorticoids, progestins, retinol, thyroxine (T4), and iron and their deficiency may lead to protein malnutrition. CPB2 and SERPINC1 inhibit fibrinolysis and blood coagulation. The negative expression of SERPINC1 in APR can reduce the increased degradation by proteolytic enzymes (elastase released from activated neutrophils). SERPINC1 also appears to directly act as an anti-inflammatory agent by binding to leukocyte receptors and blocking their communication with endothelial cells and limiting their adhesion and migration. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ: liver Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-4f10cf1a-b9ac-4296-a89b-8b730ea3c0ca Negative Acute Phase Proteins Synthesis uuid-4f10cf1a-b9ac-4296-a89b-8b730ea3c0ca PS:CellType hepatocyte PS:Description The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f10cf1a-b9ac-4296-a89b-8b730ea3c0ca PS:NodeType Pathway PS:Notes Headnote: The acute phase response (APR) is a prominent systemic reaction of an organism to infection and tissue injury. Signaling description: One of the first signs of APR is the synthesis of acute phase proteins (APPs) in the liver. The release of proinflammatory cytokines, nitric oxide, and glucocorticoids initiates the synthesis of APPs. IL6 is the key mediator for hepatocytic secretion of most APPs. An APP has been defined as one, whose plasma concentration increases (positive APP) or decreases (negative APP) by at least 25% during inflammatory disorders. Some examples of negative APPs include albumin (ALB), transferrin (TF), transthyretin (TTR), RBP1, antithrombin (SERPINC1), and transcortin (SERPINA6). The decrease of these proteins may be used as markers of inflammation. The physiological role of the reduced synthesis of these proteins is to reserve amino acids to produce positive APPs more efficiently. Some transcription factors that may be involved in regulating the synthesis of negative APPs in liver are described on the pathway. Outcome effects: It is recognized that CEBPA is downregulated in APR. ALB is an example of a negative APP and constitutes about half of blood serum protein. It transports hormones, fatty acids and other compounds, buffers pH, and maintains osmotic pressure. SERPINA6, RBP1, TTR, and TF are major transport proteins in the blood. SERPINA6, which is an alpha-globulin protein, has corticosteroid-binding properties and is a key transport protein for glucocorticoids and progestins in the blood. SERPINA6 binds to corticosteroid, glucocorticoids, progestins, retinol, thyroxine (T4), and iron and their deficiency may lead to protein malnutrition. CPB2 and SERPINC1 inhibit fibrinolysis and blood coagulation. The negative expression of SERPINC1 in APR can reduce the increased degradation by proteolytic enzymes (elastase released from activated neutrophils). SERPINC1 also appears to directly act as an anti-inflammatory agent by binding to leukocyte receptors and blocking their communication with endothelial cells and limiting their adhesion and migration. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ liver PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f11395c-4bd0-4dce-862a-31da4f3596cb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4f11395c-4bd0-4dce-862a-31da4f3596cb InsR signaling +feedback uuid-4f11395c-4bd0-4dce-862a-31da4f3596cb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f11395c-4bd0-4dce-862a-31da4f3596cb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author CellType: epithelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f4c938b-b789-4684-8d6f-89c675b8db28 NodeType: Pathway Organ: eye PMID: 18501660 PMID: 21293732 PMID: 24165276 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-4f4c938b-b789-4684-8d6f-89c675b8db28 Aqueous Humor Production by ciliary epithelium uuid-4f4c938b-b789-4684-8d6f-89c675b8db28 PS:CellType epithelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f4c938b-b789-4684-8d6f-89c675b8db28 PS:NodeType Pathway PS:Organ eye PS:PMID 18501660 PS:PMID 21293732 PS:PMID 24165276 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Type II estrogen-independent endometrial cancer (EC) includes clear-cell EC and papillary serous EC. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f503dbf-458f-4f93-928a-d68c1f7af1ad NodeType: Pathway Notes: Headnote: Headnote: Endometrial carcinoma (EC) is the most common gynecological cancer in the western countries. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma and type II estrogen-independent EC with papillary serous or clear cell morphology. Type II estrogen-independent EC is a rare type of aggressive EC. Patients with Type II estrogen-independent EC have a lower overall and disease-free survival rate than patients with type I estrogen-dependent EC. Signaling description: Type II estrogen-independent EC is characterized by mutations in the TP53 gene, overexpression of ERBB2, CLDN3/4, EPCAM, and CDKN2A in addition to the reduced expression of CDH1 (E-cadherin). The ERBB family of receptor tyrosine kinases includes four related members including epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple the extracellular growth factor ligands to intracellular signaling pathways and regulate cell processes including proliferation, differentiation, cell migration, and survival. Ligand-bound membrane EGFRs activate PIK3CA, which in turn activates AKT1 via PIP3 and PDPK1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1), which then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and the activation of apoptotic caspase cascade. EGFRs regulate Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF, which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Lastly, CLDN3/4 and EPCAM form tight junctions and their overexpression may increase cell motility and contribute to the aggressive phenotype of EC of serous papillary or clear-cell histology. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: uterus Organ_System: reproductive system PMID: 18061438 PMID: 20396392 PMID: 22498825 PMID: 22888282 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endometrium Tissue: epithelium urn:agi-pathway:uuid-4f503dbf-458f-4f93-928a-d68c1f7af1ad Clear Cell Endometrial Cancer and Papillary Serous Endometrial Cancer uuid-4f503dbf-458f-4f93-928a-d68c1f7af1ad PS:CellType cancer cell PS:CellType epithelial cell PS:Description Type II estrogen-independent endometrial cancer (EC) includes clear-cell EC and papillary serous EC. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f503dbf-458f-4f93-928a-d68c1f7af1ad PS:NodeType Pathway PS:Notes Headnote: Headnote: Endometrial carcinoma (EC) is the most common gynecological cancer in the western countries. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma and type II estrogen-independent EC with papillary serous or clear cell morphology. Type II estrogen-independent EC is a rare type of aggressive EC. Patients with Type II estrogen-independent EC have a lower overall and disease-free survival rate than patients with type I estrogen-dependent EC. Signaling description: Type II estrogen-independent EC is characterized by mutations in the TP53 gene, overexpression of ERBB2, CLDN3/4, EPCAM, and CDKN2A in addition to the reduced expression of CDH1 (E-cadherin). The ERBB family of receptor tyrosine kinases includes four related members including epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple the extracellular growth factor ligands to intracellular signaling pathways and regulate cell processes including proliferation, differentiation, cell migration, and survival. Ligand-bound membrane EGFRs activate PIK3CA, which in turn activates AKT1 via PIP3 and PDPK1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1), which then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and the activation of apoptotic caspase cascade. EGFRs regulate Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF, which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Lastly, CLDN3/4 and EPCAM form tight junctions and their overexpression may increase cell motility and contribute to the aggressive phenotype of EC of serous papillary or clear-cell histology. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 18061438 PS:PMID 20396392 PS:PMID 22498825 PS:PMID 22888282 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endometrium PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f692b06-c795-461d-932b-89b68a108918 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4f692b06-c795-461d-932b-89b68a108918 Axonal and Vesicle Transport Impairment in Huntington Disease uuid-4f692b06-c795-461d-932b-89b68a108918 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f692b06-c795-461d-932b-89b68a108918 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f9f11ec-1949-453e-ada9-e8b67bdcad16 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-4f9f11ec-1949-453e-ada9-e8b67bdcad16 TGFBR/BMPR -> SMAD2/3 Signaling uuid-4f9f11ec-1949-453e-ada9-e8b67bdcad16 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4f9f11ec-1949-453e-ada9-e8b67bdcad16 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: sebocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fa584f2-0a6f-44fe-9228-6ac7f56558bc NodeType: Pathway Notes: Hyperseborrhea, or the excessive production of sebum by sebaceous glands, results from increased fatty acid biosynthesis in sebocytes. Hyperseborrhea may be induced by various factors including IGF1, cytokines, and free fatty acids themselves. Milk consumption and growth hormone (GH1) expression (not shown) can influence the synthesis and secretion of IGF1 in the liver. Testosterone also increases sebocyte hyperfunction. Increased fatty acid biosynthesis by sebocytes and increased sebocyte proliferation lead to comedogenesis and hyperseborrhea: hyperseborrhea results in inflammation and abnormal keratinocyte function at the site that can cause the formation of acne lesions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-4fa584f2-0a6f-44fe-9228-6ac7f56558bc 3_Increased proliferation of sebocytes in acne vulgaris uuid-4fa584f2-0a6f-44fe-9228-6ac7f56558bc PS:CellType sebocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fa584f2-0a6f-44fe-9228-6ac7f56558bc PS:NodeType Pathway PS:Notes Hyperseborrhea, or the excessive production of sebum by sebaceous glands, results from increased fatty acid biosynthesis in sebocytes. Hyperseborrhea may be induced by various factors including IGF1, cytokines, and free fatty acids themselves. Milk consumption and growth hormone (GH1) expression (not shown) can influence the synthesis and secretion of IGF1 in the liver. Testosterone also increases sebocyte hyperfunction. Increased fatty acid biosynthesis by sebocytes and increased sebocyte proliferation lead to comedogenesis and hyperseborrhea: hyperseborrhea results in inflammation and abnormal keratinocyte function at the site that can cause the formation of acne lesions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron CellType: oligodendroglia Description: Effects of exposure of ammonia on brain cells are those neurological symptoms that are observed in the Urea Cycle Disorders. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fb93ac7-b3a4-413e-9a66-efd0938cc55f NodeType: Pathway Notes: Headnote: The neurological symptoms that are observed in the urea cycle disorders are caused by the effects of ammonia exposure on brain cells. Organ: brain Organ_System: nervous system PMID: 15050974 PMID: 23109059 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-4fb93ac7-b3a4-413e-9a66-efd0938cc55f Ammonia Effects on Brain Cells uuid-4fb93ac7-b3a4-413e-9a66-efd0938cc55f PS:CellType astrocyte PS:CellType neuron PS:CellType oligodendroglia PS:Description Effects of exposure of ammonia on brain cells are those neurological symptoms that are observed in the Urea Cycle Disorders. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fb93ac7-b3a4-413e-9a66-efd0938cc55f PS:NodeType Pathway PS:Notes Headnote: The neurological symptoms that are observed in the urea cycle disorders are caused by the effects of ammonia exposure on brain cells. PS:Organ brain PS:Organ_System nervous system PS:PMID 15050974 PS:PMID 23109059 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: keratinocyte CellType: macrophage CellType: mast cell CellType: osteocyte Description: The deficiency of interleukin-1 receptor antagonist (DIRA) is an autosomal recessive inherited disease caused by mutations in IL1RN on chromosome 2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fe56b5c-8e82-4bb9-b239-d1854c7bdcca NodeType: Pathway Notes: Headnote: The deficiency of interleukin-1 receptor antagonist (DIRA) is an autosomal recessive autoinflammatory disease caused by mutations in the IL1RN gene on chromosome 2. DIRA manifests itself clinically with perinatal-onset pustular dermatitis, joint swelling, painful osteolytic lesions, and periostitis. Fever is rare and neurologic inflammation is absent. Laboratory findings in DIRA include persistent elevation of acute-phase inflammatory indicators. Signaling description: Mutations in the IL1RN gene lead to the absence of IL1RN and subsequent IL1 overactivity. The IL1B signaling receptor complex has a role in the autocrine feedback induction of the pro-IL1B gene promoter region. Outcome effects: Mutations in IL1RN cause loss of inhibitory function in IL1B and IL1A signaling through IL1R1, and result in systemic inflammation with skin and bone involvement. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 19494218 PMID: 24282415 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone tissue Tissue: epidermis urn:agi-pathway:uuid-4fe56b5c-8e82-4bb9-b239-d1854c7bdcca IL1 Receptor Antagonist (IL1RN) Deficiency (DIRA) uuid-4fe56b5c-8e82-4bb9-b239-d1854c7bdcca PS:CellType dendritic cell PS:CellType keratinocyte PS:CellType macrophage PS:CellType mast cell PS:CellType osteocyte PS:Description The deficiency of interleukin-1 receptor antagonist (DIRA) is an autosomal recessive inherited disease caused by mutations in IL1RN on chromosome 2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fe56b5c-8e82-4bb9-b239-d1854c7bdcca PS:NodeType Pathway PS:Notes Headnote: The deficiency of interleukin-1 receptor antagonist (DIRA) is an autosomal recessive autoinflammatory disease caused by mutations in the IL1RN gene on chromosome 2. DIRA manifests itself clinically with perinatal-onset pustular dermatitis, joint swelling, painful osteolytic lesions, and periostitis. Fever is rare and neurologic inflammation is absent. Laboratory findings in DIRA include persistent elevation of acute-phase inflammatory indicators. Signaling description: Mutations in the IL1RN gene lead to the absence of IL1RN and subsequent IL1 overactivity. The IL1B signaling receptor complex has a role in the autocrine feedback induction of the pro-IL1B gene promoter region. Outcome effects: Mutations in IL1RN cause loss of inhibitory function in IL1B and IL1A signaling through IL1R1, and result in systemic inflammation with skin and bone involvement. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 19494218 PS:PMID 24282415 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone tissue PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: macrophage CellType: neutrophil Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ff8d1aa-13cb-4175-b64d-f6b855b97d87 NodeType: Pathway Notes: Patients with who are homozygous for the Z allele (PIZZ phenotype) of the alpha-1-antitrypsin gene often develop emphysema in the fourth to fifth decades of life due to protease-mediated tissue destruction. Alpha-1-antitrypsin (AAT), encoded by the SERPINA1 gene, is a protein that protects the body from the antibacterial enzyme neutrophil elastase (ELANE), which is released by white blood cells and can attack healthy tissues, especially the lungs if not tightly controlled by AAT. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-4ff8d1aa-13cb-4175-b64d-f6b855b97d87 1_SERPINA1-associated pulmonary emphysema uuid-4ff8d1aa-13cb-4175-b64d-f6b855b97d87 PS:CellType endothelial cell PS:CellType macrophage PS:CellType neutrophil PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4ff8d1aa-13cb-4175-b64d-f6b855b97d87 PS:NodeType Pathway PS:Notes Patients with who are homozygous for the Z allele (PIZZ phenotype) of the alpha-1-antitrypsin gene often develop emphysema in the fourth to fifth decades of life due to protease-mediated tissue destruction. Alpha-1-antitrypsin (AAT), encoded by the SERPINA1 gene, is a protein that protects the body from the antibacterial enzyme neutrophil elastase (ELANE), which is released by white blood cells and can attack healthy tissues, especially the lungs if not tightly controlled by AAT. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fff77d7-4bee-4a93-a4aa-2cf7a4a65b7e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-4fff77d7-4bee-4a93-a4aa-2cf7a4a65b7e CTNF-|Huntington uuid-4fff77d7-4bee-4a93-a4aa-2cf7a4a65b7e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-4fff77d7-4bee-4a93-a4aa-2cf7a4a65b7e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-500686a7-419c-46a3-a5b3-45310df87c37 NodeType: Pathway Notes: It was proposed that stimulation of DRD1 by dopamin leads to the release of glutamate in synapses. Organ: brain Organ_System: nervous system PMID: 15289006 PMID: 17408758 PMID: 24049187 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-500686a7-419c-46a3-a5b3-45310df87c37 Dopamine Mediated Glutamate Release/Uptake Circle in Neuron in Migraine uuid-500686a7-419c-46a3-a5b3-45310df87c37 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-500686a7-419c-46a3-a5b3-45310df87c37 PS:NodeType Pathway PS:Notes It was proposed that stimulation of DRD1 by dopamin leads to the release of glutamate in synapses. PS:Organ brain PS:Organ_System nervous system PS:PMID 15289006 PS:PMID 17408758 PS:PMID 24049187 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50086b73-33b5-4c9c-ba4d-94a752968cbc NodeType: Pathway Notes: Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by a vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: Endothelium, forming the luminal vascular surface, is continuously interacting with coagulation factors. Coagulation factors are serine proteases and act through the cleavage of protease-activated G-protein coupled receptors (PARs) such as F2R, F2RL1, F2RL2, and F2RL3 on the surface of endothelial cells. F2RL2 does not signal through G-proteins and instead acts as a cofactor that binds and localizes thrombin for activation of F2RL3. Outcome effects: G-proteins transmit signals through RHOA/Ras/MAPK, PI3K/AKT1 to JUN-FOS and NF-kB. An alternative mechanism by which F10 induces inflammation may rely on EPR1. Fibrinogen may activate inflammation through TLR4. Finally, the interaction of coagulation factors with endothelial cells results in the recruitment of immune cells, disruption of the endothelial cell barrier as well as migration and release of growth factors and cytokines. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-50086b73-33b5-4c9c-ba4d-94a752968cbc Vascular Endothelial Cell Activation by Blood Coagulation Factors uuid-50086b73-33b5-4c9c-ba4d-94a752968cbc PS:CellType endothelial cell PS:Description Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by vessel wall injury or soluble mediators of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50086b73-33b5-4c9c-ba4d-94a752968cbc PS:NodeType Pathway PS:Notes Headnote: Vascular endothelial cells (ECs) form a single layer of simple squamous lining cells and can be activated by a vessel wall injury or soluble mediators of inflammation. The activation of signaling specific to epithelial cells of blood vessels is one of the earliest processes in inflammation. Signaling description: Endothelium, forming the luminal vascular surface, is continuously interacting with coagulation factors. Coagulation factors are serine proteases and act through the cleavage of protease-activated G-protein coupled receptors (PARs) such as F2R, F2RL1, F2RL2, and F2RL3 on the surface of endothelial cells. F2RL2 does not signal through G-proteins and instead acts as a cofactor that binds and localizes thrombin for activation of F2RL3. Outcome effects: G-proteins transmit signals through RHOA/Ras/MAPK, PI3K/AKT1 to JUN-FOS and NF-kB. An alternative mechanism by which F10 induces inflammation may rely on EPR1. Fibrinogen may activate inflammation through TLR4. Finally, the interaction of coagulation factors with endothelial cells results in the recruitment of immune cells, disruption of the endothelial cell barrier as well as migration and release of growth factors and cytokines. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: macrophage CellType: monocyte Description: Atherosclerosis involves the formation of plaques in arterial walls that narrow the arterial passage restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5037abf3-65be-44ff-92e5-2f03c44f0695 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: Atherosclerosis involves the formation of plaques in arterial walls that narrow the arterial passage which restricts blood flow and increases the risk of occlusion of blood flow by a myocardial infarction. One of the first stages in the development of atherosclerosis is the passage of low-density lipoprotein (LDL) out of the arterial lumen and into the arterial wall. Once there, the lipids in LDL are chemically modified and oxidized. Oxidized LDL stimulates inflammatory signaling by neighboring endothelial cells (ECs), releasing chemokines and cytokines such as CCL5 and CCL2 in addition to ICAM1 and recruiting monocytes into the arterial wall. Outcome effects: Monocytes then differentiate into macrophages and internalize modified LDL. These macrophages continue to internalize LDL and become enlarged and full of lipid. These cells accumulate in tissue and are transformed into foam cells, dying and forming part of the atherogenic plaque. Monocyte recruitment involves their rolling, firm adhesion, lateral migration, and transendothelial diapedesis which are controlled by chemokines. While soluble chemokines mediate direct leukocyte recruitment, chemokines immobilized on the surface of activated ECs, through glycosaminoglycan, trigger leukocyte arrest via G-protein-coupled receptors, which activate leukocyte integrins. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: blood vessel Organ_System: cardiovascular system PMID: 20921438 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-5037abf3-65be-44ff-92e5-2f03c44f0695 Low-Density Lipoproteins and Chemokines in Atherosclerosis uuid-5037abf3-65be-44ff-92e5-2f03c44f0695 PS:CellType endothelial cell PS:CellType macrophage PS:CellType monocyte PS:Description Atherosclerosis involves the formation of plaques in arterial walls that narrow the arterial passage restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5037abf3-65be-44ff-92e5-2f03c44f0695 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: Atherosclerosis involves the formation of plaques in arterial walls that narrow the arterial passage which restricts blood flow and increases the risk of occlusion of blood flow by a myocardial infarction. One of the first stages in the development of atherosclerosis is the passage of low-density lipoprotein (LDL) out of the arterial lumen and into the arterial wall. Once there, the lipids in LDL are chemically modified and oxidized. Oxidized LDL stimulates inflammatory signaling by neighboring endothelial cells (ECs), releasing chemokines and cytokines such as CCL5 and CCL2 in addition to ICAM1 and recruiting monocytes into the arterial wall. Outcome effects: Monocytes then differentiate into macrophages and internalize modified LDL. These macrophages continue to internalize LDL and become enlarged and full of lipid. These cells accumulate in tissue and are transformed into foam cells, dying and forming part of the atherogenic plaque. Monocyte recruitment involves their rolling, firm adhesion, lateral migration, and transendothelial diapedesis which are controlled by chemokines. While soluble chemokines mediate direct leukocyte recruitment, chemokines immobilized on the surface of activated ECs, through glycosaminoglycan, trigger leukocyte arrest via G-protein-coupled receptors, which activate leukocyte integrins. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 20921438 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Mutations in APP gene lead to the increased production of the longer form of amyloid beta (Abeta 42). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-503826a7-3e89-4f22-9287-d3ebd0ec01ca NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The amyloid precursor protein (APP) gene encodes the precursor to Abeta, the cetral protein in the biogenesis of AD. The synthesis of Abeta occurs mainly in the membranes of cellular vesicles. The three major isoforms containing the Abeta sequence are produced by alternative splicing of the APP gene primary transcript. The two larger isoforms consisting of 751 and 770 amino acid residues (APP751 and APP770, respectively) contain a Kunitz protease inhibitor (KPI) domain and are ubiquitously expressed. The APP695 isoform does not contain a KPI domain and is predominantly expressed in neurons. The first scenario of APP processing does not include the formation of Abeta peptides and thus is called non-amyloidogenic. APP is initially cleaved by alpha-secretases (ADAM9, ADAM10, and ADAM17) to generate C83 carboxyl-terminal fragment. Then, C83 can undergo further cleavage by gamma-secretase to produce peptide P3 and the APP intracellular domain (AICD). According to the alternative scenario, APP is cleaved sequentially by beta-secretase (BACE1) and gamma-secretase, releasing an ectodomain and retaining the last 99 amino acids of APP (known as C99) within the membrane. The first amino acid of C99 corresponds to the first amino acid of Abeta. C99 is subsequently cleaved by gamma-secretase to release Abeta. This cleavage predominantly produces amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42), at a ratio of 10:1. In the AD state, the altered structure of APP causes a release of higher amounts of the Abeta 42 after sequential cleavage by BACE1 and gamma-secretase. The presenilin proteins, PSEN1 and PSEN2, which are a part of the gamma-secretase complex may also be mutated and increase the yield of the neurotoxic form, Abeta 42. Mutations in APP, PSEN1, and PSEN2 account for the majority of early-onset familial AD cases. However, most AD cases are the late-onset sporadic form that cannot be explained by a defect in these genes. AICD is a product of both non-amyloidogenic and amyloidogenic processing and participates in the activation of transcription. It interacts with APBB1 and KAT5 to regulate transcription in the nucleus. The role of APP with regard to the intracellular signaling pathways is poorly understood. Outcome effects: Abeta 42 peptides can be released into the extracellular space where they oligomerize into Abeta 40/42 and aggregate causing plaque formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 10860781 PMID: 12485888 PMID: 16458391 PMID: 17169463 PMID: 17314098 PMID: 18237558 PMID: 19674510 PMID: 22495348 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-503826a7-3e89-4f22-9287-d3ebd0ec01ca APP and Glutamate Signaling Cause Neuronal Dysfunction in Alzheimer Disease uuid-503826a7-3e89-4f22-9287-d3ebd0ec01ca PS:CellType neuron PS:Description Mutations in APP gene lead to the increased production of the longer form of amyloid beta (Abeta 42). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-503826a7-3e89-4f22-9287-d3ebd0ec01ca PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The amyloid precursor protein (APP) gene encodes the precursor to Abeta, the cetral protein in the biogenesis of AD. The synthesis of Abeta occurs mainly in the membranes of cellular vesicles. The three major isoforms containing the Abeta sequence are produced by alternative splicing of the APP gene primary transcript. The two larger isoforms consisting of 751 and 770 amino acid residues (APP751 and APP770, respectively) contain a Kunitz protease inhibitor (KPI) domain and are ubiquitously expressed. The APP695 isoform does not contain a KPI domain and is predominantly expressed in neurons. The first scenario of APP processing does not include the formation of Abeta peptides and thus is called non-amyloidogenic. APP is initially cleaved by alpha-secretases (ADAM9, ADAM10, and ADAM17) to generate C83 carboxyl-terminal fragment. Then, C83 can undergo further cleavage by gamma-secretase to produce peptide P3 and the APP intracellular domain (AICD). According to the alternative scenario, APP is cleaved sequentially by beta-secretase (BACE1) and gamma-secretase, releasing an ectodomain and retaining the last 99 amino acids of APP (known as C99) within the membrane. The first amino acid of C99 corresponds to the first amino acid of Abeta. C99 is subsequently cleaved by gamma-secretase to release Abeta. This cleavage predominantly produces amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42), at a ratio of 10:1. In the AD state, the altered structure of APP causes a release of higher amounts of the Abeta 42 after sequential cleavage by BACE1 and gamma-secretase. The presenilin proteins, PSEN1 and PSEN2, which are a part of the gamma-secretase complex may also be mutated and increase the yield of the neurotoxic form, Abeta 42. Mutations in APP, PSEN1, and PSEN2 account for the majority of early-onset familial AD cases. However, most AD cases are the late-onset sporadic form that cannot be explained by a defect in these genes. AICD is a product of both non-amyloidogenic and amyloidogenic processing and participates in the activation of transcription. It interacts with APBB1 and KAT5 to regulate transcription in the nucleus. The role of APP with regard to the intracellular signaling pathways is poorly understood. Outcome effects: Abeta 42 peptides can be released into the extracellular space where they oligomerize into Abeta 40/42 and aggregate causing plaque formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 10860781 PS:PMID 12485888 PS:PMID 16458391 PS:PMID 17169463 PS:PMID 17314098 PS:PMID 18237558 PS:PMID 19674510 PS:PMID 22495348 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Plasmacytoid DCs (pDCs) are professional antiviral cells that are primarily located in the blood and lymphoid organs and produce high levels of type 1 interferon (IFN). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5099d3a7-272e-4b46-910d-a5ba2686144b NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Plasmacytoid DCs (pDCs) are professional antiviral cells that are primarily located in the blood and lymphoid organs and produce high levels of type 1 interferon (IFN) following the engagement of toll-like receptors (TLRs) with foreign nucleic acids. pDCs express a restricted set of TLRs, including TLR7 and TLR9 which recognize foreign RNA and DNA, respectively. Outcome effects: Plasmacytoid (p)DC are thought to be involved in both pathogenesis and prevention of type 1 diabetes. Animal data: The majority of data was collected from experiments in NOD mice. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: hematological system PMID: 24367363 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5099d3a7-272e-4b46-910d-a5ba2686144b TLR7 and TLR9 in Plasmacytoid Dendritic Cell uuid-5099d3a7-272e-4b46-910d-a5ba2686144b PS:CellType dendritic cell PS:Description Plasmacytoid DCs (pDCs) are professional antiviral cells that are primarily located in the blood and lymphoid organs and produce high levels of type 1 interferon (IFN). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5099d3a7-272e-4b46-910d-a5ba2686144b PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Plasmacytoid DCs (pDCs) are professional antiviral cells that are primarily located in the blood and lymphoid organs and produce high levels of type 1 interferon (IFN) following the engagement of toll-like receptors (TLRs) with foreign nucleic acids. pDCs express a restricted set of TLRs, including TLR7 and TLR9 which recognize foreign RNA and DNA, respectively. Outcome effects: Plasmacytoid (p)DC are thought to be involved in both pathogenesis and prevention of type 1 diabetes. Animal data: The majority of data was collected from experiments in NOD mice. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System hematological system PS:PMID 24367363 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Prostaglandin F2A (PGF2alpha) analogs are effectively used in current glaucoma treatment. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-509d3cca-fbe7-4758-9a44-634be0d7da2d NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: Prostaglandin F2A (PGF2alpha) analogs are effectively used in current glaucoma treatment. These agents are the most effective of the intraocular pressure (IOP)-lowering agents and a single daily dose is effective at reducing IOP throughout the day and during the night. Outcome effects: PGF2alpha analogs increase uveoscleral outflow by increasing matrix metalloproteinase expression and altering the extracellular matrix in the ciliary muscle and trabecular meshwork. The adverse effects are lengthening and thickening of eyelashes and they can also cause hazel and blue irides with brown patches to become diffusely brown. Organ: eye Organ_System: sensory system PMID: 15851572 PMID: 16939629 PMID: 18462068 PMID: 22699774 PMID: 9418730 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-509d3cca-fbe7-4758-9a44-634be0d7da2d PGF2-alpha Effect on Treatment uuid-509d3cca-fbe7-4758-9a44-634be0d7da2d PS:CellType vascular smooth muscle cell PS:Description Prostaglandin F2A (PGF2alpha) analogs are effectively used in current glaucoma treatment. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-509d3cca-fbe7-4758-9a44-634be0d7da2d PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: Prostaglandin F2A (PGF2alpha) analogs are effectively used in current glaucoma treatment. These agents are the most effective of the intraocular pressure (IOP)-lowering agents and a single daily dose is effective at reducing IOP throughout the day and during the night. Outcome effects: PGF2alpha analogs increase uveoscleral outflow by increasing matrix metalloproteinase expression and altering the extracellular matrix in the ciliary muscle and trabecular meshwork. The adverse effects are lengthening and thickening of eyelashes and they can also cause hazel and blue irides with brown patches to become diffusely brown. PS:Organ eye PS:Organ_System sensory system PS:PMID 15851572 PS:PMID 16939629 PS:PMID 18462068 PS:PMID 22699774 PS:PMID 9418730 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: The release of excessive glutamate during status epilepticus may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated Ca2-calmodulin-dependent activation of PI3K/AKT1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50a069bf-8332-4caf-b0d1-f93c833eff3a NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Signaling description: The release of excessive glutamate during status epilepticus may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated Ca2+-calmodulin-dependent activation of PI3K/AKT1 and relieve TSC1/TSC2 inhibition of MTOR. Outcome effects: This causes a cascade of cellular events that contribute to epileptogenesis, including axonal sprouting and increased expression of ion channels and neurotransmitter receptors. The signaling through metabotropic glutamate receptors GRM1 and GRM5 may also have an impact on the increase of intracellular Ca2+ levels. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Bianchi R, Wong RK, Merlin LR (2012) Glutamate Receptors in Epilepsy: Group I mGluR-Mediated Epileptogenesis. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. Organ: brain Organ_System: nervous system PMID: 19817806 PMID: 21354266 PMID: 22578218 PMID: 22787676 PMID: 23773767 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-50a069bf-8332-4caf-b0d1-f93c833eff3a mTOR Hyperactivation after Status Epilepticus uuid-50a069bf-8332-4caf-b0d1-f93c833eff3a PS:CellType neuron PS:Description The release of excessive glutamate during status epilepticus may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated Ca2-calmodulin-dependent activation of PI3K/AKT1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50a069bf-8332-4caf-b0d1-f93c833eff3a PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Signaling description: The release of excessive glutamate during status epilepticus may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated Ca2+-calmodulin-dependent activation of PI3K/AKT1 and relieve TSC1/TSC2 inhibition of MTOR. Outcome effects: This causes a cascade of cellular events that contribute to epileptogenesis, including axonal sprouting and increased expression of ion channels and neurotransmitter receptors. The signaling through metabotropic glutamate receptors GRM1 and GRM5 may also have an impact on the increase of intracellular Ca2+ levels. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Bianchi R, Wong RK, Merlin LR (2012) Glutamate Receptors in Epilepsy: Group I mGluR-Mediated Epileptogenesis. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. PS:Organ brain PS:Organ_System nervous system PS:PMID 19817806 PS:PMID 21354266 PS:PMID 22578218 PS:PMID 22787676 PS:PMID 23773767 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte Description: Epileptogenesis is common following brain trauma, ischemia, and infection. Several studies demonstrated impaired integrity of the blood-brain barrier as an important hallmark in brain injuries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50a70aae-f128-4cd3-81fa-248ae356d5dc NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Several studies demonstrated impaired integrity of the blood-brain barrier (BBB) as an important hallmark in brain injuries. Albumin (ALB) binds to TGFBR1/TGFBR2 in astrocytes and activates the SMAD/NF-kB signaling. Further, thrombin (F2) was shown activate of persistent inward sodium (Na+) current via voltage-gated channels affecting resting membrane potential. In addition, excessive glutamate release following BBB disrupting events may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated calcium (Ca2+)-calmodulin-dependent activation of PI3K/AKT1 and activation of MTOR. Finally, signaling through metabotropic glutamate receptor GRM5 may have an impact on the increase of intracellular Ca2+ levels. Outcome effects: The activation of TGFBR/SMAD/NF-kB axis by ALB induces rapid transcriptional modifications, astrocytic transformation, and may decrease seizure threshold. Then, persistent sodium current induced by thrombin also facilitates seizures. Further, PI3K/AKT1 and MTOR activation causes a cascade of cellular events that contribute to epileptogenesis including axonal sprouting and increased expression of ion channels and neurotransmitter receptors. Lastly, the increase of intracellular Ca2+ levels via GMR5 signaling may also promote seizures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1). Bianchi R, Wong RK, Merlin LR (2012) Glutamate Receptors in Epilepsy: Group I mGluR-Mediated Epileptogenesis. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. Organ: brain Organ_System: nervous system PMID: 22378298 PMID: 22578218 PMID: 22926852 PMID: 23773767 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-50a70aae-f128-4cd3-81fa-248ae356d5dc Blood-Brain Barrier Disruption in Epileptiform Disorders uuid-50a70aae-f128-4cd3-81fa-248ae356d5dc PS:CellType astrocyte PS:Description Epileptogenesis is common following brain trauma, ischemia, and infection. Several studies demonstrated impaired integrity of the blood-brain barrier as an important hallmark in brain injuries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50a70aae-f128-4cd3-81fa-248ae356d5dc PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Several studies demonstrated impaired integrity of the blood-brain barrier (BBB) as an important hallmark in brain injuries. Albumin (ALB) binds to TGFBR1/TGFBR2 in astrocytes and activates the SMAD/NF-kB signaling. Further, thrombin (F2) was shown activate of persistent inward sodium (Na+) current via voltage-gated channels affecting resting membrane potential. In addition, excessive glutamate release following BBB disrupting events may result in N-methyl-D-aspartate (NMDA) selective glutamate receptor-mediated calcium (Ca2+)-calmodulin-dependent activation of PI3K/AKT1 and activation of MTOR. Finally, signaling through metabotropic glutamate receptor GRM5 may have an impact on the increase of intracellular Ca2+ levels. Outcome effects: The activation of TGFBR/SMAD/NF-kB axis by ALB induces rapid transcriptional modifications, astrocytic transformation, and may decrease seizure threshold. Then, persistent sodium current induced by thrombin also facilitates seizures. Further, PI3K/AKT1 and MTOR activation causes a cascade of cellular events that contribute to epileptogenesis including axonal sprouting and increased expression of ion channels and neurotransmitter receptors. Lastly, the increase of intracellular Ca2+ levels via GMR5 signaling may also promote seizures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1). Bianchi R, Wong RK, Merlin LR (2012) Glutamate Receptors in Epilepsy: Group I mGluR-Mediated Epileptogenesis. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. PS:Organ brain PS:Organ_System nervous system PS:PMID 22378298 PS:PMID 22578218 PS:PMID 22926852 PS:PMID 23773767 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ac60ae-a1b5-41e4-a405-200016793ff6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-50ac60ae-a1b5-41e4-a405-200016793ff6 PAF/Gq -> AP-1/ATF1/CREB/ERK/SRF Expression Targets uuid-50ac60ae-a1b5-41e4-a405-200016793ff6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ac60ae-a1b5-41e4-a405-200016793ff6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ad61e8-bb9e-43d5-b854-0c23545bbe78 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-50ad61e8-bb9e-43d5-b854-0c23545bbe78 ADRB1/3 -> Vasodilation uuid-50ad61e8-bb9e-43d5-b854-0c23545bbe78 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ad61e8-bb9e-43d5-b854-0c23545bbe78 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50bbf661-6ff7-4b3f-9b96-018a0ed69cf7 NodeType: Pathway Notes: All three of the complement pathways (classical, alternative, and lectin-mediated) are involved in the pathogenesis of ARMD. Complement proteins and other molecules take part in drusen formation. Drusen are small yellow or white accumulations of extracellular material, proteins and lipids, in the macula (a part of the retina) between the Bruch’s membrane and the retinal pigment epithelium of the eye. The presence of a few small drusen is normal with advancing age. However, the buildup of larger and more numerous drusen in the macula is a hallmark of ARMD. Also, complement activation may induce retinal pigment epithelial (RPE) cell death, and neutrophil and macrophage activation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-50bbf661-6ff7-4b3f-9b96-018a0ed69cf7 1_Complement activation in age-related macular degeneration uuid-50bbf661-6ff7-4b3f-9b96-018a0ed69cf7 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50bbf661-6ff7-4b3f-9b96-018a0ed69cf7 PS:NodeType Pathway PS:Notes All three of the complement pathways (classical, alternative, and lectin-mediated) are involved in the pathogenesis of ARMD. Complement proteins and other molecules take part in drusen formation. Drusen are small yellow or white accumulations of extracellular material, proteins and lipids, in the macula (a part of the retina) between the Bruch’s membrane and the retinal pigment epithelium of the eye. The presence of a few small drusen is normal with advancing age. However, the buildup of larger and more numerous drusen in the macula is a hallmark of ARMD. Also, complement activation may induce retinal pigment epithelial (RPE) cell death, and neutrophil and macrophage activation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is the most common cancer in women. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50c0222c-a606-4955-84c1-25a2f087b10b NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: It has been demonstrated that breast cancer is linked to the overexpression of insulin-like growth factor 1 receptor (IGF1R). The overexpression of IGF1R causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. Ligand-bound IGF1R activates PIK3CA via insulin receptor substrate 1 (IRS1). PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with T-cell factor 7 (TCF7) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. IGF1R mediates Janus kinases 1/2 (JAK1/2), which are involved in cell growth. IGF1R also interacts with SHC1/GRB2/SOS1 and activates RAF1, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: breast Organ_System: integumentary system PMID: 21217522 PMID: 21574055 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-50c0222c-a606-4955-84c1-25a2f087b10b IGF1R/AKT Signaling in Breast Cancer uuid-50c0222c-a606-4955-84c1-25a2f087b10b PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is the most common cancer in women. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50c0222c-a606-4955-84c1-25a2f087b10b PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: It has been demonstrated that breast cancer is linked to the overexpression of insulin-like growth factor 1 receptor (IGF1R). The overexpression of IGF1R causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. Ligand-bound IGF1R activates PIK3CA via insulin receptor substrate 1 (IRS1). PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with T-cell factor 7 (TCF7) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. IGF1R mediates Janus kinases 1/2 (JAK1/2), which are involved in cell growth. IGF1R also interacts with SHC1/GRB2/SOS1 and activates RAF1, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ breast PS:Organ_System integumentary system PS:PMID 21217522 PS:PMID 21574055 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ddc623-6cfe-4806-9e04-95bd8c3621b5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-50ddc623-6cfe-4806-9e04-95bd8c3621b5 ACE2 inhibitors uuid-50ddc623-6cfe-4806-9e04-95bd8c3621b5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50ddc623-6cfe-4806-9e04-95bd8c3621b5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50f42916-b984-45fe-93f6-09c3e5fce01d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-50f42916-b984-45fe-93f6-09c3e5fce01d CCL18-+>COL in myofibroblasts uuid-50f42916-b984-45fe-93f6-09c3e5fce01d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50f42916-b984-45fe-93f6-09c3e5fce01d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: kidney tubule cell Description: Impaired calcium (Ca2 ) reabsorption in kidney may occur in osteoporosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50f59819-5d75-426e-b60f-3fc6b1b2fb91 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. A reduction of intestinal Ca2 transport is often observed in the elderly. Signaling description: Ca2+ is absorbed in the small intestine by two general mechanisms: a transcellular active transport process which is located largely in the duodenum and upper jejunum; and a paracellular passive process that functions throughout the length of the intestine. The transcellular process begins with the Ca2+ entry through the brush border via the TRPV5/6 proteins. The expression of TRPV proteins is under the control of VDR and ESR1 transcription factors. In the absence of their ligands (estrogens and/or calcitriol) or due to polymorphisms in the genes TRPV synthesis can be impaired causing decreased Ca2 absorption in the intestine. Outcome effects: Following its entry through the brush border, Ca2+ is transported to the inner membrane by S100G protein, and then excreted by the ATP2B1 and SLC8A1 transporters into the blood. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 16322775 PMID: 24459525 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-50f59819-5d75-426e-b60f-3fc6b1b2fb91 Ca2+ Reabsorption Decline in Kidney uuid-50f59819-5d75-426e-b60f-3fc6b1b2fb91 PS:CellType kidney tubule cell PS:Description Impaired calcium (Ca2 ) reabsorption in kidney may occur in osteoporosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-50f59819-5d75-426e-b60f-3fc6b1b2fb91 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. A reduction of intestinal Ca2 transport is often observed in the elderly. Signaling description: Ca2+ is absorbed in the small intestine by two general mechanisms: a transcellular active transport process which is located largely in the duodenum and upper jejunum; and a paracellular passive process that functions throughout the length of the intestine. The transcellular process begins with the Ca2+ entry through the brush border via the TRPV5/6 proteins. The expression of TRPV proteins is under the control of VDR and ESR1 transcription factors. In the absence of their ligands (estrogens and/or calcitriol) or due to polymorphisms in the genes TRPV synthesis can be impaired causing decreased Ca2 absorption in the intestine. Outcome effects: Following its entry through the brush border, Ca2+ is transported to the inner membrane by S100G protein, and then excreted by the ATP2B1 and SLC8A1 transporters into the blood. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 16322775 PS:PMID 24459525 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA repair by means of homologous recombination takes place when an identical or a near identical sequence exists to provide the template for DNA recovery. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5100fb1e-20b1-4c50-a25b-ba9c3f0917fd NodeType: Pathway Notes: Headnote: DNA repair by means of homologous recombination takes place when an identical or a near identical sequence exists to provide the template for DNA recovery. Signaling description: The protein machinery responsible for this recovery process is similar to that in meiotic crossing-over when homologous chromatids serve as the templates. The double strand bases (DSBs) appear as the result of mistakes in filling single-nucleotide gaps in the replicative fork or as the result of unfixed errors that occurred during single-stranded DNA synthesis. After DSBs are detected by ATM, the 5' strands are removed producing long 3' single-stranded DNA tails. Outcome effects: The single-stranded 3' tails serve as the substrate for RAD51 nucleoprotein filament nucleation. RAD52, BRCA1, and BRCA2 proteins are also recruited in this process. When assembled, this protein complex screens the genome for homologous DNA sequences that can be used for the recombination. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-5100fb1e-20b1-4c50-a25b-ba9c3f0917fd Double Strand DNA Homologous Repair uuid-5100fb1e-20b1-4c50-a25b-ba9c3f0917fd PS:CellType generic PS:Description DNA repair by means of homologous recombination takes place when an identical or a near identical sequence exists to provide the template for DNA recovery. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5100fb1e-20b1-4c50-a25b-ba9c3f0917fd PS:NodeType Pathway PS:Notes Headnote: DNA repair by means of homologous recombination takes place when an identical or a near identical sequence exists to provide the template for DNA recovery. Signaling description: The protein machinery responsible for this recovery process is similar to that in meiotic crossing-over when homologous chromatids serve as the templates. The double strand bases (DSBs) appear as the result of mistakes in filling single-nucleotide gaps in the replicative fork or as the result of unfixed errors that occurred during single-stranded DNA synthesis. After DSBs are detected by ATM, the 5' strands are removed producing long 3' single-stranded DNA tails. Outcome effects: The single-stranded 3' tails serve as the substrate for RAD51 nucleoprotein filament nucleation. RAD52, BRCA1, and BRCA2 proteins are also recruited in this process. When assembled, this protein complex screens the genome for homologous DNA sequences that can be used for the recombination. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-510bc45d-b3d6-4905-a7e4-f148a44f796b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-510bc45d-b3d6-4905-a7e4-f148a44f796b IGF1R -> MEF/MYOD/MYOG Signaling uuid-510bc45d-b3d6-4905-a7e4-f148a44f796b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-510bc45d-b3d6-4905-a7e4-f148a44f796b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pancreatic cancer is characterized by mutations in TP53, CDKN2A, and ATM genes. TP53 tumor suppressor gene is mutated in over 80? of pancreatic cancer cases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51180137-dfd0-4eb2-9f02-706dd8658bf9 NodeType: Pathway Notes: Headnote: Pancreatic cancer is malignant transformation of the pancreas, and is characterized by mutations in TP53, CDKN2A, and ATM genes. TP53 tumor suppressor gene is mutated in over 80% of pancreatic cancer cases. Further, germline and sporadic mutations in CDKN2A and ATM genes have been identified in pancreatic cancer; therefore, it appears they play a central role as pancreatic tumor suppressors. CDKN2A is mutated in most cases of pancreatic ductal carcinoma. Signaling description: Normally, TP53 stimulates CDKN1A, CDKN2A, and CDKN1B, which in turn inhibit the activity of CDK2, CDK4, and CDK6 which regulate cell cycle and differentiation. In addition, TP53 promotes BAX resulting in the activation of apoptotic caspase cascade. ATM phosphorylates checkpoint kinase CHEK2 which phosphorylates and stabilizes TP53. Outcome effects: Mutations in the above mentioned genes lead to redundant proliferation, block of apoptosis, as well as disruption of cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 22806689 PMID: 23135763 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-51180137-dfd0-4eb2-9f02-706dd8658bf9 TP53 Signaling in Pancreatic Neoplasms uuid-51180137-dfd0-4eb2-9f02-706dd8658bf9 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pancreatic cancer is characterized by mutations in TP53, CDKN2A, and ATM genes. TP53 tumor suppressor gene is mutated in over 80? of pancreatic cancer cases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51180137-dfd0-4eb2-9f02-706dd8658bf9 PS:NodeType Pathway PS:Notes Headnote: Pancreatic cancer is malignant transformation of the pancreas, and is characterized by mutations in TP53, CDKN2A, and ATM genes. TP53 tumor suppressor gene is mutated in over 80% of pancreatic cancer cases. Further, germline and sporadic mutations in CDKN2A and ATM genes have been identified in pancreatic cancer; therefore, it appears they play a central role as pancreatic tumor suppressors. CDKN2A is mutated in most cases of pancreatic ductal carcinoma. Signaling description: Normally, TP53 stimulates CDKN1A, CDKN2A, and CDKN1B, which in turn inhibit the activity of CDK2, CDK4, and CDK6 which regulate cell cycle and differentiation. In addition, TP53 promotes BAX resulting in the activation of apoptotic caspase cascade. ATM phosphorylates checkpoint kinase CHEK2 which phosphorylates and stabilizes TP53. Outcome effects: Mutations in the above mentioned genes lead to redundant proliferation, block of apoptosis, as well as disruption of cell cycle and differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 22806689 PS:PMID 23135763 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: HIF1A plays a critical role in hypoxia-induced angiogenesis. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51281b60-73c9-461b-af30-438a5f4ab45d NodeType: Pathway Notes: Headnote: Vasculogenic mimicry (VM) is the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumor cells. Pathology of VM is characterized by the formation of microvascular channels de novo in the absence of endothelial cells (tumor cells line tumor vessels effectively mimicking a true vascular endothelium). Signaling description: The major signaling pathways upregulated in VM are NOTCH, NODAL/TGFB1-SMAD, EPHA2-PI3K-AKT and PTGER-RAF-MAPK pathways. PTGS2, VEGFA, TWIST1 and CDH5 are up-regulated by hypoxia-induced HIFA1 which promotes the progression of VM. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: The altered NODAL expression leads to cell dedifferentiation and reprogramming. Activation of MMP2 and MMP14 is mediated by EPHA2-PI3K-AKT and promotes the cleavage of LAMC2 into promigratory fragments. The release of these fragments (molecular messages or signals) into the tumor microenvironment can increase the migration, invasion and, ultimately, vasculogenic mimicry of aggressive tumor cells. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 12778131 PMID: 17557303 PMID: 22474319 PMID: 22944600 PMID: 27326255 PMID: 27705934 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-51281b60-73c9-461b-af30-438a5f4ab45d HIF1A in Vasculogenic Mimicry of Cancer uuid-51281b60-73c9-461b-af30-438a5f4ab45d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description HIF1A plays a critical role in hypoxia-induced angiogenesis. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51281b60-73c9-461b-af30-438a5f4ab45d PS:NodeType Pathway PS:Notes Headnote: Vasculogenic mimicry (VM) is the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumor cells. Pathology of VM is characterized by the formation of microvascular channels de novo in the absence of endothelial cells (tumor cells line tumor vessels effectively mimicking a true vascular endothelium). Signaling description: The major signaling pathways upregulated in VM are NOTCH, NODAL/TGFB1-SMAD, EPHA2-PI3K-AKT and PTGER-RAF-MAPK pathways. PTGS2, VEGFA, TWIST1 and CDH5 are up-regulated by hypoxia-induced HIFA1 which promotes the progression of VM. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: The altered NODAL expression leads to cell dedifferentiation and reprogramming. Activation of MMP2 and MMP14 is mediated by EPHA2-PI3K-AKT and promotes the cleavage of LAMC2 into promigratory fragments. The release of these fragments (molecular messages or signals) into the tumor microenvironment can increase the migration, invasion and, ultimately, vasculogenic mimicry of aggressive tumor cells. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 12778131 PS:PMID 17557303 PS:PMID 22474319 PS:PMID 22944600 PS:PMID 27326255 PS:PMID 27705934 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-512dfe05-c9da-481e-ae19-1b886308a3f1 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-512dfe05-c9da-481e-ae19-1b886308a3f1 Genes with Mutations Associated with Usher Syndrome and Retinitis Pigmentosa uuid-512dfe05-c9da-481e-ae19-1b886308a3f1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-512dfe05-c9da-481e-ae19-1b886308a3f1 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-512fbc8d-cc42-40fc-9503-2c94e449d57a NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-512fbc8d-cc42-40fc-9503-2c94e449d57a IL5R -> SOX4 Signaling uuid-512fbc8d-cc42-40fc-9503-2c94e449d57a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-512fbc8d-cc42-40fc-9503-2c94e449d57a PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51346fe3-ac8d-4b09-832a-8983d115cf26 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19812304 PMID: 25402640 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-51346fe3-ac8d-4b09-832a-8983d115cf26 mTOR Signaling_1 uuid-51346fe3-ac8d-4b09-832a-8983d115cf26 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51346fe3-ac8d-4b09-832a-8983d115cf26 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19812304 PS:PMID 25402640 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51427d93-24d4-4595-ac1c-b7c962a96b9d NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-51427d93-24d4-4595-ac1c-b7c962a96b9d H3 Serine Modification Sites uuid-51427d93-24d4-4595-ac1c-b7c962a96b9d PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51427d93-24d4-4595-ac1c-b7c962a96b9d PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-519587b7-2c46-4fb0-8111-eb19f5154005 NodeType: Pathway Notes: Ulcerative colitis initiates with the disruption of the epithelial barrier of the rectum and colon resulting in increased uptake of luminal microbiota and antigens. Dysfunction of intestine epithelial cells reduces the defense abilities of the mucosal layer and causes a loss of mucosal tolerance to luminal pathogens. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: intestines Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-519587b7-2c46-4fb0-8111-eb19f5154005 1_Intestine epithelial cell dysfunction in ulcerative colitis uuid-519587b7-2c46-4fb0-8111-eb19f5154005 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-519587b7-2c46-4fb0-8111-eb19f5154005 PS:NodeType Pathway PS:Notes Ulcerative colitis initiates with the disruption of the epithelial barrier of the rectum and colon resulting in increased uptake of luminal microbiota and antigens. Dysfunction of intestine epithelial cells reduces the defense abilities of the mucosal layer and causes a loss of mucosal tolerance to luminal pathogens. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ intestines PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51a0ef31-dde6-45a6-bc5e-8577e3c2d226 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-51a0ef31-dde6-45a6-bc5e-8577e3c2d226 omega oxidation (plasma menbrane) template uuid-51a0ef31-dde6-45a6-bc5e-8577e3c2d226 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51a0ef31-dde6-45a6-bc5e-8577e3c2d226 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51ce0f14-79e9-4b8e-9405-406d227b47f8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-51ce0f14-79e9-4b8e-9405-406d227b47f8 rs657152 uuid-51ce0f14-79e9-4b8e-9405-406d227b47f8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-51ce0f14-79e9-4b8e-9405-406d227b47f8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52947c95-bde4-4f8b-98fe-0a6daab76f68 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-52947c95-bde4-4f8b-98fe-0a6daab76f68 FGF2 -> NCOR2 Expression Targets uuid-52947c95-bde4-4f8b-98fe-0a6daab76f68 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52947c95-bde4-4f8b-98fe-0a6daab76f68 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52953675-7d76-44bc-92f4-b608944be0e1 NodeType: Pathway Notes: The precise mechanism of ALS pathogenesis is still unknown. One hypothesis is that motor neurons can be damaged by glutamate overload. In lower motor neurons, glutamate excitotoxicity raises intracellular Ca2+ levels, which in turn facilitates nitric oxide (NO) formation. Subsequently, peroxynitrite synthesis triggers damage to the lower motor neurons. The excessive influx of Ca2+ into mitochondria results in mitochondrial dysfunction and subsequent motor neuron apoptosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: brain Organ: spinal cord Organ_System: nervous system Organelle: synapse PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: nerve tissue urn:agi-pathway:uuid-52953675-7d76-44bc-92f4-b608944be0e1 1_Glutamate and calcium excitotoxicity of motor neurons in ALS uuid-52953675-7d76-44bc-92f4-b608944be0e1 PS:CellType astrocyte PS:CellType neuron PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52953675-7d76-44bc-92f4-b608944be0e1 PS:NodeType Pathway PS:Notes The precise mechanism of ALS pathogenesis is still unknown. One hypothesis is that motor neurons can be damaged by glutamate overload. In lower motor neurons, glutamate excitotoxicity raises intracellular Ca2+ levels, which in turn facilitates nitric oxide (NO) formation. Subsequently, peroxynitrite synthesis triggers damage to the lower motor neurons. The excessive influx of Ca2+ into mitochondria results in mitochondrial dysfunction and subsequent motor neuron apoptosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:Organelle synapse PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue nerve tissue PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: leukocyte Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52a588cc-a3dc-43a6-b914-c3baf19f1aef NodeType: Pathway Organ: generic Organ_System: generic Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-52a588cc-a3dc-43a6-b914-c3baf19f1aef Innate immunity in Leukocytes uuid-52a588cc-a3dc-43a6-b914-c3baf19f1aef PS:CellType dendritic cell PS:CellType leukocyte PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52a588cc-a3dc-43a6-b914-c3baf19f1aef PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52aa141b-ba8d-4504-97d1-700c9eed43a8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-52aa141b-ba8d-4504-97d1-700c9eed43a8 EREG -> FOXO3A Expression Target uuid-52aa141b-ba8d-4504-97d1-700c9eed43a8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52aa141b-ba8d-4504-97d1-700c9eed43a8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52acc9dd-daa0-458e-8c59-9d98686b8a45 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-52acc9dd-daa0-458e-8c59-9d98686b8a45 EREG -> AP-1/ATF Expression Targets uuid-52acc9dd-daa0-458e-8c59-9d98686b8a45 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52acc9dd-daa0-458e-8c59-9d98686b8a45 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52b10e2e-d55f-425f-9039-1fcfe1cefb7b NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-52b10e2e-d55f-425f-9039-1fcfe1cefb7b OPRL1 -> Ion Channels uuid-52b10e2e-d55f-425f-9039-1fcfe1cefb7b PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52b10e2e-d55f-425f-9039-1fcfe1cefb7b PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Mitochondria enlargement and apoptosis are observed in aging neurons and in Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52b59657-e85c-4934-b513-413f9de3fac5 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The enlargement of mitochondria and apoptosis, cellular processes seen in aging neurons, are observed in AD. Normally, mitochondria are dynamically fused and dissociated. The functioning of the entire cell is altered when this equilibrium shifts towards fusion or dissociation. Mutant forms of amyloid precursor protein (APP) and Abeta can either penetrate the mitochondrion or cause alterations of protein transport into the mitochondrion, which is conducted by the TOM complex. This process occurs through the interaction with BAG1 and mPTP. Whether directly or indirectly (the details of the process are not fully understood), Abeta and mutant forms of APP inhibit the expression of OPA1 and DNM1L , which are required for the dissociation. At the same time, the expression of FIS1, required for fusion, is upregulated. Further, Abeta and APP can stimulate the passage of calcium and other small molecules into the intermembrane space through the mPTP pore complex. Calcium induces the inhibition of H- ATPase-mediated ATP production through cytochrome c oxidase. In addition, calcium activates CASP3 by a yet to be identified mechanism. The activation may occur through interaction with BAD and CYCS. Outcome effects: The altered expression of OPA1, DNM1L, and FIS1 results in mitochondrial fusion (OPA1) and dissociation (DNM1L, and FIS1). Inhibition of H- ATPase-mediated ATP production causes membrane depolarization and decreases activity of the respiratory chain and mitochondrial dysfunction. Finally, the poorly functioning enlarged mitochondria gradually displace normal organelles, eventually causing decreased ATP production and failing autophagocytosis. This triggers oxidative stress and apoptosis, resulting in the degeneration and death of neurons. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 15106389 PMID: 20398440 PMID: 20798880 PMID: 22475801 PMID: 22523685 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-52b59657-e85c-4934-b513-413f9de3fac5 Mitochondria Enlargement and Apoptosis in Alzheimer's Disease uuid-52b59657-e85c-4934-b513-413f9de3fac5 PS:CellType neuron PS:Description Mitochondria enlargement and apoptosis are observed in aging neurons and in Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52b59657-e85c-4934-b513-413f9de3fac5 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The enlargement of mitochondria and apoptosis, cellular processes seen in aging neurons, are observed in AD. Normally, mitochondria are dynamically fused and dissociated. The functioning of the entire cell is altered when this equilibrium shifts towards fusion or dissociation. Mutant forms of amyloid precursor protein (APP) and Abeta can either penetrate the mitochondrion or cause alterations of protein transport into the mitochondrion, which is conducted by the TOM complex. This process occurs through the interaction with BAG1 and mPTP. Whether directly or indirectly (the details of the process are not fully understood), Abeta and mutant forms of APP inhibit the expression of OPA1 and DNM1L , which are required for the dissociation. At the same time, the expression of FIS1, required for fusion, is upregulated. Further, Abeta and APP can stimulate the passage of calcium and other small molecules into the intermembrane space through the mPTP pore complex. Calcium induces the inhibition of H- ATPase-mediated ATP production through cytochrome c oxidase. In addition, calcium activates CASP3 by a yet to be identified mechanism. The activation may occur through interaction with BAD and CYCS. Outcome effects: The altered expression of OPA1, DNM1L, and FIS1 results in mitochondrial fusion (OPA1) and dissociation (DNM1L, and FIS1). Inhibition of H- ATPase-mediated ATP production causes membrane depolarization and decreases activity of the respiratory chain and mitochondrial dysfunction. Finally, the poorly functioning enlarged mitochondria gradually displace normal organelles, eventually causing decreased ATP production and failing autophagocytosis. This triggers oxidative stress and apoptosis, resulting in the degeneration and death of neurons. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 15106389 PS:PMID 20398440 PS:PMID 20798880 PS:PMID 22475801 PS:PMID 22523685 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52dfce92-41f3-4046-a3c4-6eeb02f83dfe NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-52dfce92-41f3-4046-a3c4-6eeb02f83dfe Glucomannan biosythesis template uuid-52dfce92-41f3-4046-a3c4-6eeb02f83dfe PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52dfce92-41f3-4046-a3c4-6eeb02f83dfe PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52f3c7ac-bcc7-40d1-a539-1afd13d31c98 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-52f3c7ac-bcc7-40d1-a539-1afd13d31c98 N-Glycan Biosynthesis uuid-52f3c7ac-bcc7-40d1-a539-1afd13d31c98 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52f3c7ac-bcc7-40d1-a539-1afd13d31c98 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: antigen-presenting cell CellType: dendritic cell CellType: macrophage CellType: natural killer cell Description: Antigen processing and presentation is a specific immune response to an immunogenic peptide epitope. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52f865f5-9bef-4339-8378-09f5aa72db2d NodeType: Pathway Notes: Headnote: Antigen processing and presentation is a specific immune response to an immunogenic peptide epitope. Antigens initiate certain processes within the cell that result in the proteolysis of infectious proteins (antigen processing) and presentation of their epitopes on the surface of cells (antigen presentation). The result of these actions is the induction of a T-cell response that recruits and engages other molecular participants of the immune response. Signaling description: The endogenous/intracellular antigen pathway is connected to the processing of intracellular peptide fragments through the action of the ubiquitin-related proteolytic system and MHC class I protein complex. Viral peptides are also presented if a virus have infected the cell. Intracellular proteins are cut into short peptides in the proteasome and proteins bound for degradation are targeted to the proteasome by covalent linkage with ubiquitin. Proteasomes break the protein up into peptides suitable for fitting within MHC class I protein complex. Peptides generated in the cytosol are then transported into the rough endoplasmic reticulum to enable interaction with MHC molecules. TAPs (transporters associated with antigen processing) transport peptides into the rough endoplasmic reticulum. MHC class I molecules are tethered to the TAP transporter via TAPBP. Also, several chaperone proteins including CALR, HSPA5, and PDIA3 within rough endoplasmic reticulum (ER) facilitate the proper folding of MHC class I molecules and its association with beta-2-microglobulin (B2M). Outcome effects: Once the peptide is transported to the rough ER lumen, it binds to the cleft of the awaiting MHC class I molecule, stabilizing it and allowing it to be transported to the cell surface by the Golgi apparatus. MHC class I molecules on the cell surface are specialized for the presentation of peptides derived from endogenous proteins (intracellular antigens) to the T-cell receptor (TCR) of CD8 T-cells. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-52f865f5-9bef-4339-8378-09f5aa72db2d Endogenous Peptide Antigen Presentation uuid-52f865f5-9bef-4339-8378-09f5aa72db2d PS:CellType antigen-presenting cell PS:CellType dendritic cell PS:CellType macrophage PS:CellType natural killer cell PS:Description Antigen processing and presentation is a specific immune response to an immunogenic peptide epitope. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-52f865f5-9bef-4339-8378-09f5aa72db2d PS:NodeType Pathway PS:Notes Headnote: Antigen processing and presentation is a specific immune response to an immunogenic peptide epitope. Antigens initiate certain processes within the cell that result in the proteolysis of infectious proteins (antigen processing) and presentation of their epitopes on the surface of cells (antigen presentation). The result of these actions is the induction of a T-cell response that recruits and engages other molecular participants of the immune response. Signaling description: The endogenous/intracellular antigen pathway is connected to the processing of intracellular peptide fragments through the action of the ubiquitin-related proteolytic system and MHC class I protein complex. Viral peptides are also presented if a virus have infected the cell. Intracellular proteins are cut into short peptides in the proteasome and proteins bound for degradation are targeted to the proteasome by covalent linkage with ubiquitin. Proteasomes break the protein up into peptides suitable for fitting within MHC class I protein complex. Peptides generated in the cytosol are then transported into the rough endoplasmic reticulum to enable interaction with MHC molecules. TAPs (transporters associated with antigen processing) transport peptides into the rough endoplasmic reticulum. MHC class I molecules are tethered to the TAP transporter via TAPBP. Also, several chaperone proteins including CALR, HSPA5, and PDIA3 within rough endoplasmic reticulum (ER) facilitate the proper folding of MHC class I molecules and its association with beta-2-microglobulin (B2M). Outcome effects: Once the peptide is transported to the rough ER lumen, it binds to the cleft of the awaiting MHC class I molecule, stabilizing it and allowing it to be transported to the cell surface by the Golgi apparatus. MHC class I molecules on the cell surface are specialized for the presentation of peptides derived from endogenous proteins (intracellular antigens) to the T-cell receptor (TCR) of CD8 T-cells. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Pulmonary arterial hypertension (PAH) is sub-classified into familial (FPAH), idiopathic (IPAH), or acquired (APAH). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-530215ff-83e1-4ba0-a8d6-f7fa083feafc NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. PAH is sub-classified into familial (FPAH), idiopathic (IPAH), or acquired (APAH). Signaling description: Mutations in the bone morphogenetic protein receptor II (BMPR2) gene have been identified in over 75% of patients with FPAH and in 10-40% of patients with IPAH. Less common mutations that affect the activin-like kinase-type 1 (ACVRL1) and endoglin (ENG) are associated with both FPAH and hereditary hemorrhagic telangiectasia. There also can be a mutation in SMAD9, although it rarely occurs. In normal pulmonary artery smooth muscle cells (PASMCs), BMP and TGFB1 signaling have an anti-proliferative effect. BMPR1A, BMPR1B, and BMPR2 form a complex and phosphorylate SMAD1, 5, and 9. When activated, these proteins interact with a nuclear chaperone, SMAD4 and are translocated to the nucleus. TGFB1 signaling acts through SMAD 2 and 3 and also enrolls SMAD4 as a co-activator. Outcome effects: Normally, these events lead to the activation of CDKN2B and ID3 as well as the repression of MYC resulting in the inhibition of proliferation. In addition, BMP2 usually inhibits PASMC proliferation via the peroxisome proliferator-activated receptor gamma (PPARG) and apolipoprotein E (APOE). APOE impairs PDGFB signaling by binding to low density lipoprotein receptor-related protein 1 (LRP1), thereby initiating endocytosis and degradation of the LRP1/PDGFRB/PDGFB complex. In addition to APOE, other transcriptional targets of PPARG, such as adiponectin (ADIPOQ), can sequester PDGFB and repress PASMC proliferation. In FPAH and IPAH, these proliferation-inhibiting processes are impaired due to the previously mentioned mutations and PASMC proliferation is activated leading to the thickening of arterial walls, narrowing of the vessel lumen, and PAH development. Lastly, serotonin may antagonize the anti-proliferative BMPR2/SMAD1/5/9 pathway, inhibit ID3 activation, and facilitate proliferation in non-BMPR2-mutated cases. Therefore, there may be evidence linking serotonin to the development of PAH independently of mutations in BMPR2 gene. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. Organ: lung Organ_System: cardiovascular system PMID: 18021936 PMID: 19286424 PMID: 19555857 PMID: 21641060 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-530215ff-83e1-4ba0-a8d6-f7fa083feafc BMP/TGF-beta Signaling Impairment in Pulmonary Hypertension uuid-530215ff-83e1-4ba0-a8d6-f7fa083feafc PS:CellType vascular smooth muscle cell PS:Description Pulmonary arterial hypertension (PAH) is sub-classified into familial (FPAH), idiopathic (IPAH), or acquired (APAH). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-530215ff-83e1-4ba0-a8d6-f7fa083feafc PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. PAH is sub-classified into familial (FPAH), idiopathic (IPAH), or acquired (APAH). Signaling description: Mutations in the bone morphogenetic protein receptor II (BMPR2) gene have been identified in over 75% of patients with FPAH and in 10-40% of patients with IPAH. Less common mutations that affect the activin-like kinase-type 1 (ACVRL1) and endoglin (ENG) are associated with both FPAH and hereditary hemorrhagic telangiectasia. There also can be a mutation in SMAD9, although it rarely occurs. In normal pulmonary artery smooth muscle cells (PASMCs), BMP and TGFB1 signaling have an anti-proliferative effect. BMPR1A, BMPR1B, and BMPR2 form a complex and phosphorylate SMAD1, 5, and 9. When activated, these proteins interact with a nuclear chaperone, SMAD4 and are translocated to the nucleus. TGFB1 signaling acts through SMAD 2 and 3 and also enrolls SMAD4 as a co-activator. Outcome effects: Normally, these events lead to the activation of CDKN2B and ID3 as well as the repression of MYC resulting in the inhibition of proliferation. In addition, BMP2 usually inhibits PASMC proliferation via the peroxisome proliferator-activated receptor gamma (PPARG) and apolipoprotein E (APOE). APOE impairs PDGFB signaling by binding to low density lipoprotein receptor-related protein 1 (LRP1), thereby initiating endocytosis and degradation of the LRP1/PDGFRB/PDGFB complex. In addition to APOE, other transcriptional targets of PPARG, such as adiponectin (ADIPOQ), can sequester PDGFB and repress PASMC proliferation. In FPAH and IPAH, these proliferation-inhibiting processes are impaired due to the previously mentioned mutations and PASMC proliferation is activated leading to the thickening of arterial walls, narrowing of the vessel lumen, and PAH development. Lastly, serotonin may antagonize the anti-proliferative BMPR2/SMAD1/5/9 pathway, inhibit ID3 activation, and facilitate proliferation in non-BMPR2-mutated cases. Therefore, there may be evidence linking serotonin to the development of PAH independently of mutations in BMPR2 gene. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 18021936 PS:PMID 19286424 PS:PMID 19555857 PS:PMID 21641060 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5312fb1b-e596-4490-a718-9054e4e1dc5a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5312fb1b-e596-4490-a718-9054e4e1dc5a EDN3 Expression Targets uuid-5312fb1b-e596-4490-a718-9054e4e1dc5a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5312fb1b-e596-4490-a718-9054e4e1dc5a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53139bcd-4dac-4117-ab83-6c325cf23080 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-53139bcd-4dac-4117-ab83-6c325cf23080 HRH1/2 -> Vascular Motility uuid-53139bcd-4dac-4117-ab83-6c325cf23080 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53139bcd-4dac-4117-ab83-6c325cf23080 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5315b05a-521d-469a-99b8-fe9eef93235a NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-5315b05a-521d-469a-99b8-fe9eef93235a Genes with Mutations in Cancer-Associated DNA Methylation uuid-5315b05a-521d-469a-99b8-fe9eef93235a PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5315b05a-521d-469a-99b8-fe9eef93235a PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-531aaf68-4914-4c9a-9e2d-bfcdfb64c5f9 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-531aaf68-4914-4c9a-9e2d-bfcdfb64c5f9 Wilson's Disease uuid-531aaf68-4914-4c9a-9e2d-bfcdfb64c5f9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-531aaf68-4914-4c9a-9e2d-bfcdfb64c5f9 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: leukocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5325326e-83c1-4510-b3e4-0e37c2a41bb3 NodeType: Pathway Notes: Inflamed mucosa amplifies the extravasation of leukocytes and their accumulation in the intestinal mucosa. This process is controlled by a family of cell adhesion molecules (CAMs) including the intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), the selectins, and the integrins. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: intestines Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-5325326e-83c1-4510-b3e4-0e37c2a41bb3 3_Leukocyte migration toward the endothelial cells in the intestine microvasculature uuid-5325326e-83c1-4510-b3e4-0e37c2a41bb3 PS:CellType endothelial cell PS:CellType leukocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5325326e-83c1-4510-b3e4-0e37c2a41bb3 PS:NodeType Pathway PS:Notes Inflamed mucosa amplifies the extravasation of leukocytes and their accumulation in the intestinal mucosa. This process is controlled by a family of cell adhesion molecules (CAMs) including the intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), the selectins, and the integrins. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ intestines PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5328d147-1721-4393-8c5a-58691f9ddb1b NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5328d147-1721-4393-8c5a-58691f9ddb1b Phenylketonuria Mutated Genes uuid-5328d147-1721-4393-8c5a-58691f9ddb1b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5328d147-1721-4393-8c5a-58691f9ddb1b PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5353a8a3-b66d-412b-b84f-dc2463e976ec NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5353a8a3-b66d-412b-b84f-dc2463e976ec Proteins Involved in Hypothyroidism uuid-5353a8a3-b66d-412b-b84f-dc2463e976ec PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5353a8a3-b66d-412b-b84f-dc2463e976ec PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53687f05-6224-4de3-84d2-0d89c74a377c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-53687f05-6224-4de3-84d2-0d89c74a377c Fructan biosynthesis template uuid-53687f05-6224-4de3-84d2-0d89c74a377c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53687f05-6224-4de3-84d2-0d89c74a377c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5395b13c-067c-4f10-a580-c89d4464bfc0 NodeType: Pathway Organ: generic Organ_System: hematological system Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-5395b13c-067c-4f10-a580-c89d4464bfc0 Macrophage M1 Polarization uuid-5395b13c-067c-4f10-a580-c89d4464bfc0 PS:CellType macrophage PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5395b13c-067c-4f10-a580-c89d4464bfc0 PS:NodeType Pathway PS:Organ generic PS:Organ_System hematological system PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-539eb2f6-ad97-4184-a8c9-098ed2b4d51f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-539eb2f6-ad97-4184-a8c9-098ed2b4d51f Inborn errors of IFN type I immunity uuid-539eb2f6-ad97-4184-a8c9-098ed2b4d51f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-539eb2f6-ad97-4184-a8c9-098ed2b4d51f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53cf1392-3f55-4506-8f27-554ab5f3582a NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-53cf1392-3f55-4506-8f27-554ab5f3582a Huntington's Disease Mutated Genes uuid-53cf1392-3f55-4506-8f27-554ab5f3582a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53cf1392-3f55-4506-8f27-554ab5f3582a PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53d14e5a-9077-476f-bade-5452655a91b5 NodeType: Pathway Notes: The cochlear canals contain two types of fluid: perilymph and endolymph. Perilymph has an ionic composition similar to extracellular fluid found elsewhere in the body (i.e., it is K+-poor and Na+-rich), and it fills the scalae tympani and vestibule. Hearing depends on the high K+ concentration in endolymph that bathes the apical membranes of sensory hair cells. Dysfunctional proteins of mechanoelectrical transducer channel and K+ channels impair the K+ circulation in endolymph of the inner ear and the transduction of sound waves into neuronal signals normally produced by action potential generation in hair cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: ear Organ_System: sensory system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-53d14e5a-9077-476f-bade-5452655a91b5 3_Impairment of mechanoelectrical transduction and potassium cycling in the inner ear in hearing loss uuid-53d14e5a-9077-476f-bade-5452655a91b5 PS:CellType sensory hair cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53d14e5a-9077-476f-bade-5452655a91b5 PS:NodeType Pathway PS:Notes The cochlear canals contain two types of fluid: perilymph and endolymph. Perilymph has an ionic composition similar to extracellular fluid found elsewhere in the body (i.e., it is K+-poor and Na+-rich), and it fills the scalae tympani and vestibule. Hearing depends on the high K+ concentration in endolymph that bathes the apical membranes of sensory hair cells. Dysfunctional proteins of mechanoelectrical transducer channel and K+ channels impair the K+ circulation in endolymph of the inner ear and the transduction of sound waves into neuronal signals normally produced by action potential generation in hair cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ ear PS:Organ_System sensory system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental stimuli. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53ed5a7a-a5d0-4a22-bb1f-0709bfe6b4e2 NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Apoptosis of skin keratinocytes is an important mechanism that triggers SLE. Signaling description: Apoptotic material of dead or dying keratinocytes plays a central role in the development of innate responses that lead to inflammation in SLE. The direct absorption of ultraviolet (UV) energy in keratinocytes drives biochemical reactions that result in the production of reactive oxygen species (ROS) and DNA damage. The production of ROS in the skin can also take place through the activation of the epidermal growth factor receptor (EGFR) which leads to the NAD(P)H oxidase activation and delayed ROS production. ROS, which can act as a mediator of indirect photodamage, causes oxidative stress. Following activation by ROS generation and oxidative stress, the keratinocyte dies and releases the apoptotic material that triggers death of neighboring cells. UV radiation activates toll-like receptors (TLRs) leading to increased levels and active secretion of IL1B, IL18, IL33, and IL1A. The activation of different TLRs upon the UV exposure can lead to the opposite cytokine profiles with regard to promoting or inhibiting the immune responses. TLR3 or TLR7 activation by UV radiation produces IL12, while TLR2 or TLR4 activation leads to the IL10 induction. The activation of TLRs also leads to the expression of high-mobility group box 1 (HMGB1) protein which is when secreted causes death of neighboring cells. Other substances released from the apoptotic cell, such as damage-associated molecular patterns (DAMPs) can also activate TLRs. UV damage activates the NLRP1 and NLRP3 inflammasome complexes. The inflammasome actvation may occur via the ATP-related and calcium (Ca2+)-related pathways; however, the exact mechanism of this process is unknown. The AIM2 inflammasome is not present in healthy skin, and is found exclusively in altered keratinocytes. A possible mechanism for the AIM2 inflammasome activation includes UV irradiation-induced or IGF-mediated signaling leading to DNA fragmentation. Outcome effects: Activated inflammasomes are able to induce IL1B, IL18, IL33, and IL1A production. Dying keratinocytes release danger signals that induce apoptosis of the neighboring keratinocytes and secrete abundant proinflammatory proteins. Secreted IL1B, IL18, IL33, and IL1A in addition to the apoptotic materials of dying keratinocytes lead to the chronic innate activation of the plasmacytoid dendritic cells (pDCs) to secrete type I interferons (IFNs) which is a key early event that triggers autoimmunity in SLE. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 12730222 PMID: 17600714 PMID: 22631445 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-53ed5a7a-a5d0-4a22-bb1f-0709bfe6b4e2 Apoptotic Keratinocytes Clearance Recession in Systemic Lupus Erythematosus uuid-53ed5a7a-a5d0-4a22-bb1f-0709bfe6b4e2 PS:CellType keratinocyte PS:Description Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental stimuli. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-53ed5a7a-a5d0-4a22-bb1f-0709bfe6b4e2 PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Apoptosis of skin keratinocytes is an important mechanism that triggers SLE. Signaling description: Apoptotic material of dead or dying keratinocytes plays a central role in the development of innate responses that lead to inflammation in SLE. The direct absorption of ultraviolet (UV) energy in keratinocytes drives biochemical reactions that result in the production of reactive oxygen species (ROS) and DNA damage. The production of ROS in the skin can also take place through the activation of the epidermal growth factor receptor (EGFR) which leads to the NAD(P)H oxidase activation and delayed ROS production. ROS, which can act as a mediator of indirect photodamage, causes oxidative stress. Following activation by ROS generation and oxidative stress, the keratinocyte dies and releases the apoptotic material that triggers death of neighboring cells. UV radiation activates toll-like receptors (TLRs) leading to increased levels and active secretion of IL1B, IL18, IL33, and IL1A. The activation of different TLRs upon the UV exposure can lead to the opposite cytokine profiles with regard to promoting or inhibiting the immune responses. TLR3 or TLR7 activation by UV radiation produces IL12, while TLR2 or TLR4 activation leads to the IL10 induction. The activation of TLRs also leads to the expression of high-mobility group box 1 (HMGB1) protein which is when secreted causes death of neighboring cells. Other substances released from the apoptotic cell, such as damage-associated molecular patterns (DAMPs) can also activate TLRs. UV damage activates the NLRP1 and NLRP3 inflammasome complexes. The inflammasome actvation may occur via the ATP-related and calcium (Ca2+)-related pathways; however, the exact mechanism of this process is unknown. The AIM2 inflammasome is not present in healthy skin, and is found exclusively in altered keratinocytes. A possible mechanism for the AIM2 inflammasome activation includes UV irradiation-induced or IGF-mediated signaling leading to DNA fragmentation. Outcome effects: Activated inflammasomes are able to induce IL1B, IL18, IL33, and IL1A production. Dying keratinocytes release danger signals that induce apoptosis of the neighboring keratinocytes and secrete abundant proinflammatory proteins. Secreted IL1B, IL18, IL33, and IL1A in addition to the apoptotic materials of dying keratinocytes lead to the chronic innate activation of the plasmacytoid dendritic cells (pDCs) to secrete type I interferons (IFNs) which is a key early event that triggers autoimmunity in SLE. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 12730222 PS:PMID 17600714 PS:PMID 22631445 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5406a3f2-3815-43b6-b50e-fb97f215e7e6 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-5406a3f2-3815-43b6-b50e-fb97f215e7e6 Proteins with Altered Expression in Glomerulonephritis uuid-5406a3f2-3815-43b6-b50e-fb97f215e7e6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5406a3f2-3815-43b6-b50e-fb97f215e7e6 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-542a8155-509c-4efc-b054-790c9b01f8ab NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-542a8155-509c-4efc-b054-790c9b01f8ab BDKRB1/2 -> Interleukins Production uuid-542a8155-509c-4efc-b054-790c9b01f8ab PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-542a8155-509c-4efc-b054-790c9b01f8ab PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-546c2741-544a-4843-8ef1-b2c2bec63abb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-546c2741-544a-4843-8ef1-b2c2bec63abb acetyl CoA fermentation template uuid-546c2741-544a-4843-8ef1-b2c2bec63abb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-546c2741-544a-4843-8ef1-b2c2bec63abb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-548d6abd-7ba5-4941-ba7a-9a12a5509a41 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-548d6abd-7ba5-4941-ba7a-9a12a5509a41 NTRK -> AP-1/CREB/ELK/SRF/MYC/SMAD3/TP53 Signaling uuid-548d6abd-7ba5-4941-ba7a-9a12a5509a41 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-548d6abd-7ba5-4941-ba7a-9a12a5509a41 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Single-strand mismatch DNA repair may be impaired in cancer due to multiple mutations in proteins implicated in this process. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5490b3d2-faf2-41c1-9e7b-4c444c401b91 NodeType: Pathway Notes: Headnote: Many proteins that participate in single-strand mismatch DNA repair can be mutated and down-regulated in cancer, including MSH2/3/6, PMS1/2, MLH1, POLE, LIG1. Some of these proteins can be inhibited by MIR21 or MIR155. Signaling description: The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. MMR recognizes a wide spectrum of mismatches in base-pairing nucleotides and removes a patch of DNA including the misincorporated nucleotide. New DNA is synthesized using the complementary strand as a template. The mismatch is initially bound by MSH2/MSH6 heterodimer for base-base mismatches and one- or two-base loops or MutS beta heterodimer (MSH2/MSH3) for loops of 2-14bp. The mismatch-bound MSH2/MSH6 heterodimer is converted to a sliding clamp capable of translocating along the DNA molecule in an ATP-dependent manner. The MSH2/MSH6/ATP/DNA complex is bound by a second heterodimer, MLH1/PMS2. This complex searches a strand discontinuity and is able to translocate in either direction. MSH2 also forms a heterodimer with MSH3. This MutS beta complex binds to insertion/deletion mispairs but displays little if any affinity for base-base mismatches. In strand resynthesis, the MSH2/MSH6 sliding clamp stimulates the activity of EXO1, starting from a nick situated 5' from the mispair and traveling towards the mispair. Polymerases and their cofactors, PCNA and DNA replication factor C, fill in the resulting single-stranded gap and LIG1 seals the remaining nick. Many members of single-strand mismatch DNA repair can be mutated and downregulated in cancer, including MSH2/3/6, PMS1/2, MLH1, POLE, LIG1. Some of these proteins can be inhibited by MIR21 or MIR155. Outcome effects: Silencing of single-strand mismatch DNA repair machinery impairs direct DNA repair and promotes microsatellite instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20177397 PMID: 20965415 PMID: 24947262 PMID: 25017190 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-5490b3d2-faf2-41c1-9e7b-4c444c401b91 Single Strand Mismatch DNA Repair Suppression in Cancer uuid-5490b3d2-faf2-41c1-9e7b-4c444c401b91 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Single-strand mismatch DNA repair may be impaired in cancer due to multiple mutations in proteins implicated in this process. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5490b3d2-faf2-41c1-9e7b-4c444c401b91 PS:NodeType Pathway PS:Notes Headnote: Many proteins that participate in single-strand mismatch DNA repair can be mutated and down-regulated in cancer, including MSH2/3/6, PMS1/2, MLH1, POLE, LIG1. Some of these proteins can be inhibited by MIR21 or MIR155. Signaling description: The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. MMR recognizes a wide spectrum of mismatches in base-pairing nucleotides and removes a patch of DNA including the misincorporated nucleotide. New DNA is synthesized using the complementary strand as a template. The mismatch is initially bound by MSH2/MSH6 heterodimer for base-base mismatches and one- or two-base loops or MutS beta heterodimer (MSH2/MSH3) for loops of 2-14bp. The mismatch-bound MSH2/MSH6 heterodimer is converted to a sliding clamp capable of translocating along the DNA molecule in an ATP-dependent manner. The MSH2/MSH6/ATP/DNA complex is bound by a second heterodimer, MLH1/PMS2. This complex searches a strand discontinuity and is able to translocate in either direction. MSH2 also forms a heterodimer with MSH3. This MutS beta complex binds to insertion/deletion mispairs but displays little if any affinity for base-base mismatches. In strand resynthesis, the MSH2/MSH6 sliding clamp stimulates the activity of EXO1, starting from a nick situated 5' from the mispair and traveling towards the mispair. Polymerases and their cofactors, PCNA and DNA replication factor C, fill in the resulting single-stranded gap and LIG1 seals the remaining nick. Many members of single-strand mismatch DNA repair can be mutated and downregulated in cancer, including MSH2/3/6, PMS1/2, MLH1, POLE, LIG1. Some of these proteins can be inhibited by MIR21 or MIR155. Outcome effects: Silencing of single-strand mismatch DNA repair machinery impairs direct DNA repair and promotes microsatellite instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20177397 PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: The innate immune system is the first line of defense against invading organisms, and one of its most important intracellular regulators is NFkB. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54a8acaa-3753-450a-ad8c-f1b1a342a503 NodeType: Pathway Notes: Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Signaling description: The innate immune system is the first line of defense against invading organisms, and one of its most important intracellular regulators is NFkB. GWAS studies investigating susceptibility to PsA have identified variants in several genes in the NFkB signaling network, including TNFAIP3, TNIP1, NFKBIA, REL, NOS2 and FBXL19. TNFAIP3 encodes the inducible zinc finger protein A20 (also known as TNF-induced protein 3, TNFAIP3). Ubiquitination of TNFAIP3 in response to NFkB activation prevents subsequent NFkB activation. The product of TNIP1 (TNFAIP3-interacting protein 1) interacts with TNFAIP3 to inhibit TNF-induced NFkB-dependent gene expression, via interference with transactivation signals mediated by RIP (receptor-interacting serine/threonineprotein kinase 1) or TRAF2 (TNF receptor-associated factor 2). Similarly, the product of NFKBIA interferes with nuclear localization signals by inhibiting the activity of dimeric NFkB-REL complexes (REL genes encode a subunit of the NFkB complex that is essential for proper signaling). The product of FBXL19, a member of the F-box family, reversibly inhibits NFkB signaling, and expression of FBXL19 is significantly elevated in psoriatic compared with normal skin. Finally, expression of NOS2 (encoding inducible nitric oxide synthase iNOS) is controlled by NFkB, occurs in inflammatory dendritic cells, and is elevated in lesional psoriatic skin. Outcome effects: Activated upon liberation NFkB inhibitor, secondary to stimulation by cytokines such as TNF, IL-1 and IL-17, NFkB triggers transcription of numerous target genes involved in the pathogenesis of inflammatory diseases, including PsA, and accumulates as a result of dysregulation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 19182814 PMID: 19641206 PMID: 25445403 PMID: 8040262 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-54a8acaa-3753-450a-ad8c-f1b1a342a503 Dendritic Cell Dysfunction in Psoriatic Arthritis uuid-54a8acaa-3753-450a-ad8c-f1b1a342a503 PS:CellType dendritic cell PS:Description The innate immune system is the first line of defense against invading organisms, and one of its most important intracellular regulators is NFkB. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54a8acaa-3753-450a-ad8c-f1b1a342a503 PS:NodeType Pathway PS:Notes Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Signaling description: The innate immune system is the first line of defense against invading organisms, and one of its most important intracellular regulators is NFkB. GWAS studies investigating susceptibility to PsA have identified variants in several genes in the NFkB signaling network, including TNFAIP3, TNIP1, NFKBIA, REL, NOS2 and FBXL19. TNFAIP3 encodes the inducible zinc finger protein A20 (also known as TNF-induced protein 3, TNFAIP3). Ubiquitination of TNFAIP3 in response to NFkB activation prevents subsequent NFkB activation. The product of TNIP1 (TNFAIP3-interacting protein 1) interacts with TNFAIP3 to inhibit TNF-induced NFkB-dependent gene expression, via interference with transactivation signals mediated by RIP (receptor-interacting serine/threonineprotein kinase 1) or TRAF2 (TNF receptor-associated factor 2). Similarly, the product of NFKBIA interferes with nuclear localization signals by inhibiting the activity of dimeric NFkB-REL complexes (REL genes encode a subunit of the NFkB complex that is essential for proper signaling). The product of FBXL19, a member of the F-box family, reversibly inhibits NFkB signaling, and expression of FBXL19 is significantly elevated in psoriatic compared with normal skin. Finally, expression of NOS2 (encoding inducible nitric oxide synthase iNOS) is controlled by NFkB, occurs in inflammatory dendritic cells, and is elevated in lesional psoriatic skin. Outcome effects: Activated upon liberation NFkB inhibitor, secondary to stimulation by cytokines such as TNF, IL-1 and IL-17, NFkB triggers transcription of numerous target genes involved in the pathogenesis of inflammatory diseases, including PsA, and accumulates as a result of dysregulation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 19182814 PS:PMID 19641206 PS:PMID 25445403 PS:PMID 8040262 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Among the most commonly used drugs with ototoxic effects are aminoglycosides (e.g., gentamicin) and platinum-based chemotherapeutica (e.g., cisplatin). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54cba758-6110-4e8e-8ee4-2ec5bb878aa3 NodeType: Pathway Notes: Headnote: Hearing loss (HL) is total or partial inability to hear. HL can be categolized by the part of the hearing system that is affected and is generally divided into conductive and sensorineural HL. Signaling description: The most commonly used drugs with ototoxic effects are aminoglycosides (AGs) (eg., gentamicin) and platinum-based chemotherapeutica (eg., cisplatin), loop diuretcs, salicylates, macrolide antibiotics and antimalarials. AGs and cisplatin effect on the hearing apparatus is the most severe and leads to permanent HL. AGs and cisplatin causes HL through the induction of apoptosis in sensory hair cells. Apoptosis activation has been attributed to the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) initiated by ototoxic drugs. Supposedly, aminoglycosides (AGs) are taken up by sensory hair cells via e both endocytosis and transport through ion channels. MYO7A was hypothesized to have a role in endocytosis-mediated AG uptake. Formation of an AG-iron complex can react with electron donors to form ROS. Outcome effects: ROS trigger downstream mechanisms leading to apoptosis. ROS can activate JNK (MAPK1/3), which can translocate to the nucleus to activate genes in the cell death pathway. In addition, oxidative stress can damage mitochondria which, in turn, release pro-apoptotic factors AIFM1 and ENDOG. Gentamicin activates MAPK1/3 (ERK1/2), which leads to upregulation of HRK and finally results in cell death. Cisplatin is proposed to enter the hair cells through cation transporters SLC22A1, SLC22A2, SLC31A1 and mechanotransducer channels. NADPH oxidase 3 (NOX3) is upregulated following cisplatin treatment and was shown to play a key role in cisplatin-mediated ototoxicity. Cisplatin has been shown to increase the expression of inflammatory mediators such as NOS2, COX2 and TNF, which are downstream targets of STAT1. Cisplatin-induced activation of STAT1 is dependent on ROS generation through NOX3. Animal data: Mouse models. Organ: ear Organ_System: sensory system PMID: 17653135 PMID: 21776018 PMID: 21782914 PMID: 22121370 PMID: 23045231 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-54cba758-6110-4e8e-8ee4-2ec5bb878aa3 Aminoglycosides and Cisplatin Induced Ototoxicity (Mouse Model) uuid-54cba758-6110-4e8e-8ee4-2ec5bb878aa3 PS:CellType sensory hair cell PS:Description Among the most commonly used drugs with ototoxic effects are aminoglycosides (e.g., gentamicin) and platinum-based chemotherapeutica (e.g., cisplatin). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54cba758-6110-4e8e-8ee4-2ec5bb878aa3 PS:NodeType Pathway PS:Notes Headnote: Hearing loss (HL) is total or partial inability to hear. HL can be categolized by the part of the hearing system that is affected and is generally divided into conductive and sensorineural HL. Signaling description: The most commonly used drugs with ototoxic effects are aminoglycosides (AGs) (eg., gentamicin) and platinum-based chemotherapeutica (eg., cisplatin), loop diuretcs, salicylates, macrolide antibiotics and antimalarials. AGs and cisplatin effect on the hearing apparatus is the most severe and leads to permanent HL. AGs and cisplatin causes HL through the induction of apoptosis in sensory hair cells. Apoptosis activation has been attributed to the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) initiated by ototoxic drugs. Supposedly, aminoglycosides (AGs) are taken up by sensory hair cells via e both endocytosis and transport through ion channels. MYO7A was hypothesized to have a role in endocytosis-mediated AG uptake. Formation of an AG-iron complex can react with electron donors to form ROS. Outcome effects: ROS trigger downstream mechanisms leading to apoptosis. ROS can activate JNK (MAPK1/3), which can translocate to the nucleus to activate genes in the cell death pathway. In addition, oxidative stress can damage mitochondria which, in turn, release pro-apoptotic factors AIFM1 and ENDOG. Gentamicin activates MAPK1/3 (ERK1/2), which leads to upregulation of HRK and finally results in cell death. Cisplatin is proposed to enter the hair cells through cation transporters SLC22A1, SLC22A2, SLC31A1 and mechanotransducer channels. NADPH oxidase 3 (NOX3) is upregulated following cisplatin treatment and was shown to play a key role in cisplatin-mediated ototoxicity. Cisplatin has been shown to increase the expression of inflammatory mediators such as NOS2, COX2 and TNF, which are downstream targets of STAT1. Cisplatin-induced activation of STAT1 is dependent on ROS generation through NOX3. Animal data: Mouse models. PS:Organ ear PS:Organ_System sensory system PS:PMID 17653135 PS:PMID 21776018 PS:PMID 21782914 PS:PMID 22121370 PS:PMID 23045231 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54d21c06-23a2-4ec0-b0b8-02bd9a3fdfc7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-54d21c06-23a2-4ec0-b0b8-02bd9a3fdfc7 IFNA1/IFNR Expression Targets uuid-54d21c06-23a2-4ec0-b0b8-02bd9a3fdfc7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-54d21c06-23a2-4ec0-b0b8-02bd9a3fdfc7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55055f71-7b6f-40d1-bf6f-6887df9f8fa0 NodeType: Pathway Notes: Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: The stimulation of glucocorticoid receptor NR3C1 by dexamethasone leads to an increased production of DKK1 and SOST, which are well-known antagonists of the WNT signaling pathway required to inhibit protein kinase GSK3B. Outcome effects: In neurons, GSK3B phosphorylates and inactivates MAPT, which is essential for microtubule formation. Therefore, dexamethasone-induced downregulation of WNT signaling pathway results in the activation of GSK3B and decreased microtubule formation, which is necessary for axon outgrowth. Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-55055f71-7b6f-40d1-bf6f-6887df9f8fa0 Dexamethasone Induced Neurotoxicity uuid-55055f71-7b6f-40d1-bf6f-6887df9f8fa0 PS:CellType neuron PS:Description Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55055f71-7b6f-40d1-bf6f-6887df9f8fa0 PS:NodeType Pathway PS:Notes Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: The stimulation of glucocorticoid receptor NR3C1 by dexamethasone leads to an increased production of DKK1 and SOST, which are well-known antagonists of the WNT signaling pathway required to inhibit protein kinase GSK3B. Outcome effects: In neurons, GSK3B phosphorylates and inactivates MAPT, which is essential for microtubule formation. Therefore, dexamethasone-induced downregulation of WNT signaling pathway results in the activation of GSK3B and decreased microtubule formation, which is necessary for axon outgrowth. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5540fc8b-15df-414c-8990-0f8d320f36bd NodeType: Pathway Notes: The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. Expression of oncogenic viral proteins E6 and E7 leads to a block of apoptosis and cstimulation of cell proliferation. In some cases, overexpression of E6 and E7 can promote oncogenesis. The HPV16-E6 and HPV16-E7 proteins inhibit the tumor suppressors tumor protein p53 (TP53) and retinoblastoma protein 1 (RB1) and the nuclear transcription factor (NFX1), thus stimulating host cell survival and viral reproduction. The uninhibited expression of HPV16-E6 and HPV16-E7 proteins leads to the transformation of papillomas into malignant tumors. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-5540fc8b-15df-414c-8990-0f8d320f36bd 4_Human papilloma virus E6 and E7 proteins promote epithelial cell survival uuid-5540fc8b-15df-414c-8990-0f8d320f36bd PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5540fc8b-15df-414c-8990-0f8d320f36bd PS:NodeType Pathway PS:Notes The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. Expression of oncogenic viral proteins E6 and E7 leads to a block of apoptosis and cstimulation of cell proliferation. In some cases, overexpression of E6 and E7 can promote oncogenesis. The HPV16-E6 and HPV16-E7 proteins inhibit the tumor suppressors tumor protein p53 (TP53) and retinoblastoma protein 1 (RB1) and the nuclear transcription factor (NFX1), thus stimulating host cell survival and viral reproduction. The uninhibited expression of HPV16-E6 and HPV16-E7 proteins leads to the transformation of papillomas into malignant tumors. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-554ed261-32bc-4f50-a931-8e5b47991e9d NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-554ed261-32bc-4f50-a931-8e5b47991e9d Proteins Involved in Ependymoma uuid-554ed261-32bc-4f50-a931-8e5b47991e9d PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-554ed261-32bc-4f50-a931-8e5b47991e9d PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: The E4 HPV protein contributes to the viral genome replication, and promotes the release of viral particles. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-555dc9f1-ea87-4108-93bf-f75b5408496a NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two later proteins (L1 and L2). The open reading frame (ORF) of HPV16-E4 is contained within the E2 ORF. The primary E4 gene-product (E1-E4) is translated from a spliced mRNA that includes the E1 initiation codon and adjacent sequences. The E4 protein is detected during the amplification of the viral genome and its greatest amount is observed at the late stage of virus replication prior to the assembly and release of viral particles. The protein contributes to viral genome replication and promotes the release of viral particles. The E4 protein is phosphorylated by CDK1, CDK2, MAPK1, PKA, and PRKCA, with CDK1/2 serine 32 and MAPK1 threonine 57 phosphorylations being the two primary events observed in the cells in cycle. These kinases regulate one of the main functions of E4 protein, which is the association with the cellular keratin network and its cleavage by the protease calpain that allows assembly into amyloid-like fibers and re-organization of the keratin network. The phosphorylation of E4 by MAPK1 leads to the stabilization of E4 structure and enhances keratin binding. E4 binds directly to keratin type I such as keratin 18 but not keratin type II or vimentin. The binding is dependent on the 16 amino acids at the N-terminus of the E4 protein, with the leucine cluster being absolutely necessary. The next protein interacting with the E4 cellular protein is calpain. Protease calpain cleaves the E4 protein at the amino acid position 17 to generate species that lack the N terminus. These C-terminal fragments are able to multimerize and form amyloid-like fibers. This can lead to accumulation of E4 and disruption of the normal dynamics of the keratin networks. E4 is also phosphorylated by CDK (CCNB1/CDK1 and CCNA2/ CDK2) in the G2-phase-like/differentiating cells. This causes G2 cell cycle arrest by associating with and preventing the nuclear entry of the CDK1/CCNB1 complexes. Highlighted proteins: Exogenous proteins are shown in grey. Organ: skin PMID: 14694114 PMID: 24016539 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-555dc9f1-ea87-4108-93bf-f75b5408496a HPV E4 Contribution to Life Cycle of Virus and Cell uuid-555dc9f1-ea87-4108-93bf-f75b5408496a PS:CellType cancer cell PS:CellType keratinocyte PS:Description The E4 HPV protein contributes to the viral genome replication, and promotes the release of viral particles. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-555dc9f1-ea87-4108-93bf-f75b5408496a PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two later proteins (L1 and L2). The open reading frame (ORF) of HPV16-E4 is contained within the E2 ORF. The primary E4 gene-product (E1-E4) is translated from a spliced mRNA that includes the E1 initiation codon and adjacent sequences. The E4 protein is detected during the amplification of the viral genome and its greatest amount is observed at the late stage of virus replication prior to the assembly and release of viral particles. The protein contributes to viral genome replication and promotes the release of viral particles. The E4 protein is phosphorylated by CDK1, CDK2, MAPK1, PKA, and PRKCA, with CDK1/2 serine 32 and MAPK1 threonine 57 phosphorylations being the two primary events observed in the cells in cycle. These kinases regulate one of the main functions of E4 protein, which is the association with the cellular keratin network and its cleavage by the protease calpain that allows assembly into amyloid-like fibers and re-organization of the keratin network. The phosphorylation of E4 by MAPK1 leads to the stabilization of E4 structure and enhances keratin binding. E4 binds directly to keratin type I such as keratin 18 but not keratin type II or vimentin. The binding is dependent on the 16 amino acids at the N-terminus of the E4 protein, with the leucine cluster being absolutely necessary. The next protein interacting with the E4 cellular protein is calpain. Protease calpain cleaves the E4 protein at the amino acid position 17 to generate species that lack the N terminus. These C-terminal fragments are able to multimerize and form amyloid-like fibers. This can lead to accumulation of E4 and disruption of the normal dynamics of the keratin networks. E4 is also phosphorylated by CDK (CCNB1/CDK1 and CCNA2/ CDK2) in the G2-phase-like/differentiating cells. This causes G2 cell cycle arrest by associating with and preventing the nuclear entry of the CDK1/CCNB1 complexes. Highlighted proteins: Exogenous proteins are shown in grey. PS:Organ skin PS:PMID 14694114 PS:PMID 24016539 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-558fd8f5-609d-4c95-ae97-19f95851841a NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. There is a reduction in the number of Th17 cell during HIV infections. Signaling description: Normally, CD4 T-cell produced cytokines such as IL1B, IL23A, IL6, and TGFB1 promote naive T-cells differentiation into Th17 phenotype. The cytokines bind to their receptors and the signal is transduced to STAT3 through MYD88/IRAK/TRAF6/MAP3K1 (from via IL1B), JAK (from IL23A and IL6), and SMAD3 (from TGFB1). Outcome effects: STAT3 triggers RORC expression and they both bind to the promoters of IL21, IL22, IL17A, and IL17F genes. These cytokines promote an inflammatory response in the gut. During HIV infection, there is a reduction in the level of IL1B, IL23A, IL6, and TGFB1 cytokines due to the impairment of CD4 T-cell signaling, which results in the block of Th17 maturation. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 20543592 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-558fd8f5-609d-4c95-ae97-19f95851841a Th17-Cell Numbers Reduction in HIV uuid-558fd8f5-609d-4c95-ae97-19f95851841a PS:CellType T-cell PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-558fd8f5-609d-4c95-ae97-19f95851841a PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. There is a reduction in the number of Th17 cell during HIV infections. Signaling description: Normally, CD4 T-cell produced cytokines such as IL1B, IL23A, IL6, and TGFB1 promote naive T-cells differentiation into Th17 phenotype. The cytokines bind to their receptors and the signal is transduced to STAT3 through MYD88/IRAK/TRAF6/MAP3K1 (from via IL1B), JAK (from IL23A and IL6), and SMAD3 (from TGFB1). Outcome effects: STAT3 triggers RORC expression and they both bind to the promoters of IL21, IL22, IL17A, and IL17F genes. These cytokines promote an inflammatory response in the gut. During HIV infection, there is a reduction in the level of IL1B, IL23A, IL6, and TGFB1 cytokines due to the impairment of CD4 T-cell signaling, which results in the block of Th17 maturation. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 20543592 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55ac527e-98a5-433a-a398-52d5da15ab89 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-55ac527e-98a5-433a-a398-52d5da15ab89 BMP7/BMPR2/ACVR2 Expression Targets uuid-55ac527e-98a5-433a-a398-52d5da15ab89 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55ac527e-98a5-433a-a398-52d5da15ab89 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: regulatory T-cell Description: FOXP3+ Regulatory T cells constitute an important component of immunosuppressive circuitry of the host and it's activation plays major role in cancer immune escape. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55b15e07-cbe4-4173-a243-56b0c7351488 NodeType: Pathway Notes: Headnote: FOXP3+ Regulatory T cells (Tregs) represent an important component of the immunosuppressive circuitry of the host and it's activation is involved in cancer cell immune escape. Signaling description: TGFB1/SMAD signaling has a particularly important role in differentiation and activation of Tregs. IL-2 facilitates the induction of FOXP3 via STAT5A. The activation of T-cell receptor induces the NFKB and NFATC signaling. Following cell contact, Tregs may kill the immune cell through PRF1/GZMB or deliver a negative signal via different mechanisms. Tregs express ENTPD1 (CD39) and NT5E (CD73) generating pericellular adenosine and inhibiting the effector T-cell functions. Tregs express CTLA4 stimulating dendritic cells to produce the immunosuppressive enzyme IDO1 via interaction with CD80 and CD86 (see pathway "IDO1 in Cancer Immune Escape" for details). Production of TNFSF10 (TRIAL) and LGALS1 by Tregs potentiate cell cycle arrest and apoptosis in NK cells, dendritic cells and effector T-cells. Tregs produce IL10 and TGFB1 that have an immunosuppressive effect. Outcome effects: Tregs inhibit or induce apoptosis of effector T-cells, dendritic cells, NK cells and some other immune cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 19464986 PMID: 19737784 PMID: 22116087 PMID: 27160722 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-55b15e07-cbe4-4173-a243-56b0c7351488 Treg Cells Promote Immunosuppression in Cancer Immune Escape uuid-55b15e07-cbe4-4173-a243-56b0c7351488 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType regulatory T-cell PS:Description FOXP3+ Regulatory T cells constitute an important component of immunosuppressive circuitry of the host and it's activation plays major role in cancer immune escape. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55b15e07-cbe4-4173-a243-56b0c7351488 PS:NodeType Pathway PS:Notes Headnote: FOXP3+ Regulatory T cells (Tregs) represent an important component of the immunosuppressive circuitry of the host and it's activation is involved in cancer cell immune escape. Signaling description: TGFB1/SMAD signaling has a particularly important role in differentiation and activation of Tregs. IL-2 facilitates the induction of FOXP3 via STAT5A. The activation of T-cell receptor induces the NFKB and NFATC signaling. Following cell contact, Tregs may kill the immune cell through PRF1/GZMB or deliver a negative signal via different mechanisms. Tregs express ENTPD1 (CD39) and NT5E (CD73) generating pericellular adenosine and inhibiting the effector T-cell functions. Tregs express CTLA4 stimulating dendritic cells to produce the immunosuppressive enzyme IDO1 via interaction with CD80 and CD86 (see pathway "IDO1 in Cancer Immune Escape" for details). Production of TNFSF10 (TRIAL) and LGALS1 by Tregs potentiate cell cycle arrest and apoptosis in NK cells, dendritic cells and effector T-cells. Tregs produce IL10 and TGFB1 that have an immunosuppressive effect. Outcome effects: Tregs inhibit or induce apoptosis of effector T-cells, dendritic cells, NK cells and some other immune cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 19464986 PS:PMID 19737784 PS:PMID 22116087 PS:PMID 27160722 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Epithelial-to-mesenchymal transition, a process guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55b29c3e-1b0a-41a0-b6ad-42cc00fee1fe NodeType: Pathway Notes: Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. Signaling description: Induction of EMT in cancer cells can occur as a result of embryonic signaling. Activation of SHH, WNT, NOTCH, BMP or TGFB signaling leads to the upregulation of transcriptional factors that drive EMT. Other factors implicated in EMT signaling induction include EGFR/ERBB2, PDGFR, FGFR, DDR1/2, IGF1R, IL6R, integrins and hypoxia-induced HIF1A.Transcriptional factors that drive EMT include SNAI1/2/3, ZEB1/2, TWIST1, GSC, FOXC1/2, FOXQ1, TCF3, KLF8, PRRX1, CTNNB1, ID1/2, SMAD, MYOCD and some others. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins that inhibit cell adhesion and activate cell migration (e. g. CDH2, VIM, FN1, TNC, MMP2/9/15). Outcome effects: This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17645776 PMID: 19487818 PMID: 21672282 PMID: 23344542 PMID: 23589827 PMID: 24556840 PMID: 25107915 PMID: 25240174 PMID: 25249658 PMID: 25482613 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-55b29c3e-1b0a-41a0-b6ad-42cc00fee1fe Epithelial to Mesenchymal Transition in Cancer: Overview uuid-55b29c3e-1b0a-41a0-b6ad-42cc00fee1fe PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Epithelial-to-mesenchymal transition, a process guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55b29c3e-1b0a-41a0-b6ad-42cc00fee1fe PS:NodeType Pathway PS:Notes Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. Signaling description: Induction of EMT in cancer cells can occur as a result of embryonic signaling. Activation of SHH, WNT, NOTCH, BMP or TGFB signaling leads to the upregulation of transcriptional factors that drive EMT. Other factors implicated in EMT signaling induction include EGFR/ERBB2, PDGFR, FGFR, DDR1/2, IGF1R, IL6R, integrins and hypoxia-induced HIF1A.Transcriptional factors that drive EMT include SNAI1/2/3, ZEB1/2, TWIST1, GSC, FOXC1/2, FOXQ1, TCF3, KLF8, PRRX1, CTNNB1, ID1/2, SMAD, MYOCD and some others. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins that inhibit cell adhesion and activate cell migration (e. g. CDH2, VIM, FN1, TNC, MMP2/9/15). Outcome effects: This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17645776 PS:PMID 19487818 PS:PMID 21672282 PS:PMID 23344542 PS:PMID 23589827 PS:PMID 24556840 PS:PMID 25107915 PS:PMID 25240174 PS:PMID 25249658 PS:PMID 25482613 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55cdb2da-5fad-4aee-90fa-b7e5e169ea50 NodeType: Pathway Notes: Triggered by an inflammatory reaction and supported by the host microbiome, hyperexpression of proinflammatory proteins by dendritic cells, macrophages and epithelial cells lead to the abnormally strong activation of T-helper cell types 1 and 17 (Th1-cells and Th17-cells) in the intestinal walls. Variations in several genes, including autophagy-related 16 like 1 (ATG16L1) and NOD2, contribute to the inability of intestinal cells to provide an epithelial and mucosal barrier against commensal microflora present in the gut. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: intestines Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-55cdb2da-5fad-4aee-90fa-b7e5e169ea50 1_Defects in response to pathogens in the gut promotes inflammation in Crohn's disease uuid-55cdb2da-5fad-4aee-90fa-b7e5e169ea50 PS:CellType dendritic cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55cdb2da-5fad-4aee-90fa-b7e5e169ea50 PS:NodeType Pathway PS:Notes Triggered by an inflammatory reaction and supported by the host microbiome, hyperexpression of proinflammatory proteins by dendritic cells, macrophages and epithelial cells lead to the abnormally strong activation of T-helper cell types 1 and 17 (Th1-cells and Th17-cells) in the intestinal walls. Variations in several genes, including autophagy-related 16 like 1 (ATG16L1) and NOD2, contribute to the inability of intestinal cells to provide an epithelial and mucosal barrier against commensal microflora present in the gut. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ intestines PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55dab8bb-e423-4702-b231-5bf55e63ea9b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-55dab8bb-e423-4702-b231-5bf55e63ea9b PDCD1 -> NFATC Expression Targets uuid-55dab8bb-e423-4702-b231-5bf55e63ea9b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55dab8bb-e423-4702-b231-5bf55e63ea9b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55daf054-f808-4c40-a1df-847b766f74a4 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-55daf054-f808-4c40-a1df-847b766f74a4 Proteins Involved in YBX1 Sites Modification uuid-55daf054-f808-4c40-a1df-847b766f74a4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55daf054-f808-4c40-a1df-847b766f74a4 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55efcfdf-92f5-48c8-b813-63dd50b672b2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-55efcfdf-92f5-48c8-b813-63dd50b672b2 Lipid IVA biosynthesis (mitochondria) template uuid-55efcfdf-92f5-48c8-b813-63dd50b672b2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-55efcfdf-92f5-48c8-b813-63dd50b672b2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56167716-3c23-4d0d-9cb6-8ab42b2dddd4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-56167716-3c23-4d0d-9cb6-8ab42b2dddd4 pppGpp metabolism template uuid-56167716-3c23-4d0d-9cb6-8ab42b2dddd4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56167716-3c23-4d0d-9cb6-8ab42b2dddd4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-562fe18d-a533-4e66-ace6-094bc368d86f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-562fe18d-a533-4e66-ace6-094bc368d86f HBEGF -> MEF/MYOD Expression Target uuid-562fe18d-a533-4e66-ace6-094bc368d86f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-562fe18d-a533-4e66-ace6-094bc368d86f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-567c1ac3-cc86-4355-b6b2-5bad969d2478 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-567c1ac3-cc86-4355-b6b2-5bad969d2478 NODAL/ACVR2B Expression Targets uuid-567c1ac3-cc86-4355-b6b2-5bad969d2478 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-567c1ac3-cc86-4355-b6b2-5bad969d2478 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56923950-0c03-40fd-9dab-74f95d32d86f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-56923950-0c03-40fd-9dab-74f95d32d86f PDGF->EMT uuid-56923950-0c03-40fd-9dab-74f95d32d86f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56923950-0c03-40fd-9dab-74f95d32d86f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-569e7ae6-72b7-4960-bdb7-ed6f9d3313b3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-569e7ae6-72b7-4960-bdb7-ed6f9d3313b3 AGT -> CREB Expression Targets uuid-569e7ae6-72b7-4960-bdb7-ed6f9d3313b3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-569e7ae6-72b7-4960-bdb7-ed6f9d3313b3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56a2548f-8a8a-4114-b0d9-8e6eb1367378 NodeType: Pathway Notes: Headnote: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Signaling description: Ritonavir is capable of directly binding HSP90AA1 in the endoplasmic reticulum and inhibiting its chaperone activity, thus promoting unfolded protein response (UPR). HSP90AA1 normally participates in NOS3 protein folding that is essential for nitric oxide (NO) production by endothelial cells. NO promotes the relaxation of vascular smooth muscle cells and the same pathway is involved in diastolic relaxation of the heart muscle. Outcome effects: By inhibiting NOS3 folding and NO production, ritonavir generally impairs vasculature relaxation, particularly myocardial contraction-relaxation cycle, leading to hypertension and hypertrophic cardiomyopathy. Organ: heart Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-56a2548f-8a8a-4114-b0d9-8e6eb1367378 Ritonavir Induced Cardiovascular Dysfunction uuid-56a2548f-8a8a-4114-b0d9-8e6eb1367378 PS:Description Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56a2548f-8a8a-4114-b0d9-8e6eb1367378 PS:NodeType Pathway PS:Notes Headnote: Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS. Signaling description: Ritonavir is capable of directly binding HSP90AA1 in the endoplasmic reticulum and inhibiting its chaperone activity, thus promoting unfolded protein response (UPR). HSP90AA1 normally participates in NOS3 protein folding that is essential for nitric oxide (NO) production by endothelial cells. NO promotes the relaxation of vascular smooth muscle cells and the same pathway is involved in diastolic relaxation of the heart muscle. Outcome effects: By inhibiting NOS3 folding and NO production, ritonavir generally impairs vasculature relaxation, particularly myocardial contraction-relaxation cycle, leading to hypertension and hypertrophic cardiomyopathy. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: In a mouse model it was shown that impaired functioning of melatonin receptors triggered by MAPT mutation and abnormal microtubule dynamics could underlie sleep disturbances in Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56e7c56c-bf0a-4603-a779-2c971e5f6b9c NodeType: Pathway Notes: Headnote: In a mouse model it was shown that impaired functioning of melatonin receptors triggered by MAPT (microtubule-associated protein tau) mutation and abnormal microtubule dynamics could underlie sleep disturbances in Alzheimer's disease patients. Signaling description: Tau protein stabilizes microtubules. It is abundant in neurons of the central nervous system and is less common elsewhere. Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease can result when tau proteins become defective and no longer stabilize microtubules properly. Organ: brain Organ_System: nervous system PMID: 20555133 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-56e7c56c-bf0a-4603-a779-2c971e5f6b9c Sleep Disturbance (Hypothesis) uuid-56e7c56c-bf0a-4603-a779-2c971e5f6b9c PS:CellType neuron PS:Description In a mouse model it was shown that impaired functioning of melatonin receptors triggered by MAPT mutation and abnormal microtubule dynamics could underlie sleep disturbances in Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56e7c56c-bf0a-4603-a779-2c971e5f6b9c PS:NodeType Pathway PS:Notes Headnote: In a mouse model it was shown that impaired functioning of melatonin receptors triggered by MAPT (microtubule-associated protein tau) mutation and abnormal microtubule dynamics could underlie sleep disturbances in Alzheimer's disease patients. Signaling description: Tau protein stabilizes microtubules. It is abundant in neurons of the central nervous system and is less common elsewhere. Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease can result when tau proteins become defective and no longer stabilize microtubules properly. PS:Organ brain PS:Organ_System nervous system PS:PMID 20555133 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56e9fe7e-6709-4389-bb66-f62b0975a8cb NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-56e9fe7e-6709-4389-bb66-f62b0975a8cb PDGF -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-56e9fe7e-6709-4389-bb66-f62b0975a8cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56e9fe7e-6709-4389-bb66-f62b0975a8cb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56f1a701-daaf-4e6e-82f4-7f52b593d7d3 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-56f1a701-daaf-4e6e-82f4-7f52b593d7d3 GDNF -> HSF1 Signaling uuid-56f1a701-daaf-4e6e-82f4-7f52b593d7d3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56f1a701-daaf-4e6e-82f4-7f52b593d7d3 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56fba5ad-cfa1-4cdb-88a0-af0c2fa9bf0e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-56fba5ad-cfa1-4cdb-88a0-af0c2fa9bf0e Erythropoietin -> FOXO3A Expression Targets uuid-56fba5ad-cfa1-4cdb-88a0-af0c2fa9bf0e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-56fba5ad-cfa1-4cdb-88a0-af0c2fa9bf0e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: plasma cell Description: Multiple myeloma (MM) cells express Notch 1, 2, and 3 receptors which are activated by Jagged-1 and 2 (JAG1 and JAG2) ligands expressed by MM cells and bone marrow stromal cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5708ca90-cc5b-4054-8947-485f6e703961 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: Multiple myeloma (MM) cells express Notch 1, 2, and 3 receptors which are activated by Jagged-1 and 2 (JAG1 and JAG2) ligands expressed by MM cells and bone marrow stromal cells. JAG2 is overexpressed in MM and plays a central role in this malignancy. Upon ligand binding, ADAM17 metalloproteinase and gamma-secretase cleave the Notch receptors leading to the release of the Notch intracellular portion (ICN) and allowing it to translocate into the nucleus. It has been shown that the Notch pathway may have both a proliferative and anti-proliferative effect. Notch-induced resistance to chemotherapy-induced apoptosis is attributed to the arrest of the cell cycle in G0/G1 phase associated with the up-regulation of CDKN1A. Conversely, CDKN1B, CCND1, and MYC may drive cell cycle progression and proliferation. Further, Notch signaling in MM cells does not affect the expression of major antiapoptotic proteins such as BCL2, BCL2L1, and survivin and also does not activate NF-kB. Outcome effects: Once ICN is in the nucleus, it recruits co-activators, such as EP300 and MAML1, thereby activating the transcription of several downstream target genes. This results in MM cell proliferation, resistance to apoptosis and chemotherapy as well as the secretion of IL6, VEGFA, and other cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: skeletal system PMID: 16291593 PMID: 21652011 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-5708ca90-cc5b-4054-8947-485f6e703961 NOTCH Signaling in Multiple Myeloma uuid-5708ca90-cc5b-4054-8947-485f6e703961 PS:CellType cancer cell PS:CellType plasma cell PS:Description Multiple myeloma (MM) cells express Notch 1, 2, and 3 receptors which are activated by Jagged-1 and 2 (JAG1 and JAG2) ligands expressed by MM cells and bone marrow stromal cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5708ca90-cc5b-4054-8947-485f6e703961 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: Multiple myeloma (MM) cells express Notch 1, 2, and 3 receptors which are activated by Jagged-1 and 2 (JAG1 and JAG2) ligands expressed by MM cells and bone marrow stromal cells. JAG2 is overexpressed in MM and plays a central role in this malignancy. Upon ligand binding, ADAM17 metalloproteinase and gamma-secretase cleave the Notch receptors leading to the release of the Notch intracellular portion (ICN) and allowing it to translocate into the nucleus. It has been shown that the Notch pathway may have both a proliferative and anti-proliferative effect. Notch-induced resistance to chemotherapy-induced apoptosis is attributed to the arrest of the cell cycle in G0/G1 phase associated with the up-regulation of CDKN1A. Conversely, CDKN1B, CCND1, and MYC may drive cell cycle progression and proliferation. Further, Notch signaling in MM cells does not affect the expression of major antiapoptotic proteins such as BCL2, BCL2L1, and survivin and also does not activate NF-kB. Outcome effects: Once ICN is in the nucleus, it recruits co-activators, such as EP300 and MAML1, thereby activating the transcription of several downstream target genes. This results in MM cell proliferation, resistance to apoptosis and chemotherapy as well as the secretion of IL6, VEGFA, and other cytokines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System skeletal system PS:PMID 16291593 PS:PMID 21652011 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-571f3999-4978-45f6-9817-abb23a170bdd NodeType: Pathway Notes: Eosinophils, mast cells, and basophils release histamine and other mediators that induce excessive narrowing of the airways and to bronchoconstriction. Excessive shortening (contraction) of airway smooth muscle (ASM) cells and airway tissue remodeling develops as the disease progress is responsible for breathing difficulty. Eventually, the muscles around the airways may enlarge through hypertrophy, further narrowing the airways. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-571f3999-4978-45f6-9817-abb23a170bdd 4_1_Airway smooth muscle cells contraction uuid-571f3999-4978-45f6-9817-abb23a170bdd PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-571f3999-4978-45f6-9817-abb23a170bdd PS:NodeType Pathway PS:Notes Eosinophils, mast cells, and basophils release histamine and other mediators that induce excessive narrowing of the airways and to bronchoconstriction. Excessive shortening (contraction) of airway smooth muscle (ASM) cells and airway tissue remodeling develops as the disease progress is responsible for breathing difficulty. Eventually, the muscles around the airways may enlarge through hypertrophy, further narrowing the airways. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5726dc61-8129-4c70-bdf5-0c6f16cf10fc NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-5726dc61-8129-4c70-bdf5-0c6f16cf10fc ALB-|oxidative stress uuid-5726dc61-8129-4c70-bdf5-0c6f16cf10fc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5726dc61-8129-4c70-bdf5-0c6f16cf10fc PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: Th17 cell CellType: cancer cell CellType: cancer stem cell CellType: fibroblast CellType: macrophage Description: IL17A is thought to be an important factor of tumor-promoting inflammation and is regarded as a potential therapeutic target. IL23A induce IL17A production by Th17 cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-572ac450-d870-48ae-8cfb-be8994b7e007 NodeType: Pathway Notes: Headnote: IL23A, IL6 and TGFB1, produced by antigen-presenting cells, tumor infiltrating macrophages and other myeloid cells in the site of inflammation, are essential for activation of Th17 cells. Signaling description: IL23A, IL6 and TGFB1 act through their receptors and induce STAT3 activation in Th17 cells. STAT3 is responsible for IL17A expression. In turn, IL17A may act on macrophages, fibroblasts and cancer cells initiating NFkB signaling. Outcome effects: NFkB induce expression of multiple proteins involved in cancer progression. In addition, TNF, IL6, IL1B, PTGS2, ICAM1 exacerbate inflammation. VEGFA induce vasculogenesis which promotes tumor development. IL17A can be blocked by different monoclonal antibodies (secukinumab, ixekizumab, brodalumab) now being investigated in clinical trials. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ: oncogenic Organ_System: oncogenic PMID: 17476347 PMID: 19513943 PMID: 19767566 PMID: 20018552 PMID: 28716888 PMID: 29396054 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-572ac450-d870-48ae-8cfb-be8994b7e007 IL23A and IL17A Provoke Cancer-Associated Inflammation uuid-572ac450-d870-48ae-8cfb-be8994b7e007 PS:CellType Th17 cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType fibroblast PS:CellType macrophage PS:Description IL17A is thought to be an important factor of tumor-promoting inflammation and is regarded as a potential therapeutic target. IL23A induce IL17A production by Th17 cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-572ac450-d870-48ae-8cfb-be8994b7e007 PS:NodeType Pathway PS:Notes Headnote: IL23A, IL6 and TGFB1, produced by antigen-presenting cells, tumor infiltrating macrophages and other myeloid cells in the site of inflammation, are essential for activation of Th17 cells. Signaling description: IL23A, IL6 and TGFB1 act through their receptors and induce STAT3 activation in Th17 cells. STAT3 is responsible for IL17A expression. In turn, IL17A may act on macrophages, fibroblasts and cancer cells initiating NFkB signaling. Outcome effects: NFkB induce expression of multiple proteins involved in cancer progression. In addition, TNF, IL6, IL1B, PTGS2, ICAM1 exacerbate inflammation. VEGFA induce vasculogenesis which promotes tumor development. IL17A can be blocked by different monoclonal antibodies (secukinumab, ixekizumab, brodalumab) now being investigated in clinical trials. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17476347 PS:PMID 19513943 PS:PMID 19767566 PS:PMID 20018552 PS:PMID 28716888 PS:PMID 29396054 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-574f7b94-1a9e-4fb1-a088-16e9a13f542e NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-574f7b94-1a9e-4fb1-a088-16e9a13f542e Proteins Involved in Multiple Sclerosis uuid-574f7b94-1a9e-4fb1-a088-16e9a13f542e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-574f7b94-1a9e-4fb1-a088-16e9a13f542e PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57562ec6-9cff-49b0-ab47-a823b4ab699c NodeType: Pathway Organ: Tooth Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-57562ec6-9cff-49b0-ab47-a823b4ab699c Proteins Involved in Dental Caries uuid-57562ec6-9cff-49b0-ab47-a823b4ab699c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57562ec6-9cff-49b0-ab47-a823b4ab699c PS:NodeType Pathway PS:Organ Tooth PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: The contraction and proliferation of pulmonary artery smooth muscle cells (PASMCs) are key processes in pulmonary artery hypertension (PAH) development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5756f1c0-23a3-4a43-909b-15346fe62931 NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. The contraction and proliferation of pulmonary artery smooth muscle cells (PASMCs) are key processes in PAH development. PAH is characterized by the decreased production of vasodilators and growth inhibitors such as nitric oxide (NO) and prostacyclin (PGI2) and the increased production of the vasoconstrictor/co-mitogens such as endothelin 1 (EDN1) and serotonin. Signaling description: The main mechanisms of contraction and proliferation induction in PASMCs are RHOA/ROCK1 activation, reactive oxygen spices (ROS) hyperproduction, intracellular calcium (Ca2+) overload, and the decreased expression/function of potassium (K+) channels. In PASMCs, vasoconstrictors activate G-protein-coupled receptors which trigger guanine nucleotide exchange factor (GEF) and induce RHOA. Then, RHOA activates ROCK1 which has multiple effects with the most widely studied being the inhibition of myosin light chain phosphatase (MLCP). This promotes the phosphorylation of MYL12B and as a result contraction occurs. ROCK1 is also involved in actin cytoskeleton dynamics through the phosphorylation of LIMK1/2, which in turn phosphorylates and inhibits CFL1, leading to smooth muscle cell actin (ACTA2) filament stabilization. This may have an impact on cell differentiation, proliferation, and migration. The expression of TAGLN and CNN1 are regulated by SRF and cofactors such as MYOCD and myocardin-related transcription factors (MKL1/2) which also influence the contractile phenotype in PASMCs. Conversely, the activation of RHOA/ROCK1 pathway increases PASMC proliferation. RHOA has been shown to be required for sustained Ras/MAPK1/3 activation. ROCK1 also causes decreased CDKN1A and CDKN1B expression. Serotonin has both contractile and mitogenic effects in PASMCs. The contractile action of serotonin is mediated via the activation of HTR1B, HTR2A, and HTR2B receptors. The mitogenic effect of serotonin requires internalization through the serotonin transporter, SLC6A4. The breakdown of serotonin by monoamine oxidase A (MAOA) results in the generation of ROS. Serotonin also induces ROS through the activation of NADPH oxidases (CYBB and NOX4) via RAC1. In addition, ROS is responsible for the nuclear translocation of phosphorylated MAPK1/3. Subsequently, phosphorylated MAPK1/3 binds transcription factors such as GATA4, EGR1, and ELK1 and thus increases the expression of proteins which are involved in cellular proliferation. In PASMCs, free Ca2+ concentration in the cytosol is an important determinant of contraction, migration, and proliferation. The cytosolic Ca2+ concentration can be increased by Ca2+ influx through voltage-dependent Ca2+ channels (CACNA1C) and transient receptor potential cation channels (TRPC1/3/6) in addition to Ca2+ release from sarcoplasmic reticulum through ITPR2 and RYR3. Ca2+/calmodulin complex activates MYLK leading to MYL12B phosphorylation and PASMC contraction. Also, the decreased expression and function of potassium (K+) channels (KCNA5 and KCNB1) leads to membrane depolarization and contributes to the sustained elevation of cytosol Ca2+. In addition, PAH is characterized by overexpression of NOTCH3 in PASMCs. It has been demonstrated that there is a link between NOTCH3 receptor signaling through HES5, cell proliferation, and a shift to an undifferentiated PASMC phenotype. Furthermore, TNC, EGF, PDGFA/PDGFB, and IGF1 are all believed to be significant in PAH development. Outcome effects: In conclusion, the final common outcome in PAH is the elevation of pulmonary vascular resistance mediated by vasoconstriction and obstructive cellular proliferation of PASMCs and endothelial cells. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. Organ: lung Organ_System: cardiovascular system PMID: 18596905 PMID: 19286424 PMID: 19555855 PMID: 19855400 PMID: 20833255 PMID: 21641060 PMID: 22401856 PMID: 23662189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-5756f1c0-23a3-4a43-909b-15346fe62931 Smooth Muscle Cell Dysfunction in Pulmonary Hypertension uuid-5756f1c0-23a3-4a43-909b-15346fe62931 PS:CellType vascular smooth muscle cell PS:Description The contraction and proliferation of pulmonary artery smooth muscle cells (PASMCs) are key processes in pulmonary artery hypertension (PAH) development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5756f1c0-23a3-4a43-909b-15346fe62931 PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. The contraction and proliferation of pulmonary artery smooth muscle cells (PASMCs) are key processes in PAH development. PAH is characterized by the decreased production of vasodilators and growth inhibitors such as nitric oxide (NO) and prostacyclin (PGI2) and the increased production of the vasoconstrictor/co-mitogens such as endothelin 1 (EDN1) and serotonin. Signaling description: The main mechanisms of contraction and proliferation induction in PASMCs are RHOA/ROCK1 activation, reactive oxygen spices (ROS) hyperproduction, intracellular calcium (Ca2+) overload, and the decreased expression/function of potassium (K+) channels. In PASMCs, vasoconstrictors activate G-protein-coupled receptors which trigger guanine nucleotide exchange factor (GEF) and induce RHOA. Then, RHOA activates ROCK1 which has multiple effects with the most widely studied being the inhibition of myosin light chain phosphatase (MLCP). This promotes the phosphorylation of MYL12B and as a result contraction occurs. ROCK1 is also involved in actin cytoskeleton dynamics through the phosphorylation of LIMK1/2, which in turn phosphorylates and inhibits CFL1, leading to smooth muscle cell actin (ACTA2) filament stabilization. This may have an impact on cell differentiation, proliferation, and migration. The expression of TAGLN and CNN1 are regulated by SRF and cofactors such as MYOCD and myocardin-related transcription factors (MKL1/2) which also influence the contractile phenotype in PASMCs. Conversely, the activation of RHOA/ROCK1 pathway increases PASMC proliferation. RHOA has been shown to be required for sustained Ras/MAPK1/3 activation. ROCK1 also causes decreased CDKN1A and CDKN1B expression. Serotonin has both contractile and mitogenic effects in PASMCs. The contractile action of serotonin is mediated via the activation of HTR1B, HTR2A, and HTR2B receptors. The mitogenic effect of serotonin requires internalization through the serotonin transporter, SLC6A4. The breakdown of serotonin by monoamine oxidase A (MAOA) results in the generation of ROS. Serotonin also induces ROS through the activation of NADPH oxidases (CYBB and NOX4) via RAC1. In addition, ROS is responsible for the nuclear translocation of phosphorylated MAPK1/3. Subsequently, phosphorylated MAPK1/3 binds transcription factors such as GATA4, EGR1, and ELK1 and thus increases the expression of proteins which are involved in cellular proliferation. In PASMCs, free Ca2+ concentration in the cytosol is an important determinant of contraction, migration, and proliferation. The cytosolic Ca2+ concentration can be increased by Ca2+ influx through voltage-dependent Ca2+ channels (CACNA1C) and transient receptor potential cation channels (TRPC1/3/6) in addition to Ca2+ release from sarcoplasmic reticulum through ITPR2 and RYR3. Ca2+/calmodulin complex activates MYLK leading to MYL12B phosphorylation and PASMC contraction. Also, the decreased expression and function of potassium (K+) channels (KCNA5 and KCNB1) leads to membrane depolarization and contributes to the sustained elevation of cytosol Ca2+. In addition, PAH is characterized by overexpression of NOTCH3 in PASMCs. It has been demonstrated that there is a link between NOTCH3 receptor signaling through HES5, cell proliferation, and a shift to an undifferentiated PASMC phenotype. Furthermore, TNC, EGF, PDGFA/PDGFB, and IGF1 are all believed to be significant in PAH development. Outcome effects: In conclusion, the final common outcome in PAH is the elevation of pulmonary vascular resistance mediated by vasoconstriction and obstructive cellular proliferation of PASMCs and endothelial cells. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 18596905 PS:PMID 19286424 PS:PMID 19555855 PS:PMID 19855400 PS:PMID 20833255 PS:PMID 21641060 PS:PMID 22401856 PS:PMID 23662189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Circadian clocks are molecular cell-autonomous clocks that maintain their own 24-hour molecular rhythm and drive the rhythmic expression of genes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-578838fb-b546-4cd7-81e7-b001fabb1843 NodeType: Pathway Notes: Headnote: Circadian clock is a molecular cell-autonomous regulator that maintains its own 24-hour molecular rhythm and drives the rhythmic expression of genes critical for the proper regulation of behavioral and physiological rhythms. Signaling description: Light is the most prominent stimulus capable of synchronizing circadian oscillations to the environment. The primary positive transcriptional elements in the circadian oscillator include CLOCK and ARNTL proteins. In neurons of suprachiasmatic nucleus of the anterior hypathalamus, the intracellular levels of CLOCK remain steady throughout the 24-hour period, whereas ARNTL expression levels are high at the beginning of a subjective day and low at the beginning of a subjective night. Outcome effects: The increased levels of ARNTL promote the formation of ARNTL-CLOCK heterodimers, which initiate the transcription of target genes containing CACGTG E-Box elements present in the promoters of CLOCK-driven genes. In some brain regions, NPAS2 substitutes for CLOCK. ARNTL-CLOCK activates the transcription of PER1/2/3 and CRY1/2 genes. PER proteins accumulate in the cytoplasm and can be phosphorylated by CSNK1E. The phosphorylated forms of PER are unstable and degraded by means of ubiquitylation. However late in the subjective day, CRY accumulates in the cytoplasm and promotes the formation of stable CSNK1E/PER/CRY complexes, which translocate back to the nucleus to repress their own transcription by disrupting the ARNTL-CLOCK complex. The interacting positive and negative feedback loops of circadian genes establish low levels of PER and CRY and a high level of ARNTL at the beginning of a new circadian day. Another regulatory loop is induced when ARNTL-CLOCK heterodimers activate the transcription of NR1D1 and RORA, two retinoic acid-related orphan nuclear receptors. NR1D1 and RORA compete to bind to the promoter of ARNTL. Since ARNTL homodimers are incapable of activating transcription, the susceptibility of the heterodimeric ARNTL-CLOCK to redox electron transfer through NADH and NAD potential establishes a molecular switch for activating the ARNTL-CLOCK transcription complex. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-578838fb-b546-4cd7-81e7-b001fabb1843 Circadian Clock in Sleep Regulation uuid-578838fb-b546-4cd7-81e7-b001fabb1843 PS:CellType neuron PS:Description Circadian clocks are molecular cell-autonomous clocks that maintain their own 24-hour molecular rhythm and drive the rhythmic expression of genes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-578838fb-b546-4cd7-81e7-b001fabb1843 PS:NodeType Pathway PS:Notes Headnote: Circadian clock is a molecular cell-autonomous regulator that maintains its own 24-hour molecular rhythm and drives the rhythmic expression of genes critical for the proper regulation of behavioral and physiological rhythms. Signaling description: Light is the most prominent stimulus capable of synchronizing circadian oscillations to the environment. The primary positive transcriptional elements in the circadian oscillator include CLOCK and ARNTL proteins. In neurons of suprachiasmatic nucleus of the anterior hypathalamus, the intracellular levels of CLOCK remain steady throughout the 24-hour period, whereas ARNTL expression levels are high at the beginning of a subjective day and low at the beginning of a subjective night. Outcome effects: The increased levels of ARNTL promote the formation of ARNTL-CLOCK heterodimers, which initiate the transcription of target genes containing CACGTG E-Box elements present in the promoters of CLOCK-driven genes. In some brain regions, NPAS2 substitutes for CLOCK. ARNTL-CLOCK activates the transcription of PER1/2/3 and CRY1/2 genes. PER proteins accumulate in the cytoplasm and can be phosphorylated by CSNK1E. The phosphorylated forms of PER are unstable and degraded by means of ubiquitylation. However late in the subjective day, CRY accumulates in the cytoplasm and promotes the formation of stable CSNK1E/PER/CRY complexes, which translocate back to the nucleus to repress their own transcription by disrupting the ARNTL-CLOCK complex. The interacting positive and negative feedback loops of circadian genes establish low levels of PER and CRY and a high level of ARNTL at the beginning of a new circadian day. Another regulatory loop is induced when ARNTL-CLOCK heterodimers activate the transcription of NR1D1 and RORA, two retinoic acid-related orphan nuclear receptors. NR1D1 and RORA compete to bind to the promoter of ARNTL. Since ARNTL homodimers are incapable of activating transcription, the susceptibility of the heterodimeric ARNTL-CLOCK to redox electron transfer through NADH and NAD potential establishes a molecular switch for activating the ARNTL-CLOCK transcription complex. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: B cells in lymphoid tissue obtain signals from T cells acting as antigen-presenting cells for the maturation of B cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57a4aead-b02a-4577-8d03-23ea051a3b24 NodeType: Pathway Notes: Headnote: B-cells in lymphoid tissue obtain signals from T-cells acting as antigen-presenting cells for the maturation of B-cells. T-dependent antigens are presented on MHC class II protein complex (MHC2) to a special subtype of T-cell calledTh2-cell, which are the main activators for B-cells. Signaling description: Th2-cells deliver antigens in the MHC2 complex to the B-cell receptor (BCR). BCR is a transmembrane protein complex composed of membrane immunoglobulin (IgM) and disulfide-linked heterodimers CD79A/CD79B. Activated by antigen, the BCR complex stimulates B-cell proliferation and differentiation. BCR can influence intracellular signaling through PLCG2/calcium/NFATC2, PI3K, IKBK/NF-kB, and canonical ERK (MAPK) signaling. Following antigen internalization and re-expression on their surface, B-cells can in the reverse order activate T-cells, which recognize a different part of the same antigen. In turn, T-cells produce cytokines Il2, Il4, and CD40 (B-cell growth factor), which leads to B-cell division and maturation to antibody secreting cells. The secretion of cytokines by T-cells is the second signal provided by T-cells for B-cell proliferation and differentiation into plasma cells. Outcome effects: Genetic recombination and isotype switching of immunoglobulin genes occurs during B-cell maturation. This is necessary for the initiation of transcription of immunoglobulins. The binding of CD40 on Bcells to the CD40 ligand (CD40LG) on T-cells induces isotype switching from the initial IgM response. AICDA expression is the primary step in the process of isotype switching of immunoglobulin genes. Cytokine-induced STAT6 is a transcription factor that also contributes to AICDA expression and immunoglobulin synthesis. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-57a4aead-b02a-4577-8d03-23ea051a3b24 T-Cell Dependent B-Cell Activation uuid-57a4aead-b02a-4577-8d03-23ea051a3b24 PS:CellType B-cell PS:Description B cells in lymphoid tissue obtain signals from T cells acting as antigen-presenting cells for the maturation of B cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57a4aead-b02a-4577-8d03-23ea051a3b24 PS:NodeType Pathway PS:Notes Headnote: B-cells in lymphoid tissue obtain signals from T-cells acting as antigen-presenting cells for the maturation of B-cells. T-dependent antigens are presented on MHC class II protein complex (MHC2) to a special subtype of T-cell calledTh2-cell, which are the main activators for B-cells. Signaling description: Th2-cells deliver antigens in the MHC2 complex to the B-cell receptor (BCR). BCR is a transmembrane protein complex composed of membrane immunoglobulin (IgM) and disulfide-linked heterodimers CD79A/CD79B. Activated by antigen, the BCR complex stimulates B-cell proliferation and differentiation. BCR can influence intracellular signaling through PLCG2/calcium/NFATC2, PI3K, IKBK/NF-kB, and canonical ERK (MAPK) signaling. Following antigen internalization and re-expression on their surface, B-cells can in the reverse order activate T-cells, which recognize a different part of the same antigen. In turn, T-cells produce cytokines Il2, Il4, and CD40 (B-cell growth factor), which leads to B-cell division and maturation to antibody secreting cells. The secretion of cytokines by T-cells is the second signal provided by T-cells for B-cell proliferation and differentiation into plasma cells. Outcome effects: Genetic recombination and isotype switching of immunoglobulin genes occurs during B-cell maturation. This is necessary for the initiation of transcription of immunoglobulins. The binding of CD40 on Bcells to the CD40 ligand (CD40LG) on T-cells induces isotype switching from the initial IgM response. AICDA expression is the primary step in the process of isotype switching of immunoglobulin genes. Cytokine-induced STAT6 is a transcription factor that also contributes to AICDA expression and immunoglobulin synthesis. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Mitochondrial SIRT3 plays role in reduction of oxidative damage. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57b08d98-a7e7-4958-a65a-d523c815b831 NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. Mitochondrial SIRT3 plays role in reduction of oxidative damage. Signaling description: SIRT3 requires NAD for its deacetylase activity. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT3 plays role in reduction of oxidative damage in the cell via regulation of mitochondrial enzymes as well as tricarboxylic acid cycle and overall cell signalings regulation. Outcome effects: NAD+ dependency of SIRT3 can provide the one of the link between metabolic activity and mitochondrial function during aging. SIRT3 also was shown to important in the caloric restriction - related prevention of age-related hearing loss in mammals. Mutated proteins: G477T polymorphism of the SIRT3 gene, was found in the elderly to be associated with longevity. See all references in ""Genes with Mutations Associated with Aging"" pathway. Organ: generic Organ_System: generic PMID: 23086954 PMID: 24046746 PMID: 26121691 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-57b08d98-a7e7-4958-a65a-d523c815b831 SIRT3 Signaling in Aging uuid-57b08d98-a7e7-4958-a65a-d523c815b831 PS:CellType generic PS:Description Mitochondrial SIRT3 plays role in reduction of oxidative damage. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57b08d98-a7e7-4958-a65a-d523c815b831 PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. Mitochondrial SIRT3 plays role in reduction of oxidative damage. Signaling description: SIRT3 requires NAD for its deacetylase activity. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT3 plays role in reduction of oxidative damage in the cell via regulation of mitochondrial enzymes as well as tricarboxylic acid cycle and overall cell signalings regulation. Outcome effects: NAD+ dependency of SIRT3 can provide the one of the link between metabolic activity and mitochondrial function during aging. SIRT3 also was shown to important in the caloric restriction - related prevention of age-related hearing loss in mammals. Mutated proteins: G477T polymorphism of the SIRT3 gene, was found in the elderly to be associated with longevity. See all references in ""Genes with Mutations Associated with Aging"" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 23086954 PS:PMID 24046746 PS:PMID 26121691 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: The synthesis of Abeta occurs mainly in the membranes of cellular vesicles in neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57b43235-77ad-4390-8079-e33a07002b97 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: APP gene encodes the precursor to amyloid beta (Abeta). The synthesis of Abeta occurs mainly in the membranes of cellular vesicles. The three major isoforms containing the Abeta sequence are produced by alternative splicing of the APP gene primary transcript. The two larger isoforms consisting of 751 and 770 amino acid residues (APP751 and APP770, respectively) contain a Kunitz protease inhibitor (KPI) domain and are ubiquitously expressed. The APP695 isoform does not contain a KPI domain and is predominantly expressed in neurons. The first scenario of APP processing does not include the formation of Abeta peptides, and thus is called non-amyloidogenic. APP is initially cleaved by alpha-secretase (ADAM9, ADAM10, and ADAM17) to generate C83 carboxyl-terminal fragment. Then C83 can also undergo cleavage by gamma-secretase into the peptide P3 and the APP intracellular domain (AICD). According to the alternative scenario, APP is cleaved sequentially by BACE1 and gamma-secretase, releasing an ectodomain and retaining the last 99 amino acids of APP (known as C99) within the membrane. The first amino acid of C99 is the first amino acid of Abeta. C99 is subsequently cleaved by gamma-secretase to 38-43 amino acids from the amino terminus to release Abeta. This cleavage predominantly produces amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42), at a ratio of 10:1. In the AD state, the altered structure of APP causes a release of higher amounts of the Abeta 42 following sequential cleavage by BACE1 and gamma-secretase. The presenilin proteins, PSEN1 and PSEN2, that are a part of the gamma-secretase complex may also be mutated and increase the yield of the neurotoxic form, Abeta 42. Mutations in APP, PSEN1, and PSEN2 account for the majority of early-onset familial AD cases. However, most AD cases are the late-onset sporadic form that cannot be explained by a defect in these genes. AICD is a product of both non-amyloidogenic and amyloidogenic processing and participates in the activation of transcription. It interacts with APBB1 and KAT5 to regulate transcription in the nucleus. The role of APP regarding intracellular signaling pathways is poorly understood. Outcome effects: Finally, Abeta 42 can be released into the extracellular space where they oligomerize into Abeta 40/42 and aggregate causing plaque formation. Mutated genes: Mutated genes are shown in white-out style. Organ_System: nervous system PMID: 10653281 PMID: 10959033 PMID: 14598315 PMID: 16256140 PMID: 17962197 PMID: 22086493 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-57b43235-77ad-4390-8079-e33a07002b97 APP Processing in Alzheimer Disease uuid-57b43235-77ad-4390-8079-e33a07002b97 PS:CellType neuron PS:Description The synthesis of Abeta occurs mainly in the membranes of cellular vesicles in neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57b43235-77ad-4390-8079-e33a07002b97 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: APP gene encodes the precursor to amyloid beta (Abeta). The synthesis of Abeta occurs mainly in the membranes of cellular vesicles. The three major isoforms containing the Abeta sequence are produced by alternative splicing of the APP gene primary transcript. The two larger isoforms consisting of 751 and 770 amino acid residues (APP751 and APP770, respectively) contain a Kunitz protease inhibitor (KPI) domain and are ubiquitously expressed. The APP695 isoform does not contain a KPI domain and is predominantly expressed in neurons. The first scenario of APP processing does not include the formation of Abeta peptides, and thus is called non-amyloidogenic. APP is initially cleaved by alpha-secretase (ADAM9, ADAM10, and ADAM17) to generate C83 carboxyl-terminal fragment. Then C83 can also undergo cleavage by gamma-secretase into the peptide P3 and the APP intracellular domain (AICD). According to the alternative scenario, APP is cleaved sequentially by BACE1 and gamma-secretase, releasing an ectodomain and retaining the last 99 amino acids of APP (known as C99) within the membrane. The first amino acid of C99 is the first amino acid of Abeta. C99 is subsequently cleaved by gamma-secretase to 38-43 amino acids from the amino terminus to release Abeta. This cleavage predominantly produces amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42), at a ratio of 10:1. In the AD state, the altered structure of APP causes a release of higher amounts of the Abeta 42 following sequential cleavage by BACE1 and gamma-secretase. The presenilin proteins, PSEN1 and PSEN2, that are a part of the gamma-secretase complex may also be mutated and increase the yield of the neurotoxic form, Abeta 42. Mutations in APP, PSEN1, and PSEN2 account for the majority of early-onset familial AD cases. However, most AD cases are the late-onset sporadic form that cannot be explained by a defect in these genes. AICD is a product of both non-amyloidogenic and amyloidogenic processing and participates in the activation of transcription. It interacts with APBB1 and KAT5 to regulate transcription in the nucleus. The role of APP regarding intracellular signaling pathways is poorly understood. Outcome effects: Finally, Abeta 42 can be released into the extracellular space where they oligomerize into Abeta 40/42 and aggregate causing plaque formation. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System nervous system PS:PMID 10653281 PS:PMID 10959033 PS:PMID 14598315 PS:PMID 16256140 PS:PMID 17962197 PS:PMID 22086493 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57bf280a-2e38-4bdc-a635-f9fb8b8a87e5 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-57bf280a-2e38-4bdc-a635-f9fb8b8a87e5 Respiratory chain and oxidative phosphorylation template uuid-57bf280a-2e38-4bdc-a635-f9fb8b8a87e5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57bf280a-2e38-4bdc-a635-f9fb8b8a87e5 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57edbd9f-7185-4ad6-8cf5-3b651417004e NodeType: Pathway Notes: Headnote: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Classical non-homologous end-joining (C-NHEJ) is a DNA repair process that joins non-homologous DNA ends together using the core components including DNA-PK complex (XRCC6, XRCC5, and PRKDC), Artemis, XRCC4, and DNA ligase IV. Signaling description: The MRN complex, which includes MRE11A, RAD50, and NBS1, is an early sensor of activation-induced cytidine deaminase (AICDA)-induced double-strand breaks (DSBs). The MRN complex localizes to damage sites where it recruits and activates serine-protein kinase ATM. Outcome effects: ATM phosphorylates NBS1 in the MRN complex and downstream DNA damage response proteins, thereby strengthening the DNA damage response. ATM also activates the phosphorylation of histone H2AFX and p53-binding protein 1 (TP53BP1) that mediate the synapsis of upstream and downstream DSBs. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-57edbd9f-7185-4ad6-8cf5-3b651417004e Immunoglobulin Class-Switch Recombination via Classical non-Homologous End-Joining uuid-57edbd9f-7185-4ad6-8cf5-3b651417004e PS:CellType B-cell PS:Description Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57edbd9f-7185-4ad6-8cf5-3b651417004e PS:NodeType Pathway PS:Notes Headnote: Class-switch recombination (CSR) of the immunoglobulin heavy chain locus is essential for the maturation of the antibody response. Classical non-homologous end-joining (C-NHEJ) is a DNA repair process that joins non-homologous DNA ends together using the core components including DNA-PK complex (XRCC6, XRCC5, and PRKDC), Artemis, XRCC4, and DNA ligase IV. Signaling description: The MRN complex, which includes MRE11A, RAD50, and NBS1, is an early sensor of activation-induced cytidine deaminase (AICDA)-induced double-strand breaks (DSBs). The MRN complex localizes to damage sites where it recruits and activates serine-protein kinase ATM. Outcome effects: ATM phosphorylates NBS1 in the MRN complex and downstream DNA damage response proteins, thereby strengthening the DNA damage response. ATM also activates the phosphorylation of histone H2AFX and p53-binding protein 1 (TP53BP1) that mediate the synapsis of upstream and downstream DSBs. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57fb5175-d9e8-456b-9888-1b289673bbb1 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue Tissue: epidermis urn:agi-pathway:uuid-57fb5175-d9e8-456b-9888-1b289673bbb1 Proteins Involved in Acne Vulgaris uuid-57fb5175-d9e8-456b-9888-1b289673bbb1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57fb5175-d9e8-456b-9888-1b289673bbb1 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: IL13/STAT6/ZEB1 signaling plays a critical role in the epithelial-mesenchymal transition, cell invasion and metastases in cancer. IL13 and it's receptors are regarded as potential therapeutic targets. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57ff93b2-c3e0-4e62-9568-92fd3de64d88 NodeType: Pathway Notes: Headnote: IL13 is produced by dendritic cells and Th2-cells and may activate it's receptors on the surface of cancer cells. Signaling description: IL13 acts on the receptor complex which consists of IL13RA1, IL13RA2 and IL4R and activates JAK/STAT6/ZEB1 signaling. ZEB1 controls expression of multiple proteins responsible for epithelial-mesenchymal transition and metastatic progression. Outcome effects: ZEB1 induces expression of CDH2, VIM, MMP9, FN1, TJP1 and inhibits expression of CDH1 thereby promoting cancer cell invasion and metastatic progression.Anti-IL13 monoclonal antibodies tralokinumab and lebrikizumab and anti-IL4R medicine AMG 317 are being investigated in clinical trials to prove their anti-cancer efficacy. Animal data: not shown Highlighted proteins: not shown. Mutated proteins: not shown. Organ_System: lymphatic system PMID: 24649010 PMID: 27533463 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-57ff93b2-c3e0-4e62-9568-92fd3de64d88 IL13/STAT6/ZEB1 Signalling Promotes Cancer Metastatic Progression uuid-57ff93b2-c3e0-4e62-9568-92fd3de64d88 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description IL13/STAT6/ZEB1 signaling plays a critical role in the epithelial-mesenchymal transition, cell invasion and metastases in cancer. IL13 and it's receptors are regarded as potential therapeutic targets. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-57ff93b2-c3e0-4e62-9568-92fd3de64d88 PS:NodeType Pathway PS:Notes Headnote: IL13 is produced by dendritic cells and Th2-cells and may activate it's receptors on the surface of cancer cells. Signaling description: IL13 acts on the receptor complex which consists of IL13RA1, IL13RA2 and IL4R and activates JAK/STAT6/ZEB1 signaling. ZEB1 controls expression of multiple proteins responsible for epithelial-mesenchymal transition and metastatic progression. Outcome effects: ZEB1 induces expression of CDH2, VIM, MMP9, FN1, TJP1 and inhibits expression of CDH1 thereby promoting cancer cell invasion and metastatic progression.Anti-IL13 monoclonal antibodies tralokinumab and lebrikizumab and anti-IL4R medicine AMG 317 are being investigated in clinical trials to prove their anti-cancer efficacy. Animal data: not shown Highlighted proteins: not shown. Mutated proteins: not shown. PS:Organ_System lymphatic system PS:PMID 24649010 PS:PMID 27533463 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58185dd4-5920-429e-a58b-0a1535a4daad NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-58185dd4-5920-429e-a58b-0a1535a4daad VEGFR->endothelial proliferation uuid-58185dd4-5920-429e-a58b-0a1535a4daad PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58185dd4-5920-429e-a58b-0a1535a4daad PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-581a6c41-65d0-4432-af5a-56a28275f879 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-581a6c41-65d0-4432-af5a-56a28275f879 TMPRSS2 inhibitors uuid-581a6c41-65d0-4432-af5a-56a28275f879 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-581a6c41-65d0-4432-af5a-56a28275f879 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58321822-6588-4a6a-ab80-bfaa41f95842 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-58321822-6588-4a6a-ab80-bfaa41f95842 OSM/OSMR Expression Targets uuid-58321822-6588-4a6a-ab80-bfaa41f95842 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58321822-6588-4a6a-ab80-bfaa41f95842 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Many studies support a diabetogenic role for conventional dendritic cells (cDCs) in the initiation steps of type 1 diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-583ad15f-ae84-469c-9b52-e4aaac9fd607 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: There is ample evidence for a diabetogenic role of conventional dendritic cells (cDCs) in the initiatory steps of type 1 diabetes. Studies confirm that self-antigens released after beta-cell death are taken up by cDCs in the pancreatic islets and are processed and presented to islet-specific T-cells in the pancreatic lymph nodes with the involvement of TLR2. Outcome effects: cDCs-mediated presentation of beta-cell antigens to T-cells initiates the diabetogenic response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system PMID: 20577267 PMID: 21712017 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-583ad15f-ae84-469c-9b52-e4aaac9fd607 Conventional Dendritic Cell Role in Diabetes Mellitus Type 1 uuid-583ad15f-ae84-469c-9b52-e4aaac9fd607 PS:CellType dendritic cell PS:Description Many studies support a diabetogenic role for conventional dendritic cells (cDCs) in the initiation steps of type 1 diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-583ad15f-ae84-469c-9b52-e4aaac9fd607 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: There is ample evidence for a diabetogenic role of conventional dendritic cells (cDCs) in the initiatory steps of type 1 diabetes. Studies confirm that self-antigens released after beta-cell death are taken up by cDCs in the pancreatic islets and are processed and presented to islet-specific T-cells in the pancreatic lymph nodes with the involvement of TLR2. Outcome effects: cDCs-mediated presentation of beta-cell antigens to T-cells initiates the diabetogenic response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:PMID 20577267 PS:PMID 21712017 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-583ef388-3617-43b8-b412-f4969477ed5c NodeType: Pathway Notes: The excess levels of triglycerides in adipose tissue caused by a highfat diet provoke local inflammation. However, the precise molecular mechanism underlying this phenomenon remains elusive. Pathway 4. Insulin resistance: Inflammation-related insulin resistance (Fig. 8). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-583ef388-3617-43b8-b412-f4969477ed5c 4_2_Insulin resistance: inflammation-related insulin resistance uuid-583ef388-3617-43b8-b412-f4969477ed5c PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-583ef388-3617-43b8-b412-f4969477ed5c PS:NodeType Pathway PS:Notes The excess levels of triglycerides in adipose tissue caused by a highfat diet provoke local inflammation. However, the precise molecular mechanism underlying this phenomenon remains elusive. Pathway 4. Insulin resistance: Inflammation-related insulin resistance (Fig. 8). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5865c014-3b3c-44c3-8dca-630f59357fdf NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-5865c014-3b3c-44c3-8dca-630f59357fdf Proteins Involved in Low-Grade Serous Ovarian Carcinoma uuid-5865c014-3b3c-44c3-8dca-630f59357fdf PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5865c014-3b3c-44c3-8dca-630f59357fdf PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-586bb0f6-691f-420d-8147-a7917d1b6c61 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PMID: 11585703 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-586bb0f6-691f-420d-8147-a7917d1b6c61 HIF1 Signaling uuid-586bb0f6-691f-420d-8147-a7917d1b6c61 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-586bb0f6-691f-420d-8147-a7917d1b6c61 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 11585703 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5876a175-f4fb-4d1d-9ce7-a56393067cad NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-5876a175-f4fb-4d1d-9ce7-a56393067cad Elevated Receptors -> Expression Targets in Blood vessel uuid-5876a175-f4fb-4d1d-9ce7-a56393067cad PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5876a175-f4fb-4d1d-9ce7-a56393067cad PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Glycolysis is the metabolic pathway that converts glucose to pyruvate. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58b7afd4-a08d-450a-aadb-b5227e743518 NodeType: Pathway Notes: Headnote: Glycolysis is the metabolic pathway that converts glucose to pyruvate. Glycolysis can occur with or without oxygen. In the presence of oxygen, glycolysis is the first stage of cellular respiration. Signaling description: Glycolysis includes ten reactions involving ten intermediate compounds. The intermediates provide entry points to glycolysis and can be divided into two phases including preparatory and pay-off. The first five reactions are regarded as the preparatory phase resulting in the formation of two three-carbon sugar phosphates such as dihydroxyacetone-P and glyceraldehyde-3-P. The pay-off phase leads to the production of pyruvate, ATP, and NAPH. There are several enzymes catalyzing the same reactions which indicate that different protein isomers exist in different tissues. Outcome effects: In addition to pyruvate, which enters the following stages of energy metabolism, glycolysis also yields two molecules of ATP and two high energy electrons carrying molecules of NADH. References: 1). Berg JM, Tymoczko JL, Stryer L. (2007) Biochemistry (6th ed.). New York: Freeman. p. 622. 2). Garrett R, Grisham CM (2005) Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. p.584. Organ: generic Organ_System: generic PMID: 23159371 PMID: 26273330 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-58b7afd4-a08d-450a-aadb-b5227e743518 Glycolysis uuid-58b7afd4-a08d-450a-aadb-b5227e743518 PS:CellType generic PS:Description Glycolysis is the metabolic pathway that converts glucose to pyruvate. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58b7afd4-a08d-450a-aadb-b5227e743518 PS:NodeType Pathway PS:Notes Headnote: Glycolysis is the metabolic pathway that converts glucose to pyruvate. Glycolysis can occur with or without oxygen. In the presence of oxygen, glycolysis is the first stage of cellular respiration. Signaling description: Glycolysis includes ten reactions involving ten intermediate compounds. The intermediates provide entry points to glycolysis and can be divided into two phases including preparatory and pay-off. The first five reactions are regarded as the preparatory phase resulting in the formation of two three-carbon sugar phosphates such as dihydroxyacetone-P and glyceraldehyde-3-P. The pay-off phase leads to the production of pyruvate, ATP, and NAPH. There are several enzymes catalyzing the same reactions which indicate that different protein isomers exist in different tissues. Outcome effects: In addition to pyruvate, which enters the following stages of energy metabolism, glycolysis also yields two molecules of ATP and two high energy electrons carrying molecules of NADH. References: 1). Berg JM, Tymoczko JL, Stryer L. (2007) Biochemistry (6th ed.). New York: Freeman. p. 622. 2). Garrett R, Grisham CM (2005) Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. p.584. PS:Organ generic PS:Organ_System generic PS:PMID 23159371 PS:PMID 26273330 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58baf52d-b145-4661-8882-0de1a5a087dc NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-58baf52d-b145-4661-8882-0de1a5a087dc Panic Disorder: Posible Role of GABA uuid-58baf52d-b145-4661-8882-0de1a5a087dc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58baf52d-b145-4661-8882-0de1a5a087dc PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Type 1 diabetes mellitus is an autoimmune pathology caused by autoreactive CD8 cytotoxic T-lymphocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58cac525-125e-4954-96b7-c11fb302f385 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Type 1 diabetes mellitus is an autoimmune pathology in which autoreactive CD8 cytotoxic T-lymphocytes destroy pancreatic beta-cells. Signaling description: In diabetes, autoreactive CD8 T-lymphocytes do not undergo suppression by regulatory T (Treg) cells due to mutations in genes critical for Treg maturation. A viral infection may serve as a trigger for type 1 diabetes by initiating an autoimmune reaction against pancreatic beta-cells. Autoaggressive CD8 cytotoxic T-lymphocytes kill pancreatic beta-cells in their usual manner. The recognition of the MHC class I protein complex with self-antigens on the surface of beta-cells, as well as CD2-CD58 and ITGAL-ICAM1 interaction result in T-cell activation, release of granzymes (GZMA/GZMB), and the synthesis of FASLG and IFNG. Outcome effects: Further, FASLG, GZMB, IFNG, IL1B and LTA promote apoptosis. IFNG binds to IFNGR1 on the surface of B-cells. The receptor activates JAK1 and JAK2 which transduce the signal to STAT1, a positive transcriptional regulator of IRF1. In turn, IRF1 binds to the CASP1 promoter, and, further CASP1 cleaves and activates CASP3 which initiates apoptosis. Macrophage-derived TNFB (LTA) and IL1B also contribute to the beta-cell death. LTA binds to its receptor, TNFRSF1A and the resulting signal transduction occurs through the TRADD/FADD/CASP8/CASP10 and TRADD/RIPK1/CRADD/CASP2 pathways. IL1B markedly stimulates the induction of IL1R1 which precedes the induction of NOS2. Nitric oxide (NO) generated by NOS2 triggers TP53 expression which initiates apoptosis. Low amounts of IL1RN (IL1R1 inactivator) were shown to be present in in diabetic patients. GZMA/GZMB and perforin (PRF1) are proteins released by the CD8 cytotoxic T cells which can induce apoptosis in target cells by forming transmembrane pores, as well as through the cleavage of the effector caspases such as CASP3. In addition, there is a caspase-independent mechanism of GZMB-mediated apoptosis with the DFFB involvement. DFFB is activated through the cleavage of its associated inhibitor, DFFA by CASP3. Then, DFFB is able to interact with entities such as topoisomerase II (TOP2B) to condense chromatin leading to DNA fragmentation and ultimately apoptosis. The binding of FAS to oligimerized FASLG on another cell activates apoptotic signaling through the cytoplasmic domain termed the death domain which interacts with signaling adaptors including FADD and DAXX to activate the caspase proteolytic cascade. First, CASP8 and CASP10 are activated then they cleave and activate downstream caspases and several cellular substrates, which leads to cell death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: pancreas Organ_System: endocrine system PMID: 15464423 PMID: 16306347 PMID: 18438526 PMID: 20217509 PMID: 20424842 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-58cac525-125e-4954-96b7-c11fb302f385 beta-Cell Destruction in Diabetes Mellitus Type 1 uuid-58cac525-125e-4954-96b7-c11fb302f385 PS:CellType insulin-secreting cell PS:Description Type 1 diabetes mellitus is an autoimmune pathology caused by autoreactive CD8 cytotoxic T-lymphocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58cac525-125e-4954-96b7-c11fb302f385 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Type 1 diabetes mellitus is an autoimmune pathology in which autoreactive CD8 cytotoxic T-lymphocytes destroy pancreatic beta-cells. Signaling description: In diabetes, autoreactive CD8 T-lymphocytes do not undergo suppression by regulatory T (Treg) cells due to mutations in genes critical for Treg maturation. A viral infection may serve as a trigger for type 1 diabetes by initiating an autoimmune reaction against pancreatic beta-cells. Autoaggressive CD8 cytotoxic T-lymphocytes kill pancreatic beta-cells in their usual manner. The recognition of the MHC class I protein complex with self-antigens on the surface of beta-cells, as well as CD2-CD58 and ITGAL-ICAM1 interaction result in T-cell activation, release of granzymes (GZMA/GZMB), and the synthesis of FASLG and IFNG. Outcome effects: Further, FASLG, GZMB, IFNG, IL1B and LTA promote apoptosis. IFNG binds to IFNGR1 on the surface of B-cells. The receptor activates JAK1 and JAK2 which transduce the signal to STAT1, a positive transcriptional regulator of IRF1. In turn, IRF1 binds to the CASP1 promoter, and, further CASP1 cleaves and activates CASP3 which initiates apoptosis. Macrophage-derived TNFB (LTA) and IL1B also contribute to the beta-cell death. LTA binds to its receptor, TNFRSF1A and the resulting signal transduction occurs through the TRADD/FADD/CASP8/CASP10 and TRADD/RIPK1/CRADD/CASP2 pathways. IL1B markedly stimulates the induction of IL1R1 which precedes the induction of NOS2. Nitric oxide (NO) generated by NOS2 triggers TP53 expression which initiates apoptosis. Low amounts of IL1RN (IL1R1 inactivator) were shown to be present in in diabetic patients. GZMA/GZMB and perforin (PRF1) are proteins released by the CD8 cytotoxic T cells which can induce apoptosis in target cells by forming transmembrane pores, as well as through the cleavage of the effector caspases such as CASP3. In addition, there is a caspase-independent mechanism of GZMB-mediated apoptosis with the DFFB involvement. DFFB is activated through the cleavage of its associated inhibitor, DFFA by CASP3. Then, DFFB is able to interact with entities such as topoisomerase II (TOP2B) to condense chromatin leading to DNA fragmentation and ultimately apoptosis. The binding of FAS to oligimerized FASLG on another cell activates apoptotic signaling through the cytoplasmic domain termed the death domain which interacts with signaling adaptors including FADD and DAXX to activate the caspase proteolytic cascade. First, CASP8 and CASP10 are activated then they cleave and activate downstream caspases and several cellular substrates, which leads to cell death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 15464423 PS:PMID 16306347 PS:PMID 18438526 PS:PMID 20217509 PS:PMID 20424842 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58efba05-e91a-485f-9651-84f50f86e7b5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-58efba05-e91a-485f-9651-84f50f86e7b5 Ataxias: Classification uuid-58efba05-e91a-485f-9651-84f50f86e7b5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-58efba05-e91a-485f-9651-84f50f86e7b5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59088b97-83e3-4dd4-b647-2e4f5776ec9d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-59088b97-83e3-4dd4-b647-2e4f5776ec9d Hexose transformations template uuid-59088b97-83e3-4dd4-b647-2e4f5776ec9d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59088b97-83e3-4dd4-b647-2e4f5776ec9d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: Hepatocellular carcinoma (HCC) is one of most lethal cancers. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-592ff107-2bcb-4742-a7ba-a7525448d59d NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. The transmembrane receptors NOTCH (1-4) interact with surface-bound ligands including JAG1, JAG2, DLL1, and DLL4. NOTCH1 has been identified as a proto-oncogene HCC is characterized by the overexpression of NOTCH1. Activated membrane-bound NOTCH1 receptor is cleaved by gamma-secretase complex and ADAM17. NOTCH intracellular domain (NICD) is transported to the nucleus and participates in the formation of chromatin remodeling complexes including KAT2B/MYSM1 and KAT2A/TADA2A/TADA3. Outcome effects: The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of hepatocytes. In addition, NICD interacts with LEF1/TCF4/CTNNB1 and SMAD2/3/4 complexes which induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 20175032 PMID: 22212931 PMID: 23426905 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-592ff107-2bcb-4742-a7ba-a7525448d59d NOTCH Signaling in Hepatocellular Carcinoma uuid-592ff107-2bcb-4742-a7ba-a7525448d59d PS:CellType cancer cell PS:CellType hepatocyte PS:Description Hepatocellular carcinoma (HCC) is one of most lethal cancers. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-592ff107-2bcb-4742-a7ba-a7525448d59d PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. The transmembrane receptors NOTCH (1-4) interact with surface-bound ligands including JAG1, JAG2, DLL1, and DLL4. NOTCH1 has been identified as a proto-oncogene HCC is characterized by the overexpression of NOTCH1. Activated membrane-bound NOTCH1 receptor is cleaved by gamma-secretase complex and ADAM17. NOTCH intracellular domain (NICD) is transported to the nucleus and participates in the formation of chromatin remodeling complexes including KAT2B/MYSM1 and KAT2A/TADA2A/TADA3. Outcome effects: The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of hepatocytes. In addition, NICD interacts with LEF1/TCF4/CTNNB1 and SMAD2/3/4 complexes which induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 20175032 PS:PMID 22212931 PS:PMID 23426905 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: BMP2 regulates pulmonary artery smooth muscle cell (PASMC) cytoskeleton organization and motility via consecutive canonical and non-canonical WNT signaling activation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59478af5-8922-4e1b-9735-8b74495e791a NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 regulates pulmonary artery smooth muscle cell (PASMC) cytoskeleton organization and motility via consecutive canonical and non-canonical WNT signaling activation. BMP2 triggers beta-catenin (CTNNB1) accumulation via AKT1-mediated GSK3B inhibition followed by the production and release of fibronectin (FN1) to the extracellular space. Outcome effects: FN1 binds to the VLA-4 receptor and activates ILK leading to the formation of a complex between ILK and DVL1 with subsequent RHOA and RAC1 activation and cytoskeleton rearrangement. Organ: lung Organ_System: cardiovascular system PMID: 21220513 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-59478af5-8922-4e1b-9735-8b74495e791a BMP2 and WNT Signaling in Pulmonary Artery Smooth Muscle Cells uuid-59478af5-8922-4e1b-9735-8b74495e791a PS:CellType vascular smooth muscle cell PS:Description BMP2 regulates pulmonary artery smooth muscle cell (PASMC) cytoskeleton organization and motility via consecutive canonical and non-canonical WNT signaling activation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59478af5-8922-4e1b-9735-8b74495e791a PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 regulates pulmonary artery smooth muscle cell (PASMC) cytoskeleton organization and motility via consecutive canonical and non-canonical WNT signaling activation. BMP2 triggers beta-catenin (CTNNB1) accumulation via AKT1-mediated GSK3B inhibition followed by the production and release of fibronectin (FN1) to the extracellular space. Outcome effects: FN1 binds to the VLA-4 receptor and activates ILK leading to the formation of a complex between ILK and DVL1 with subsequent RHOA and RAC1 activation and cytoskeleton rearrangement. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 21220513 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5956eba0-16b7-487f-ab16-118bce99a12c NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5956eba0-16b7-487f-ab16-118bce99a12c NOTCH -> EP300/ASCL Signaling uuid-5956eba0-16b7-487f-ab16-118bce99a12c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5956eba0-16b7-487f-ab16-118bce99a12c PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5969ca17-723f-4b83-922a-d7be8ff558cf NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-5969ca17-723f-4b83-922a-d7be8ff558cf BDKRB1/2 -> Vasodilation uuid-5969ca17-723f-4b83-922a-d7be8ff558cf PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5969ca17-723f-4b83-922a-d7be8ff558cf PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59742028-1d81-4029-9d6b-cd2867ecd0bf NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-59742028-1d81-4029-9d6b-cd2867ecd0bf NSP15 interactions uuid-59742028-1d81-4029-9d6b-cd2867ecd0bf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59742028-1d81-4029-9d6b-cd2867ecd0bf PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: High concentrations of phenylalanine in the brain disrupt protein and cholesterol biosynthesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5976df4a-aa72-48ff-9bda-8d27631ce2ee NodeType: Pathway Notes: Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. In addition, PKU is characterized by impaired myelination. Signaling description: Protein and cholesterol are essential parts of myelin. High concentrations of phenylalanine in the brain may disrupt protein and cholesterol biosynthesis. Phenylalanine enters the brain using the L-type amino acid transporter SLC7A5 in competition with other L-type amino acids (valine, isoleucine, leucine, and methionine). Outcome effects: In PKU, increased levels of L-phenylalanine in the brain coincide with the lack of other large L-type amino acids which may cause a disruption of proper protein biosynthesis in the neuron. Also, phenylalanine at high concentrations reduces the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-controlling enzyme of cholesterol synthesis. Cholesterol is one of the primary constituents of the myelin lipid, thus decreased HMGCR activity results in reduced myelination in PKU. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 11043156 PMID: 19191004 PMID: 19201235 PMID: 20123477 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5976df4a-aa72-48ff-9bda-8d27631ce2ee Myelination Impairement in Phenylketonuria uuid-5976df4a-aa72-48ff-9bda-8d27631ce2ee PS:CellType neuron PS:Description High concentrations of phenylalanine in the brain disrupt protein and cholesterol biosynthesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5976df4a-aa72-48ff-9bda-8d27631ce2ee PS:NodeType Pathway PS:Notes Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. In addition, PKU is characterized by impaired myelination. Signaling description: Protein and cholesterol are essential parts of myelin. High concentrations of phenylalanine in the brain may disrupt protein and cholesterol biosynthesis. Phenylalanine enters the brain using the L-type amino acid transporter SLC7A5 in competition with other L-type amino acids (valine, isoleucine, leucine, and methionine). Outcome effects: In PKU, increased levels of L-phenylalanine in the brain coincide with the lack of other large L-type amino acids which may cause a disruption of proper protein biosynthesis in the neuron. Also, phenylalanine at high concentrations reduces the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-controlling enzyme of cholesterol synthesis. Cholesterol is one of the primary constituents of the myelin lipid, thus decreased HMGCR activity results in reduced myelination in PKU. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 11043156 PS:PMID 19191004 PS:PMID 19201235 PS:PMID 20123477 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59a8ca1d-d8b5-4410-8ae1-d64e2b78cf96 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-59a8ca1d-d8b5-4410-8ae1-d64e2b78cf96 IFNB1/IFNR Expression Targets uuid-59a8ca1d-d8b5-4410-8ae1-d64e2b78cf96 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59a8ca1d-d8b5-4410-8ae1-d64e2b78cf96 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59ba40d1-90a6-49ea-a434-04fed1d3c0c0 NodeType: Pathway Notes: Different molecular mechanisms increase vasoconstriction and weaken vasodilation in PAH. Dysfunction of endothelial cells shifts the balance to vasoconstriction and is present in all types of PAH. The decreased production of NO and prostacyclin by endothelial cells provokes vasoconstriction. Increased secretion of the EDN1, vascular endothelial growth factor A (VEGFA), and serotonin causes endothelial cell proliferation, which in turn leads to artery lumen narrowing and a predisposition to thrombosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-59ba40d1-90a6-49ea-a434-04fed1d3c0c0 1_Endothelial cells stimulate vasoconstriction and thrombosis in pulmonary hypertension uuid-59ba40d1-90a6-49ea-a434-04fed1d3c0c0 PS:CellType endothelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59ba40d1-90a6-49ea-a434-04fed1d3c0c0 PS:NodeType Pathway PS:Notes Different molecular mechanisms increase vasoconstriction and weaken vasodilation in PAH. Dysfunction of endothelial cells shifts the balance to vasoconstriction and is present in all types of PAH. The decreased production of NO and prostacyclin by endothelial cells provokes vasoconstriction. Increased secretion of the EDN1, vascular endothelial growth factor A (VEGFA), and serotonin causes endothelial cell proliferation, which in turn leads to artery lumen narrowing and a predisposition to thrombosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59bc4c9b-80d0-4db8-8733-e7a73fd66d70 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-59bc4c9b-80d0-4db8-8733-e7a73fd66d70 B-Cell Receptor -> NF-kB Signaling uuid-59bc4c9b-80d0-4db8-8733-e7a73fd66d70 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59bc4c9b-80d0-4db8-8733-e7a73fd66d70 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59bc7047-f9d1-49ea-a168-26a93b985ae3 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-59bc7047-f9d1-49ea-a168-26a93b985ae3 Genes with Mutations Associated with Muscular Dystrophy, Facioscapulohumeral uuid-59bc7047-f9d1-49ea-a168-26a93b985ae3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59bc7047-f9d1-49ea-a168-26a93b985ae3 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59c47e8b-a9d7-4a2b-a245-922c1d900db7 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-59c47e8b-a9d7-4a2b-a245-922c1d900db7 Asp/Asn metabolism template uuid-59c47e8b-a9d7-4a2b-a245-922c1d900db7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59c47e8b-a9d7-4a2b-a245-922c1d900db7 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59f3a1b9-702c-4ecc-96f9-aaef48ac6cae NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-59f3a1b9-702c-4ecc-96f9-aaef48ac6cae TGFA -> CTNNB/CTNND Expression Targets uuid-59f3a1b9-702c-4ecc-96f9-aaef48ac6cae PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-59f3a1b9-702c-4ecc-96f9-aaef48ac6cae PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a077cbe-cc53-494b-bb37-fb58bd225b3a NodeType: Pathway Notes: Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors, whose type and copy number vary from cell to cell. Signaling description: The two major NK cell-mediated responses include the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. Along with a positive feedback loop, NK cell activator receptors act through the phosphorylation of VAVs and actin organization. A number of coactivating receptors have been implicated in NK cell activation. Non-ITAM or ITSM motif stimulatory receptors such as CD226 receptor alone are not sufficient to induce activation of NK cells; however the engagement of specific pairwise combinations of receptors can induce synergistic intracellular calcium mobilization as well as degranulation and cytokine production. Outcome effects: CD2 receptor can rapidly activate lipid raft formation and actin-dependent clustering of activator receptors. The adhesion receptors including ITGA5, ITGA4, and ITGB1 may also contribute to NK cell activation. CD226 and ITGB2 can rapidly induce signals for the activation of ITGB2 thus promoting adhesion between NK cells and a target cell. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-5a077cbe-cc53-494b-bb37-fb58bd225b3a Natural Killer Cell Activation through Integrins and non-ITAM-Containing Receptors uuid-5a077cbe-cc53-494b-bb37-fb58bd225b3a PS:CellType natural killer cell PS:Description Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a077cbe-cc53-494b-bb37-fb58bd225b3a PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors, whose type and copy number vary from cell to cell. Signaling description: The two major NK cell-mediated responses include the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. Along with a positive feedback loop, NK cell activator receptors act through the phosphorylation of VAVs and actin organization. A number of coactivating receptors have been implicated in NK cell activation. Non-ITAM or ITSM motif stimulatory receptors such as CD226 receptor alone are not sufficient to induce activation of NK cells; however the engagement of specific pairwise combinations of receptors can induce synergistic intracellular calcium mobilization as well as degranulation and cytokine production. Outcome effects: CD2 receptor can rapidly activate lipid raft formation and actin-dependent clustering of activator receptors. The adhesion receptors including ITGA5, ITGA4, and ITGB1 may also contribute to NK cell activation. CD226 and ITGB2 can rapidly induce signals for the activation of ITGB2 thus promoting adhesion between NK cells and a target cell. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: The overexpression of LRP6, FZD7, TCF4, HIF1A, and mutations in APC, AXIN1, CTNNB1 genes are associated with Hepatocellular Carcinoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a37862f-1f2e-4177-848b-e1f7b3c13d63 NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: WNT/beta-catenin (WNT/CTNNB1) signaling pathway controls various cellular functions including proliferation, differentiation, and migration. It has been demonstrated that the overexpression of LRP6, FZD7, TCF4, and HIF1A in addition to mutations of APC, AXIN1, and CTNNB1 genes are associated with HCC. In the absence of WNT proteins, CTNNB1 is related to a complex that consists of APC, AXIN1, GSK3B, and CSNK1A1. This complex formation induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B which leads to the ubiquitination and degradation of CTNNB1 protein by the proteasome. When WNT proteins bind to LRP5/6 and FZD7, DVL1 is activated and inhibits GSK3B which results in the stabilization of cytosolic CTNNB1 protein. In addition, transcription factor HIF1A modulates WNT/CTNNB1 signaling by enhancing CTNNB1 activation. Outcome effects: Activated CTNNB1 protein translocates into the nucleus where it interacts with TCF4/LEF1 to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. The constitutive activation of WNT/CTNNB1 signaling pathway leads to loss of differentiation, redundant proliferation, and migration of hepatocytes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 20175032 PMID: 22212931 PMID: 23426905 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-5a37862f-1f2e-4177-848b-e1f7b3c13d63 WNT Signaling in Hepatocellular Carcinoma uuid-5a37862f-1f2e-4177-848b-e1f7b3c13d63 PS:CellType cancer cell PS:CellType hepatocyte PS:Description The overexpression of LRP6, FZD7, TCF4, HIF1A, and mutations in APC, AXIN1, CTNNB1 genes are associated with Hepatocellular Carcinoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a37862f-1f2e-4177-848b-e1f7b3c13d63 PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: WNT/beta-catenin (WNT/CTNNB1) signaling pathway controls various cellular functions including proliferation, differentiation, and migration. It has been demonstrated that the overexpression of LRP6, FZD7, TCF4, and HIF1A in addition to mutations of APC, AXIN1, and CTNNB1 genes are associated with HCC. In the absence of WNT proteins, CTNNB1 is related to a complex that consists of APC, AXIN1, GSK3B, and CSNK1A1. This complex formation induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B which leads to the ubiquitination and degradation of CTNNB1 protein by the proteasome. When WNT proteins bind to LRP5/6 and FZD7, DVL1 is activated and inhibits GSK3B which results in the stabilization of cytosolic CTNNB1 protein. In addition, transcription factor HIF1A modulates WNT/CTNNB1 signaling by enhancing CTNNB1 activation. Outcome effects: Activated CTNNB1 protein translocates into the nucleus where it interacts with TCF4/LEF1 to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. The constitutive activation of WNT/CTNNB1 signaling pathway leads to loss of differentiation, redundant proliferation, and migration of hepatocytes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 20175032 PS:PMID 22212931 PS:PMID 23426905 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a47d62b-3013-473a-a153-32e203bd8753 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5a47d62b-3013-473a-a153-32e203bd8753 Bile acids synthesis template uuid-5a47d62b-3013-473a-a153-32e203bd8753 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a47d62b-3013-473a-a153-32e203bd8753 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: Osteopetrosis is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a58516e-454f-49a6-8384-fa7b2529873e NodeType: Pathway Notes: Headnote: Osteopetrosis (known as marble bone disease) is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. Osteopetrotic conditions vary in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure, to the incidental finding of osteopetrosis on radiographs. Osteopetrosis is caused by the failure of osteoclast development or function. Mutations in at least 10 genes have been identified as causative in humans. Signaling description: Many forms of osteoclast-rich osteopetrosis are caused by defects in gene products involved in the acidification machinery.Acid secretion is dependent on two key molecules which facilitate proton transport: vacuolar proton-transporting V-ATPase and chloride-specific ion channel, CLCN7. Mutations in the genes encoding the subunit of V-ATPase (TCIRG1) and CLCN7 produce severe malignant osteopetrosis. CLCN7 is closely associated with another membrane protein, OSTM1. Mutations in OSTM1 gene are found in a subset of autosomal recessive osteopetrosis (ARO) patients with neurological involvement. The protons and chloride ions that are expended in the acidification process need to be replenished intracellularly to avoid alkalization. This is achieved by carbonic anhydrase type II (CA2) and an anion exchanger. CA2 plays a key role in kidney function and mutations in CA2 result in ARO with tubular acidosis. In addition, homozygous mutations in CTSK gene lead to pycnodysostosis, a condition accompanied by osteopetrosis. The formation and maintenance of osteoclast polarized membrane domains requires complex vesicular trafficking mechanisms and continuous remodeling of the osteoclast cytoskeleton. PLEKHM1 plays a critical function in vesicle trafficking and acidification. Heterozygous mutations in this gene have been associated with intermediate forms of osteopetrosis. Furthermore, TNFSF11 and TNFRSF11A gene mutations lead to failure of osteoclast differentiation and function. IKBKG mutations cause osteopetrosis with ectodermal dysplasia and immune defects. Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which plays a role in WNT signaling. Outcome effects: The impairment of WNT signaling has been shown to cause osteopetrosis. PORCN mutations are associated with osteopathia striata in Goltz Syndrome, while FAM123B mutations are linked to osteopathia striata with cranial stenosis. OSTM1 regulates CTNNB1/LEF1 interaction and causes rare forms of osteopetrosis. LRP1 mutations also lead to rare forms of the disorder. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 16525474 PMID: 17936098 PMID: 19232111 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-5a58516e-454f-49a6-8384-fa7b2529873e Osteoclasts Function in Osteopetrosis uuid-5a58516e-454f-49a6-8384-fa7b2529873e PS:CellType osteoclast PS:Description Osteopetrosis is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a58516e-454f-49a6-8384-fa7b2529873e PS:NodeType Pathway PS:Notes Headnote: Osteopetrosis (known as marble bone disease) is a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. Osteopetrotic conditions vary in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure, to the incidental finding of osteopetrosis on radiographs. Osteopetrosis is caused by the failure of osteoclast development or function. Mutations in at least 10 genes have been identified as causative in humans. Signaling description: Many forms of osteoclast-rich osteopetrosis are caused by defects in gene products involved in the acidification machinery.Acid secretion is dependent on two key molecules which facilitate proton transport: vacuolar proton-transporting V-ATPase and chloride-specific ion channel, CLCN7. Mutations in the genes encoding the subunit of V-ATPase (TCIRG1) and CLCN7 produce severe malignant osteopetrosis. CLCN7 is closely associated with another membrane protein, OSTM1. Mutations in OSTM1 gene are found in a subset of autosomal recessive osteopetrosis (ARO) patients with neurological involvement. The protons and chloride ions that are expended in the acidification process need to be replenished intracellularly to avoid alkalization. This is achieved by carbonic anhydrase type II (CA2) and an anion exchanger. CA2 plays a key role in kidney function and mutations in CA2 result in ARO with tubular acidosis. In addition, homozygous mutations in CTSK gene lead to pycnodysostosis, a condition accompanied by osteopetrosis. The formation and maintenance of osteoclast polarized membrane domains requires complex vesicular trafficking mechanisms and continuous remodeling of the osteoclast cytoskeleton. PLEKHM1 plays a critical function in vesicle trafficking and acidification. Heterozygous mutations in this gene have been associated with intermediate forms of osteopetrosis. Furthermore, TNFSF11 and TNFRSF11A gene mutations lead to failure of osteoclast differentiation and function. IKBKG mutations cause osteopetrosis with ectodermal dysplasia and immune defects. Osteoblasts regulate osteoclast function through the production of paracrine factors, mainly TNFSF11, which plays a role in WNT signaling. Outcome effects: The impairment of WNT signaling has been shown to cause osteopetrosis. PORCN mutations are associated with osteopathia striata in Goltz Syndrome, while FAM123B mutations are linked to osteopathia striata with cranial stenosis. OSTM1 regulates CTNNB1/LEF1 interaction and causes rare forms of osteopetrosis. LRP1 mutations also lead to rare forms of the disorder. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 16525474 PS:PMID 17936098 PS:PMID 19232111 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: General of hypothetical mechanisms that lead to activation of eNOS in endothelial cells of dura mater by PGE2 and histamine in familial hemiplegic migraine is presented on the pathway. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a71a0ec-662c-4183-8eae-4a9350b296c1 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. Signaling description: Increased amounts of PGE2 and histamine are found in patients prior to and during migraine attack. Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Histamine from histamine-rich foods has been shown to provoke a migraine attack. The effects of histamine in vascular endothelial cells are mediated by histamine receptor H1 (HRH1), which activates phospholipase C, beta 1 (PLCB1) through the G protein q polypeptide (GNAQ). Inositol 1,4,5-triphosphate (IP3) synthesized by this enzyme activates inositol 1,4,5-triphosphate receptor 1 (ITPR1), which releases calcium (Ca2+) from the endoplasmic reticulum. In turn, prostaglandin E2 (PGE2) interacts with prostaglandin E2 receptor (PTGER2) and activates adenylate cyclase (ADCY) through Gs alpha (GNAS) initiating the production of cAMP, which then activates protein kinase A (PKA). Outcome effects: Activated PKA phosphorylates and thus activates endothelial nitric oxide synthase (NOS3 or eNOS), and also triggers the transient receptor potential cation channel (TRPV1) pathway which leads intracellular Ca2+ flux. Ca2+ then activates calmodulin resulting in the phosphorylation of NOS3 by calcium/calmodulin-dependent protein kinase (CAMK2A). The activation of NOS3 leads to the overproduction of nitric oxide (NO). Increased endothelial NO amounts cause vasodilation in dura mater. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: brain Organ_System: cardiovascular system PMID: 12426051 PMID: 12964492 PMID: 19499287 PMID: 21068832 PMID: 21458376 PMID: 23519238 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-5a71a0ec-662c-4183-8eae-4a9350b296c1 eNOS (NOS3) Activation via Prostaglandin E2 and Histamine uuid-5a71a0ec-662c-4183-8eae-4a9350b296c1 PS:CellType endothelial cell PS:Description General of hypothetical mechanisms that lead to activation of eNOS in endothelial cells of dura mater by PGE2 and histamine in familial hemiplegic migraine is presented on the pathway. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a71a0ec-662c-4183-8eae-4a9350b296c1 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. Signaling description: Increased amounts of PGE2 and histamine are found in patients prior to and during migraine attack. Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Histamine from histamine-rich foods has been shown to provoke a migraine attack. The effects of histamine in vascular endothelial cells are mediated by histamine receptor H1 (HRH1), which activates phospholipase C, beta 1 (PLCB1) through the G protein q polypeptide (GNAQ). Inositol 1,4,5-triphosphate (IP3) synthesized by this enzyme activates inositol 1,4,5-triphosphate receptor 1 (ITPR1), which releases calcium (Ca2+) from the endoplasmic reticulum. In turn, prostaglandin E2 (PGE2) interacts with prostaglandin E2 receptor (PTGER2) and activates adenylate cyclase (ADCY) through Gs alpha (GNAS) initiating the production of cAMP, which then activates protein kinase A (PKA). Outcome effects: Activated PKA phosphorylates and thus activates endothelial nitric oxide synthase (NOS3 or eNOS), and also triggers the transient receptor potential cation channel (TRPV1) pathway which leads intracellular Ca2+ flux. Ca2+ then activates calmodulin resulting in the phosphorylation of NOS3 by calcium/calmodulin-dependent protein kinase (CAMK2A). The activation of NOS3 leads to the overproduction of nitric oxide (NO). Increased endothelial NO amounts cause vasodilation in dura mater. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ brain PS:Organ_System cardiovascular system PS:PMID 12426051 PS:PMID 12964492 PS:PMID 19499287 PS:PMID 21068832 PS:PMID 21458376 PS:PMID 23519238 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a9b1996-5fe6-4462-92a0-2962d3607519 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5a9b1996-5fe6-4462-92a0-2962d3607519 FGF8 -> AP-1/CREB/MYC Expression Targets uuid-5a9b1996-5fe6-4462-92a0-2962d3607519 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5a9b1996-5fe6-4462-92a0-2962d3607519 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: sebocyte Description: Increased sebum production by the sebaceous gland, known as hyperseborrhea, is a common factor in acne vulgaris. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ac9c78a-92ad-4c10-9ac1-870e1bad2005 NodeType: Pathway Notes: Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Increased sebum production by the sebaceous gland, known as hyperseborrhea, is an important factor in the formation of acne lesions. Signaling description: Hyperseborrhea results from the increased fatty acid biosynthesis provoked by the following factors: IGF1, INS, FGF7, FGF10, POMC, and free fatty acids. Milk consumption and growth hormone (GH1) are shown to induce the hepatic synthesis and secretion of IGF1. In turn, IGF1, INS, FGF7, and FGF10 activate PI3K/AKT1 pathway. AKT1-mediated FOXO1 phosphorylation leads to the relief of SREBF1 and promotes fatty acid biosynthesis. In addition, increased MC1R expression is also observed in sebocytes in acne vulgaris. Proopiomelanocortin (POMC) binds to MC1R and via the PKA axis activates CREB1. Outcome effects: Free fatty acids contribute to the increased lipogenesis in sebocytes. Following their translocation via LDLR and SLC27A4 into the cell, the free fatty acids bind PPARG and PPARA. CREB1, PPARG, and PPARA are transcription factors that promote fatty acid biosynthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 15556719 PMID: 19555434 PMID: 19588637 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-5ac9c78a-92ad-4c10-9ac1-870e1bad2005 Hyperseborrhea in Acne Vulgaris uuid-5ac9c78a-92ad-4c10-9ac1-870e1bad2005 PS:CellType sebocyte PS:Description Increased sebum production by the sebaceous gland, known as hyperseborrhea, is a common factor in acne vulgaris. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ac9c78a-92ad-4c10-9ac1-870e1bad2005 PS:NodeType Pathway PS:Notes Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Increased sebum production by the sebaceous gland, known as hyperseborrhea, is an important factor in the formation of acne lesions. Signaling description: Hyperseborrhea results from the increased fatty acid biosynthesis provoked by the following factors: IGF1, INS, FGF7, FGF10, POMC, and free fatty acids. Milk consumption and growth hormone (GH1) are shown to induce the hepatic synthesis and secretion of IGF1. In turn, IGF1, INS, FGF7, and FGF10 activate PI3K/AKT1 pathway. AKT1-mediated FOXO1 phosphorylation leads to the relief of SREBF1 and promotes fatty acid biosynthesis. In addition, increased MC1R expression is also observed in sebocytes in acne vulgaris. Proopiomelanocortin (POMC) binds to MC1R and via the PKA axis activates CREB1. Outcome effects: Free fatty acids contribute to the increased lipogenesis in sebocytes. Following their translocation via LDLR and SLC27A4 into the cell, the free fatty acids bind PPARG and PPARA. CREB1, PPARG, and PPARA are transcription factors that promote fatty acid biosynthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15556719 PS:PMID 19555434 PS:PMID 19588637 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ae8600c-7811-46ca-8784-0735364aaae2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5ae8600c-7811-46ca-8784-0735364aaae2 TNF -> ELK-SRF Expression Targets uuid-5ae8600c-7811-46ca-8784-0735364aaae2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ae8600c-7811-46ca-8784-0735364aaae2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5aed5245-3a56-4bcd-a9b0-1248e53ec7e5 NodeType: Pathway Organ: joint Organ: kidney Organ_System: skeletal system Organ_System: urinary tract PathwayType: network Source: Diseases urn:agi-pathway:uuid-5aed5245-3a56-4bcd-a9b0-1248e53ec7e5 Genes with Mutations Associated with Gout uuid-5aed5245-3a56-4bcd-a9b0-1248e53ec7e5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5aed5245-3a56-4bcd-a9b0-1248e53ec7e5 PS:NodeType Pathway PS:Organ joint PS:Organ kidney PS:Organ_System skeletal system PS:Organ_System urinary tract PS:PathwayType network PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5af75aac-67a3-41ad-8e10-83f99ee0e500 NodeType: Pathway Notes: Dilated cardiomyopathy (DCM) is a heart muscle disorder. Organ: heart Organ_System: cardiovascular system PMID: 20716751 PMID: 21859740 PMID: 23900355 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-5af75aac-67a3-41ad-8e10-83f99ee0e500 Desmosomes Role in Dilated Cardiomyopathy uuid-5af75aac-67a3-41ad-8e10-83f99ee0e500 PS:CellType cardiac myocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5af75aac-67a3-41ad-8e10-83f99ee0e500 PS:NodeType Pathway PS:Notes Dilated cardiomyopathy (DCM) is a heart muscle disorder. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20716751 PS:PMID 21859740 PS:PMID 23900355 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: In osteoporosis, impaired bone mineralization occurs when the cause of the disease is due to lack of calcium (Ca2 ). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5af9c003-d3c4-40c4-a537-f5994dc8febc NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. Signaling description: Hydroxylapatite is a major component of healthy bones and is formed in membrane-bound matrix vesicles (MV) in osteoblasts. The process includes several steps. ENPP1 is a membrane protein of MV which converts ATP into AMP with PPi release. PPi is hydrolyzed by the ALPL enzyme in the MV outer membrane yielding monophosphate ions (Pi) for incorporation into bone mineral. In addition, another enzyme, PHOSPHO1 hydrolyzes phosphorylcholine and phosphoethanolamine to produce Pi inside the MV. Outcome effects: Pi complexes with Ca2+ in the form of hydroxylapatite crystal. They initially deposit as non-crystalline compounds and are subsequently converted to hydroxylapatite, the main crystalline salt of the bone. Hydroxylapatite functions to store ions and gives bone its compressional strength. Some of the hydroxylapatite remains in the non-crystalline form to facilitate a rapid resorption when needed. A polymorphism of the first intron of the gene coding for COL1A1 and increased levels of homocysteine can influence fracture risk. This may be due to differences in helix formation or cross-linking of collagen, which challenges the concept of normal mineral and matrix composition in osteoporosis with only structural abnormalities being the cause of skeletal fragility. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Sapir-Koren R, Livshits G (2011) Bone mineralization and regulation of phosphate homeostasis. IBMS BoneKEy. 8, 286-300. Organ: bone Organ_System: skeletal system PMID: 16322775 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-5af9c003-d3c4-40c4-a537-f5994dc8febc Bone Mineralization Impairement in Osteoporosis uuid-5af9c003-d3c4-40c4-a537-f5994dc8febc PS:Description In osteoporosis, impaired bone mineralization occurs when the cause of the disease is due to lack of calcium (Ca2 ). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5af9c003-d3c4-40c4-a537-f5994dc8febc PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. In osteoporosis, calcium (Ca2+) deficiency can be the cause of impaired bone mineralization. Signaling description: Hydroxylapatite is a major component of healthy bones and is formed in membrane-bound matrix vesicles (MV) in osteoblasts. The process includes several steps. ENPP1 is a membrane protein of MV which converts ATP into AMP with PPi release. PPi is hydrolyzed by the ALPL enzyme in the MV outer membrane yielding monophosphate ions (Pi) for incorporation into bone mineral. In addition, another enzyme, PHOSPHO1 hydrolyzes phosphorylcholine and phosphoethanolamine to produce Pi inside the MV. Outcome effects: Pi complexes with Ca2+ in the form of hydroxylapatite crystal. They initially deposit as non-crystalline compounds and are subsequently converted to hydroxylapatite, the main crystalline salt of the bone. Hydroxylapatite functions to store ions and gives bone its compressional strength. Some of the hydroxylapatite remains in the non-crystalline form to facilitate a rapid resorption when needed. A polymorphism of the first intron of the gene coding for COL1A1 and increased levels of homocysteine can influence fracture risk. This may be due to differences in helix formation or cross-linking of collagen, which challenges the concept of normal mineral and matrix composition in osteoporosis with only structural abnormalities being the cause of skeletal fragility. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Sapir-Koren R, Livshits G (2011) Bone mineralization and regulation of phosphate homeostasis. IBMS BoneKEy. 8, 286-300. PS:Organ bone PS:Organ_System skeletal system PS:PMID 16322775 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b17321c-3c0a-4eb7-8497-b00fda6ec67b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5b17321c-3c0a-4eb7-8497-b00fda6ec67b TLR3 Expression Targets uuid-5b17321c-3c0a-4eb7-8497-b00fda6ec67b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b17321c-3c0a-4eb7-8497-b00fda6ec67b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Guanylyl cyclase C (GUCY2C) is the main regulator of intestinal fluidity and water release into the intestinal lumen. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b2e22df-e5f2-4240-805f-f47f04a1658e NodeType: Pathway Notes: Headnote: Guanylyl cyclase C (GUCY2C), a transmembrane enzyme expressed in the intestine and brain, is the main regulator of intestinal fluidity and secretion of water into the intestinal lumen which is necessary for the lubrication and breakdown of the bolus of food. Signaling description: GUCY2C is activated by two known endogenous peptide hormones, GUCA2A and GUCA2B, which are also produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion. GUCY2C is also activated by the exogenous ligand, heat-stable enterotoxin, which is produced by enterotoxigenic Escherichia coli which is responsible for travelers or secretory diarrhea. The binding of these three known cognate ligands activates GUCY2C to convert GTP to cGMP. cGMP activates PRKG2 and inhibits the activity of the cAMP-phosphodiesterases PDE3, thereby cross-activating cAMP-dependent protein kinase (PKA). PRKG2 and PKA phosphorylate CFTR and CLCN2 increasing its Cl- secreting activity. cGMP also enhances duodenal bicarbonate secretion in a CFTR-dependent manner. cGMP also inhibits SLC9A2 /SLC9A3 channel, reducing sodium (Na ) uptake. Although this mechanism is well established, it has been recently debated that water accumulation in the intestinal lumen is not as much a result of an active secretion of electrolytes as it is a consequence of impaired fluid absorption. GUCY2C signaling is terminated by the hydrolysis of cGMP to GMP by PDE5A. Heat-stable enterotoxin is a super-agonist of GUCY2C and induces abnormally high levels of intracellular cGMP which causes aberrant fluid-ion efflux, leading to diarrhea. Outcome effects: As the main regulator of intestinal fluidity, GUCY2C is a therapeutic target for the treatment of constipation-related disorders. Linaclotide, an agonist of GUCY2C, is an investigational drug against constipation-predominant irritable bowel syndrome and chronic constipation. Organ: colon Organ: intestine Organ_System: digestive system Organ_System: nervous system PMID: 22069671 PMID: 22069681 PMID: 22819815 PMID: 22877138 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-5b2e22df-e5f2-4240-805f-f47f04a1658e GUCY2C in Intestinal Ion and Fluid Homeostasis uuid-5b2e22df-e5f2-4240-805f-f47f04a1658e PS:Description Guanylyl cyclase C (GUCY2C) is the main regulator of intestinal fluidity and water release into the intestinal lumen. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b2e22df-e5f2-4240-805f-f47f04a1658e PS:NodeType Pathway PS:Notes Headnote: Guanylyl cyclase C (GUCY2C), a transmembrane enzyme expressed in the intestine and brain, is the main regulator of intestinal fluidity and secretion of water into the intestinal lumen which is necessary for the lubrication and breakdown of the bolus of food. Signaling description: GUCY2C is activated by two known endogenous peptide hormones, GUCA2A and GUCA2B, which are also produced in the intestinal epithelium and activate GUCY2C in a paracrine fashion. GUCY2C is also activated by the exogenous ligand, heat-stable enterotoxin, which is produced by enterotoxigenic Escherichia coli which is responsible for travelers or secretory diarrhea. The binding of these three known cognate ligands activates GUCY2C to convert GTP to cGMP. cGMP activates PRKG2 and inhibits the activity of the cAMP-phosphodiesterases PDE3, thereby cross-activating cAMP-dependent protein kinase (PKA). PRKG2 and PKA phosphorylate CFTR and CLCN2 increasing its Cl- secreting activity. cGMP also enhances duodenal bicarbonate secretion in a CFTR-dependent manner. cGMP also inhibits SLC9A2 /SLC9A3 channel, reducing sodium (Na ) uptake. Although this mechanism is well established, it has been recently debated that water accumulation in the intestinal lumen is not as much a result of an active secretion of electrolytes as it is a consequence of impaired fluid absorption. GUCY2C signaling is terminated by the hydrolysis of cGMP to GMP by PDE5A. Heat-stable enterotoxin is a super-agonist of GUCY2C and induces abnormally high levels of intracellular cGMP which causes aberrant fluid-ion efflux, leading to diarrhea. Outcome effects: As the main regulator of intestinal fluidity, GUCY2C is a therapeutic target for the treatment of constipation-related disorders. Linaclotide, an agonist of GUCY2C, is an investigational drug against constipation-predominant irritable bowel syndrome and chronic constipation. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:Organ_System nervous system PS:PMID 22069671 PS:PMID 22069681 PS:PMID 22819815 PS:PMID 22877138 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Proliferative diabetic retinopathy is a late diabetic complication caused by microangiopathy in the retina. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b31a688-040e-4d39-8a9f-ae0c1aedaee8 NodeType: Pathway Notes: Headnote: Proliferative diabetic retinopathy is a late diabetic complication caused by microangiopathy in the retina. The pathology includes hypoxia, breakage of newly grown capillaries, bleeding, and subsequent fibrosis. Signaling description: Hypoxia and high glucose levels in diabetes induce VEGFA, EDN1, and AGT expression. The factors that provoke intensive vascularization in the retina are VEGFA (via NF-kB and FOS), EDN1 (via FOS), JUN, MYC, as well as CREBBP and AGT (via STAT3 transcription factor). EDN1, along with its receptor (EDNRA), promotes PLCB1 and PLCB3 activation. These proteins participate in the IP3 and diacylglycerol generation. IP3 causes the release of calcium (Ca2+) through ITPR1. Ca2+ affects calmodulin which transduces the signal to MYLK and then to MYL9 which causes vasoconstriction. In addition, diacylglycerol, activates CREBBP through the Ras/RAF1/MAPK cascade, which leads to differentiation and cell proliferation. Further, VEGFA promotes vascularization via the activation of JUN/FOS transcription factors through SRC/CTNND1/LEF and PI3K/AKT1/CTNNB1/LEF, which promote PTGS2 and NOS2 expression. Hexosamine and advanced glycation end products (AGE) pathways also participate in the manifestation of the pathology. The activation of the hexosamine pathway occurs when excessive intracellular glucose converts into glucosamine-6-P and then to UDP-acetyl-D-glucosamine (UDP-GlcNAc) which is translocated into the nucleus and presumably activates SP1, which initiates transcription of SERPINE1 and TGFB1. SERPINE1 inhibits the plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. AGE binds to its receptor (AGER) and through PI3K activates AKT1. AKT1 initiates the release of NF-kB from its inhibitor, NFKBIA activating it. NF-kB promotes TGFB1, NOS2, and NOS3 transcription which promotes vascularization. TGFB1 activates FN1, collagen IV, and collagen VI expression increasing blood vessel permeability and thickening of capillary basement membranes. Outcome effects: The activation of CREBBP through the Ras/RAF1/MAPK cascade plays a central role in cell differentiation and proliferation by interacting with a large number of nuclear factors. The disruption of fibrinolysis by SERPINE1 is the cause of vascular occlusion in diabetes. Increased blood vessel permeability and the thickening of capillary basement membranes are the origins of macular edema and the exchange diffusion impairment (metabolites and oxygen) in tissues. Newly grown capillaries have a thin wall and are easily broken. These vessels bleed easily and may also pull on the retina causing retinal traction and detachment. Fibrosis of the hemorrhage causes blindness in diabetic patients. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: Retina Organ: eye Organ_System: sensory system PMID: 18288248 PMID: 21139669 PMID: 21584427 PMID: 21814413 PMID: 23028203 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-5b31a688-040e-4d39-8a9f-ae0c1aedaee8 Proliferative Diabetic Retinopathy uuid-5b31a688-040e-4d39-8a9f-ae0c1aedaee8 PS:Description Proliferative diabetic retinopathy is a late diabetic complication caused by microangiopathy in the retina. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b31a688-040e-4d39-8a9f-ae0c1aedaee8 PS:NodeType Pathway PS:Notes Headnote: Proliferative diabetic retinopathy is a late diabetic complication caused by microangiopathy in the retina. The pathology includes hypoxia, breakage of newly grown capillaries, bleeding, and subsequent fibrosis. Signaling description: Hypoxia and high glucose levels in diabetes induce VEGFA, EDN1, and AGT expression. The factors that provoke intensive vascularization in the retina are VEGFA (via NF-kB and FOS), EDN1 (via FOS), JUN, MYC, as well as CREBBP and AGT (via STAT3 transcription factor). EDN1, along with its receptor (EDNRA), promotes PLCB1 and PLCB3 activation. These proteins participate in the IP3 and diacylglycerol generation. IP3 causes the release of calcium (Ca2+) through ITPR1. Ca2+ affects calmodulin which transduces the signal to MYLK and then to MYL9 which causes vasoconstriction. In addition, diacylglycerol, activates CREBBP through the Ras/RAF1/MAPK cascade, which leads to differentiation and cell proliferation. Further, VEGFA promotes vascularization via the activation of JUN/FOS transcription factors through SRC/CTNND1/LEF and PI3K/AKT1/CTNNB1/LEF, which promote PTGS2 and NOS2 expression. Hexosamine and advanced glycation end products (AGE) pathways also participate in the manifestation of the pathology. The activation of the hexosamine pathway occurs when excessive intracellular glucose converts into glucosamine-6-P and then to UDP-acetyl-D-glucosamine (UDP-GlcNAc) which is translocated into the nucleus and presumably activates SP1, which initiates transcription of SERPINE1 and TGFB1. SERPINE1 inhibits the plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. AGE binds to its receptor (AGER) and through PI3K activates AKT1. AKT1 initiates the release of NF-kB from its inhibitor, NFKBIA activating it. NF-kB promotes TGFB1, NOS2, and NOS3 transcription which promotes vascularization. TGFB1 activates FN1, collagen IV, and collagen VI expression increasing blood vessel permeability and thickening of capillary basement membranes. Outcome effects: The activation of CREBBP through the Ras/RAF1/MAPK cascade plays a central role in cell differentiation and proliferation by interacting with a large number of nuclear factors. The disruption of fibrinolysis by SERPINE1 is the cause of vascular occlusion in diabetes. Increased blood vessel permeability and the thickening of capillary basement membranes are the origins of macular edema and the exchange diffusion impairment (metabolites and oxygen) in tissues. Newly grown capillaries have a thin wall and are easily broken. These vessels bleed easily and may also pull on the retina causing retinal traction and detachment. Fibrosis of the hemorrhage causes blindness in diabetic patients. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 18288248 PS:PMID 21139669 PS:PMID 21584427 PS:PMID 21814413 PS:PMID 23028203 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b44aae3-f679-42f1-b93c-ef1f99b7b3b3 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5b44aae3-f679-42f1-b93c-ef1f99b7b3b3 FGFR -> RUNX2 Signaling uuid-5b44aae3-f679-42f1-b93c-ef1f99b7b3b3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b44aae3-f679-42f1-b93c-ef1f99b7b3b3 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b5e65ff-b68c-4e24-9db2-13883f98d410 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Seizures induce the massive influx of calcium (Ca2+) through N-methyl-D-aspartate (NMDA) selective glutamate receptors and voltage-gated Ca2+ channels. Elevated intracellular Ca2+ levels may directly trigger mitochondrial dysfunction or activate Ca2+ phosphatases such as calcineurin, which releases BAD from mitochondria leading to BAX activation. Subsequently, CYCS is released which triggers caspase-9 (CASP9) activation and apoptosis. Alternatively, death receptor activation leads to the formation of a death-inducing signaling complex and caspase-8 (CASP8) processing. Both TNF and FASLG are present in the brain following seizures. Seizures also activate caspase-independent apoptosis pathways in the brain where calpains are thought to be critical. Calpain I (CAPN1) has been shown to be responsible for triggering the release of AIFM1 during excitotoxicity. In addition, BBC3 upregulation following seizures is mainly TP53-mediated. DNA damage may be the trigger for TP53 accumulation after seizures. Serotonin and dopamine signaling modulate seizure-induced CREB1 phosphorylation via the activation of PPP1R1B and MAPK1/3. Dopamine acts through two different types of G-protein coupled receptors, D1-like and D2-like receptors. The activation of D1-like (DRD1 and DRD5) receptors results in the reduction of seizure threshold and increased seizure severity. Conversely, the effect of D2-like (including DRD2, DRD3, and DRD4) receptors on seizure modulation is predominantly inhibitory. The canonical pathway of dopamine receptor activity in neurons involves the modulation of adenylate cyclase (ADCY) to regulate cAMP production and subsequent activation of protein kinase A (PKA). D1-like receptors are coupled to GNAS and stimulate ADCY which leads to increased levels of cAMP. Conversely, D2-like receptors are coupled to Gi/o proteins and inhibit ADCY and decrease cAMP production. Recent evidence suggests a role for an alternative pathway in DRD2-modulated inhibition of seizures. A role of signaling complex composed of DRD2, AKT1, PP2A, and ARRB2 has been demonstrated. The activation of this pathway results in the dephosphorylation of AKT1 (inactivation), followed by dephosphorylation (activation) of GSK3B. Decreased dopamine/DRD2/DRD3 binding has been shown in temporal lobe epilepsy and juvenile monoclinic epilepsy. In addition, serotonin acts through a family of G-protein coupled receptors to modulate neuronal excitability. Similar to dopamine, most serotonin receptors act on the ADCY/cAMP/PKA pathway. The influx of Ca2+ leads to CREB1 phosphorylation via Ras/MAPK and calmodulin-dependent signaling. Outcome effects: CREB1 promotes the induction of "immediate early genes" JUN-FOS and switch on apoptotic cascades. In addition, CREB1 induces the synthesis of BDNF which may contribute to long-term excitability. NPY induced by CREB1 has been shown to have anticonvulsant properties. Several downstream effector proteins including NMDA, AMPA, GABA receptors, and Ca2+ and Na+ channels may be induced by "immediate early genes" which is proposed to be the mechanism of proconvulsant action. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 12461549 PMID: 15889042 PMID: 16922886 PMID: 17827063 PMID: 20384765 PMID: 21852968 PMID: 23882182 PMID: 24062645 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-5b5e65ff-b68c-4e24-9db2-13883f98d410 Apoptosis and Immediate Early Gene Activation in Epileptiform Disorders uuid-5b5e65ff-b68c-4e24-9db2-13883f98d410 PS:CellType neuron PS:Description Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b5e65ff-b68c-4e24-9db2-13883f98d410 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Seizures induce the massive influx of calcium (Ca2+) through N-methyl-D-aspartate (NMDA) selective glutamate receptors and voltage-gated Ca2+ channels. Elevated intracellular Ca2+ levels may directly trigger mitochondrial dysfunction or activate Ca2+ phosphatases such as calcineurin, which releases BAD from mitochondria leading to BAX activation. Subsequently, CYCS is released which triggers caspase-9 (CASP9) activation and apoptosis. Alternatively, death receptor activation leads to the formation of a death-inducing signaling complex and caspase-8 (CASP8) processing. Both TNF and FASLG are present in the brain following seizures. Seizures also activate caspase-independent apoptosis pathways in the brain where calpains are thought to be critical. Calpain I (CAPN1) has been shown to be responsible for triggering the release of AIFM1 during excitotoxicity. In addition, BBC3 upregulation following seizures is mainly TP53-mediated. DNA damage may be the trigger for TP53 accumulation after seizures. Serotonin and dopamine signaling modulate seizure-induced CREB1 phosphorylation via the activation of PPP1R1B and MAPK1/3. Dopamine acts through two different types of G-protein coupled receptors, D1-like and D2-like receptors. The activation of D1-like (DRD1 and DRD5) receptors results in the reduction of seizure threshold and increased seizure severity. Conversely, the effect of D2-like (including DRD2, DRD3, and DRD4) receptors on seizure modulation is predominantly inhibitory. The canonical pathway of dopamine receptor activity in neurons involves the modulation of adenylate cyclase (ADCY) to regulate cAMP production and subsequent activation of protein kinase A (PKA). D1-like receptors are coupled to GNAS and stimulate ADCY which leads to increased levels of cAMP. Conversely, D2-like receptors are coupled to Gi/o proteins and inhibit ADCY and decrease cAMP production. Recent evidence suggests a role for an alternative pathway in DRD2-modulated inhibition of seizures. A role of signaling complex composed of DRD2, AKT1, PP2A, and ARRB2 has been demonstrated. The activation of this pathway results in the dephosphorylation of AKT1 (inactivation), followed by dephosphorylation (activation) of GSK3B. Decreased dopamine/DRD2/DRD3 binding has been shown in temporal lobe epilepsy and juvenile monoclinic epilepsy. In addition, serotonin acts through a family of G-protein coupled receptors to modulate neuronal excitability. Similar to dopamine, most serotonin receptors act on the ADCY/cAMP/PKA pathway. The influx of Ca2+ leads to CREB1 phosphorylation via Ras/MAPK and calmodulin-dependent signaling. Outcome effects: CREB1 promotes the induction of "immediate early genes" JUN-FOS and switch on apoptotic cascades. In addition, CREB1 induces the synthesis of BDNF which may contribute to long-term excitability. NPY induced by CREB1 has been shown to have anticonvulsant properties. Several downstream effector proteins including NMDA, AMPA, GABA receptors, and Ca2+ and Na+ channels may be induced by "immediate early genes" which is proposed to be the mechanism of proconvulsant action. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 12461549 PS:PMID 15889042 PS:PMID 16922886 PS:PMID 17827063 PS:PMID 20384765 PS:PMID 21852968 PS:PMID 23882182 PS:PMID 24062645 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: VEGFA is a key mediator of angiogenesis in cancer. VEGFA is produces and released by tumor cells as well as tumor-infiltrating cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b6971e3-2a05-49a7-b632-f7d71ab47b5f NodeType: Pathway Notes: Headnote: VEGFA (vascular endothelial growth factor A) is a key mediator of angiogenesis in cancer. The pathology of VEGFA signaling in cancers is characterized with hyperproduction of VEGFA by tumor cells, as well as, tumor-infiltrating cells, including fibroblasts and monocytes/macrophages with subsequent VEGFA signaling hyper-activation. Signaling description: Tumor-associated hypoxia with increased expression of HIF1A is the most important regulator of VEGFA. Multiple growth factors, including FGF2, FGF4, FGF7, PDGFB and cytokines, including TNF, IL1A, IL1B, IL6 may induce VEGFA hyper-expression. The up-regulation of multiple transcription factors, including JUN-FOS, MYC, MYCN, STAT3, ESR1, AR, PGR may lead to hyper-expression of VEGFA in cancer. The specific role of carcinogenic mutations in TP53, MYC, MYCN, PTEN, KRAS, HRAS, ERBB2, EGFR related to the up-regulation of VEGFA was shown in cancer cells. Outcome effects: VEGFA expression is up-regulated due to signaling activation. It's altered expression leads to activation of both angiogenesis and vasculogenesis. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 11147671 PMID: 16954424 PMID: 17324579 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-5b6971e3-2a05-49a7-b632-f7d71ab47b5f VEGFA Dependent Angiogenesis in Cancer uuid-5b6971e3-2a05-49a7-b632-f7d71ab47b5f PS:CellType cancer cell PS:CellType cancer stem cell PS:Description VEGFA is a key mediator of angiogenesis in cancer. VEGFA is produces and released by tumor cells as well as tumor-infiltrating cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5b6971e3-2a05-49a7-b632-f7d71ab47b5f PS:NodeType Pathway PS:Notes Headnote: VEGFA (vascular endothelial growth factor A) is a key mediator of angiogenesis in cancer. The pathology of VEGFA signaling in cancers is characterized with hyperproduction of VEGFA by tumor cells, as well as, tumor-infiltrating cells, including fibroblasts and monocytes/macrophages with subsequent VEGFA signaling hyper-activation. Signaling description: Tumor-associated hypoxia with increased expression of HIF1A is the most important regulator of VEGFA. Multiple growth factors, including FGF2, FGF4, FGF7, PDGFB and cytokines, including TNF, IL1A, IL1B, IL6 may induce VEGFA hyper-expression. The up-regulation of multiple transcription factors, including JUN-FOS, MYC, MYCN, STAT3, ESR1, AR, PGR may lead to hyper-expression of VEGFA in cancer. The specific role of carcinogenic mutations in TP53, MYC, MYCN, PTEN, KRAS, HRAS, ERBB2, EGFR related to the up-regulation of VEGFA was shown in cancer cells. Outcome effects: VEGFA expression is up-regulated due to signaling activation. It's altered expression leads to activation of both angiogenesis and vasculogenesis. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 11147671 PS:PMID 16954424 PS:PMID 17324579 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: cancer cell CellType: cancer stem cell Description: Lipolysis is activated in cancer-associated adipocytes and lipogenesis is activated in cancer cells in order to provide building blocks for membrane biogenesis in actively dividing cancer cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bc89ba1-827e-4cc0-821f-2793731949ae NodeType: Pathway Notes: Headnote: Lipolysis is activated in cancer-associated adipocytes (CAAs) and lipogenesis is activated in cancer cells in order to provide building blocks for membrane biogenesis in actively dividing cancer cells. Signaling description: Lipolysis is activated in CAAs in order to provide fatty acids and glycerol to actively dividing adjacent cancer cells. It is not quite clear how exactly cancer cells make adipocytes "melt", and probably may occur via the production and local action of different cytokines. Lipolytic enzymes ATGL (PNPLA2), LIPE, MGLL and fatty acid transport protein FABP4 were shown to be up-regulated in CAAs. NFKB and PKA may be involved in their activation. Anabolic cancer cells also were shown to be able to produce lipids de novo from glucose. EGFR/PI3K/AKT1 signaling may regulate this process. A number of lipogenic enzymes including ACLY, ACACA/B, FASN, SCD, AGPAT2 were shown to be up-regulated in cancer cells. Outcome effects: Cancer cells produce triglycerides for membrane synthesis. The activation of ATGL and LIPE has a role in cancer-associated cachexia. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" for details. PMID: 22037646 PMID: 24001676 PMID: 24203995 PMID: 25374912 PMID: 27658529 PMID: 28053954 PMID: 28330687 PMID: 28399876 PMID: 28412757 PMID: 28620264 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: adipose tissue urn:agi-pathway:uuid-5bc89ba1-827e-4cc0-821f-2793731949ae Lipogenesis/Lipolysis Activation in Cancer Cells and Cancer-Associated Adipocytes uuid-5bc89ba1-827e-4cc0-821f-2793731949ae PS:CellType adipocyte PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Lipolysis is activated in cancer-associated adipocytes and lipogenesis is activated in cancer cells in order to provide building blocks for membrane biogenesis in actively dividing cancer cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bc89ba1-827e-4cc0-821f-2793731949ae PS:NodeType Pathway PS:Notes Headnote: Lipolysis is activated in cancer-associated adipocytes (CAAs) and lipogenesis is activated in cancer cells in order to provide building blocks for membrane biogenesis in actively dividing cancer cells. Signaling description: Lipolysis is activated in CAAs in order to provide fatty acids and glycerol to actively dividing adjacent cancer cells. It is not quite clear how exactly cancer cells make adipocytes "melt", and probably may occur via the production and local action of different cytokines. Lipolytic enzymes ATGL (PNPLA2), LIPE, MGLL and fatty acid transport protein FABP4 were shown to be up-regulated in CAAs. NFKB and PKA may be involved in their activation. Anabolic cancer cells also were shown to be able to produce lipids de novo from glucose. EGFR/PI3K/AKT1 signaling may regulate this process. A number of lipogenic enzymes including ACLY, ACACA/B, FASN, SCD, AGPAT2 were shown to be up-regulated in cancer cells. Outcome effects: Cancer cells produce triglycerides for membrane synthesis. The activation of ATGL and LIPE has a role in cancer-associated cachexia. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" for details. PS:PMID 22037646 PS:PMID 24001676 PS:PMID 24203995 PS:PMID 25374912 PS:PMID 27658529 PS:PMID 28053954 PS:PMID 28330687 PS:PMID 28399876 PS:PMID 28412757 PS:PMID 28620264 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue adipose tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Prostaglandin D2 (PGD2) and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bc97257-4209-4e85-bfa1-80cb030cce35 NodeType: Pathway Notes: Headnote: Prostaglandin D2 (PGD2) and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. Signaling description: PGD2 is produced in the brain by prostaglandin synthase (PTGS), which is localized mainly in the leptomeninges, choroid plexus, and oligodendrocytes. It circulates in the cerebrospinal fluid as a sleep hormone and stimulates prostaglandin D2 receptor (PTGDR) on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep. Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Outcome effects: It is currently hypothesized that the drive to sleep is determined by the activity of the basal forebrain cholinergic neurons, which release adenosine, possibly due to the increased metabolic activity associated with neuronal discharge during waking. Prostaglandin E2 (PGE2) has the opposite effect on sleep regulation and induces wakefulness. Organ: brain Organ_System: nervous system PMID: 12853415 PMID: 17129762 PMID: 22024172 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-5bc97257-4209-4e85-bfa1-80cb030cce35 Prostaglandins Role in Sleep Regulation uuid-5bc97257-4209-4e85-bfa1-80cb030cce35 PS:CellType neuron PS:Description Prostaglandin D2 (PGD2) and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bc97257-4209-4e85-bfa1-80cb030cce35 PS:NodeType Pathway PS:Notes Headnote: Prostaglandin D2 (PGD2) and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. Signaling description: PGD2 is produced in the brain by prostaglandin synthase (PTGS), which is localized mainly in the leptomeninges, choroid plexus, and oligodendrocytes. It circulates in the cerebrospinal fluid as a sleep hormone and stimulates prostaglandin D2 receptor (PTGDR) on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep. Adenosine is a secondary by-product from the breakdown of ATP and cAMP. Outcome effects: It is currently hypothesized that the drive to sleep is determined by the activity of the basal forebrain cholinergic neurons, which release adenosine, possibly due to the increased metabolic activity associated with neuronal discharge during waking. Prostaglandin E2 (PGE2) has the opposite effect on sleep regulation and induces wakefulness. PS:Organ brain PS:Organ_System nervous system PS:PMID 12853415 PS:PMID 17129762 PS:PMID 22024172 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bd4dcbe-64e3-4f86-b568-2e83aca2c7fa NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-5bd4dcbe-64e3-4f86-b568-2e83aca2c7fa ADRA1 -> Ion Channels uuid-5bd4dcbe-64e3-4f86-b568-2e83aca2c7fa PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bd4dcbe-64e3-4f86-b568-2e83aca2c7fa PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bfa1c16-7de3-4b1a-ade2-62fe34fe1b93 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5bfa1c16-7de3-4b1a-ade2-62fe34fe1b93 CD2 -> STAT Signaling uuid-5bfa1c16-7de3-4b1a-ade2-62fe34fe1b93 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5bfa1c16-7de3-4b1a-ade2-62fe34fe1b93 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c046dc8-e648-4ab7-accb-5ae1cce70939 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-5c046dc8-e648-4ab7-accb-5ae1cce70939 AGE-+>IR uuid-5c046dc8-e648-4ab7-accb-5ae1cce70939 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c046dc8-e648-4ab7-accb-5ae1cce70939 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c054c1e-dfd2-4e5f-8a16-e9f5229170dc NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-5c054c1e-dfd2-4e5f-8a16-e9f5229170dc Vitamin B6 (Pyridoxine) Metabolism uuid-5c054c1e-dfd2-4e5f-8a16-e9f5229170dc PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c054c1e-dfd2-4e5f-8a16-e9f5229170dc PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c069c24-ca86-4358-8b83-0dcabc1a0ff7 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-5c069c24-ca86-4358-8b83-0dcabc1a0ff7 NSP6 inetractions uuid-5c069c24-ca86-4358-8b83-0dcabc1a0ff7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c069c24-ca86-4358-8b83-0dcabc1a0ff7 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: regulatory T-cell Description: Activation of STAT3 in Treg cells leads to overexpression of IL10 and TGFB1 and inhibition of Th1/2 and CD8+ T-cell antitumor function. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c0caac4-a9bf-44a0-8c0b-01025a6082b9 NodeType: Pathway Notes: Headnote: IL23A and IL10 are produced at the site of inflammation by immune cells and may act on Treg cells. Signaling description: IL23A and IL10 signaling activates JAK/STAT. Further, STAT3 upregulates the expression of IL10 and TGFB1 and is a major player in inhibition of antitumor function. STAT5A, which controls the expression of FOXP3 and Treg cell fate commitment is also activated. Outcome effects: IL10 and TGFB1 inhibit Th1/2 and CD8+ T-cells, which normally have antitumor functions. IL-10 inhibits tyrosine phosphorylation of CD28 on Th1 and Th2 cells; thus, blocking PI3K binding to CD28 and further signaling in Th cells (PI3K is not shown on the pathway). TGFB1 directly acts on TGFBR on the surface of Th1/2 and CD8+ T-cell (TGFBR is not shown on the pathway). The antitumor function of these cells is inhibited. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ_System: lymphatic system PMID: 11412299 PMID: 16556256 PMID: 17186030 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-5c0caac4-a9bf-44a0-8c0b-01025a6082b9 STAT3 Facilitates the Function of Treg Cells and Cancer Progression uuid-5c0caac4-a9bf-44a0-8c0b-01025a6082b9 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType regulatory T-cell PS:Description Activation of STAT3 in Treg cells leads to overexpression of IL10 and TGFB1 and inhibition of Th1/2 and CD8+ T-cell antitumor function. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c0caac4-a9bf-44a0-8c0b-01025a6082b9 PS:NodeType Pathway PS:Notes Headnote: IL23A and IL10 are produced at the site of inflammation by immune cells and may act on Treg cells. Signaling description: IL23A and IL10 signaling activates JAK/STAT. Further, STAT3 upregulates the expression of IL10 and TGFB1 and is a major player in inhibition of antitumor function. STAT5A, which controls the expression of FOXP3 and Treg cell fate commitment is also activated. Outcome effects: IL10 and TGFB1 inhibit Th1/2 and CD8+ T-cells, which normally have antitumor functions. IL-10 inhibits tyrosine phosphorylation of CD28 on Th1 and Th2 cells; thus, blocking PI3K binding to CD28 and further signaling in Th cells (PI3K is not shown on the pathway). TGFB1 directly acts on TGFBR on the surface of Th1/2 and CD8+ T-cell (TGFBR is not shown on the pathway). The antitumor function of these cells is inhibited. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ_System lymphatic system PS:PMID 11412299 PS:PMID 16556256 PS:PMID 17186030 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: kidney tubule cell Description: Diabetic nephropathy (DN) is usually considered a primarily glomerular disease, although this contention has been challenged. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c524eb5-d13a-4f16-9f21-69058a1f5c7a NodeType: Pathway Notes: Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. DN is usually considered a primarily glomerular disease, although this contention has been challenged. The role of tubulointerstitial injury in the development of DN has recently been considered. The tubulointerstitial abnormalities are involved at a later stage in the evolution of DN than the glomerulus disturbances, but the damage to this compartment correlates much better with renal dysfunction. Signaling description: Many mechanisms relevant to tubulointerstitial pathobiology are similar to those in the renal glomerulus. Epithelial cells of the renal tubules play a central role in the development of tubulointerstitial damage. The activation of the epithelium is due to permanent reabsorption of protein. Persistent albuminuria has a toxic effect on the interstitium. Glucose induces the formation of diacylglycerol which activates PRKCA and stimulates NOX4 which is involved in reactive oxygen species (ROS) production. Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER activates mitogen-activated protein kinase (MAPK) pathway and via PI3K activates the AKT1/NF-kB signaling pathway. Overexpressed TGFB1 activates TGFBR2 and interacts with SMAD 2/3/4 which mediates mitogen-activated protein kinase (MAPK) and Janus kinase (JAK) cascades. In the tubular interstitium during progressive DN, there is an increased expression of STAT1,3,4,5A, and 5B and a reduced expression of PIAS1,2,3,4, which inhibit STAT activation. Outcome effects: The activation of these pathways leads to the epithelial tubular cell proliferation and oxidative stress, the production of collagen (I, III, IV, VI types), fibronectin (FN1), and matrix metallopeptidases (MMP 2, 3, 9, and 12) which are involved in fibrosis and extracellular matrix degradation, macrophage chemotaxis, and ultimately inflammation and tubulointerstitial sclerosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 18726161 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-5c524eb5-d13a-4f16-9f21-69058a1f5c7a Tubular Cell Dysfunction in Progressive Diabetic Nephropathy uuid-5c524eb5-d13a-4f16-9f21-69058a1f5c7a PS:CellType kidney tubule cell PS:Description Diabetic nephropathy (DN) is usually considered a primarily glomerular disease, although this contention has been challenged. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c524eb5-d13a-4f16-9f21-69058a1f5c7a PS:NodeType Pathway PS:Notes Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. DN is usually considered a primarily glomerular disease, although this contention has been challenged. The role of tubulointerstitial injury in the development of DN has recently been considered. The tubulointerstitial abnormalities are involved at a later stage in the evolution of DN than the glomerulus disturbances, but the damage to this compartment correlates much better with renal dysfunction. Signaling description: Many mechanisms relevant to tubulointerstitial pathobiology are similar to those in the renal glomerulus. Epithelial cells of the renal tubules play a central role in the development of tubulointerstitial damage. The activation of the epithelium is due to permanent reabsorption of protein. Persistent albuminuria has a toxic effect on the interstitium. Glucose induces the formation of diacylglycerol which activates PRKCA and stimulates NOX4 which is involved in reactive oxygen species (ROS) production. Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER activates mitogen-activated protein kinase (MAPK) pathway and via PI3K activates the AKT1/NF-kB signaling pathway. Overexpressed TGFB1 activates TGFBR2 and interacts with SMAD 2/3/4 which mediates mitogen-activated protein kinase (MAPK) and Janus kinase (JAK) cascades. In the tubular interstitium during progressive DN, there is an increased expression of STAT1,3,4,5A, and 5B and a reduced expression of PIAS1,2,3,4, which inhibit STAT activation. Outcome effects: The activation of these pathways leads to the epithelial tubular cell proliferation and oxidative stress, the production of collagen (I, III, IV, VI types), fibronectin (FN1), and matrix metallopeptidases (MMP 2, 3, 9, and 12) which are involved in fibrosis and extracellular matrix degradation, macrophage chemotaxis, and ultimately inflammation and tubulointerstitial sclerosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 18726161 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c70d185-2fea-4e33-9955-522495935a9f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5c70d185-2fea-4e33-9955-522495935a9f de-arsenification template uuid-5c70d185-2fea-4e33-9955-522495935a9f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c70d185-2fea-4e33-9955-522495935a9f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c7823c3-0088-4078-8652-b0ac6150e580 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5c7823c3-0088-4078-8652-b0ac6150e580 CCL4 Expression Targets uuid-5c7823c3-0088-4078-8652-b0ac6150e580 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c7823c3-0088-4078-8652-b0ac6150e580 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c93ec18-b788-45a1-94c6-738a3fe28497 NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated with impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Mast cells serve as the major effector cells in AD associated immediate hypersensitivity through their activation via the high affinity IgE receptor, FCER1. Signaling description: Mast cells are believed to be involved in the pathogenesis of AD due to the large number of proinflammatory mediators secreted from the FCER1-activated mast cells and their role in IgE-mediated immediate hypersensitivity, as well as increased number of mast cells in the majority of AD patients. The ethiology of AD is not completely understood. Trigger factors such as allergens, bacteria, mechanical injury, and exogenous proteases induce the release of IL33 and thymic stromal lymphopoietin (TSLP) from keratinocytes leading to mast cell activation. Outcome effects: IL33, alone or in combination with other cytokines and chemokines, activates mast cells and dendritic cells in inflamed skin. IL33-dependent activation of IL1RL1 signaling leads to the activation of MAPK and NF-kB signaling pathways, which are involved in the pathogenesis of AD. Highlighted proteins: IL33 with increased expression is highlighted in red. Mutated genes: Mutated IL4 is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 19828304 PMID: 22499037 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-5c93ec18-b788-45a1-94c6-738a3fe28497 Mast-Cells Activation in Atopic Dermatitis uuid-5c93ec18-b788-45a1-94c6-738a3fe28497 PS:CellType mast cell PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c93ec18-b788-45a1-94c6-738a3fe28497 PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated with impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Mast cells serve as the major effector cells in AD associated immediate hypersensitivity through their activation via the high affinity IgE receptor, FCER1. Signaling description: Mast cells are believed to be involved in the pathogenesis of AD due to the large number of proinflammatory mediators secreted from the FCER1-activated mast cells and their role in IgE-mediated immediate hypersensitivity, as well as increased number of mast cells in the majority of AD patients. The ethiology of AD is not completely understood. Trigger factors such as allergens, bacteria, mechanical injury, and exogenous proteases induce the release of IL33 and thymic stromal lymphopoietin (TSLP) from keratinocytes leading to mast cell activation. Outcome effects: IL33, alone or in combination with other cytokines and chemokines, activates mast cells and dendritic cells in inflamed skin. IL33-dependent activation of IL1RL1 signaling leads to the activation of MAPK and NF-kB signaling pathways, which are involved in the pathogenesis of AD. Highlighted proteins: IL33 with increased expression is highlighted in red. Mutated genes: Mutated IL4 is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 19828304 PS:PMID 22499037 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c95bae0-2659-43e0-a8ce-b90f7b31e5d9 NodeType: Pathway Notes: Headnote: The LH surge terminates preovulatory follicle growth and initiates the processes of ovulation, oocyte meiosis, expansion of the cumulus cell oocyte complex (during which cumulus cells make a hyaluronan-rich matrix that surrounds the oocyte prior to ovulation), and luteinization. Signaling description: As a consequence, the FSH program of gene expression is turned off while genes controlling matrix formation and luteinization are turned on. LH rapidly induces in granulosa cells the expression of the EGF-like factors amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG) in a PKA-dependent manner. AREG and/or EREG in turn activate the EGFR signaling cascade, including RAS and ERK1/2leading to phosphorylation and inactivation of gap junctions proteins. Outcome effects: The tight contact between oocyte and cumulus cells is lost and cGMP transfer to oocyte is decreases leading to resumption of meiosis. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ovary Organ_System: reproductive system PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-5c95bae0-2659-43e0-a8ce-b90f7b31e5d9 Luteinizing Hormone in Oocyte Meiotic Resumption uuid-5c95bae0-2659-43e0-a8ce-b90f7b31e5d9 PS:CellType oocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5c95bae0-2659-43e0-a8ce-b90f7b31e5d9 PS:NodeType Pathway PS:Notes Headnote: The LH surge terminates preovulatory follicle growth and initiates the processes of ovulation, oocyte meiosis, expansion of the cumulus cell oocyte complex (during which cumulus cells make a hyaluronan-rich matrix that surrounds the oocyte prior to ovulation), and luteinization. Signaling description: As a consequence, the FSH program of gene expression is turned off while genes controlling matrix formation and luteinization are turned on. LH rapidly induces in granulosa cells the expression of the EGF-like factors amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG) in a PKA-dependent manner. AREG and/or EREG in turn activate the EGFR signaling cascade, including RAS and ERK1/2leading to phosphorylation and inactivation of gap junctions proteins. Outcome effects: The tight contact between oocyte and cumulus cells is lost and cGMP transfer to oocyte is decreases leading to resumption of meiosis. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ca0361c-9e9f-452b-96c7-a49622f6927b NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PMID: http://www.iiserpune.ac.in/~coee/histome/ PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-5ca0361c-9e9f-452b-96c7-a49622f6927b Histones Modifications Sites in Cell Vitality uuid-5ca0361c-9e9f-452b-96c7-a49622f6927b PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ca0361c-9e9f-452b-96c7-a49622f6927b PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PMID http://www.iiserpune.ac.in/~coee/histome/ PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ca6918e-5130-4ec9-be63-665c4752dc55 NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-5ca6918e-5130-4ec9-be63-665c4752dc55 Proteins Involved in Bronchiectasis uuid-5ca6918e-5130-4ec9-be63-665c4752dc55 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ca6918e-5130-4ec9-be63-665c4752dc55 PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cb4c47e-bf5f-4b89-bedf-22a0751f53bf NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5cb4c47e-bf5f-4b89-bedf-22a0751f53bf IAA storage via glucoside conjugation template uuid-5cb4c47e-bf5f-4b89-bedf-22a0751f53bf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cb4c47e-bf5f-4b89-bedf-22a0751f53bf PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: Pyelonephritis is nonspecific microbial inflammatory kidney disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cb5aca3-8516-47c1-b105-4442db273f97 NodeType: Pathway Notes: Pyelonephritis is nonspecific microbial inflammatory kidney disease. Interstitial fibroblasts produce the extracellular matrix and constitute the cellular skeleton. Overexpression of TGFB and TNF leads to extracellular matrix degradation and fibrosis. Organ: kidney Organ_System: urinary tract PMID: 16198274 PMID: 16339963 PMID: 24198613 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: interstitium urn:agi-pathway:uuid-5cb5aca3-8516-47c1-b105-4442db273f97 Interstitial Fibroblasts in Pyelonephritis uuid-5cb5aca3-8516-47c1-b105-4442db273f97 PS:CellType fibroblast PS:Description Pyelonephritis is nonspecific microbial inflammatory kidney disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cb5aca3-8516-47c1-b105-4442db273f97 PS:NodeType Pathway PS:Notes Pyelonephritis is nonspecific microbial inflammatory kidney disease. Interstitial fibroblasts produce the extracellular matrix and constitute the cellular skeleton. Overexpression of TGFB and TNF leads to extracellular matrix degradation and fibrosis. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 16198274 PS:PMID 16339963 PS:PMID 24198613 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue interstitium PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cde31ca-d5a0-4724-bd18-77c9993298f4 NodeType: Pathway Notes: Endothelial dysfunction and lipid accumulation initiate a robust inflammatory response leading to macrophage and VSMC remodeling and arterial calcification. Intima and plaque calcification in atherosclerosis are often detected in older patients. Calcifying vesicles can be observed microscopically in the collagen-rich matrix. Calcification escalates arterial stiffness and pulse wave velocity. There are known mutations in some genes implicated in phosphate/ hydroxyapatite metabolism in some cases of idiopathic infantile arterial calcification. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-5cde31ca-d5a0-4724-bd18-77c9993298f4 3_Arterial wall inflammation and calcification in atherosclerosis uuid-5cde31ca-d5a0-4724-bd18-77c9993298f4 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cde31ca-d5a0-4724-bd18-77c9993298f4 PS:NodeType Pathway PS:Notes Endothelial dysfunction and lipid accumulation initiate a robust inflammatory response leading to macrophage and VSMC remodeling and arterial calcification. Intima and plaque calcification in atherosclerosis are often detected in older patients. Calcifying vesicles can be observed microscopically in the collagen-rich matrix. Calcification escalates arterial stiffness and pulse wave velocity. There are known mutations in some genes implicated in phosphate/ hydroxyapatite metabolism in some cases of idiopathic infantile arterial calcification. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cf97e8b-cf7c-4ea2-bc9d-179ca7170f40 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5cf97e8b-cf7c-4ea2-bc9d-179ca7170f40 FibronectinR -> AP-1/ELK/SRF/SREBF Signaling uuid-5cf97e8b-cf7c-4ea2-bc9d-179ca7170f40 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cf97e8b-cf7c-4ea2-bc9d-179ca7170f40 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cff6752-9a20-42f6-b561-fb5a7d435d7e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-5cff6752-9a20-42f6-b561-fb5a7d435d7e Tryptophan Metabolism uuid-5cff6752-9a20-42f6-b561-fb5a7d435d7e PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5cff6752-9a20-42f6-b561-fb5a7d435d7e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d0825a6-1a6c-4265-b43c-bfaa849753c2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-5d0825a6-1a6c-4265-b43c-bfaa849753c2 Peripheral circadian rhythm uuid-5d0825a6-1a6c-4265-b43c-bfaa849753c2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d0825a6-1a6c-4265-b43c-bfaa849753c2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d0f6ec8-4224-48af-abac-2a59aee13ffc NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5d0f6ec8-4224-48af-abac-2a59aee13ffc NGF -> FOXO/MYCN/ELK-SRF Expression Targets uuid-5d0f6ec8-4224-48af-abac-2a59aee13ffc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d0f6ec8-4224-48af-abac-2a59aee13ffc PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d15bc13-1868-437f-953b-b81f81889f57 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-5d15bc13-1868-437f-953b-b81f81889f57 Genes with Mutations Associated with Ichthyosis uuid-5d15bc13-1868-437f-953b-b81f81889f57 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d15bc13-1868-437f-953b-b81f81889f57 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d1d0245-034c-4bce-9b91-7db1c18ff69d NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-5d1d0245-034c-4bce-9b91-7db1c18ff69d Keep out Signal: LTF Inhibits Neutrophil Recruitment and Inflammation uuid-5d1d0245-034c-4bce-9b91-7db1c18ff69d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d1d0245-034c-4bce-9b91-7db1c18ff69d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pancreatic adenocarcinoma (PA) is a highly lethal disease, the most common type of Pancreatic cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d23cb0c-6e14-4ede-ba91-99d52842f547 NodeType: Pathway Notes: Pancreatic cancer refers to malignant transformation of the pancreas. Pancreatic adenocarcinoma (PA) is a highly lethal disease and is the most common type of pancreatic cancer. TRPM8 and TRPM7 are aberrantly overexpressed in PA. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: pancreas Organ_System: digestive system Organ_System: endocrine system PMID: 21183474 PMID: 22323115 PMID: 22555807 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-5d23cb0c-6e14-4ede-ba91-99d52842f547 TRPM7/8 in Pancreatic Adenocarcinoma uuid-5d23cb0c-6e14-4ede-ba91-99d52842f547 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pancreatic adenocarcinoma (PA) is a highly lethal disease, the most common type of Pancreatic cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d23cb0c-6e14-4ede-ba91-99d52842f547 PS:NodeType Pathway PS:Notes Pancreatic cancer refers to malignant transformation of the pancreas. Pancreatic adenocarcinoma (PA) is a highly lethal disease and is the most common type of pancreatic cancer. TRPM8 and TRPM7 are aberrantly overexpressed in PA. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ pancreas PS:Organ_System digestive system PS:Organ_System endocrine system PS:PMID 21183474 PS:PMID 22323115 PS:PMID 22555807 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d4ff7ea-4ac4-437e-8da9-460bcb3ea2c7 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-5d4ff7ea-4ac4-437e-8da9-460bcb3ea2c7 Heme-|oxidative stress uuid-5d4ff7ea-4ac4-437e-8da9-460bcb3ea2c7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d4ff7ea-4ac4-437e-8da9-460bcb3ea2c7 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d522aae-a7fd-449e-b7ae-075a7f702a36 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Atherosclerotic lesions frequently become calcified. This process can begin early and accelerates as the disease progresses and more complex lesions develop. Signaling description: Calcium deposits in coronary arteries indicate the presence of plaques. On the surface of vascular cells, ENPP1 converts ATP to AMP and pyrophosphate (PPi), while NT5E converts AMP to adenosine and inorganic phosphate (Pi). PPi inhibits calcification, while tissue-nonspecific alkaline phosphatase (ALPL) degrades PPi and adenosine inhibits ALPL. A deficiency of NT5E results in decreased adenosine levels, which eliminates the inhibition of ALPL from the pathway either directly or by way of adenosine receptor signaling. Outcome effects: The higher levels of ALPL results in reduced PPi and increased cell calcification. Mutated proteins: Mutated genes are shown in white-out style. Organ: blood vessel Organ_System: cardiovascular system PMID: 21288095 PMID: 22095980 PMID: 22209248 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-5d522aae-a7fd-449e-b7ae-075a7f702a36 Arterial Calcification uuid-5d522aae-a7fd-449e-b7ae-075a7f702a36 PS:CellType endothelial cell PS:Description Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d522aae-a7fd-449e-b7ae-075a7f702a36 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Atherosclerotic lesions frequently become calcified. This process can begin early and accelerates as the disease progresses and more complex lesions develop. Signaling description: Calcium deposits in coronary arteries indicate the presence of plaques. On the surface of vascular cells, ENPP1 converts ATP to AMP and pyrophosphate (PPi), while NT5E converts AMP to adenosine and inorganic phosphate (Pi). PPi inhibits calcification, while tissue-nonspecific alkaline phosphatase (ALPL) degrades PPi and adenosine inhibits ALPL. A deficiency of NT5E results in decreased adenosine levels, which eliminates the inhibition of ALPL from the pathway either directly or by way of adenosine receptor signaling. Outcome effects: The higher levels of ALPL results in reduced PPi and increased cell calcification. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 21288095 PS:PMID 22095980 PS:PMID 22209248 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d6106da-88e0-424f-8c4e-99a317323039 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5d6106da-88e0-424f-8c4e-99a317323039 ActivinR/BMPR -> SMAD1/5/9 Signaling uuid-5d6106da-88e0-424f-8c4e-99a317323039 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d6106da-88e0-424f-8c4e-99a317323039 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d8bb412-dbe1-4d5b-ac2f-cc042e534d18 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-5d8bb412-dbe1-4d5b-ac2f-cc042e534d18 Motor neuron differentiation uuid-5d8bb412-dbe1-4d5b-ac2f-cc042e534d18 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5d8bb412-dbe1-4d5b-ac2f-cc042e534d18 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5db3d18a-602f-42d5-9675-6d2da65f24e8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5db3d18a-602f-42d5-9675-6d2da65f24e8 TGFB1-TGFBR2 Expression Targets uuid-5db3d18a-602f-42d5-9675-6d2da65f24e8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5db3d18a-602f-42d5-9675-6d2da65f24e8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5dba778f-8e04-4dc8-952d-cfd19e18c321 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5dba778f-8e04-4dc8-952d-cfd19e18c321 IL5 Expression Targets uuid-5dba778f-8e04-4dc8-952d-cfd19e18c321 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5dba778f-8e04-4dc8-952d-cfd19e18c321 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5dc2a0d6-d67e-49ce-839b-ad0396c58d50 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-5dc2a0d6-d67e-49ce-839b-ad0396c58d50 ADRA2C/ADRB2 -> Synaptic Endocytosis uuid-5dc2a0d6-d67e-49ce-839b-ad0396c58d50 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5dc2a0d6-d67e-49ce-839b-ad0396c58d50 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ddbbc35-3eb5-4543-a78b-d2f06ef52c14 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-5ddbbc35-3eb5-4543-a78b-d2f06ef52c14 Purine Metabolism uuid-5ddbbc35-3eb5-4543-a78b-d2f06ef52c14 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ddbbc35-3eb5-4543-a78b-d2f06ef52c14 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: lymphocyte Description: Myocarditis is a major cause of heart failure in young adults that is typically precipitated by cardiac infection with organisms such as Coxsackie B virus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ddcfe77-0c7b-4aa0-b8ac-27f15f161f5c NodeType: Pathway Notes: Myocarditis is a major cause of heart failure in young adults that is typically precipitated by cardiac infection with organisms such as Coxsackie B virus.Highlighed proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 19451363 PMID: 21705357 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-5ddcfe77-0c7b-4aa0-b8ac-27f15f161f5c Lymphocyte Mediated Myocardial Injury in Myocarditis uuid-5ddcfe77-0c7b-4aa0-b8ac-27f15f161f5c PS:CellType lymphocyte PS:Description Myocarditis is a major cause of heart failure in young adults that is typically precipitated by cardiac infection with organisms such as Coxsackie B virus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ddcfe77-0c7b-4aa0-b8ac-27f15f161f5c PS:NodeType Pathway PS:Notes Myocarditis is a major cause of heart failure in young adults that is typically precipitated by cardiac infection with organisms such as Coxsackie B virus.Highlighed proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 19451363 PS:PMID 21705357 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: The hexosamine pathway (HP) is one of the processes leading to the manifestation of diabetic microangiopathy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de18fce-39b2-4669-bffd-d61911963b67 NodeType: Pathway Notes: Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: The hexosamine pathway (HP) is ibvolved in the development of diabetic microangiopathy. HP represents a consecutive conversion of glucose into UDP-acetyl-D-glucosamine (UDP-GlcNAc), which is a substrate for O-GlcNAc transferase (OGT). The enzyme catalyzes the O-linked addition of GlcNAc to serine and threonine residues of cytosolic and nuclear proteins. The mechanism by which an increased flux through HP mediates hyperglycemia-induced transcription activation remains elusive, but there are data suggesting that the covalent modification of SP1 by N-acetylglucosamine (GlcNAc) may explain the link between the activation of HP and hyperglycemia-induced changes in transcription of SERPINE1 and TGFB1 genes in vascular smooth muscle cells. Outcome effects: SERPINE1 inhibits plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. The disruption of fibrinolysis is the cause for vascular occlusion in diabetes. TGFB1 causes FN1, collagen IV, and collagen VI expression increasing blood vessel permeability and thickening of capillary basement membranes. These processes are the origin of the edema and the cause of exchange diffusion impairment (metabolites and oxygen) in tissue. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, small molecules with elevated level are highlighted in red. Organ: blood vessel Organ_System: endocrine system PMID: 11050244 PMID: 15944815 PMID: 16339923 PMID: 18230954 PMID: 18793542 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5de18fce-39b2-4669-bffd-d61911963b67 Hexosamine Pathway in Diabetic Microangiopathy uuid-5de18fce-39b2-4669-bffd-d61911963b67 PS:CellType vascular smooth muscle cell PS:Description The hexosamine pathway (HP) is one of the processes leading to the manifestation of diabetic microangiopathy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de18fce-39b2-4669-bffd-d61911963b67 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: The hexosamine pathway (HP) is ibvolved in the development of diabetic microangiopathy. HP represents a consecutive conversion of glucose into UDP-acetyl-D-glucosamine (UDP-GlcNAc), which is a substrate for O-GlcNAc transferase (OGT). The enzyme catalyzes the O-linked addition of GlcNAc to serine and threonine residues of cytosolic and nuclear proteins. The mechanism by which an increased flux through HP mediates hyperglycemia-induced transcription activation remains elusive, but there are data suggesting that the covalent modification of SP1 by N-acetylglucosamine (GlcNAc) may explain the link between the activation of HP and hyperglycemia-induced changes in transcription of SERPINE1 and TGFB1 genes in vascular smooth muscle cells. Outcome effects: SERPINE1 inhibits plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. The disruption of fibrinolysis is the cause for vascular occlusion in diabetes. TGFB1 causes FN1, collagen IV, and collagen VI expression increasing blood vessel permeability and thickening of capillary basement membranes. These processes are the origin of the edema and the cause of exchange diffusion impairment (metabolites and oxygen) in tissue. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, small molecules with elevated level are highlighted in red. PS:Organ blood vessel PS:Organ_System endocrine system PS:PMID 11050244 PS:PMID 15944815 PS:PMID 16339923 PS:PMID 18230954 PS:PMID 18793542 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron CellType: oligodendroglia Description: Prostaglandin D2 (PTGDS) is a potent endogenous hormone for promoting sleep. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de1f4c4-97a1-411a-bd18-4accda29f017 NodeType: Pathway Notes: Prostaglandin D2 (PTGDS) is a potent endogenous hormone for promoting sleep. Down-regulation of PTGDS in the aged hypothalamus and cortex may contribute to the sleep disorders associated with aging. Decrease of PTGDS in cerebrospinal fluid was detected in depressed patients, which could contribute to sleep disturbances in these patients. Organ: brain Organ_System: nervous system PMID: 11172053 PMID: 22169944 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-5de1f4c4-97a1-411a-bd18-4accda29f017 Prostaglandin D2 Synthase Downregulation uuid-5de1f4c4-97a1-411a-bd18-4accda29f017 PS:CellType neuron PS:CellType oligodendroglia PS:Description Prostaglandin D2 (PTGDS) is a potent endogenous hormone for promoting sleep. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de1f4c4-97a1-411a-bd18-4accda29f017 PS:NodeType Pathway PS:Notes Prostaglandin D2 (PTGDS) is a potent endogenous hormone for promoting sleep. Down-regulation of PTGDS in the aged hypothalamus and cortex may contribute to the sleep disorders associated with aging. Decrease of PTGDS in cerebrospinal fluid was detected in depressed patients, which could contribute to sleep disturbances in these patients. PS:Organ brain PS:Organ_System nervous system PS:PMID 11172053 PS:PMID 22169944 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Most mitochondrial proteins are synthesized as precursor proteins in the cytosol and are imported mainly by a post-translational mechanism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de29879-ef6e-4f3c-8f88-8cb0a5e4d14a NodeType: Pathway Notes: Headnote: Mitochondrial proteins are synthesized as precursor proteins in the cytosol and are imported mainly by a post-translational mechanism. Mitochondrial precursor proteins can be subdivided into two major classes including preproteins that carry N-terminal cleavable extensions called presequences and the second class of precursor proteins that are synthesized without cleavable extensions and have the same primary structure as the mature protein. Signaling description: The mitochondrial preproteins are believed to be maintained in a translocation competent state by cytosolic chaperones, particularly members of the HSP70 protein family (HSPA1A). The presence of a peptide in the binding domain stimulates the ATPase activity of HSPA1A, increasing its rate of ATP hydrolysis which is normally low. The translocase of the outer mitochondrial membrane (TOM complex) specifically recognizes and binds the precursors prior to their translocation. The TOM complex consists of seven different subunits including TOMM20, TOMM22, TOMM70A, TOMM40, TOMM5, TOMM6, and TOMM7. One half of the amphipathic alpha-helix of a typical presequence possesses a hydrophobic surface that is recognized by a binding groove within TOMM20, whereas the other half is positively charged and recognized by the TOMM22 receptor. Outcome effects: The preprotein is then transported to the general import pore formed by the essential beta-barrel protein TOMM40. The precursor proteins follow one of three major pathways after passing through the TOM complex. Preproteins with presequence are transferred to TIMM23 complex, the presequence translocase of the inner membrane. Most inner membrane proteins are synthesized without a presequence. After recognition by TOMM70A and translocation by the TOM pore across the outer membrane, these precursor proteins are bound by a complex of small TIM proteins in the intermembrane space, the Tim9-Tim10 complex. The precursors of outer membrane proteins, such as the abundant protein porin, are integrated into the outer membrane by the sorting and assembly machinery (SAM complex). Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-5de29879-ef6e-4f3c-8f88-8cb0a5e4d14a Mitochondrial Protein Transport uuid-5de29879-ef6e-4f3c-8f88-8cb0a5e4d14a PS:CellType generic PS:Description Most mitochondrial proteins are synthesized as precursor proteins in the cytosol and are imported mainly by a post-translational mechanism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5de29879-ef6e-4f3c-8f88-8cb0a5e4d14a PS:NodeType Pathway PS:Notes Headnote: Mitochondrial proteins are synthesized as precursor proteins in the cytosol and are imported mainly by a post-translational mechanism. Mitochondrial precursor proteins can be subdivided into two major classes including preproteins that carry N-terminal cleavable extensions called presequences and the second class of precursor proteins that are synthesized without cleavable extensions and have the same primary structure as the mature protein. Signaling description: The mitochondrial preproteins are believed to be maintained in a translocation competent state by cytosolic chaperones, particularly members of the HSP70 protein family (HSPA1A). The presence of a peptide in the binding domain stimulates the ATPase activity of HSPA1A, increasing its rate of ATP hydrolysis which is normally low. The translocase of the outer mitochondrial membrane (TOM complex) specifically recognizes and binds the precursors prior to their translocation. The TOM complex consists of seven different subunits including TOMM20, TOMM22, TOMM70A, TOMM40, TOMM5, TOMM6, and TOMM7. One half of the amphipathic alpha-helix of a typical presequence possesses a hydrophobic surface that is recognized by a binding groove within TOMM20, whereas the other half is positively charged and recognized by the TOMM22 receptor. Outcome effects: The preprotein is then transported to the general import pore formed by the essential beta-barrel protein TOMM40. The precursor proteins follow one of three major pathways after passing through the TOM complex. Preproteins with presequence are transferred to TIMM23 complex, the presequence translocase of the inner membrane. Most inner membrane proteins are synthesized without a presequence. After recognition by TOMM70A and translocation by the TOM pore across the outer membrane, these precursor proteins are bound by a complex of small TIM proteins in the intermembrane space, the Tim9-Tim10 complex. The precursors of outer membrane proteins, such as the abundant protein porin, are integrated into the outer membrane by the sorting and assembly machinery (SAM complex). PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5df87724-dfcf-4e47-b2ec-f211809f97aa NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5df87724-dfcf-4e47-b2ec-f211809f97aa IL3R -> STAT Signaling uuid-5df87724-dfcf-4e47-b2ec-f211809f97aa PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5df87724-dfcf-4e47-b2ec-f211809f97aa PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e05a7c5-8b51-4f6f-b240-461946e9a7e3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5e05a7c5-8b51-4f6f-b240-461946e9a7e3 LipidA biosynthesis template uuid-5e05a7c5-8b51-4f6f-b240-461946e9a7e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e05a7c5-8b51-4f6f-b240-461946e9a7e3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: ISL1 is a transcription factor that is present in all types of islet cells and can activate insulin somatostatin, glucagon, and amylin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e1aeb34-eb11-4a12-8074-1341497563c4 NodeType: Pathway Notes: Headnote: The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta-cells and four other endocrine cell types. Signaling description: ISL1 is a transcription factor that is present in all types of islet cells and can activate insulin, somatostatin, glucagon, and amylin expression. Leptin (LEP) suppresses ISL1 expression and insulin secretion in rodent and human islets in physiological and pathophysiological conditions. Outcome effects: ISL1 may act as a direct downstream target of the LEP signaling molecule STAT3, but insulin has feedback regulating effects on ISL1 expression through JAK2-STAT3 pathway. LEP may also inhibit insulin secretion by inhibiting PDE3B. ISL1 can synergistically activate insulin (INS) transcription with NEUROD1 in pancreatic beta-cells. LEP has been shown to inhibit insulin secretion by activating PDE3B. In isolated rat islets, IGF1 also directly suppresses insulin secretion most likely mediated through the activation of PDE3B. Organ: pancreas Organ_System: endocrine system PMID: 22974359 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-5e1aeb34-eb11-4a12-8074-1341497563c4 Leptin in Insulin Synthesis and Secretion uuid-5e1aeb34-eb11-4a12-8074-1341497563c4 PS:CellType insulin-secreting cell PS:Description ISL1 is a transcription factor that is present in all types of islet cells and can activate insulin somatostatin, glucagon, and amylin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e1aeb34-eb11-4a12-8074-1341497563c4 PS:NodeType Pathway PS:Notes Headnote: The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta-cells and four other endocrine cell types. Signaling description: ISL1 is a transcription factor that is present in all types of islet cells and can activate insulin, somatostatin, glucagon, and amylin expression. Leptin (LEP) suppresses ISL1 expression and insulin secretion in rodent and human islets in physiological and pathophysiological conditions. Outcome effects: ISL1 may act as a direct downstream target of the LEP signaling molecule STAT3, but insulin has feedback regulating effects on ISL1 expression through JAK2-STAT3 pathway. LEP may also inhibit insulin secretion by inhibiting PDE3B. ISL1 can synergistically activate insulin (INS) transcription with NEUROD1 in pancreatic beta-cells. LEP has been shown to inhibit insulin secretion by activating PDE3B. In isolated rat islets, IGF1 also directly suppresses insulin secretion most likely mediated through the activation of PDE3B. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22974359 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e2ea56b-9137-41f3-80aa-2022b59f5a9d NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. The impairment of CD8 T-cell action is an important step in HIV infection. Signaling description: Normally, T-cell receptor (TCR) with its coreceptor CD8A (of CD8 T cells) recognizes MHC class I protein complex with the infected cell antigen. In T-cells, the signal is transduced to ZAP70 and (via LAT/PLCG1) promotes the release of calcium (Ca2) from intracellular stores. Ca2 interacts with calmodulin-calcineurin complex, which leads to NF-AT activation. In turn, ZAP70 activates ERK (MAPK) pathway through PTK2B, which leads to JUN and FOS activation. At the same time, viral Nef protein downregulates the expression of MHC class I protein complex which blocks the described signal transduction and CD8 T-cell activation. Outcome effects: NF-AT and JUN/FOS bind to the promoter regions of FASLG, LTA, and IFNG resulting in their transcription. These ligands are death signals for the infected cells. In addition, MAPK3, which is involved in the MAPK pathway, promotes the expression of PRF1 in activated cytotoxic lymphocytes and is required for the release of granzymes (GZMA/GZMB) into the target cell. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. Reference: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 25165102 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-5e2ea56b-9137-41f3-80aa-2022b59f5a9d CD8+ T-Cell Action Impairment in HIV Type 1 Infection uuid-5e2ea56b-9137-41f3-80aa-2022b59f5a9d PS:CellType T-cell PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e2ea56b-9137-41f3-80aa-2022b59f5a9d PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. The impairment of CD8 T-cell action is an important step in HIV infection. Signaling description: Normally, T-cell receptor (TCR) with its coreceptor CD8A (of CD8 T cells) recognizes MHC class I protein complex with the infected cell antigen. In T-cells, the signal is transduced to ZAP70 and (via LAT/PLCG1) promotes the release of calcium (Ca2) from intracellular stores. Ca2 interacts with calmodulin-calcineurin complex, which leads to NF-AT activation. In turn, ZAP70 activates ERK (MAPK) pathway through PTK2B, which leads to JUN and FOS activation. At the same time, viral Nef protein downregulates the expression of MHC class I protein complex which blocks the described signal transduction and CD8 T-cell activation. Outcome effects: NF-AT and JUN/FOS bind to the promoter regions of FASLG, LTA, and IFNG resulting in their transcription. These ligands are death signals for the infected cells. In addition, MAPK3, which is involved in the MAPK pathway, promotes the expression of PRF1 in activated cytotoxic lymphocytes and is required for the release of granzymes (GZMA/GZMB) into the target cell. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. Reference: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival . HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 25165102 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of the DNA base itself. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e397b01-cdd4-4a4f-a7d8-26a274e76a38 NodeType: Pathway Notes: Headnote: Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of the DNA base itself. Signaling description: BER facilitates the repair of damaged DNA via two general pathways including short-patch and long-patch, both of which are initiated by a DNA glycosylase. These DNA glycosylases specifically hydrolyze the N-glycosylic bond of a target base which causes the release of the ineligible base while keeping the sugar phosphate backbone of the DNA intact. Glycosylase action creates an apurinic/apyrimidinic site (AP) or abasic site, which is processed by APEX1, which cleaves the phosphodiester backbone immediately 5' to the AP site, resulting in a 3' hydroxyl group and a transient 5' abasic deoxyribose phosphate (dRP). In the short-patch pathway, the removal of the dRP is accomplished by the action of POLB which adds one nucleotide to the 3' end of the nick and removes the dRP moiety through its associated AP lyase activity. Outcome effects: The integrity of the DNA is then restored by DNA ligase (LIG3) which seals the strand nick. POLB and LIG3 are brought together at the site of repair by means of XRCC1 that acts as a scaffold protein. In the long-patch pathway, DNA synthesis of multiple nucleotides occurs and the displaced oligonucleotide is removed by the FEN1 endonuclease. The strand integrity is finally restored by a DNA ligase (LIG1). Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-5e397b01-cdd4-4a4f-a7d8-26a274e76a38 Single-Strand Base Excision uuid-5e397b01-cdd4-4a4f-a7d8-26a274e76a38 PS:CellType generic PS:Description Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of the DNA base itself. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e397b01-cdd4-4a4f-a7d8-26a274e76a38 PS:NodeType Pathway PS:Notes Headnote: Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of the DNA base itself. Signaling description: BER facilitates the repair of damaged DNA via two general pathways including short-patch and long-patch, both of which are initiated by a DNA glycosylase. These DNA glycosylases specifically hydrolyze the N-glycosylic bond of a target base which causes the release of the ineligible base while keeping the sugar phosphate backbone of the DNA intact. Glycosylase action creates an apurinic/apyrimidinic site (AP) or abasic site, which is processed by APEX1, which cleaves the phosphodiester backbone immediately 5' to the AP site, resulting in a 3' hydroxyl group and a transient 5' abasic deoxyribose phosphate (dRP). In the short-patch pathway, the removal of the dRP is accomplished by the action of POLB which adds one nucleotide to the 3' end of the nick and removes the dRP moiety through its associated AP lyase activity. Outcome effects: The integrity of the DNA is then restored by DNA ligase (LIG3) which seals the strand nick. POLB and LIG3 are brought together at the site of repair by means of XRCC1 that acts as a scaffold protein. In the long-patch pathway, DNA synthesis of multiple nucleotides occurs and the displaced oligonucleotide is removed by the FEN1 endonuclease. The strand integrity is finally restored by a DNA ligase (LIG1). PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Double strand DNA homologous repair can may be impaired in cancer due to mutation or deregulation of multiple proteins involved in this process. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e5ab159-e31e-4104-aa9e-8a31786e4ba8 NodeType: Pathway Notes: Headnote: Many proteins that participate in double strand DNA homologous repair can be mutated and dysregulated in cancer: ATM, RAD50/51, BRCA1/2, XRCC2, ATRX, BARD1, H2AFX, MRE11A, NBN, SMC1A, RBBP8. Specifically, ATM can be inhibited by MIR100/421/18A/101-1. Signaling description: DNA repair by means of homologous recombination takes place when an identical or a near identical sequence is available to provide the template for DNA recovery. The protein machinery responsible for this recovery process is similar to that of the process of meiotic crossing-over when homologous chromatids serve as templates. The double strand bases (DSBs) appear as a result of mistakes in filling single-nucleotide gaps in the replicative fork or as a result of unfixed errors that occurred during single-stranded DNA synthesis. After DSBs are detected by ATM, the 5' strands are removed producing long 3' single-stranded DNA tails. These 3' tails serve as the substrate for RAD51 nucleoprotein filament nucleation. RAD52, BRCA1, and BRCA2 proteins are also recruited in this process. Once assembled, this protein complex screens the genome for homologous DNA sequences that can be used for the recombination.Transcription of BRCA1 is negatively regulated by HMGA2. The latter can be mutated and overexpressed or activated by downregulation of MIR15A/161/26A1, MIRLET7A1. BRCA1 also can be inhibited by MIR182. Outcome effects: The deregulation of double strand DNA homologous repair machinery leads to genomic instability in cancer cells. Persistent DNA repair affects cell cycle regulation and may be associated with oncogenesis. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20177397 PMID: 20965415 PMID: 24947262 PMID: 25017190 PMID: 25579208 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-5e5ab159-e31e-4104-aa9e-8a31786e4ba8 Persistent Double Strand DNA Homologous Repair in Cancer uuid-5e5ab159-e31e-4104-aa9e-8a31786e4ba8 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Double strand DNA homologous repair can may be impaired in cancer due to mutation or deregulation of multiple proteins involved in this process. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e5ab159-e31e-4104-aa9e-8a31786e4ba8 PS:NodeType Pathway PS:Notes Headnote: Many proteins that participate in double strand DNA homologous repair can be mutated and dysregulated in cancer: ATM, RAD50/51, BRCA1/2, XRCC2, ATRX, BARD1, H2AFX, MRE11A, NBN, SMC1A, RBBP8. Specifically, ATM can be inhibited by MIR100/421/18A/101-1. Signaling description: DNA repair by means of homologous recombination takes place when an identical or a near identical sequence is available to provide the template for DNA recovery. The protein machinery responsible for this recovery process is similar to that of the process of meiotic crossing-over when homologous chromatids serve as templates. The double strand bases (DSBs) appear as a result of mistakes in filling single-nucleotide gaps in the replicative fork or as a result of unfixed errors that occurred during single-stranded DNA synthesis. After DSBs are detected by ATM, the 5' strands are removed producing long 3' single-stranded DNA tails. These 3' tails serve as the substrate for RAD51 nucleoprotein filament nucleation. RAD52, BRCA1, and BRCA2 proteins are also recruited in this process. Once assembled, this protein complex screens the genome for homologous DNA sequences that can be used for the recombination.Transcription of BRCA1 is negatively regulated by HMGA2. The latter can be mutated and overexpressed or activated by downregulation of MIR15A/161/26A1, MIRLET7A1. BRCA1 also can be inhibited by MIR182. Outcome effects: The deregulation of double strand DNA homologous repair machinery leads to genomic instability in cancer cells. Persistent DNA repair affects cell cycle regulation and may be associated with oncogenesis. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20177397 PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PMID 25579208 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e7a5b4f-a8a0-4ebe-826c-f6513f8e0200 NodeType: Pathway Notes: Headnote: Maintaining of glucose levels within a narrow physiological range is an important for human health. AMPK regulates cellular metabolism in response to the level of cellular energy due to the ability of AMPK activated when intracellular ATP production decreases. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PMID: 21892142 PMID: 25592535 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-5e7a5b4f-a8a0-4ebe-826c-f6513f8e0200 AMPK Related Catabolism Deceleration in Glucose Insufficiency uuid-5e7a5b4f-a8a0-4ebe-826c-f6513f8e0200 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e7a5b4f-a8a0-4ebe-826c-f6513f8e0200 PS:NodeType Pathway PS:Notes Headnote: Maintaining of glucose levels within a narrow physiological range is an important for human health. AMPK regulates cellular metabolism in response to the level of cellular energy due to the ability of AMPK activated when intracellular ATP production decreases. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 21892142 PS:PMID 25592535 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e83eadf-71ca-4492-8678-d9aaf0707140 NodeType: Pathway Notes: Angiogenesis is a critical process in the establishment and growth of endometriotic lesions. The process of angiogenesis is stimulated by two central pathways that involve vascular endothelial growth factor A (VEGFA) and angiopoietin 1 (ANGPT1). Both VEGFA and ANGPT1 are strongly overexpressed in endometriotic lesions. VEGFA and ANGPT1 act as endothelial cell (EC) mitogens, enhancing cell proliferation and migration and increasing the vascular permeability in ectopic endometrium. Vascularization is necessary for the formation and function of ectopic endometrium lesions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: uterus Organ_System: reproductive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-5e83eadf-71ca-4492-8678-d9aaf0707140 3_Enhanced angiogenesis in endometriosis uuid-5e83eadf-71ca-4492-8678-d9aaf0707140 PS:CellType endometrium cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5e83eadf-71ca-4492-8678-d9aaf0707140 PS:NodeType Pathway PS:Notes Angiogenesis is a critical process in the establishment and growth of endometriotic lesions. The process of angiogenesis is stimulated by two central pathways that involve vascular endothelial growth factor A (VEGFA) and angiopoietin 1 (ANGPT1). Both VEGFA and ANGPT1 are strongly overexpressed in endometriotic lesions. VEGFA and ANGPT1 act as endothelial cell (EC) mitogens, enhancing cell proliferation and migration and increasing the vascular permeability in ectopic endometrium. Vascularization is necessary for the formation and function of ectopic endometrium lesions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ed4f568-139f-4be3-b348-5e6cbc74a71f NodeType: Pathway Organ: generic Organ_System: generic PMID: 23481039 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: generic urn:agi-pathway:uuid-5ed4f568-139f-4be3-b348-5e6cbc74a71f Co-Translational ER Protein Import uuid-5ed4f568-139f-4be3-b348-5e6cbc74a71f PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ed4f568-139f-4be3-b348-5e6cbc74a71f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 23481039 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: A positive feedback regulation between TERT and NFKB potentiating cancer progression. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5edc22bd-a441-4aa7-9dd3-827a5b867801 NodeType: Pathway Notes: Headnote: A positive feedback regulatory loop between TERT and NFKB potentiates cancer progression. Signaling description: TERT directly regulates NFKB-dependent gene expression by binding to the RELA, which, in turn, modulates nuclear translocation of TERT and is also responsible for expression of telomeric repeat binding factor 2 (TERF2IP). NFKB signaling may also activate TERT via NFKB1 and MYC. Outcome effects: The interplay between TERT and NFKB promotes tumor growth and chronic inflammation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21346783 PMID: 23932019 PMID: 23993966 PMID: 24599132 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-5edc22bd-a441-4aa7-9dd3-827a5b867801 Telomeric Proteins/NFKB Positive Feedback Interplay in Cancer uuid-5edc22bd-a441-4aa7-9dd3-827a5b867801 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description A positive feedback regulation between TERT and NFKB potentiating cancer progression. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5edc22bd-a441-4aa7-9dd3-827a5b867801 PS:NodeType Pathway PS:Notes Headnote: A positive feedback regulatory loop between TERT and NFKB potentiates cancer progression. Signaling description: TERT directly regulates NFKB-dependent gene expression by binding to the RELA, which, in turn, modulates nuclear translocation of TERT and is also responsible for expression of telomeric repeat binding factor 2 (TERF2IP). NFKB signaling may also activate TERT via NFKB1 and MYC. Outcome effects: The interplay between TERT and NFKB promotes tumor growth and chronic inflammation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21346783 PS:PMID 23932019 PS:PMID 23993966 PS:PMID 24599132 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ef6fb42-977e-4a70-8604-42a1434dd291 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5ef6fb42-977e-4a70-8604-42a1434dd291 Sulfate metabolism template uuid-5ef6fb42-977e-4a70-8604-42a1434dd291 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5ef6fb42-977e-4a70-8604-42a1434dd291 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Insoluble aggregations of proteins impair the cell function and may lead to the cell senescence. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5efb486f-44b9-42b7-8d7f-c3147df6b211 NodeType: Pathway Notes: Headnote: Protein oxidation refers to the oxidative damage which occurs as a result of direct or indirect reactions of proteins with reactive oxygen species (ROS). The pathology of oxidative damage is characterized with changes in the protein function, unfolding of the protein, formation of a variety of various toxicity products. According to the "oxidative stress theory of aging", oxidative stress initiates changes associated with aging and determine the maximum longevity (Reinald Pamplona, 2008). The aging of proteome in terms of the "oxidative stress theory" may be caused by a disturbed balance between the production of oxidized proteins and their clearance, and the accumulation of damaged, oxidized, and aggregated proteins such as lipofuscin. Signaling description: ROS harms the cell directly by damaging the amino acids (protein side chains) or protein backbones and indirectly by lipid peroxidation products. For example, methionine sulfoxide is the major amino acid oxidation product, which results from methionine oxidation. Oxidized proteins could be repaired by specific enzymes such as TXN or peptide-methionine (S)-S-oxide reductase. The 20S core proteasome is involved in the proteolic degradation of oxidized proteins via the ubiquitin-proteasome system (UPS). Oxidative stress and an excessive amount of oxidized proteins can lead to UPS dysfunction. Oxidized proteins which were not eliminated or repaired may form aggregates and accumulate within the cell at different compartments. Such protein aggregates are insoluble and nondegradable. Lipofuscin is a highly oxidized aggregate formed by covalently cross-linked proteins (30-70%) and lipids (20-50%). Lipofuscin accumulates in the lysosomal lumen and the cytosol. The "mitochondrial-lysosomal axis theory of aging" (Brunk and Terman) suggests that lipofuscin is formed in lysosomes as result of lysosomal membrane permeabilization (LMP); in addition, highly reactive ROS are generated within lysosomes. Outcome effects: Aggregates of oxidized proteins inhibit the proteasomal system which, in turn leads to further protein aggregation. Lipofuscin inhibits both proteasomal and lysosomal-autophagic degradation pathways. Insoluble aggregations of proteins impair the cell function and may lead to the cell senescence. Lipofuscin may be involved in lysosomal membrane degradation, release of the lysosomal content and cell death. Organ: generic Organ_System: generic PMID: 23333925 PMID: 25178482 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-5efb486f-44b9-42b7-8d7f-c3147df6b211 Protein Oxidation and Aggregation in Aging uuid-5efb486f-44b9-42b7-8d7f-c3147df6b211 PS:CellType generic PS:Description Insoluble aggregations of proteins impair the cell function and may lead to the cell senescence. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5efb486f-44b9-42b7-8d7f-c3147df6b211 PS:NodeType Pathway PS:Notes Headnote: Protein oxidation refers to the oxidative damage which occurs as a result of direct or indirect reactions of proteins with reactive oxygen species (ROS). The pathology of oxidative damage is characterized with changes in the protein function, unfolding of the protein, formation of a variety of various toxicity products. According to the "oxidative stress theory of aging", oxidative stress initiates changes associated with aging and determine the maximum longevity (Reinald Pamplona, 2008). The aging of proteome in terms of the "oxidative stress theory" may be caused by a disturbed balance between the production of oxidized proteins and their clearance, and the accumulation of damaged, oxidized, and aggregated proteins such as lipofuscin. Signaling description: ROS harms the cell directly by damaging the amino acids (protein side chains) or protein backbones and indirectly by lipid peroxidation products. For example, methionine sulfoxide is the major amino acid oxidation product, which results from methionine oxidation. Oxidized proteins could be repaired by specific enzymes such as TXN or peptide-methionine (S)-S-oxide reductase. The 20S core proteasome is involved in the proteolic degradation of oxidized proteins via the ubiquitin-proteasome system (UPS). Oxidative stress and an excessive amount of oxidized proteins can lead to UPS dysfunction. Oxidized proteins which were not eliminated or repaired may form aggregates and accumulate within the cell at different compartments. Such protein aggregates are insoluble and nondegradable. Lipofuscin is a highly oxidized aggregate formed by covalently cross-linked proteins (30-70%) and lipids (20-50%). Lipofuscin accumulates in the lysosomal lumen and the cytosol. The "mitochondrial-lysosomal axis theory of aging" (Brunk and Terman) suggests that lipofuscin is formed in lysosomes as result of lysosomal membrane permeabilization (LMP); in addition, highly reactive ROS are generated within lysosomes. Outcome effects: Aggregates of oxidized proteins inhibit the proteasomal system which, in turn leads to further protein aggregation. Lipofuscin inhibits both proteasomal and lysosomal-autophagic degradation pathways. Insoluble aggregations of proteins impair the cell function and may lead to the cell senescence. Lipofuscin may be involved in lysosomal membrane degradation, release of the lysosomal content and cell death. PS:Organ generic PS:Organ_System generic PS:PMID 23333925 PS:PMID 25178482 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5efefcb8-f03c-4496-8889-aa711ba20e64 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-5efefcb8-f03c-4496-8889-aa711ba20e64 IFI27 biomarker for severe COVID-19 uuid-5efefcb8-f03c-4496-8889-aa711ba20e64 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5efefcb8-f03c-4496-8889-aa711ba20e64 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f058f09-6686-402b-8817-3cdc81398079 NodeType: Pathway Organ: generic Organ_System: generic PMID: 11897488 PMID: 21962830 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-5f058f09-6686-402b-8817-3cdc81398079 TNF-alpha/TNFRSF1B Signaling uuid-5f058f09-6686-402b-8817-3cdc81398079 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f058f09-6686-402b-8817-3cdc81398079 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 11897488 PS:PMID 21962830 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f082c0e-c52e-4e82-941a-10164f373009 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-5f082c0e-c52e-4e82-941a-10164f373009 Endosome sorting uuid-5f082c0e-c52e-4e82-941a-10164f373009 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f082c0e-c52e-4e82-941a-10164f373009 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f099a8c-8e82-4154-9a5f-e9d5f62660cf NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-5f099a8c-8e82-4154-9a5f-e9d5f62660cf insect pheromone biosynthesis template uuid-5f099a8c-8e82-4154-9a5f-e9d5f62660cf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f099a8c-8e82-4154-9a5f-e9d5f62660cf PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f0d6a3f-fe8e-4bf5-8f2a-60f1443a31a5 NodeType: Pathway Notes: Eosinophilic and/or neutrophilic inflammation is an important sign of allergic asthma. In asthma, eosinophils are attracted to the lungs by cytokines released by Th2 cells. In the lungs, eosinophils release the content of their granules, which leads to cellular damage. On the other hand, airway neutrophilia is one of the hallmarks of severe asthma. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-5f0d6a3f-fe8e-4bf5-8f2a-60f1443a31a5 2_1_Eosinophilia and neutrophilia in asthma: eosinophil migration and activation uuid-5f0d6a3f-fe8e-4bf5-8f2a-60f1443a31a5 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f0d6a3f-fe8e-4bf5-8f2a-60f1443a31a5 PS:NodeType Pathway PS:Notes Eosinophilic and/or neutrophilic inflammation is an important sign of allergic asthma. In asthma, eosinophils are attracted to the lungs by cytokines released by Th2 cells. In the lungs, eosinophils release the content of their granules, which leads to cellular damage. On the other hand, airway neutrophilia is one of the hallmarks of severe asthma. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Neonatal Severe Hyperparathyroidism is characterized by life-threatening hypersecretion of parathormone. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f21c100-0f97-4cc3-9867-c4677eb37951 NodeType: Pathway Notes: Headnote: Neonatal severe hyperparathyroidism is characterized by life-threatening hypersecretion of parathormone which usually manifests itself in the first six months of life. Neonatal severe hyperparathyroidism can be a devastating neurodevelopmental disorder with failure to thrive and demineralization of bone which in some cases is lethal without parathyroidectomy. Signaling description: Germline-inactivating homozygous CASR mutations result in neonatal severe hyperparathyroidism. Heterozygous mutations in CASR usually result in mild hypercalcemia seen in familial hypocalciuric hypercalcemia. It is known that mutations in CASR cause the disruption of PTH secretion. At the same time, the precise mechanisms of the PTH expression regulation are not well understood. One of hypotheses is depicted on the pathway. Outcome effects: CASR is implicated in calcium homeostasis. Under normal conditions, increasing extracellular calcium activates CASR, thus diminishing the PTH release and augmenting renal calcium excretion. Activation of CASR stimulates PLCB1 via GNAQ resulting in the PKC/MAPK/CREB cascade activation. CREB promotes SP1 which interacts with PIN1.In turn, PIN1 regulates KHSRP and HNRNPD involved in PTH expression. Highlighted proteins: PTH highlighted in red has increased expression in neonatal severe hyperparathyroidism. Mutated genes: CASR with mutations in neonatal severe hyperparathyroidism is shown in white-out style. Organ: Parathyroid gland Organ_System: endocrine system PMID: 11994364 PMID: 20032048 PMID: 20729338 PMID: 21642377 PMID: 22989537 PMID: 25576451 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-5f21c100-0f97-4cc3-9867-c4677eb37951 Hyperparathyroidism, Neonatal Severe uuid-5f21c100-0f97-4cc3-9867-c4677eb37951 PS:CellType parathyroid cell PS:Description Neonatal Severe Hyperparathyroidism is characterized by life-threatening hypersecretion of parathormone. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f21c100-0f97-4cc3-9867-c4677eb37951 PS:NodeType Pathway PS:Notes Headnote: Neonatal severe hyperparathyroidism is characterized by life-threatening hypersecretion of parathormone which usually manifests itself in the first six months of life. Neonatal severe hyperparathyroidism can be a devastating neurodevelopmental disorder with failure to thrive and demineralization of bone which in some cases is lethal without parathyroidectomy. Signaling description: Germline-inactivating homozygous CASR mutations result in neonatal severe hyperparathyroidism. Heterozygous mutations in CASR usually result in mild hypercalcemia seen in familial hypocalciuric hypercalcemia. It is known that mutations in CASR cause the disruption of PTH secretion. At the same time, the precise mechanisms of the PTH expression regulation are not well understood. One of hypotheses is depicted on the pathway. Outcome effects: CASR is implicated in calcium homeostasis. Under normal conditions, increasing extracellular calcium activates CASR, thus diminishing the PTH release and augmenting renal calcium excretion. Activation of CASR stimulates PLCB1 via GNAQ resulting in the PKC/MAPK/CREB cascade activation. CREB promotes SP1 which interacts with PIN1.In turn, PIN1 regulates KHSRP and HNRNPD involved in PTH expression. Highlighted proteins: PTH highlighted in red has increased expression in neonatal severe hyperparathyroidism. Mutated genes: CASR with mutations in neonatal severe hyperparathyroidism is shown in white-out style. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 11994364 PS:PMID 20032048 PS:PMID 20729338 PS:PMID 21642377 PS:PMID 22989537 PS:PMID 25576451 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: TLR3 plays dual role in RPE cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f3bbfab-580f-4691-bfd8-d9b342466cbc NodeType: Pathway Notes: Headnote: Although the specific roles macrophages in age-related macular degeneration (AMD) at different disease stages remain controversial, both pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages may be involved in the development and progression of AMD. Recent studies have revealed that macrophages recruited under the retina at the initial stage of AMD exhibit a pro-inflammatory M1 phenotype. M2 macrophages are likely activated in later AMD stages rather than in early stages. M2 macrophages are described as anti-inflammatory/pro-angiogenic, and promote immunoregulation, tissue remodeling. Signaling description: Increased IL10 in senescent eyes activates STAT3 signalling that induces activation of M2 macrophages and vascular proliferation. STAT3 regulates expression of pro-angiogenic factors VEGFA, FGF2, PGF. Impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes M2 macrophage activation and pathological neovascularization. Organ: eye Organ_System: sensory system PMID: 21712495 PMID: 21988875 PMID: 23267850 PMID: 25264029 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-5f3bbfab-580f-4691-bfd8-d9b342466cbc TLR3 Role in Retinal Pigment Epithelial Cell uuid-5f3bbfab-580f-4691-bfd8-d9b342466cbc PS:CellType epithelial cell PS:Description TLR3 plays dual role in RPE cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f3bbfab-580f-4691-bfd8-d9b342466cbc PS:NodeType Pathway PS:Notes Headnote: Although the specific roles macrophages in age-related macular degeneration (AMD) at different disease stages remain controversial, both pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages may be involved in the development and progression of AMD. Recent studies have revealed that macrophages recruited under the retina at the initial stage of AMD exhibit a pro-inflammatory M1 phenotype. M2 macrophages are likely activated in later AMD stages rather than in early stages. M2 macrophages are described as anti-inflammatory/pro-angiogenic, and promote immunoregulation, tissue remodeling. Signaling description: Increased IL10 in senescent eyes activates STAT3 signalling that induces activation of M2 macrophages and vascular proliferation. STAT3 regulates expression of pro-angiogenic factors VEGFA, FGF2, PGF. Impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes M2 macrophage activation and pathological neovascularization. PS:Organ eye PS:Organ_System sensory system PS:PMID 21712495 PS:PMID 21988875 PS:PMID 23267850 PS:PMID 25264029 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f3fefe9-0f56-4b5f-9af8-a87b2a8e42d6 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-5f3fefe9-0f56-4b5f-9af8-a87b2a8e42d6 Biosynthesis of Cholesterol uuid-5f3fefe9-0f56-4b5f-9af8-a87b2a8e42d6 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f3fefe9-0f56-4b5f-9af8-a87b2a8e42d6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f474bee-b8b5-46d3-a0e8-4ad69af382cd NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5f474bee-b8b5-46d3-a0e8-4ad69af382cd AGER -> CREB/SP1 Signaling uuid-5f474bee-b8b5-46d3-a0e8-4ad69af382cd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f474bee-b8b5-46d3-a0e8-4ad69af382cd PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f7393bb-5ea7-402f-ba32-c69551748158 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5f7393bb-5ea7-402f-ba32-c69551748158 TGFA -> FOXO3A Expression Targets uuid-5f7393bb-5ea7-402f-ba32-c69551748158 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f7393bb-5ea7-402f-ba32-c69551748158 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f852e14-29ae-48a0-aa41-ad9056b221fd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5f852e14-29ae-48a0-aa41-ad9056b221fd Insulin -> CEBPA/CTNNB/FOXA/FOXO Expression Targets uuid-5f852e14-29ae-48a0-aa41-ad9056b221fd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f852e14-29ae-48a0-aa41-ad9056b221fd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f85ac27-580e-4c63-8b82-382906bcded6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-5f85ac27-580e-4c63-8b82-382906bcded6 VEGFR -> NFATC Signaling uuid-5f85ac27-580e-4c63-8b82-382906bcded6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5f85ac27-580e-4c63-8b82-382906bcded6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fb74e52-8288-4587-a27a-13723ae2af3b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-5fb74e52-8288-4587-a27a-13723ae2af3b BMP15/BMPR2 Expression Targets uuid-5fb74e52-8288-4587-a27a-13723ae2af3b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fb74e52-8288-4587-a27a-13723ae2af3b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA replication stress is a major source of genomic instability. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fbc9753-e8fb-45e5-8f31-3f4b1c9313ea NodeType: Pathway Notes: Headnote: DNA replication errors are a major source of unrepaired single-stranded (ss) or double-stranded DNA (dsDNA) lesions. As a result, inaccuracies in maintaining telomeres and nucleosomes, transcription of genes and remodeling of chromatin accumulate. Signaling description: Initiation of DNA replication is a two-step process: origin licensing and firing. Origin licensing starts in early G1 with the assembly of a pre-replicative complex (pre-RC). The pre-RC consists of the origin of replication recognition complex, CDC6, CDT1 and MCM helicase complex. The second step, origin firing, involves the activation MCM helicase complex in S phase. Replication stress induced by trigger results in the generation of single strand DNA bound by RPA protein. Outcome effects: Under conditions of persistent replication stress, the cell may not be able to repair DNA double strand break which is lead to activation DNA damage signaling and persisted DNA repair. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see pathway "Proteins with Altered Expression in Aging". Organ: generic Organ_System: generic PMID: 25281304 PMID: 26378584 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-5fbc9753-e8fb-45e5-8f31-3f4b1c9313ea Replication Stress Triggers Genomic Instability uuid-5fbc9753-e8fb-45e5-8f31-3f4b1c9313ea PS:CellType generic PS:Description DNA replication stress is a major source of genomic instability. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fbc9753-e8fb-45e5-8f31-3f4b1c9313ea PS:NodeType Pathway PS:Notes Headnote: DNA replication errors are a major source of unrepaired single-stranded (ss) or double-stranded DNA (dsDNA) lesions. As a result, inaccuracies in maintaining telomeres and nucleosomes, transcription of genes and remodeling of chromatin accumulate. Signaling description: Initiation of DNA replication is a two-step process: origin licensing and firing. Origin licensing starts in early G1 with the assembly of a pre-replicative complex (pre-RC). The pre-RC consists of the origin of replication recognition complex, CDC6, CDT1 and MCM helicase complex. The second step, origin firing, involves the activation MCM helicase complex in S phase. Replication stress induced by trigger results in the generation of single strand DNA bound by RPA protein. Outcome effects: Under conditions of persistent replication stress, the cell may not be able to repair DNA double strand break which is lead to activation DNA damage signaling and persisted DNA repair. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see pathway "Proteins with Altered Expression in Aging". PS:Organ generic PS:Organ_System generic PS:PMID 25281304 PS:PMID 26378584 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fcebcd9-55ba-4d42-8d1a-5b08019a93ef NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: stomach Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-5fcebcd9-55ba-4d42-8d1a-5b08019a93ef Elevated Receptors -> Expression Targets in Stomach uuid-5fcebcd9-55ba-4d42-8d1a-5b08019a93ef PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-5fcebcd9-55ba-4d42-8d1a-5b08019a93ef PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ stomach PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6025f312-3f11-4e78-ac2a-28b7ccc213f5 NodeType: Pathway Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-6025f312-3f11-4e78-ac2a-28b7ccc213f5 Proteins Involved in Breast Cancer Related to ESR1 Signaling Pathway uuid-6025f312-3f11-4e78-ac2a-28b7ccc213f5 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6025f312-3f11-4e78-ac2a-28b7ccc213f5 PS:NodeType Pathway PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: The aqueous humor (AH) is a transparent fluid consisting of water (98?), ions, amino acids, and biomolecules including signaling molecules, growth factors, and extracellular matrix molecules. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6052a844-837b-469e-9c13-1c02c1a5f7b0 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. The aqueous humor (AH) of the eye is a transparent fluid consisting of water (98%), ions, amino acids, and biomolecules such as signaling molecules, growth factors, and extracellular matrix molecules. Signaling description: Three mechanisms are involved in AH formation including diffusion, ultrafiltration, and active secretion.The AH fills the anterior and posterior chambers of the eye and has two main functions: nutrient supply to the avascular structures of the eye, cornea, and lens and intraocular pressure (IOP) homeostatsis. AH undergoes a constant turnover. It is secreted to the posterior chamber of the eye by the ciliary body epithelium (CBE), circulates throughout the posterior and anterior chambers, and drains through the trabecular meshwork in the iridocorneal angle. A number of transporters are involved in AH production including Na+/K+ ATPases, Na+-K+-Cl- symporters, Na+/H+ antiporters, Cl-/ HCO3- exchangers, and other channels. Outcome effects: The balance between the production and outflow of AH ultimately determines IOP. Carbonic anhydrases is a family of enzymes that catalyze the reversible conversion of carbon dioxide and water to bicarbonate and protons. Carbonic anhydrase inhibitors decrease the amount of AH production and are used to treat glaucoma. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 18501660 PMID: 21293732 PMID: 24165276 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6052a844-837b-469e-9c13-1c02c1a5f7b0 Aqueous Humor Production uuid-6052a844-837b-469e-9c13-1c02c1a5f7b0 PS:CellType epithelial cell PS:Description The aqueous humor (AH) is a transparent fluid consisting of water (98?), ions, amino acids, and biomolecules including signaling molecules, growth factors, and extracellular matrix molecules. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6052a844-837b-469e-9c13-1c02c1a5f7b0 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. The aqueous humor (AH) of the eye is a transparent fluid consisting of water (98%), ions, amino acids, and biomolecules such as signaling molecules, growth factors, and extracellular matrix molecules. Signaling description: Three mechanisms are involved in AH formation including diffusion, ultrafiltration, and active secretion.The AH fills the anterior and posterior chambers of the eye and has two main functions: nutrient supply to the avascular structures of the eye, cornea, and lens and intraocular pressure (IOP) homeostatsis. AH undergoes a constant turnover. It is secreted to the posterior chamber of the eye by the ciliary body epithelium (CBE), circulates throughout the posterior and anterior chambers, and drains through the trabecular meshwork in the iridocorneal angle. A number of transporters are involved in AH production including Na+/K+ ATPases, Na+-K+-Cl- symporters, Na+/H+ antiporters, Cl-/ HCO3- exchangers, and other channels. Outcome effects: The balance between the production and outflow of AH ultimately determines IOP. Carbonic anhydrases is a family of enzymes that catalyze the reversible conversion of carbon dioxide and water to bicarbonate and protons. Carbonic anhydrase inhibitors decrease the amount of AH production and are used to treat glaucoma. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 18501660 PS:PMID 21293732 PS:PMID 24165276 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-60537add-708f-45cf-8a0e-9957834107fa NodeType: Pathway Organ: generic Organ_System: generic PMID: 22898666 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-60537add-708f-45cf-8a0e-9957834107fa Hippo/YAP1 Signaling uuid-60537add-708f-45cf-8a0e-9957834107fa PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-60537add-708f-45cf-8a0e-9957834107fa PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 22898666 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma. PMBL tumor cells B1904 seem to originate from a rare B-cell subpopulation which resides in the thymus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-607632c9-0fb5-470e-976e-c93d20baadad NodeType: Pathway Notes: Headnote: Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBL mainly affects young female patients with a median age of 30-35 years with the mediastinum being the predominant site of lymphoma manifestation. PMBL tumor cells seem to originate from a rare B-cell subpopulation which resides in the thymus. In the past, PMBL patients were mainly diagnosed by clinical and pathological criteria. Several gene expression profiling studies have demonstrated that PMBLs are characterized by a specific gene expression profile that clearly distinguishes them from GCB and ABC DLBCLs. However, these studies also indicate that PMBL cannot be diagnosed reliably by current diagnostic methods alone since approximately 25% of cases assigned as PMBL by conventional criteria was not confirmed by gene expression profiling. These cases represented other DLBCL subtypes with mediastinal involvement. Interestingly, PMBLs clinically and biologically resemble nodular sclerosis Hodgkin's lymphoma. Signaling description: PMBL is characterized by the constitutive activation of NF-kB signaling. Approximately 30% of all cases harbor inactivating aberrations of TNFAIP3 (A20), which is an ubiquitin-modifying enzyme that inhibits NF-kB activation. In about 20% of samples, the amplification and overexpression of the REL locus have been identified. REL is a transcription factor that is a member of the REL/NF-kB family which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NF-kB inhibitor. In addition, a recurrent genetic aberration detected in approximately 45% of PMBL samples is the gain or amplification of JAK2. SOCS1, which is a negative regulator of the JAK2/STAT pathway, is recurrently inactivated in PMBL. Thus, the overexpression of JAK2 and/or inactivation of SOCS1 contribute to continuous JAK2/STAT signaling in PMBL. Furthermore, CIITA translocations are highly recurrent in PMBL and occur in roughly 40% of cases. Overall, PMBL may be successfully treated with conventional chemotherapy plus rituximab. Outcome effects: CIITA translocations are associated with the downregulation of surface HLA class II expression and the overexpression of ligands of the receptor molecule programmed cell death 1 or PDL1 (CD274) and PDCD1LG2 (CD273 and PDL2). This leads to the suppression of antitumor T-cell response. CD274 and PDCD1LG2 may also be overexpressed due to mutations. In conclusion, the resulting signaling in PMBL inhibits plasma cell differentiation and leads to increased proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 16720849 PMID: 19577170 PMID: 20393178 PMID: 22224767 PMID: 22409819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-607632c9-0fb5-470e-976e-c93d20baadad Primary Mediastinal B-cell Lymphoma (PMBL) Subtype uuid-607632c9-0fb5-470e-976e-c93d20baadad PS:CellType B-cell PS:CellType cancer cell PS:Description Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma. PMBL tumor cells B1904 seem to originate from a rare B-cell subpopulation which resides in the thymus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-607632c9-0fb5-470e-976e-c93d20baadad PS:NodeType Pathway PS:Notes Headnote: Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBL mainly affects young female patients with a median age of 30-35 years with the mediastinum being the predominant site of lymphoma manifestation. PMBL tumor cells seem to originate from a rare B-cell subpopulation which resides in the thymus. In the past, PMBL patients were mainly diagnosed by clinical and pathological criteria. Several gene expression profiling studies have demonstrated that PMBLs are characterized by a specific gene expression profile that clearly distinguishes them from GCB and ABC DLBCLs. However, these studies also indicate that PMBL cannot be diagnosed reliably by current diagnostic methods alone since approximately 25% of cases assigned as PMBL by conventional criteria was not confirmed by gene expression profiling. These cases represented other DLBCL subtypes with mediastinal involvement. Interestingly, PMBLs clinically and biologically resemble nodular sclerosis Hodgkin's lymphoma. Signaling description: PMBL is characterized by the constitutive activation of NF-kB signaling. Approximately 30% of all cases harbor inactivating aberrations of TNFAIP3 (A20), which is an ubiquitin-modifying enzyme that inhibits NF-kB activation. In about 20% of samples, the amplification and overexpression of the REL locus have been identified. REL is a transcription factor that is a member of the REL/NF-kB family which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NF-kB inhibitor. In addition, a recurrent genetic aberration detected in approximately 45% of PMBL samples is the gain or amplification of JAK2. SOCS1, which is a negative regulator of the JAK2/STAT pathway, is recurrently inactivated in PMBL. Thus, the overexpression of JAK2 and/or inactivation of SOCS1 contribute to continuous JAK2/STAT signaling in PMBL. Furthermore, CIITA translocations are highly recurrent in PMBL and occur in roughly 40% of cases. Overall, PMBL may be successfully treated with conventional chemotherapy plus rituximab. Outcome effects: CIITA translocations are associated with the downregulation of surface HLA class II expression and the overexpression of ligands of the receptor molecule programmed cell death 1 or PDL1 (CD274) and PDCD1LG2 (CD273 and PDL2). This leads to the suppression of antitumor T-cell response. CD274 and PDCD1LG2 may also be overexpressed due to mutations. In conclusion, the resulting signaling in PMBL inhibits plasma cell differentiation and leads to increased proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 16720849 PS:PMID 19577170 PS:PMID 20393178 PS:PMID 22224767 PS:PMID 22409819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-607bc54d-d969-4bac-afaf-15685fa0cdb4 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-607bc54d-d969-4bac-afaf-15685fa0cdb4 HTR2 -> Membrane Transport uuid-607bc54d-d969-4bac-afaf-15685fa0cdb4 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-607bc54d-d969-4bac-afaf-15685fa0cdb4 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Canonical (WNT3A-regulated) and non-canonical (WNT5A-regulated) WNT-signaling pathways play different roles at different stages of melanoma development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6083f735-d6b2-43a3-a0b1-4a26446db0a6 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies, yet it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Wnt signalling is known to have a role in melanoma. Signaling description: During embryogenesis, the canonical WNT signaling is important for the positioning of stem cells and differentiation of melanoblasts into melanocytes; whereas, the non-canonical WNT signaling causes de-differentiation of melanocytes and other cell types through the suppression of CTNNB, thus maintaining the pluripotency of stem cells. Both WNT signaling pathways are critical in melanoma. WNT3A signaling is important in the early stages of tumor development promoting cell proliferation and tumor transformation; however, this pathway may inhibit metastasis. In contrast, WNT5A signaling is absent in the early stages of the tumor. Following melanocyte transformation, WNT5A activation represses the canonical WNT sinaling and promotes metastasis mainly via the PKC-mediated downregulation of KISS1 and CDH1 and the up-regulation of VIM and CD44. Outcome effects: Canonical (WNT3A-regulated) and non-canonical (WNT5A-regulated) WNT-signaling pathways are implicated at different stages of melanoma development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: skin Organ_System: integumentary system PMID: 19708915 PMID: 20576942 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6083f735-d6b2-43a3-a0b1-4a26446db0a6 WNT Signaling in Melanoma uuid-6083f735-d6b2-43a3-a0b1-4a26446db0a6 PS:CellType cancer cell PS:CellType melanocyte PS:Description Canonical (WNT3A-regulated) and non-canonical (WNT5A-regulated) WNT-signaling pathways play different roles at different stages of melanoma development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6083f735-d6b2-43a3-a0b1-4a26446db0a6 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies, yet it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Wnt signalling is known to have a role in melanoma. Signaling description: During embryogenesis, the canonical WNT signaling is important for the positioning of stem cells and differentiation of melanoblasts into melanocytes; whereas, the non-canonical WNT signaling causes de-differentiation of melanocytes and other cell types through the suppression of CTNNB, thus maintaining the pluripotency of stem cells. Both WNT signaling pathways are critical in melanoma. WNT3A signaling is important in the early stages of tumor development promoting cell proliferation and tumor transformation; however, this pathway may inhibit metastasis. In contrast, WNT5A signaling is absent in the early stages of the tumor. Following melanocyte transformation, WNT5A activation represses the canonical WNT sinaling and promotes metastasis mainly via the PKC-mediated downregulation of KISS1 and CDH1 and the up-regulation of VIM and CD44. Outcome effects: Canonical (WNT3A-regulated) and non-canonical (WNT5A-regulated) WNT-signaling pathways are implicated at different stages of melanoma development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ skin PS:Organ_System integumentary system PS:PMID 19708915 PS:PMID 20576942 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-608bbce4-5d6b-4237-a1f7-e59cd7f99733 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-608bbce4-5d6b-4237-a1f7-e59cd7f99733 IL7,IFN-|TGFB1 in myofibroblats uuid-608bbce4-5d6b-4237-a1f7-e59cd7f99733 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-608bbce4-5d6b-4237-a1f7-e59cd7f99733 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-609b73d0-0410-4b68-a6c1-7608b1a59e92 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-609b73d0-0410-4b68-a6c1-7608b1a59e92 EphrinB -> MAPK/JUN/FOS Signaling uuid-609b73d0-0410-4b68-a6c1-7608b1a59e92 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-609b73d0-0410-4b68-a6c1-7608b1a59e92 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-60c7472a-ecb5-413d-9bcb-881fa7627322 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-60c7472a-ecb5-413d-9bcb-881fa7627322 MRGX2+>Asthma AOP uuid-60c7472a-ecb5-413d-9bcb-881fa7627322 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-60c7472a-ecb5-413d-9bcb-881fa7627322 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61516df9-1d71-4c8b-8a81-c4b2d117937e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-61516df9-1d71-4c8b-8a81-c4b2d117937e CD86-> NFATC Expression Targets uuid-61516df9-1d71-4c8b-8a81-c4b2d117937e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61516df9-1d71-4c8b-8a81-c4b2d117937e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top most studied mutated genes and SNVs assotiated with disease Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6163f64c-7346-4a01-a5c7-d5fda715eea8 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6163f64c-7346-4a01-a5c7-d5fda715eea8 Ovarian Cancer Mutated Genes uuid-6163f64c-7346-4a01-a5c7-d5fda715eea8 PS:Description Top most studied mutated genes and SNVs assotiated with disease PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6163f64c-7346-4a01-a5c7-d5fda715eea8 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-617ef949-3fc4-4512-9e9d-5a37d9d5cd79 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-617ef949-3fc4-4512-9e9d-5a37d9d5cd79 Beta-alanine synthesis template uuid-617ef949-3fc4-4512-9e9d-5a37d9d5cd79 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-617ef949-3fc4-4512-9e9d-5a37d9d5cd79 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61962ddf-0d05-4212-bedc-2b1aa89be407 NodeType: Pathway PMID: 17211480 PMID: 18508627 PMID: 19584271 PMID: 22647938 PMID: 23618806 PMID: 24008668 PMID: 25477371 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-61962ddf-0d05-4212-bedc-2b1aa89be407 EPCAM in Cancer Cells Motility and Proliferation uuid-61962ddf-0d05-4212-bedc-2b1aa89be407 PS:CellType cancer stem cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61962ddf-0d05-4212-bedc-2b1aa89be407 PS:NodeType Pathway PS:PMID 17211480 PS:PMID 18508627 PS:PMID 19584271 PS:PMID 22647938 PS:PMID 23618806 PS:PMID 24008668 PS:PMID 25477371 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61a494be-ee40-4a4f-be5b-451df41abd3a NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-61a494be-ee40-4a4f-be5b-451df41abd3a Migraine Anatomy Biomarkers uuid-61a494be-ee40-4a4f-be5b-451df41abd3a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-61a494be-ee40-4a4f-be5b-451df41abd3a PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: Skin fibrosis, the hallmark of systemic sclerosis or scleroderma (SSc), is defined as excess deposition and accumulation of extracellular matrix, mainly type I collagen, in the dermis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-620aa17c-c871-4b40-aea4-0d19c69a3927 NodeType: Pathway Notes: Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Skin fibrosis, the hallmark of SSc, is defined as excess deposition and accumulation of extracellular matrix, mainly type I collagen, in the dermis. Signaling description: Endothelial cells, T-helper (Th) cells, and B -cells produce several profibrotic factors including PDGF, VEGF, IGF1, AGT, EDN1, and TGFB. B-cells promote collagen production by fibroblasts through the release of cytokines or autoantibodies. Antifibrillin-1 antibodies, which are highly specific for systemic sclerosis (SSc), activate normal fibroblasts to differentiate into a profibrotic phenotype through the TGF-dependent pathway. Autoantibodies to PDGF receptors are stimulatory and induce the production of reactive oxygen species and the expression of collagen genes in fibroblasts. Extracellular matrix degradation is primarily regulated by matrix metalloproteinases (MMPs). Outcome effects: Auto anti-MMP1 Abs are suggested to inhibit MMP1 and are involved in the development of fibrosis in SSc; while, auto anti-MMP3 Abs are likely to inhibit MMP3 activity and thus promote fibrosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 17133253 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-620aa17c-c871-4b40-aea4-0d19c69a3927 Skin Fibrosis uuid-620aa17c-c871-4b40-aea4-0d19c69a3927 PS:CellType fibroblast PS:Description Skin fibrosis, the hallmark of systemic sclerosis or scleroderma (SSc), is defined as excess deposition and accumulation of extracellular matrix, mainly type I collagen, in the dermis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-620aa17c-c871-4b40-aea4-0d19c69a3927 PS:NodeType Pathway PS:Notes Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Skin fibrosis, the hallmark of SSc, is defined as excess deposition and accumulation of extracellular matrix, mainly type I collagen, in the dermis. Signaling description: Endothelial cells, T-helper (Th) cells, and B -cells produce several profibrotic factors including PDGF, VEGF, IGF1, AGT, EDN1, and TGFB. B-cells promote collagen production by fibroblasts through the release of cytokines or autoantibodies. Antifibrillin-1 antibodies, which are highly specific for systemic sclerosis (SSc), activate normal fibroblasts to differentiate into a profibrotic phenotype through the TGF-dependent pathway. Autoantibodies to PDGF receptors are stimulatory and induce the production of reactive oxygen species and the expression of collagen genes in fibroblasts. Extracellular matrix degradation is primarily regulated by matrix metalloproteinases (MMPs). Outcome effects: Auto anti-MMP1 Abs are suggested to inhibit MMP1 and are involved in the development of fibrosis in SSc; while, auto anti-MMP3 Abs are likely to inhibit MMP3 activity and thus promote fibrosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 17133253 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell CellType: cancer cell CellType: lymphoblast Description: B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy but it can occur at any age. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-620d64b9-e93b-42a4-ab5b-50f3f36edd38 NodeType: Pathway Notes: Headnote: B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy, but it can occur at any age.B-ALL is classified into subgroups based on the stage of neoplasm B-cell differentiation: pre-pre-B ALL (pro-B ALL), common ALL (cALL), and pre-B ALL.The clinical presentation is variable: fever, fatigue, bone pain, arthralgia, headache, vomiting, and alteration of mental status can be observed. Rarely, patients are asymptomatic. B-ALL is diagnosed initially by routine peripheral blood smear examination. Lymphadenopathy, hepatosplenomegaly, and other extramedullary sites of disease are common, with a predilection for the central nervous system and testes involvement. B-ALL cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations. Recurrent cytogenetic abnormalities occur in 80% of children and in 60-70% of adults with B-ALL. The various forms of B-ALL can be differentiated by their gene expression profiles, which are highly associated with specific chromosomal alterations. Signaling description: MLL gene rearrangements occur in approximately two thirds of infantile ALL cases. MLL is a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The MLL fusion gene, MLL-AF4, contains more than 50% of the rearrangements in pediatric B-ALL cases and occurs in only 4-8% of adult B-ALL cases. It activates HOXA7 and thereby drives leukemic progression. Another fusion gene that occurs in B-ALL is TEL-AML, which is frequent in pediatric cases (30%), but is rare in adults. TEL-AML1 induces a B-cell differentiation arrest and promotes self-renewal in B- cell progenitors. Furthermore, the BCR-ABL1 gene rearrangement is relatively rare (3%) in pediatric patients, but is a common (25%) cytogenetic abnormality in adults. BCR-ABL1 activates SRC, LYN, HCK, and FGR kinases leading to the downstream activation of PI3K/Akt. BCR-ABL1 also activates the RAS/MAPK pathway. In addition, the E2A-HLF oncogenic fusion protein promotes progenitor B-cell survival by up-regulating LMO2 expression and activating the apoptotic inhibitor, BCL2. Another fusion gene, E2A-PBX1, enhances the expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of CDKN2A. Deletion of CDKN2A/B is present in 21-36% of pediatric B-ALL and nearly 50% of adult and adolescent B-ALL cases resulting in increased cell proliferation. Deletions and mutations of PAX5, RAG1/2, IKZF1/3, TCF3, BLNK, CREBBP, and LEF1 impair B-cell differentiation, while mutations of RB1 lead to cell cycle progression. In addition, mutations of TP53 lead to apoptosis impairment. In P2RY8-CRLF2 translocation, CRLF1 and JAK2 activating mutations are strongly associated with B-ALL of Down syndrome patients, but these genetic changes are also observed in non-Down syndrome patients at a much lower rate. Outcome effects: The resulting events are block of differentiation and apoptosis, as well as uncontrolled proliferation which all lead to B-ALL progression. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: hematological system PMID: 15098032 PMID: 20807819 PMID: 21149616 PMID: 22575265 PMID: 22730540 PMID: 23023711 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-620d64b9-e93b-42a4-ab5b-50f3f36edd38 B-Cell Acute Lymphoblastic Leukemia uuid-620d64b9-e93b-42a4-ab5b-50f3f36edd38 PS:CellType B-cell PS:CellType cancer cell PS:CellType lymphoblast PS:Description B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy but it can occur at any age. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-620d64b9-e93b-42a4-ab5b-50f3f36edd38 PS:NodeType Pathway PS:Notes Headnote: B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy, but it can occur at any age.B-ALL is classified into subgroups based on the stage of neoplasm B-cell differentiation: pre-pre-B ALL (pro-B ALL), common ALL (cALL), and pre-B ALL.The clinical presentation is variable: fever, fatigue, bone pain, arthralgia, headache, vomiting, and alteration of mental status can be observed. Rarely, patients are asymptomatic. B-ALL is diagnosed initially by routine peripheral blood smear examination. Lymphadenopathy, hepatosplenomegaly, and other extramedullary sites of disease are common, with a predilection for the central nervous system and testes involvement. B-ALL cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations. Recurrent cytogenetic abnormalities occur in 80% of children and in 60-70% of adults with B-ALL. The various forms of B-ALL can be differentiated by their gene expression profiles, which are highly associated with specific chromosomal alterations. Signaling description: MLL gene rearrangements occur in approximately two thirds of infantile ALL cases. MLL is a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The MLL fusion gene, MLL-AF4, contains more than 50% of the rearrangements in pediatric B-ALL cases and occurs in only 4-8% of adult B-ALL cases. It activates HOXA7 and thereby drives leukemic progression. Another fusion gene that occurs in B-ALL is TEL-AML, which is frequent in pediatric cases (30%), but is rare in adults. TEL-AML1 induces a B-cell differentiation arrest and promotes self-renewal in B- cell progenitors. Furthermore, the BCR-ABL1 gene rearrangement is relatively rare (3%) in pediatric patients, but is a common (25%) cytogenetic abnormality in adults. BCR-ABL1 activates SRC, LYN, HCK, and FGR kinases leading to the downstream activation of PI3K/Akt. BCR-ABL1 also activates the RAS/MAPK pathway. In addition, the E2A-HLF oncogenic fusion protein promotes progenitor B-cell survival by up-regulating LMO2 expression and activating the apoptotic inhibitor, BCL2. Another fusion gene, E2A-PBX1, enhances the expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of CDKN2A. Deletion of CDKN2A/B is present in 21-36% of pediatric B-ALL and nearly 50% of adult and adolescent B-ALL cases resulting in increased cell proliferation. Deletions and mutations of PAX5, RAG1/2, IKZF1/3, TCF3, BLNK, CREBBP, and LEF1 impair B-cell differentiation, while mutations of RB1 lead to cell cycle progression. In addition, mutations of TP53 lead to apoptosis impairment. In P2RY8-CRLF2 translocation, CRLF1 and JAK2 activating mutations are strongly associated with B-ALL of Down syndrome patients, but these genetic changes are also observed in non-Down syndrome patients at a much lower rate. Outcome effects: The resulting events are block of differentiation and apoptosis, as well as uncontrolled proliferation which all lead to B-ALL progression. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System hematological system PS:PMID 15098032 PS:PMID 20807819 PS:PMID 21149616 PS:PMID 22575265 PS:PMID 22730540 PS:PMID 23023711 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6254f06b-e6f7-4362-bd3c-7314cce7ca8c NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-6254f06b-e6f7-4362-bd3c-7314cce7ca8c TACR1 -> Membrane Transport uuid-6254f06b-e6f7-4362-bd3c-7314cce7ca8c PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6254f06b-e6f7-4362-bd3c-7314cce7ca8c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62606167-d118-429f-98a4-73ddf7511a89 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-62606167-d118-429f-98a4-73ddf7511a89 IL7 Expression Targets uuid-62606167-d118-429f-98a4-73ddf7511a89 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62606167-d118-429f-98a4-73ddf7511a89 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62743468-cce2-43a5-a47b-97a698e006be NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-62743468-cce2-43a5-a47b-97a698e006be IL13 Expression Targets uuid-62743468-cce2-43a5-a47b-97a698e006be PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62743468-cce2-43a5-a47b-97a698e006be PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-627f29c7-27be-4c37-889b-af4810ac038f NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-627f29c7-27be-4c37-889b-af4810ac038f Proteins Involved in Urolithiasis uuid-627f29c7-27be-4c37-889b-af4810ac038f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-627f29c7-27be-4c37-889b-af4810ac038f PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6280c191-3fa4-4c21-a867-be7bf1ba9f09 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6280c191-3fa4-4c21-a867-be7bf1ba9f09 NRG1 -> EP300/ETS/ETV/SP1 Expression Targets uuid-6280c191-3fa4-4c21-a867-be7bf1ba9f09 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6280c191-3fa4-4c21-a867-be7bf1ba9f09 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-628eef24-41d8-4f28-9050-c6e5bc810a6e NodeType: Pathway Notes: Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol interacts with a nuclear vitamin D receptor (VDRn). Activated VDRn forms a heterodimeric complex with Retinoid-X-Receptor (RXR) and regulate in different ways the expression of genes which have vitamin D3 response element in their promoters. Organ: generic Organ_System: generic PMID: 15225768 PMID: 16322098 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-628eef24-41d8-4f28-9050-c6e5bc810a6e Vitamin D Represses Transcription uuid-628eef24-41d8-4f28-9050-c6e5bc810a6e PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-628eef24-41d8-4f28-9050-c6e5bc810a6e PS:NodeType Pathway PS:Notes Headnote: 7-dehydrocholesterol is converted in the skin under Ultraviolet light band B (UVB) to vitamin D3 (cholecalciferol). Cholecalciferol is converted to the biologically active vitamin D3 metabolite, calcitriol. Signaling description: Calcitriol interacts with a nuclear vitamin D receptor (VDRn). Activated VDRn forms a heterodimeric complex with Retinoid-X-Receptor (RXR) and regulate in different ways the expression of genes which have vitamin D3 response element in their promoters. PS:Organ generic PS:Organ_System generic PS:PMID 15225768 PS:PMID 16322098 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62a7bdd3-4523-458f-9ddc-384a040ff1a6 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-62a7bdd3-4523-458f-9ddc-384a040ff1a6 Proteins Involved in Tyrosinemias uuid-62a7bdd3-4523-458f-9ddc-384a040ff1a6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62a7bdd3-4523-458f-9ddc-384a040ff1a6 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62b092d5-a171-455e-9e66-4ba1f17c16eb NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-62b092d5-a171-455e-9e66-4ba1f17c16eb Proteins Involved in Hashimoto's Thyroiditis uuid-62b092d5-a171-455e-9e66-4ba1f17c16eb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62b092d5-a171-455e-9e66-4ba1f17c16eb PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62b98944-a3a4-4892-bff7-2902650f8b35 NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-62b98944-a3a4-4892-bff7-2902650f8b35 SWI/SNF BRG1/PBAF in Chromatin Remodeling uuid-62b98944-a3a4-4892-bff7-2902650f8b35 PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62b98944-a3a4-4892-bff7-2902650f8b35 PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62bc9075-bbdf-4e78-b3ee-5ca28882f7f2 NodeType: Pathway Notes: Interaction of oxidated LDL (oxLDL) with vascular endothelial cells (ECs) plays an important role in the progression of atherosclerosis. oxLDL triggers endothelium dysfunction that is characterized by the decline of anticoagulants and vasodilating properties while increasing the release of proinflammatory mediators and ROS. A decrease in NO is considered a hallmark of endothelial dysfunction. The rapid increase of intracellular ROS results in vascular endothelium dysfunction leading to ECM degradation, the attraction of leukocytes and platelets, stimulation of blood clotting, and vasoconstriction. Also, ROS cause apoptosis of epithelial cells, thus enhancing the inflammatory reaction within the vessel. Reduction of NO causes constriction of vascular smooth muscle cells (VSMCs) and narrowing of the arterial lumen. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-62bc9075-bbdf-4e78-b3ee-5ca28882f7f2 2_Oxidized LDL causes endothelial dysfunction in atherosclerosis uuid-62bc9075-bbdf-4e78-b3ee-5ca28882f7f2 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62bc9075-bbdf-4e78-b3ee-5ca28882f7f2 PS:NodeType Pathway PS:Notes Interaction of oxidated LDL (oxLDL) with vascular endothelial cells (ECs) plays an important role in the progression of atherosclerosis. oxLDL triggers endothelium dysfunction that is characterized by the decline of anticoagulants and vasodilating properties while increasing the release of proinflammatory mediators and ROS. A decrease in NO is considered a hallmark of endothelial dysfunction. The rapid increase of intracellular ROS results in vascular endothelium dysfunction leading to ECM degradation, the attraction of leukocytes and platelets, stimulation of blood clotting, and vasoconstriction. Also, ROS cause apoptosis of epithelial cells, thus enhancing the inflammatory reaction within the vessel. Reduction of NO causes constriction of vascular smooth muscle cells (VSMCs) and narrowing of the arterial lumen. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62c42479-677d-4f2d-b8d3-141e1e2278bf NodeType: Pathway Notes: Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. NO is synthesized from L-arginine by NO synthase (NOS), and three main isoforms of NOS have been identified. In patients with Raynaud Disease (RD), NO production by NOS3 in endothelial cells is decreased. Outcome effects: Reduced NOS3 expression and microcirculatory dysfunction contribute to the development of RD. NOS3 levels are controlled by NOS inhibitor asymmetric dimethylarginine (ADMA). There is evidence to indicate increased circulatory levels of ADMA in the serum of RD patients, suggesting a NOS reduction later on in the disease. Further, S-nitrosylation of the ADMA regulating enzyme dimethylarginine dimethylaminohydrolase (DDAH) diminishes DDAH activity and leads to an accumulation of ADMA. Thus, it appears that NO deficiency contributes to the pathogenesis of RD. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ: bone Organ_System: musculoskeletal system PMID: 12847693 PMID: 22782008 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage urn:agi-pathway:uuid-62c42479-677d-4f2d-b8d3-141e1e2278bf NO and ADMA Signaling in Raynaud Disease uuid-62c42479-677d-4f2d-b8d3-141e1e2278bf PS:CellType endothelial cell PS:Description Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62c42479-677d-4f2d-b8d3-141e1e2278bf PS:NodeType Pathway PS:Notes Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. NO is synthesized from L-arginine by NO synthase (NOS), and three main isoforms of NOS have been identified. In patients with Raynaud Disease (RD), NO production by NOS3 in endothelial cells is decreased. Outcome effects: Reduced NOS3 expression and microcirculatory dysfunction contribute to the development of RD. NOS3 levels are controlled by NOS inhibitor asymmetric dimethylarginine (ADMA). There is evidence to indicate increased circulatory levels of ADMA in the serum of RD patients, suggesting a NOS reduction later on in the disease. Further, S-nitrosylation of the ADMA regulating enzyme dimethylarginine dimethylaminohydrolase (DDAH) diminishes DDAH activity and leads to an accumulation of ADMA. Thus, it appears that NO deficiency contributes to the pathogenesis of RD. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ bone PS:Organ_System musculoskeletal system PS:PMID 12847693 PS:PMID 22782008 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62f44503-fb40-4030-aa0e-10b6aea477de NodeType: Pathway Organ_System: digestive system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-62f44503-fb40-4030-aa0e-10b6aea477de Proteins Involved in Cholesteatoma uuid-62f44503-fb40-4030-aa0e-10b6aea477de PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-62f44503-fb40-4030-aa0e-10b6aea477de PS:NodeType Pathway PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-630618f4-6d64-4545-8cc9-1278540d8822 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-630618f4-6d64-4545-8cc9-1278540d8822 Angiogenesis|-Netrin-|Immune cells uuid-630618f4-6d64-4545-8cc9-1278540d8822 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-630618f4-6d64-4545-8cc9-1278540d8822 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6310f060-c645-4949-af7e-d23c89062f66 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-6310f060-c645-4949-af7e-d23c89062f66 SPARC+>Cell migration uuid-6310f060-c645-4949-af7e-d23c89062f66 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6310f060-c645-4949-af7e-d23c89062f66 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-631550c7-2764-4e66-ac5e-6b9d11e50b7d NodeType: Pathway Notes: Headnote: Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. As a result, the synthesis of thyroid hormones, metabolism, and the size of the thyroid gland increase. GD, Hashimoto's thyroiditis, and idiopathic thyroid failure are closely related and are essentially overlapping syndromes. Signaling description: TSHR may act as an antigen that triggers the division and differentiation of lymphocytes and production of antibodies. Occasionally, thyroid peroxidase (TPO) or thyroglobulin (TG) may also serve as antigens. Autoantibody production in GD may be triggered in several ways. Generally, B-cells are activated through Th2 cells to produce TSHR antibodies. Mutations in MHC components (HLA-B8 and HLA-DRB3), CTLA4, and CD40 genes are considered the major congenital triggers of this process. Outcome effects: HLA-B8 and HLA-DRB3 are expressed on the surface of antigen-presenting cells, and when mutated can cause recognition of TSHR as an antigen. CTLA4 receptor is an important co-stimulator of the T cell receptor (TCR) complex that initiates T-cell differentiation following antigen binding. The CD40 receptor is expressed on B-cells and is required for their activation. B-cells stimulate the proliferation of T cells predominantly through the CD80 synthesis, thus maintaining the chronic course of the immune response. B-cells may receive a stimulus for differentiation and production of autoantibodies through the direct interaction between antigen (TSHR) and B-cell receptor (BCR) complex. B-cells also produce immunoglobulin to TSHR. Patients have stimulating, blocking and neutral self-antibodies to TSHR simultaneously. The extent of their participation in the development of the disease can vary greatly from patient to patient. Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. References: 1). Ben-Skowronek Iwona (2011). Graves Disease - The Interaction of Lymphocytes and Thyroid Cells, Autoimmune Disorders - Pathogenetic Aspects, Dr. Clio Mavragani (Ed.), ISBN: 978-953-307-643-0, InTech, Available from: http://www.intechopen.com/books/autoimmune-disorders-pathogenetic-aspects/gravesdisease-the-interaction-of-lymphocytes-and-thyroid-cells 2). Sattler S, et al. (2012). Regulatory B Cells - Implications in Autoimmune and Allergic Disorders, Recent Advances in Immunology to Target Cancer, Inflammation and Infections, Dr. Jagat Kanwar (Ed.), ISBN: 978-953-51-0592- 3, InTech, Available from: http://www.intechopen.com/books/recent-advances-in-immunology-to-target-cancerinflammation-and-infections/regulatory-B-cells-implications-in-autoimmune-and-allergic-disorders Organ_System: lymphatic system PMID: 19258680 PMID: 19438904 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-631550c7-2764-4e66-ac5e-6b9d11e50b7d Immune System Activation in Hyperthyroidism uuid-631550c7-2764-4e66-ac5e-6b9d11e50b7d PS:CellType T-cell PS:Description Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-631550c7-2764-4e66-ac5e-6b9d11e50b7d PS:NodeType Pathway PS:Notes Headnote: Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. As a result, the synthesis of thyroid hormones, metabolism, and the size of the thyroid gland increase. GD, Hashimoto's thyroiditis, and idiopathic thyroid failure are closely related and are essentially overlapping syndromes. Signaling description: TSHR may act as an antigen that triggers the division and differentiation of lymphocytes and production of antibodies. Occasionally, thyroid peroxidase (TPO) or thyroglobulin (TG) may also serve as antigens. Autoantibody production in GD may be triggered in several ways. Generally, B-cells are activated through Th2 cells to produce TSHR antibodies. Mutations in MHC components (HLA-B8 and HLA-DRB3), CTLA4, and CD40 genes are considered the major congenital triggers of this process. Outcome effects: HLA-B8 and HLA-DRB3 are expressed on the surface of antigen-presenting cells, and when mutated can cause recognition of TSHR as an antigen. CTLA4 receptor is an important co-stimulator of the T cell receptor (TCR) complex that initiates T-cell differentiation following antigen binding. The CD40 receptor is expressed on B-cells and is required for their activation. B-cells stimulate the proliferation of T cells predominantly through the CD80 synthesis, thus maintaining the chronic course of the immune response. B-cells may receive a stimulus for differentiation and production of autoantibodies through the direct interaction between antigen (TSHR) and B-cell receptor (BCR) complex. B-cells also produce immunoglobulin to TSHR. Patients have stimulating, blocking and neutral self-antibodies to TSHR simultaneously. The extent of their participation in the development of the disease can vary greatly from patient to patient. Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. References: 1). Ben-Skowronek Iwona (2011). Graves Disease - The Interaction of Lymphocytes and Thyroid Cells, Autoimmune Disorders - Pathogenetic Aspects, Dr. Clio Mavragani (Ed.), ISBN: 978-953-307-643-0, InTech, Available from: http://www.intechopen.com/books/autoimmune-disorders-pathogenetic-aspects/gravesdisease-the-interaction-of-lymphocytes-and-thyroid-cells 2). Sattler S, et al. (2012). Regulatory B Cells - Implications in Autoimmune and Allergic Disorders, Recent Advances in Immunology to Target Cancer, Inflammation and Infections, Dr. Jagat Kanwar (Ed.), ISBN: 978-953-51-0592- 3, InTech, Available from: http://www.intechopen.com/books/recent-advances-in-immunology-to-target-cancerinflammation-and-infections/regulatory-B-cells-implications-in-autoimmune-and-allergic-disorders PS:Organ_System lymphatic system PS:PMID 19258680 PS:PMID 19438904 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-633d70e1-a40c-475d-bf73-3ad6ff1fec2a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-633d70e1-a40c-475d-bf73-3ad6ff1fec2a FGF10 -> FOXO3A Expression Target uuid-633d70e1-a40c-475d-bf73-3ad6ff1fec2a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-633d70e1-a40c-475d-bf73-3ad6ff1fec2a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63421209-c73f-4dc6-ae87-7a581cf12073 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-63421209-c73f-4dc6-ae87-7a581cf12073 Congenital Hypothyroidism Drugs uuid-63421209-c73f-4dc6-ae87-7a581cf12073 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63421209-c73f-4dc6-ae87-7a581cf12073 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-634fa7e9-68ec-4dc2-b970-2b0f1684c972 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-634fa7e9-68ec-4dc2-b970-2b0f1684c972 PDGFR -> FOXO3A Signaling uuid-634fa7e9-68ec-4dc2-b970-2b0f1684c972 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-634fa7e9-68ec-4dc2-b970-2b0f1684c972 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-635fd698-b829-4b3e-8ef9-28d360be511f NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-635fd698-b829-4b3e-8ef9-28d360be511f PPARG expressed in cells associated with psoriasis uuid-635fd698-b829-4b3e-8ef9-28d360be511f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-635fd698-b829-4b3e-8ef9-28d360be511f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-639be165-d879-49dd-8f6f-be0dff81f0b4 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-639be165-d879-49dd-8f6f-be0dff81f0b4 Proteins with Altered Expression in Ichthyosis uuid-639be165-d879-49dd-8f6f-be0dff81f0b4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-639be165-d879-49dd-8f6f-be0dff81f0b4 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63a24218-dec5-49b3-8200-cf79037afdd3 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-63a24218-dec5-49b3-8200-cf79037afdd3 Angelman Syndrome: Effects of Mutation of Maternal Copy of UBE3A Gene uuid-63a24218-dec5-49b3-8200-cf79037afdd3 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63a24218-dec5-49b3-8200-cf79037afdd3 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: T-helper cells (Th cells) are lymphocytes that release cytokines and present antigen-MHC protein complex on their surface. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c6c77f-af3b-4e89-a0d2-27a31f4a0894 NodeType: Pathway Notes: Headnote: T-helper cells (Th-cells) are lymphocytes that release cytokines and present antigen-MHC protein complex on their surface. Th-cells develop into two major subtypes of cells including Type 1 (Th1) and Type 2 (Th2) helper T-cells. Th2-cells have a key role in directing immune responses against helminthes. Additionally, Th2-cells are crucial for many types of allergic reactions. Signaling description: IL4 is a major Th2 cytokine and Th2-cells require IL4 and its downstream effector signal transducer and activator of transcription, STAT6 for their development. STAT6 participates in Th2-differentiation, in part, by enhancing the expression of the master regulator of Th2 differentiation, GATA3. STAT6 and GATA3, in concert with IL2-mediated STAT5 activation, induce the secretion of copious amounts of IL4, IL5, and IL13 by activated Th2-cells. The expression of these transcription factors is also necessary for the Th2-lineage commitment. Outcome effects: Th2-lymphocytes produce IL4, IL5, and IL13. IL5 stimulates the differentiation of eosinophils, which are important for killing helminthes and other parasites. IL4 and IL13 stimulate the contraction of smooth muscle and overproduction of mucus, which helps in the expulsion of helminthes from the gut and lung. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-63c6c77f-af3b-4e89-a0d2-27a31f4a0894 Th2-Cell Differentiation uuid-63c6c77f-af3b-4e89-a0d2-27a31f4a0894 PS:CellType T-cell PS:Description T-helper cells (Th cells) are lymphocytes that release cytokines and present antigen-MHC protein complex on their surface. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c6c77f-af3b-4e89-a0d2-27a31f4a0894 PS:NodeType Pathway PS:Notes Headnote: T-helper cells (Th-cells) are lymphocytes that release cytokines and present antigen-MHC protein complex on their surface. Th-cells develop into two major subtypes of cells including Type 1 (Th1) and Type 2 (Th2) helper T-cells. Th2-cells have a key role in directing immune responses against helminthes. Additionally, Th2-cells are crucial for many types of allergic reactions. Signaling description: IL4 is a major Th2 cytokine and Th2-cells require IL4 and its downstream effector signal transducer and activator of transcription, STAT6 for their development. STAT6 participates in Th2-differentiation, in part, by enhancing the expression of the master regulator of Th2 differentiation, GATA3. STAT6 and GATA3, in concert with IL2-mediated STAT5 activation, induce the secretion of copious amounts of IL4, IL5, and IL13 by activated Th2-cells. The expression of these transcription factors is also necessary for the Th2-lineage commitment. Outcome effects: Th2-lymphocytes produce IL4, IL5, and IL13. IL5 stimulates the differentiation of eosinophils, which are important for killing helminthes and other parasites. IL4 and IL13 stimulate the contraction of smooth muscle and overproduction of mucus, which helps in the expulsion of helminthes from the gut and lung. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: In humans, the genome is packaged into 46 pairs of sister chromatids during mitosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c6e3a2-a695-46dc-a621-be77b09e923e NodeType: Pathway Notes: Headnote: In humans, the genome is packaged into 46 pairs of sister chromatids. The accurate partition of the genome during mitosis occurs owing to proper chromosome condensation and cohesion. Signaling description: DNA topoisomerase (ATP-hydrolyzing), condensing, and cohesin complexes are essential to these processes. The cohesin complex is critical for sister chromatid cohesion, while condensin and topoisomerase II are the major regulators of chromosome condensation. The mechanism of cohesin binding to DNA may share similarities with DNA binding of condensing. Namely, both complexes consist of heterodimers of SMC (structural maintenance of chromosomes) subunits which form gigantic tripartite ring structures. Condensin acts as an intramolecular crosslinker by grabbing sites on a single DNA strand and bringing them together, whereas cohesin acts as an intermolecular crosslinker by grabbing and holding two different sister chromatids. Topoisomerase II interacts with two DNA strands to effect strand passage. Outcome effects: The association between topoisomerase II and CDK1 likely represents the earliest step in mitotic chromatin condensation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-63c6e3a2-a695-46dc-a621-be77b09e923e Chromosome Condensation uuid-63c6e3a2-a695-46dc-a621-be77b09e923e PS:CellType generic PS:Description In humans, the genome is packaged into 46 pairs of sister chromatids during mitosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c6e3a2-a695-46dc-a621-be77b09e923e PS:NodeType Pathway PS:Notes Headnote: In humans, the genome is packaged into 46 pairs of sister chromatids. The accurate partition of the genome during mitosis occurs owing to proper chromosome condensation and cohesion. Signaling description: DNA topoisomerase (ATP-hydrolyzing), condensing, and cohesin complexes are essential to these processes. The cohesin complex is critical for sister chromatid cohesion, while condensin and topoisomerase II are the major regulators of chromosome condensation. The mechanism of cohesin binding to DNA may share similarities with DNA binding of condensing. Namely, both complexes consist of heterodimers of SMC (structural maintenance of chromosomes) subunits which form gigantic tripartite ring structures. Condensin acts as an intramolecular crosslinker by grabbing sites on a single DNA strand and bringing them together, whereas cohesin acts as an intermolecular crosslinker by grabbing and holding two different sister chromatids. Topoisomerase II interacts with two DNA strands to effect strand passage. Outcome effects: The association between topoisomerase II and CDK1 likely represents the earliest step in mitotic chromatin condensation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c938d2-af73-4d53-8560-a29f97f5b5f9 NodeType: Pathway Notes: Per-Arnt-Sim kinase (PASK) is a nutrient sensing protein kinase which senses the energy or nutrient glucose and other nutrients availability and regulates cell metabolism status. Organ: generic Organ_System: generic PMID: 24265199 PMID: 24445950 PMID: 26371032 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-63c938d2-af73-4d53-8560-a29f97f5b5f9 PASK Senses and Regulates Glucose Homeostasis uuid-63c938d2-af73-4d53-8560-a29f97f5b5f9 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63c938d2-af73-4d53-8560-a29f97f5b5f9 PS:NodeType Pathway PS:Notes Per-Arnt-Sim kinase (PASK) is a nutrient sensing protein kinase which senses the energy or nutrient glucose and other nutrients availability and regulates cell metabolism status. PS:Organ generic PS:Organ_System generic PS:PMID 24265199 PS:PMID 24445950 PS:PMID 26371032 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: The chronic inflammatory response in Crohn's disease is triggered by defects in the first defense mechanisms to commensal microflora in the gut. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63d84261-8ea1-4f92-b8aa-a722e25e6c23 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The chronic inflammatory response in the gastrointestinal tract of patients with Crohn's disease is thought to be triggered by defects in the first defense mechanisms to commensal microflora in the gut. Signaling description: Alterations in the genes involved in pathogen pattern recognition in macrophages may be the reason for an increased response of antigen-presenting cells to microbes as well as NF-kB cascade activation leading to the production of pro-inflammatory cytokines in Crohn's disease. NOD2 is an intracellular protein expressed in a variety of immune and non-immune cells where it is involved in recognition and defense against pathogens. Polymorphisms in NOD2 gene are strongly associated with Crohn's disease. NOD2 dysfunction results in qualitative or quantitative changes of the commensal organisms present in the terminal ileum. This occurs through three main molecular mechanisms. NOD2 is involved in autophagy and consequently in the trafficking of ingested organisms to lysosomes where they are eliminated. Patients with Crohn's disease-associated NOD2 abnormalities have decreased autophagic responses to infection and defective killing of ingested pathogenic bacteria. Alterations in ATG16L1, a protein required for autophagy results in deficient autophagic responses to bacteria and therefore uncontrolled bacterial expansion. Polymorphisms in ATG16L1 are also associated with Crohn's disease. Through autophagy, antigens from pathogens are transmitted to MHC class II protein complex and activate B cells and a T-cell response. ATG16L1 may also alter the process of apoptosis of macrophages through TRAF2 signaling. Additionally, NOD2 can enhance NF-kB related pro-inflammatory cytokine expression. Cytokines from macrophages activate themselves and T cell maturation. NOD2 also activates NLRP3 inflammasome. NLPR3 inflammasome is required for IL1B, IL18, and IL33 production by macrophages. Outcome effects: The altered function of macrophages leads to the entry of pathogenic organisms or their parts from the terminal ileum into the lamina propria through Peyer's patches and therefore initiates Crohn's-like inflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 19026604 PMID: 19652016 PMID: 19687225 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-63d84261-8ea1-4f92-b8aa-a722e25e6c23 Macrophage Dysfunction uuid-63d84261-8ea1-4f92-b8aa-a722e25e6c23 PS:CellType macrophage PS:Description The chronic inflammatory response in Crohn's disease is triggered by defects in the first defense mechanisms to commensal microflora in the gut. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63d84261-8ea1-4f92-b8aa-a722e25e6c23 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The chronic inflammatory response in the gastrointestinal tract of patients with Crohn's disease is thought to be triggered by defects in the first defense mechanisms to commensal microflora in the gut. Signaling description: Alterations in the genes involved in pathogen pattern recognition in macrophages may be the reason for an increased response of antigen-presenting cells to microbes as well as NF-kB cascade activation leading to the production of pro-inflammatory cytokines in Crohn's disease. NOD2 is an intracellular protein expressed in a variety of immune and non-immune cells where it is involved in recognition and defense against pathogens. Polymorphisms in NOD2 gene are strongly associated with Crohn's disease. NOD2 dysfunction results in qualitative or quantitative changes of the commensal organisms present in the terminal ileum. This occurs through three main molecular mechanisms. NOD2 is involved in autophagy and consequently in the trafficking of ingested organisms to lysosomes where they are eliminated. Patients with Crohn's disease-associated NOD2 abnormalities have decreased autophagic responses to infection and defective killing of ingested pathogenic bacteria. Alterations in ATG16L1, a protein required for autophagy results in deficient autophagic responses to bacteria and therefore uncontrolled bacterial expansion. Polymorphisms in ATG16L1 are also associated with Crohn's disease. Through autophagy, antigens from pathogens are transmitted to MHC class II protein complex and activate B cells and a T-cell response. ATG16L1 may also alter the process of apoptosis of macrophages through TRAF2 signaling. Additionally, NOD2 can enhance NF-kB related pro-inflammatory cytokine expression. Cytokines from macrophages activate themselves and T cell maturation. NOD2 also activates NLRP3 inflammasome. NLPR3 inflammasome is required for IL1B, IL18, and IL33 production by macrophages. Outcome effects: The altered function of macrophages leads to the entry of pathogenic organisms or their parts from the terminal ileum into the lamina propria through Peyer's patches and therefore initiates Crohn's-like inflammation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 19026604 PS:PMID 19652016 PS:PMID 19687225 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Deregulation of HDACs leads to impairment of histone acetylation and impairment of chromatin remodeling making impact to oncogenic progression Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63ed1342-9ee3-40e6-a66e-d90c465bddd9 NodeType: Pathway Notes: Headnote: The epigenetic changes including histone acetylation/deacetylation are thought to participate in the onset of genomic instability and progression of cancer in numerous tumor types. Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone acetylation conducted by HATs removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active euchromatin). The reverse process of chromatin condensation is conducted by HDACs. There exist four classes of HDACs: class I consists of HDAC 1, 2, 3, and 8; class II consists of HDAC 4, 5, 6, 7, 9, and 10; class III consists of sirtuins (SIRT 1-7); and class IV consists of HDAC 11, which have features of both class I and II HDACs. HDAC 2, 4, SIRT 1, 6, 7 may be mutated in cancer. HDAC 1, 2, 3, 6, 7, 8, SIRT 1 and 7 may be overexpressed in cancer, SIRT 4 and 6 may be down-regulated. Outcome effects: Deregulation of HDACs creates an impairment of histone acetylation and chromatin remodeling leading to oncogenic progression. An extensive number of HDAC inhibitors are developed and explored in clinical trials showing anti-tumor activities. The most extensively studied HDAC inhibitors target class I and or II, and a separate set of inhibitors target class III HDACs (sirtuins). Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Deacetylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Deacetylation" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17613546 PMID: 17694074 PMID: 19509247 PMID: 21074720 PMID: 23927873 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-63ed1342-9ee3-40e6-a66e-d90c465bddd9 Deacetylases Activation in Histone Deacetylation in Cancer uuid-63ed1342-9ee3-40e6-a66e-d90c465bddd9 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Deregulation of HDACs leads to impairment of histone acetylation and impairment of chromatin remodeling making impact to oncogenic progression PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-63ed1342-9ee3-40e6-a66e-d90c465bddd9 PS:NodeType Pathway PS:Notes Headnote: The epigenetic changes including histone acetylation/deacetylation are thought to participate in the onset of genomic instability and progression of cancer in numerous tumor types. Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone acetylation conducted by HATs removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active euchromatin). The reverse process of chromatin condensation is conducted by HDACs. There exist four classes of HDACs: class I consists of HDAC 1, 2, 3, and 8; class II consists of HDAC 4, 5, 6, 7, 9, and 10; class III consists of sirtuins (SIRT 1-7); and class IV consists of HDAC 11, which have features of both class I and II HDACs. HDAC 2, 4, SIRT 1, 6, 7 may be mutated in cancer. HDAC 1, 2, 3, 6, 7, 8, SIRT 1 and 7 may be overexpressed in cancer, SIRT 4 and 6 may be down-regulated. Outcome effects: Deregulation of HDACs creates an impairment of histone acetylation and chromatin remodeling leading to oncogenic progression. An extensive number of HDAC inhibitors are developed and explored in clinical trials showing anti-tumor activities. The most extensively studied HDAC inhibitors target class I and or II, and a separate set of inhibitors target class III HDACs (sirtuins). Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Deacetylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Deacetylation" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17613546 PS:PMID 17694074 PS:PMID 19509247 PS:PMID 21074720 PS:PMID 23927873 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6404bfa2-21a4-4161-85df-6830eda4474b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6404bfa2-21a4-4161-85df-6830eda4474b IL1B Expression Targets uuid-6404bfa2-21a4-4161-85df-6830eda4474b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6404bfa2-21a4-4161-85df-6830eda4474b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: About 20-25 percent of familial ALS cases arise from mutations in SOD1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-640de925-d463-42ba-80c0-b0bc6de7c803 NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Most incidences (90%) of ALS are sporadic and around 10% are familial. Signaling description: About 20-25% of family ALS cases arise from mutations in the superoxide dismutase 1 (SOD1) gene. Normally, SOD1 converts the superoxide anion to hydrogen peroxide (H2O2) and protects the cell from OS. This enzyme plays an important role as a cellular antioxidant, and mutant SOD1 (mSOD1) can selectively kill motor neurons due to loss of dismutase function. At the same time, mSOD1 can impair multiple cellular functions with misfolding and aggregation being the most probable source of mSOD1 toxicity. mSOD1 is directly involved in the initiation of caspase activation and apoptotic cell death as it sequesters the anti-apoptotic protein BCL2 in aggregates at the mitochondria making it nonfunctional and toxic. mSOD1 also impairs the association of CYCS with the inner membrane of the mitochondrion leading to cytoplasmic CYCS release and subsequent caspase activation. In addition, mSOD1 can activate TP53, a nuclear phosphoprotein that may play a causative role in apoptosis. Furthermore, the activation of caspase 1 (CASP1) is involved in both apoptosis and inflammation and its prolonged activation exacerbates chronic neural inflammation. mSOD1 disrupts the regulation of CYBB (which is a producer of superoxide anion) through a direct interaction with RAC1. Mitochondrial dysfunction is prominent in ALS. A fraction of toxic mSOD1 aggregated is localized in the mitochondria and may directly damage them. mSOD1 may impair the function of the protein translocation machinery (TOM and TIMM complexes) of the mitochondrion and limit the import of functional proteins into the mitochondrion. Additionally, mSOD1 directly binds to VDAC1 and depolarizes the mitochondrion membrane and disrupts the normal functioning of the electron transport chain. mSOD1 also impairs the anterograde and retrograde axonal transport through the interaction with KIFAP3 and dynein, respectively. Also, DCTN1 is responsible for retrograde axonal transport and may be mutated in some ALS cases. In addition, protein quality control by ER-associated degradation (ERAD) is impaired in ALS. mSOD1 binds to DERL1, a transmembrane protein responsible for the translocation of misfolded proteins from the ER lumen. Dysfunction or overloading of ERAD results in the accumulation of unfolded proteins and triggers the unfolded protein response (UPR). mSOD1 also induces the overexpression of HSPA5, a key regulator of UPR. mSOD1 interacts with heat shock proteins such as HSPA1A, DNAJB1, HSPB1, and CRYAB impairing chaperone function of these proteins. Additionally, mSOD1 may bind to TAR DNA-binding protein 43 (TARDBP) and recruit it to aggregates thereby disrupting RNA processing. TARDBP may also be mutated and form aggregates in SOD1-independent cases of ALS. mSOD1 directly contributes to VEGFA deficiency leading to the lack of its neuroprotective function. In addition, mSOD1 may be secreted from the motor neuron through an interaction with CHGA/B. At the same time, RNF19A and HSPB8 were found to reduce the amount of intracellular mSOD1. Outcome effects: In conclusion, the above-described molecular events lead to the dysfunction and apoptotic death of motor neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 17015226 PMID: 19715760 PMID: 22051914 PMID: 22482452 PMID: 22705710 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-640de925-d463-42ba-80c0-b0bc6de7c803 SOD1 Mutation uuid-640de925-d463-42ba-80c0-b0bc6de7c803 PS:CellType neuron PS:Description About 20-25 percent of familial ALS cases arise from mutations in SOD1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-640de925-d463-42ba-80c0-b0bc6de7c803 PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Most incidences (90%) of ALS are sporadic and around 10% are familial. Signaling description: About 20-25% of family ALS cases arise from mutations in the superoxide dismutase 1 (SOD1) gene. Normally, SOD1 converts the superoxide anion to hydrogen peroxide (H2O2) and protects the cell from OS. This enzyme plays an important role as a cellular antioxidant, and mutant SOD1 (mSOD1) can selectively kill motor neurons due to loss of dismutase function. At the same time, mSOD1 can impair multiple cellular functions with misfolding and aggregation being the most probable source of mSOD1 toxicity. mSOD1 is directly involved in the initiation of caspase activation and apoptotic cell death as it sequesters the anti-apoptotic protein BCL2 in aggregates at the mitochondria making it nonfunctional and toxic. mSOD1 also impairs the association of CYCS with the inner membrane of the mitochondrion leading to cytoplasmic CYCS release and subsequent caspase activation. In addition, mSOD1 can activate TP53, a nuclear phosphoprotein that may play a causative role in apoptosis. Furthermore, the activation of caspase 1 (CASP1) is involved in both apoptosis and inflammation and its prolonged activation exacerbates chronic neural inflammation. mSOD1 disrupts the regulation of CYBB (which is a producer of superoxide anion) through a direct interaction with RAC1. Mitochondrial dysfunction is prominent in ALS. A fraction of toxic mSOD1 aggregated is localized in the mitochondria and may directly damage them. mSOD1 may impair the function of the protein translocation machinery (TOM and TIMM complexes) of the mitochondrion and limit the import of functional proteins into the mitochondrion. Additionally, mSOD1 directly binds to VDAC1 and depolarizes the mitochondrion membrane and disrupts the normal functioning of the electron transport chain. mSOD1 also impairs the anterograde and retrograde axonal transport through the interaction with KIFAP3 and dynein, respectively. Also, DCTN1 is responsible for retrograde axonal transport and may be mutated in some ALS cases. In addition, protein quality control by ER-associated degradation (ERAD) is impaired in ALS. mSOD1 binds to DERL1, a transmembrane protein responsible for the translocation of misfolded proteins from the ER lumen. Dysfunction or overloading of ERAD results in the accumulation of unfolded proteins and triggers the unfolded protein response (UPR). mSOD1 also induces the overexpression of HSPA5, a key regulator of UPR. mSOD1 interacts with heat shock proteins such as HSPA1A, DNAJB1, HSPB1, and CRYAB impairing chaperone function of these proteins. Additionally, mSOD1 may bind to TAR DNA-binding protein 43 (TARDBP) and recruit it to aggregates thereby disrupting RNA processing. TARDBP may also be mutated and form aggregates in SOD1-independent cases of ALS. mSOD1 directly contributes to VEGFA deficiency leading to the lack of its neuroprotective function. In addition, mSOD1 may be secreted from the motor neuron through an interaction with CHGA/B. At the same time, RNF19A and HSPB8 were found to reduce the amount of intracellular mSOD1. Outcome effects: In conclusion, the above-described molecular events lead to the dysfunction and apoptotic death of motor neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 17015226 PS:PMID 19715760 PS:PMID 22051914 PS:PMID 22482452 PS:PMID 22705710 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-643e0620-6808-4faf-955f-33a904ac5398 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-643e0620-6808-4faf-955f-33a904ac5398 Photosynthesis light reaction template uuid-643e0620-6808-4faf-955f-33a904ac5398 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-643e0620-6808-4faf-955f-33a904ac5398 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-645b19c7-303b-4e79-aeb0-6babbbb75f16 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-645b19c7-303b-4e79-aeb0-6babbbb75f16 IAA activation from glucoside conjugates template uuid-645b19c7-303b-4e79-aeb0-6babbbb75f16 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-645b19c7-303b-4e79-aeb0-6babbbb75f16 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-649515e1-7249-4aa2-afed-effc57d887bf NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-649515e1-7249-4aa2-afed-effc57d887bf Starch, Glycogen metabolism template uuid-649515e1-7249-4aa2-afed-effc57d887bf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-649515e1-7249-4aa2-afed-effc57d887bf PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-649afe9f-baf4-42b9-ac5e-a88d94e056b2 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-649afe9f-baf4-42b9-ac5e-a88d94e056b2 TNFRSF6 -> DDIT3 Signaling uuid-649afe9f-baf4-42b9-ac5e-a88d94e056b2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-649afe9f-baf4-42b9-ac5e-a88d94e056b2 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell CellType: lymphocyte CellType: neutrophil Description: Glomerulonephritis (GN) is an immune-mediated renal disease caused by antibody-antigen complexes in the kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64aa21ce-2eac-4aea-977d-255384a6bde9 NodeType: Pathway Notes: Glomerulonephritis (GN) is an immune-mediated renal disease caused by antibody-antigen complexes in the kidney. Renal complement production is increased in GN. This is achieved directly through the formation of the membrane attack complex. Organ: blood vessel Organ_System: urinary tract PMID: 23479095 PMID: 24408117 PMID: 25664245 PMID: 25929733 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endothelium urn:agi-pathway:uuid-64aa21ce-2eac-4aea-977d-255384a6bde9 Complement Activation in Glomerulonephritis uuid-64aa21ce-2eac-4aea-977d-255384a6bde9 PS:CellType endothelial cell PS:CellType lymphocyte PS:CellType neutrophil PS:Description Glomerulonephritis (GN) is an immune-mediated renal disease caused by antibody-antigen complexes in the kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64aa21ce-2eac-4aea-977d-255384a6bde9 PS:NodeType Pathway PS:Notes Glomerulonephritis (GN) is an immune-mediated renal disease caused by antibody-antigen complexes in the kidney. Renal complement production is increased in GN. This is achieved directly through the formation of the membrane attack complex. PS:Organ blood vessel PS:Organ_System urinary tract PS:PMID 23479095 PS:PMID 24408117 PS:PMID 25664245 PS:PMID 25929733 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endothelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64b872b0-a54d-4be8-a2e4-aafce7327235 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-64b872b0-a54d-4be8-a2e4-aafce7327235 Isiquinoline biosynthesis template uuid-64b872b0-a54d-4be8-a2e4-aafce7327235 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64b872b0-a54d-4be8-a2e4-aafce7327235 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64bcdcae-ff33-4a4a-9733-decb547de2ea NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-64bcdcae-ff33-4a4a-9733-decb547de2ea CSF3 Expression Targets uuid-64bcdcae-ff33-4a4a-9733-decb547de2ea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64bcdcae-ff33-4a4a-9733-decb547de2ea PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64be67d5-4da9-4db8-93ab-f127a581f129 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-64be67d5-4da9-4db8-93ab-f127a581f129 Calvin cycle template uuid-64be67d5-4da9-4db8-93ab-f127a581f129 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64be67d5-4da9-4db8-93ab-f127a581f129 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Description: Interleukin-22 (IL22) is a recently discovered cytokine that has been found to significantly induce proliferation of human keratinocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64ce80a6-f7c7-41ed-8908-13ccc13315c4 NodeType: Pathway Notes: Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. Interleukin-22 (IL22) is a recently discovered cytokine that has been found to significantly induce the proliferation of human keratinocytes. IL22 is implicated in the pathogenesis of a number of autoimmune diseases characterized by hyperproliferation of keratinocytes including psoriasis. Signaling description: IL22 is mostly produced by a specific subset of T cells.It acts through the IL22 receptor which is a complex of two subunits: IL22RA1 and IL10RB. Following binding to IL22RA1, IL22 primarily activates Janus kinase 1 (JAK1), signal transducer and activator of transcription protein 3 (STAT3), mitogen activated protein kinases (MAPKs), such as the c-Jun N-terminal kinase (JNK), p38 and extracellular signal regulated kinase 1/2 (ERK1/2). Outcome effects: The interaction of IL22 and JAK1 activates the JAK/STAT/ERK/MAPK pathway, as well as the PI3K/AKT1/MTOR signaling pathway leading to the proliferation of keratinocytes. In the PI3K/AKT1/MTOR pathway, PI3K and protein kinase B (AKT1) are the key upstream molecules that link ligation of growth factor receptors and kinases to the activation of MTOR, similarly leading to keratinocyte proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: skin Organ_System: integumentary system PMID: 21098725 PMID: 22840496 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-64ce80a6-f7c7-41ed-8908-13ccc13315c4 IL22 Induces Keratinocyte Proliferation in Psoriasis uuid-64ce80a6-f7c7-41ed-8908-13ccc13315c4 PS:CellType keratinocyte PS:Description Interleukin-22 (IL22) is a recently discovered cytokine that has been found to significantly induce proliferation of human keratinocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64ce80a6-f7c7-41ed-8908-13ccc13315c4 PS:NodeType Pathway PS:Notes Headnote: Psoriasis is a chronic autoimmune skin disorder characterized by scaly and itchy patches of red skin, and is generally considered to be a hereditary disease triggered by environmental factors. Most of the genetic changes associated with psoriasis relate to the immune system. Interleukin-22 (IL22) is a recently discovered cytokine that has been found to significantly induce the proliferation of human keratinocytes. IL22 is implicated in the pathogenesis of a number of autoimmune diseases characterized by hyperproliferation of keratinocytes including psoriasis. Signaling description: IL22 is mostly produced by a specific subset of T cells.It acts through the IL22 receptor which is a complex of two subunits: IL22RA1 and IL10RB. Following binding to IL22RA1, IL22 primarily activates Janus kinase 1 (JAK1), signal transducer and activator of transcription protein 3 (STAT3), mitogen activated protein kinases (MAPKs), such as the c-Jun N-terminal kinase (JNK), p38 and extracellular signal regulated kinase 1/2 (ERK1/2). Outcome effects: The interaction of IL22 and JAK1 activates the JAK/STAT/ERK/MAPK pathway, as well as the PI3K/AKT1/MTOR signaling pathway leading to the proliferation of keratinocytes. In the PI3K/AKT1/MTOR pathway, PI3K and protein kinase B (AKT1) are the key upstream molecules that link ligation of growth factor receptors and kinases to the activation of MTOR, similarly leading to keratinocyte proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ skin PS:Organ_System integumentary system PS:PMID 21098725 PS:PMID 22840496 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: There are increased levels of TNF and receptor TNFRSF1B in the synovium of rheumatoid arthritis patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64f86f29-9d65-4002-8bef-4d19a3c680a3 NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: TNF and IL1B are the principal cytokines that promote cell activation. In the synovium of RA patients, the levels of TNF and TNFRSF1B receptor are elevated. Cytokines bind to their receptors on the synovial fibroblast surface and promote JUN, FOS, and NF-kB activation. TNF signaling involves TRAF2 which provides NF-kB activation through MAPK14 and NF-kB pathways. TRAF2 activates MAPK9 through binding to MAP3K1. In turn, MAPK9 interacts with JUN and FOS transcription factors. IL1B affects the same pathways through the MYD88/IRAK axis. In addition, WNT pathway is also involved in the pathological process, specifically, WNT5A promotes VEGFA and TNFSF11 expression. Outcome effects: JUN, FOS, and NF-kB transcription factors promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), IL8 (recruitment of inflammatory cells in the synovium that leads to pannus formation), CXCL12, IL15, IL16, IL17A (T-cell activation), IL6 (osteoclast activation and bone resorption), as well as VEGFA, ANGPT1, ANGPT2, and IL18 (new vessel growth). CXCL10, CCL5, CCL20, and IFNB1 are responsible for additional immune reactions in RA. LIF, IL11, and OSM promote cell invasion in the joint. TNFSF11 increases bone resorption. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 11759230 PMID: 15353290 PMID: 16824621 PMID: 17549500 PMID: 20739221 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-64f86f29-9d65-4002-8bef-4d19a3c680a3 Synovial Fibroblast Activation by Citokines in Rheumatoid Arthritis uuid-64f86f29-9d65-4002-8bef-4d19a3c680a3 PS:CellType fibroblast PS:Description There are increased levels of TNF and receptor TNFRSF1B in the synovium of rheumatoid arthritis patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-64f86f29-9d65-4002-8bef-4d19a3c680a3 PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: TNF and IL1B are the principal cytokines that promote cell activation. In the synovium of RA patients, the levels of TNF and TNFRSF1B receptor are elevated. Cytokines bind to their receptors on the synovial fibroblast surface and promote JUN, FOS, and NF-kB activation. TNF signaling involves TRAF2 which provides NF-kB activation through MAPK14 and NF-kB pathways. TRAF2 activates MAPK9 through binding to MAP3K1. In turn, MAPK9 interacts with JUN and FOS transcription factors. IL1B affects the same pathways through the MYD88/IRAK axis. In addition, WNT pathway is also involved in the pathological process, specifically, WNT5A promotes VEGFA and TNFSF11 expression. Outcome effects: JUN, FOS, and NF-kB transcription factors promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), IL8 (recruitment of inflammatory cells in the synovium that leads to pannus formation), CXCL12, IL15, IL16, IL17A (T-cell activation), IL6 (osteoclast activation and bone resorption), as well as VEGFA, ANGPT1, ANGPT2, and IL18 (new vessel growth). CXCL10, CCL5, CCL20, and IFNB1 are responsible for additional immune reactions in RA. LIF, IL11, and OSM promote cell invasion in the joint. TNFSF11 increases bone resorption. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11759230 PS:PMID 15353290 PS:PMID 16824621 PS:PMID 17549500 PS:PMID 20739221 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Tissue bone tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65118376-8544-4a4c-9567-088c4244d7a4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-65118376-8544-4a4c-9567-088c4244d7a4 VEGFC -> ATF Expression Target uuid-65118376-8544-4a4c-9567-088c4244d7a4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65118376-8544-4a4c-9567-088c4244d7a4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65122df5-a6d8-482c-8b6a-1964874044f5 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-65122df5-a6d8-482c-8b6a-1964874044f5 Clavulanate biosynthesis template uuid-65122df5-a6d8-482c-8b6a-1964874044f5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65122df5-a6d8-482c-8b6a-1964874044f5 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Misfolded proteins are selectively transferred from the endoplasmic reticulum (ER) into the cytosol where they undergo subsequent ubiquitylation and degradation by the proteasome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-652cc301-7ebe-4dd8-9ef8-c4f46c180deb NodeType: Pathway Notes: Headnote: Misfolded proteins are selectively transferred from the endoplasmic reticulum (ER) into the cytosol where they undergo subsequent ubiquitylation and degradation by the proteasome. This process is called ER-associated degradation (ERAD). Signaling description: Unfolded polypeptides enter the ER through SEC61 translocon. These polypeptides are bound by chaperones and glycosylating enzymes that facilitate their structural maturation. The polypeptides that are terminally misfolded are dislocated back into the cytoplasm to undergo polyubiquitylation and subsequent degradation. The export of such aberrant polypeptides from the ER is determined by members of the ERAD machinery including DERL1, DERL2, DERL3, HERPUD1, SEL1L, and SYVN1 that dynamically form oligomeric pore complexes. DERL1 and DERL2 interact with VCP and potentiate it to directly bind the substrate and deliver it to the proteasome for final degradation. AMFR protein then interacts with VCP to accelerate the degradation. Outcome effects: After deglycosylation of the aberrant polypeptide by NGLY1, RAD23A, and UBQLN, the polypeptide becomes available to be bound by polyubiquitin and RPN1 protein for final targeting to the proteasome. Organ: generic Organ_System: generic PMID: 20599420 PMID: 25100021 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-652cc301-7ebe-4dd8-9ef8-c4f46c180deb ER Associated Protein Degradation in Vesicular Transport uuid-652cc301-7ebe-4dd8-9ef8-c4f46c180deb PS:CellType generic PS:Description Misfolded proteins are selectively transferred from the endoplasmic reticulum (ER) into the cytosol where they undergo subsequent ubiquitylation and degradation by the proteasome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-652cc301-7ebe-4dd8-9ef8-c4f46c180deb PS:NodeType Pathway PS:Notes Headnote: Misfolded proteins are selectively transferred from the endoplasmic reticulum (ER) into the cytosol where they undergo subsequent ubiquitylation and degradation by the proteasome. This process is called ER-associated degradation (ERAD). Signaling description: Unfolded polypeptides enter the ER through SEC61 translocon. These polypeptides are bound by chaperones and glycosylating enzymes that facilitate their structural maturation. The polypeptides that are terminally misfolded are dislocated back into the cytoplasm to undergo polyubiquitylation and subsequent degradation. The export of such aberrant polypeptides from the ER is determined by members of the ERAD machinery including DERL1, DERL2, DERL3, HERPUD1, SEL1L, and SYVN1 that dynamically form oligomeric pore complexes. DERL1 and DERL2 interact with VCP and potentiate it to directly bind the substrate and deliver it to the proteasome for final degradation. AMFR protein then interacts with VCP to accelerate the degradation. Outcome effects: After deglycosylation of the aberrant polypeptide by NGLY1, RAD23A, and UBQLN, the polypeptide becomes available to be bound by polyubiquitin and RPN1 protein for final targeting to the proteasome. PS:Organ generic PS:Organ_System generic PS:PMID 20599420 PS:PMID 25100021 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65522cd8-cb59-42c6-907e-1d80b308dde9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-65522cd8-cb59-42c6-907e-1d80b308dde9 Very long chain fatty acid elongation (ER, peroxisome) uuid-65522cd8-cb59-42c6-907e-1d80b308dde9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65522cd8-cb59-42c6-907e-1d80b308dde9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65579db7-0084-4b8d-9b25-b7a9d3b1e8a3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-65579db7-0084-4b8d-9b25-b7a9d3b1e8a3 Phytate metabolism template template uuid-65579db7-0084-4b8d-9b25-b7a9d3b1e8a3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65579db7-0084-4b8d-9b25-b7a9d3b1e8a3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-655a40fb-cca4-44f8-bf4b-b8ca06671bd3 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-655a40fb-cca4-44f8-bf4b-b8ca06671bd3 VEGFR -> CTNND Signaling uuid-655a40fb-cca4-44f8-bf4b-b8ca06671bd3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-655a40fb-cca4-44f8-bf4b-b8ca06671bd3 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65744f30-e53a-48f0-8bb7-43d2f59fe520 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-65744f30-e53a-48f0-8bb7-43d2f59fe520 UrokinaseR -> STAT Signaling uuid-65744f30-e53a-48f0-8bb7-43d2f59fe520 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65744f30-e53a-48f0-8bb7-43d2f59fe520 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6591e086-b140-49cc-af4d-4331a4d4547c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-6591e086-b140-49cc-af4d-4331a4d4547c Autophagy in mammalian cells uuid-6591e086-b140-49cc-af4d-4331a4d4547c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6591e086-b140-49cc-af4d-4331a4d4547c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: granulosa cell Description: Premature ovarian failure (POF) is the loss of function of the ovaries before age of 40. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65b1ce8a-a1f2-4d59-81d2-25da7d29925a NodeType: Pathway Notes: Headnote: Premature ovarian failure, also known as premature ovarian insufficiency, primary ovarian insufficiency, premature menopause, or hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. It is characterized by amenorrhea, hypergonadotropinism, and hypoestrogenism. Mutations in BMP15 and GDF9 are associated with primary ovarian insufficiency. Signaling description: bone morphogenetic proteins 15 and 6 (BMP15/6) are expressed in the ovaries by oocytes and is involved in folliculogenesis by forming heterodimers with GDF9. BMP15/16 and GDF9 stimulate granulosa cell proliferation, folliculogenesis and oocyte-cumulus matrix formation. BMPs and GDF9 were shown to induce expression of hyaluronan synthase 2 (HAS2), cyclooxygenase 2 (PTGS2), tumour necrosis factor-induced protein-6 (TNFIP6), pentraxin 3 (PTX3), gremlin 1 (GREM1), versican (VCAN) and perlecan (HSPG2). Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 15836953 PMID: 16645022 PMID: 17826728 PMID: 18164539 PMID: 18175787 PMID: 20362963 PMID: 20382564 PMID: 20668067 PMID: 20716613 PMID: 24696764 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-65b1ce8a-a1f2-4d59-81d2-25da7d29925a BMP Signaling Impairment in Granulosa Cell in POF uuid-65b1ce8a-a1f2-4d59-81d2-25da7d29925a PS:CellType granulosa cell PS:Description Premature ovarian failure (POF) is the loss of function of the ovaries before age of 40. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65b1ce8a-a1f2-4d59-81d2-25da7d29925a PS:NodeType Pathway PS:Notes Headnote: Premature ovarian failure, also known as premature ovarian insufficiency, primary ovarian insufficiency, premature menopause, or hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. It is characterized by amenorrhea, hypergonadotropinism, and hypoestrogenism. Mutations in BMP15 and GDF9 are associated with primary ovarian insufficiency. Signaling description: bone morphogenetic proteins 15 and 6 (BMP15/6) are expressed in the ovaries by oocytes and is involved in folliculogenesis by forming heterodimers with GDF9. BMP15/16 and GDF9 stimulate granulosa cell proliferation, folliculogenesis and oocyte-cumulus matrix formation. BMPs and GDF9 were shown to induce expression of hyaluronan synthase 2 (HAS2), cyclooxygenase 2 (PTGS2), tumour necrosis factor-induced protein-6 (TNFIP6), pentraxin 3 (PTX3), gremlin 1 (GREM1), versican (VCAN) and perlecan (HSPG2). Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 15836953 PS:PMID 16645022 PS:PMID 17826728 PS:PMID 18164539 PS:PMID 18175787 PS:PMID 20362963 PS:PMID 20382564 PS:PMID 20668067 PS:PMID 20716613 PS:PMID 24696764 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Transfer RNA (tRNA) is a small RNA chain of 74-93 nucleotides that transfers a specific amino acid to a growing polypeptide chain during translation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65c7247c-8031-4cd5-9dc1-bc035a687c75 NodeType: Pathway Notes: Headnote: Transfer RNA (tRNA) is a small RNA chain of 74-93 nucleotides that transfers a specific amino acid to a growing polypeptide chain during translation. A multi-subunit complex TFIIIC initiates tRNA transcription by RNA polymerase III. Signaling description: TFIIIC recognizes tRNA gene promoters that consist of two separated 10bp elements (A-BOX and B-BOX) located downstream of the transcription start site. The binding of TFIIIC recruits TFIIIB which is a complex of polypeptides including TBP, BRF1, and BDP1. TFIIIB then recruits RNA polymerase III. This DNA/TFIIIB/RNA polymerase III initiation complex is stable enough to pass through many rounds of tRNA transcription. Once the initiation complex is assembled, transcription and elongation begins. RNA polymerase III slides along the DNA molecule and matches the DNA nucleotides with complementary RNA nucleotides generating a new RNA molecule that is patterned after the DNA. Unlike RNA polymerase I and II, RNA polymerase III termination occurs efficiently at four or more T residues without other protein factors. Outcome effects: The initial transcripts of tRNA genes must be properly processed into mature tRNAs. Pre-tRNA has four loops, a 5'-terminal 16-nucleotide sequence and a 3'-terminal U nucleotide with -OH group. During processing, one loop (14-nucleotide intron) is removed by splicing, the 16-nucleotide sequence at the 5' end is cleaved by ribonuclease P, and U residues at the 3' end are replaced by the CCA sequence. Therefore, tRNA consists of a 5'-terminal phosphate group, a CCA sequence at the 3' end of the tRNA molecule which is important for the recognition of tRNA by enzymes critical in translation, and three loops (D-arm, anticodon arm, and T-arm). Some pre-tRNAs contain introns that are spliced out during processing, and all pre-tRNAs undergo modification of some bases into dihydrouridine and pseudouridine. Finally, mature tRNAs are exported to the cytoplasm to participate in protein synthesis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-65c7247c-8031-4cd5-9dc1-bc035a687c75 tRNA Transcription and Processing uuid-65c7247c-8031-4cd5-9dc1-bc035a687c75 PS:CellType generic PS:Description Transfer RNA (tRNA) is a small RNA chain of 74-93 nucleotides that transfers a specific amino acid to a growing polypeptide chain during translation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65c7247c-8031-4cd5-9dc1-bc035a687c75 PS:NodeType Pathway PS:Notes Headnote: Transfer RNA (tRNA) is a small RNA chain of 74-93 nucleotides that transfers a specific amino acid to a growing polypeptide chain during translation. A multi-subunit complex TFIIIC initiates tRNA transcription by RNA polymerase III. Signaling description: TFIIIC recognizes tRNA gene promoters that consist of two separated 10bp elements (A-BOX and B-BOX) located downstream of the transcription start site. The binding of TFIIIC recruits TFIIIB which is a complex of polypeptides including TBP, BRF1, and BDP1. TFIIIB then recruits RNA polymerase III. This DNA/TFIIIB/RNA polymerase III initiation complex is stable enough to pass through many rounds of tRNA transcription. Once the initiation complex is assembled, transcription and elongation begins. RNA polymerase III slides along the DNA molecule and matches the DNA nucleotides with complementary RNA nucleotides generating a new RNA molecule that is patterned after the DNA. Unlike RNA polymerase I and II, RNA polymerase III termination occurs efficiently at four or more T residues without other protein factors. Outcome effects: The initial transcripts of tRNA genes must be properly processed into mature tRNAs. Pre-tRNA has four loops, a 5'-terminal 16-nucleotide sequence and a 3'-terminal U nucleotide with -OH group. During processing, one loop (14-nucleotide intron) is removed by splicing, the 16-nucleotide sequence at the 5' end is cleaved by ribonuclease P, and U residues at the 3' end are replaced by the CCA sequence. Therefore, tRNA consists of a 5'-terminal phosphate group, a CCA sequence at the 3' end of the tRNA molecule which is important for the recognition of tRNA by enzymes critical in translation, and three loops (D-arm, anticodon arm, and T-arm). Some pre-tRNAs contain introns that are spliced out during processing, and all pre-tRNAs undergo modification of some bases into dihydrouridine and pseudouridine. Finally, mature tRNAs are exported to the cytoplasm to participate in protein synthesis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65e08472-70e0-4042-b85d-a92a20e367a5 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-65e08472-70e0-4042-b85d-a92a20e367a5 TGFBR1/AP-1 Signaling uuid-65e08472-70e0-4042-b85d-a92a20e367a5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65e08472-70e0-4042-b85d-a92a20e367a5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Plasmacytoid DCs (pDCs) are professional antiviral cells that are able to detect viral RNA or DNA through TLR7 and TLR9 and in turn produce large amounts of antiviral cytokines, such as type 1 IFNs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65edd5a9-635b-49f6-8aa1-68781814aa5e NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Studies support a diabetogenic role of plasmacytoid DCs (pDCs) in the initiatory steps of type 1 diabetes. pDCs are professional antiviral cells that are able to detect viral RNA or DNA through TLR7 and TLR9 and in turn produce large amounts of antiviral cytokines, such as type 1 IFNs. In humans, conflicting results have been obtained regarding the frequency of pDCs in the blood of diabetic patients compared to healthy controls. However, pDCs from early diagnosed patients are able to present antigen to T-cells and activate them. Outcome effects: In type 1 diabetes, type 1 IFNs produced in pancreatic islets by pDCs may induce or promote the development of the disease. Animal data: A pathogenic role of pDCs in type 1 diabetes is supported by observations in both humans and rodent models. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system PMID: 20577267 PMID: 21712017 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-65edd5a9-635b-49f6-8aa1-68781814aa5e Plasmacytoid Dendritic Cell in Diabetes Mellitus Type 1 uuid-65edd5a9-635b-49f6-8aa1-68781814aa5e PS:CellType dendritic cell PS:Description Plasmacytoid DCs (pDCs) are professional antiviral cells that are able to detect viral RNA or DNA through TLR7 and TLR9 and in turn produce large amounts of antiviral cytokines, such as type 1 IFNs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65edd5a9-635b-49f6-8aa1-68781814aa5e PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Studies support a diabetogenic role of plasmacytoid DCs (pDCs) in the initiatory steps of type 1 diabetes. pDCs are professional antiviral cells that are able to detect viral RNA or DNA through TLR7 and TLR9 and in turn produce large amounts of antiviral cytokines, such as type 1 IFNs. In humans, conflicting results have been obtained regarding the frequency of pDCs in the blood of diabetic patients compared to healthy controls. However, pDCs from early diagnosed patients are able to present antigen to T-cells and activate them. Outcome effects: In type 1 diabetes, type 1 IFNs produced in pancreatic islets by pDCs may induce or promote the development of the disease. Animal data: A pathogenic role of pDCs in type 1 diabetes is supported by observations in both humans and rodent models. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:PMID 20577267 PS:PMID 21712017 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65f7fd87-c770-4a2e-814f-136e03f78a67 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-65f7fd87-c770-4a2e-814f-136e03f78a67 EGFR-> Expression Targets in Lymphoid System and Blood uuid-65f7fd87-c770-4a2e-814f-136e03f78a67 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-65f7fd87-c770-4a2e-814f-136e03f78a67 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Oxytocin, along with prolactin, is essential for milk delivery to the baby during lactation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-661471f3-8406-40f2-9971-5e7bc329ef0a NodeType: Pathway Notes: Headnote: Oxytocin, along with prolactin, is essential for milk delivery to the baby during lactation. Signaling description: Suckling stimulates the nipple to send a neural signal through an ascending neuronal pathway from the nipple to the hypothalamus to stimulate oxytocin release from the posterior lobe of the pituitary gland, which in turn acts on the mammary glands to cause milk ejection, this is called the milk ejection reflex. Organ: breast Organ_System: integumentary system PMID: 19649775 PMID: 25589271 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-661471f3-8406-40f2-9971-5e7bc329ef0a Oxytocin Action in Mammary Gland uuid-661471f3-8406-40f2-9971-5e7bc329ef0a PS:Description Oxytocin, along with prolactin, is essential for milk delivery to the baby during lactation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-661471f3-8406-40f2-9971-5e7bc329ef0a PS:NodeType Pathway PS:Notes Headnote: Oxytocin, along with prolactin, is essential for milk delivery to the baby during lactation. Signaling description: Suckling stimulates the nipple to send a neural signal through an ascending neuronal pathway from the nipple to the hypothalamus to stimulate oxytocin release from the posterior lobe of the pituitary gland, which in turn acts on the mammary glands to cause milk ejection, this is called the milk ejection reflex. PS:Organ breast PS:Organ_System integumentary system PS:PMID 19649775 PS:PMID 25589271 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell CellType: lymphocyte CellType: neutrophil Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6615ca33-8b7e-4448-b9b0-e5c63d062a00 NodeType: Pathway Notes: The genetic changes related to glomerulonephritis increase activation levels of the complement system. The main purpose of complement activation is to remove invading pathogens and purify cells. This is achieved directly either through the formation of the membrane attack complex (MAC) or indirectly by opsonization and phagocytosis stimulation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: Blood Vessels Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: endothelium urn:agi-pathway:uuid-6615ca33-8b7e-4448-b9b0-e5c63d062a00 1_The role of complement in glomerulonephritis uuid-6615ca33-8b7e-4448-b9b0-e5c63d062a00 PS:CellType endothelial cell PS:CellType lymphocyte PS:CellType neutrophil PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6615ca33-8b7e-4448-b9b0-e5c63d062a00 PS:NodeType Pathway PS:Notes The genetic changes related to glomerulonephritis increase activation levels of the complement system. The main purpose of complement activation is to remove invading pathogens and purify cells. This is achieved directly either through the formation of the membrane attack complex (MAC) or indirectly by opsonization and phagocytosis stimulation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ Blood Vessels PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue endothelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: plasma cell Description: The alternative NF-kB pathway in multiple myeloma (MM) cell activation results from signaling by TNFSF13B through the TNFRSF13C receptor. MAP3K14 then activates CHUK, which phosphorylates NFKB2 (p100). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66242aa1-e3c9-49e2-95d8-5c454cc07135 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: The alternative NF-kB pathway in multiple myeloma (MM) cell activation results from signaling by TNFSF13B through the TNFRSF13C receptor. MAP3K14 then activates CHUK, which phosphorylates NFKB2 (p100). This results in the proteasomal removal of the inhibitory C-terminal domain, generating the active NF-kB (p52) subunit. Alternative NF-kB signaling is regulated through the control of MAP3K14 turnover, with TRAF3, TRAF2, and BIRC2 involved in this process. In addition, mutations in MAP3K14, CD40, LTBR, BIRC2, TRAF2, TRAF3, and NFKB2 genes were shown to be important in MM pathogenesis. Outcome effects: The NF-kB/RELB complex activates the transcription of several downstream target genes (cytokines, adhesion molecules, and cell cycle regulators) resulting in block of apoptosis, tumor cell proliferation, vascularization (angiogenesis), and neoplasm metastasis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ_System: skeletal system PMID: 17692805 PMID: 20430962 PMID: 20890394 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-66242aa1-e3c9-49e2-95d8-5c454cc07135 TNFR/NF-kB Alternative Pathway in Multiple Myeloma Plasma Cells uuid-66242aa1-e3c9-49e2-95d8-5c454cc07135 PS:CellType cancer cell PS:CellType plasma cell PS:Description The alternative NF-kB pathway in multiple myeloma (MM) cell activation results from signaling by TNFSF13B through the TNFRSF13C receptor. MAP3K14 then activates CHUK, which phosphorylates NFKB2 (p100). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66242aa1-e3c9-49e2-95d8-5c454cc07135 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: The alternative NF-kB pathway in multiple myeloma (MM) cell activation results from signaling by TNFSF13B through the TNFRSF13C receptor. MAP3K14 then activates CHUK, which phosphorylates NFKB2 (p100). This results in the proteasomal removal of the inhibitory C-terminal domain, generating the active NF-kB (p52) subunit. Alternative NF-kB signaling is regulated through the control of MAP3K14 turnover, with TRAF3, TRAF2, and BIRC2 involved in this process. In addition, mutations in MAP3K14, CD40, LTBR, BIRC2, TRAF2, TRAF3, and NFKB2 genes were shown to be important in MM pathogenesis. Outcome effects: The NF-kB/RELB complex activates the transcription of several downstream target genes (cytokines, adhesion molecules, and cell cycle regulators) resulting in block of apoptosis, tumor cell proliferation, vascularization (angiogenesis), and neoplasm metastasis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ_System skeletal system PS:PMID 17692805 PS:PMID 20430962 PS:PMID 20890394 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-662de29f-3560-4ab2-a397-512833fecff4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-662de29f-3560-4ab2-a397-512833fecff4 T-Cell Receptor -> NFATC Signaling uuid-662de29f-3560-4ab2-a397-512833fecff4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-662de29f-3560-4ab2-a397-512833fecff4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6664d1bd-0147-4a40-b75c-3c507e4295ce NodeType: Pathway Organ_System: musculoskeletal system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-6664d1bd-0147-4a40-b75c-3c507e4295ce AGE Related Insulin Resistance in Skeletal Muscles uuid-6664d1bd-0147-4a40-b75c-3c507e4295ce PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6664d1bd-0147-4a40-b75c-3c507e4295ce PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: goblet cell Description: Mucus overproduction is a main feature of bronchial asthma, contributing to mortality in the disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-666ce08e-616d-4c07-93cf-a3537eb0af47 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Mucus overproduction is an important feature of bronchial asthma, contributing to mortality in the disease, and goblet cells are major mucus-producing cells. Signaling description: Airway mucus is a heterogeneous mixture of secreted polypeptides, cells, and cellular debris that are tethered together at the fluid surface by oligomeric mucin complexes. Oversecreted mucins contribute significantly to the viscoelastic properties of the extracellular mucous layer. MUC5AC is probably the dominant mucin gene induced in the asthma mouse model.TNF-alfa, EGFR signaling and Th2 cytokines upregulate mucin synthesis and the development of goblet cell hyperplasia. IL9 may act predominantly via calcium-activated chloride channels (CLCA), IL1beta via PTGS2. IL-4 and IL-13 trigger airway hyperreactivity and goblet cell metaplasia and mucin overproduction through MUC5AC expression and modulation of the expression of a variety of ion channels and transporters (aquaporins (AQPs), CLCA, SLC26A4) within the respiratory epithelium. IL13RA2 has been suggested to act as a 'decoy receptor' in the airway epithelium by inhibiting the IL-13 signal. Outcome effects: Pendrin (SLC26A4) is an integral membrane protein exchanging anions such as bicarbonate, iodide and others for chloride. SLC26A4 expression increases in respiratory diseases including bronchial asthma, chronic obstructive pulmonary disease (COPD) and rhinovirus infection. SLC26A4 stimulates Cl-/HCO3- exchange activity, which increases the production of mucus and increases viscosity of the airway surface liquid (ASL). Epithelial ALOX15 expression increases in asthma. IL-13 induction of 15-HETE-PE enhances MUC5AC expression in human airway epithelial cells. There is a (Hypothesis) that ALOX15/15HETE-PE could interact with PEBP1 to activate Raf-1/MEK/ERK and amplify the IL-4Ralfa downstream pathways. ALOX15 and PEBP1 interactions occur primarily at the cell membrane. DENND1B, which may be involved in TNF signaling was recently identified as an asthma susceptibility gene in a GWAS on children. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 18954282 PMID: 19218191 PMID: 19689269 PMID: 21831839 PMID: 22116372 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-666ce08e-616d-4c07-93cf-a3537eb0af47 Goblet-Cell Related Mucus Secretion in Asthma uuid-666ce08e-616d-4c07-93cf-a3537eb0af47 PS:CellType goblet cell PS:Description Mucus overproduction is a main feature of bronchial asthma, contributing to mortality in the disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-666ce08e-616d-4c07-93cf-a3537eb0af47 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Mucus overproduction is an important feature of bronchial asthma, contributing to mortality in the disease, and goblet cells are major mucus-producing cells. Signaling description: Airway mucus is a heterogeneous mixture of secreted polypeptides, cells, and cellular debris that are tethered together at the fluid surface by oligomeric mucin complexes. Oversecreted mucins contribute significantly to the viscoelastic properties of the extracellular mucous layer. MUC5AC is probably the dominant mucin gene induced in the asthma mouse model.TNF-alfa, EGFR signaling and Th2 cytokines upregulate mucin synthesis and the development of goblet cell hyperplasia. IL9 may act predominantly via calcium-activated chloride channels (CLCA), IL1beta via PTGS2. IL-4 and IL-13 trigger airway hyperreactivity and goblet cell metaplasia and mucin overproduction through MUC5AC expression and modulation of the expression of a variety of ion channels and transporters (aquaporins (AQPs), CLCA, SLC26A4) within the respiratory epithelium. IL13RA2 has been suggested to act as a 'decoy receptor' in the airway epithelium by inhibiting the IL-13 signal. Outcome effects: Pendrin (SLC26A4) is an integral membrane protein exchanging anions such as bicarbonate, iodide and others for chloride. SLC26A4 expression increases in respiratory diseases including bronchial asthma, chronic obstructive pulmonary disease (COPD) and rhinovirus infection. SLC26A4 stimulates Cl-/HCO3- exchange activity, which increases the production of mucus and increases viscosity of the airway surface liquid (ASL). Epithelial ALOX15 expression increases in asthma. IL-13 induction of 15-HETE-PE enhances MUC5AC expression in human airway epithelial cells. There is a (Hypothesis) that ALOX15/15HETE-PE could interact with PEBP1 to activate Raf-1/MEK/ERK and amplify the IL-4Ralfa downstream pathways. ALOX15 and PEBP1 interactions occur primarily at the cell membrane. DENND1B, which may be involved in TNF signaling was recently identified as an asthma susceptibility gene in a GWAS on children. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18954282 PS:PMID 19218191 PS:PMID 19689269 PS:PMID 21831839 PS:PMID 22116372 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66e5b080-9328-434e-9cc9-66642267e63c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-66e5b080-9328-434e-9cc9-66642267e63c NOS-|myofibroblats uuid-66e5b080-9328-434e-9cc9-66642267e63c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66e5b080-9328-434e-9cc9-66642267e63c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66fa97f4-c6e4-459f-81fb-8d588fbbb7d4 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-66fa97f4-c6e4-459f-81fb-8d588fbbb7d4 IGF1R -> ARRB1/ERK1/3 Signaling uuid-66fa97f4-c6e4-459f-81fb-8d588fbbb7d4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-66fa97f4-c6e4-459f-81fb-8d588fbbb7d4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6700a36f-1113-4f06-93cb-6fd33fe4500d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6700a36f-1113-4f06-93cb-6fd33fe4500d CCL11 Expression Targets uuid-6700a36f-1113-4f06-93cb-6fd33fe4500d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6700a36f-1113-4f06-93cb-6fd33fe4500d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuroglia CellType: photoreceptor cell CellType: retina cell Description: Glutamate is the predominant excitatory amino acid in many regions of the central nervous system (CNS) including the retina. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6705ca21-700f-4165-9641-17b8385b6592 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Glutamate is the predominant excitatory amino acid in various regions of the central nervous system (CNS) including the retina. Glutamate excitotoxicity is believed to be one of the reasons for glaucomatous retinal ganglion cell (RGC) death. Signaling description: Glutamate is released from the pre-synaptic photoreceptor membrane and binds to glutamate receptors, including N-methyl-D-aspartate selective glutamate receptor (NMDA), AMPA, and metabotropic glutamate receptors in the post-synaptic membrane. This in turn induces the rapid build-up of cytosolic calcium (Ca2+) levels. The prolonged activation of glutamate receptors by increased levels of glutamate leads to high Ca2+ levels in the cytosol and thus facilitates the opening of mitochondrial mPTP. Outcome effects: The opening of mPTP leads to the passage of cytochrome C (CYCS), AIFM1, and ENDOG to the cytosol and initiates the cascade of apoptotic cell death. Muller glial cells are responsible for the uptake of excess glutamate in the retina via glutamate/aspartate transporters (SLC1A2/3). These transporters have been shown to be downregulated in glaucomatous retina. Muller cells are extraordinarily sensitive to NMDA and respond rapidly by upregulating NF-kB activity and TNF production. TNF increases the surface levels of AMPA receptors on RGCs. Wild-type OPTN has been shown to inhibit GRM1/5 signaling. When OPTN is mutated, this function may be impaired leading to the further rise in intracellular Ca2+. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 16091361 PMID: 17607354 PMID: 22155051 PMID: 24386591 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6705ca21-700f-4165-9641-17b8385b6592 Glutamate Mediated Excitotoxicity in Glaucoma uuid-6705ca21-700f-4165-9641-17b8385b6592 PS:CellType neuroglia PS:CellType photoreceptor cell PS:CellType retina cell PS:Description Glutamate is the predominant excitatory amino acid in many regions of the central nervous system (CNS) including the retina. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6705ca21-700f-4165-9641-17b8385b6592 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Glutamate is the predominant excitatory amino acid in various regions of the central nervous system (CNS) including the retina. Glutamate excitotoxicity is believed to be one of the reasons for glaucomatous retinal ganglion cell (RGC) death. Signaling description: Glutamate is released from the pre-synaptic photoreceptor membrane and binds to glutamate receptors, including N-methyl-D-aspartate selective glutamate receptor (NMDA), AMPA, and metabotropic glutamate receptors in the post-synaptic membrane. This in turn induces the rapid build-up of cytosolic calcium (Ca2+) levels. The prolonged activation of glutamate receptors by increased levels of glutamate leads to high Ca2+ levels in the cytosol and thus facilitates the opening of mitochondrial mPTP. Outcome effects: The opening of mPTP leads to the passage of cytochrome C (CYCS), AIFM1, and ENDOG to the cytosol and initiates the cascade of apoptotic cell death. Muller glial cells are responsible for the uptake of excess glutamate in the retina via glutamate/aspartate transporters (SLC1A2/3). These transporters have been shown to be downregulated in glaucomatous retina. Muller cells are extraordinarily sensitive to NMDA and respond rapidly by upregulating NF-kB activity and TNF production. TNF increases the surface levels of AMPA receptors on RGCs. Wild-type OPTN has been shown to inhibit GRM1/5 signaling. When OPTN is mutated, this function may be impaired leading to the further rise in intracellular Ca2+. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 16091361 PS:PMID 17607354 PS:PMID 22155051 PS:PMID 24386591 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of NFKB signaling pathway contributes to uncontrolled cell proliferation, inhibition of apoptosis and induction of inflammation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-670ae50c-82c7-4b12-af33-f8590be7c28b NodeType: Pathway Notes: Headnote: NFKB is a protein complex that controls DNA transcription, cytokine production and cell survival. Pathologic activation of NFKB has been linked to cancer. Signaling description: Mammalian NFKB dimers are generated via homodimeric and heterodimeric interactions of 5 REL subunits expressed from distinct but related genes: RELA, RELB, REL, NFKB1 and NFKB2. The canonical NFKB activation pathway results in activation of gene transcription by the RELA/NFKB1 dimer. This heterodimer cycles between the cytoplasm and the nucleus complexed with an inhibitory protein NFKBIA which reduces the efficiency of nuclear transport and prevents DNA binding of RELA/NFKB1. Upon interaction with their cell surface receptors, extracellular stimuli such as bacterial LPS and TNFA, activate RELA/NFKB1 dimer via a series of signaling events which are channeled through the IKK complex. This complex is comprised of three major components known as IKBKA (CHUK), IKBKB and IKBKG. The general consensus is that the catalytic component IKBKB and the scaffold component IKBKG transduce signals to the canonical pathway. IKBKB catalyzes phosphorylation of NFKBIA which leads to its poly-ubiquitination and degradation via the 26S proteasome to generate "free" RELA/NFKB1 and, as a result, transcriptional activation of target genes. NFKB activation is reported to be associated with tumorigenesis. This may be due to activating mutations in LTBR, CD40, TNFRSF13B, TNFRSF14, MYD88, CD79A/B, IKBKE, REL and other proteins. NFKB signaling may also be activated by viral proteins HHV8GK18_gp80 (HHV-8 protein), tax (HTLV-1 protein), LMP1 (EBV protein) and hepatitis C RNA. Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation, inhibition of apoptosis and induction of inflammation. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: HHV8GK18_gp80, tax, LMP1 shown in grey are viral proteins. Organ: oncogenic Organ_System: oncogenic PMID: 15102437 PMID: 16485028 PMID: 17072331 PMID: 17119127 PMID: 18056430 PMID: 20001209 PMID: 20066113 PMID: 23915189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-670ae50c-82c7-4b12-af33-f8590be7c28b NFKB Canonical Signaling Activation in Cancer uuid-670ae50c-82c7-4b12-af33-f8590be7c28b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of NFKB signaling pathway contributes to uncontrolled cell proliferation, inhibition of apoptosis and induction of inflammation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-670ae50c-82c7-4b12-af33-f8590be7c28b PS:NodeType Pathway PS:Notes Headnote: NFKB is a protein complex that controls DNA transcription, cytokine production and cell survival. Pathologic activation of NFKB has been linked to cancer. Signaling description: Mammalian NFKB dimers are generated via homodimeric and heterodimeric interactions of 5 REL subunits expressed from distinct but related genes: RELA, RELB, REL, NFKB1 and NFKB2. The canonical NFKB activation pathway results in activation of gene transcription by the RELA/NFKB1 dimer. This heterodimer cycles between the cytoplasm and the nucleus complexed with an inhibitory protein NFKBIA which reduces the efficiency of nuclear transport and prevents DNA binding of RELA/NFKB1. Upon interaction with their cell surface receptors, extracellular stimuli such as bacterial LPS and TNFA, activate RELA/NFKB1 dimer via a series of signaling events which are channeled through the IKK complex. This complex is comprised of three major components known as IKBKA (CHUK), IKBKB and IKBKG. The general consensus is that the catalytic component IKBKB and the scaffold component IKBKG transduce signals to the canonical pathway. IKBKB catalyzes phosphorylation of NFKBIA which leads to its poly-ubiquitination and degradation via the 26S proteasome to generate "free" RELA/NFKB1 and, as a result, transcriptional activation of target genes. NFKB activation is reported to be associated with tumorigenesis. This may be due to activating mutations in LTBR, CD40, TNFRSF13B, TNFRSF14, MYD88, CD79A/B, IKBKE, REL and other proteins. NFKB signaling may also be activated by viral proteins HHV8GK18_gp80 (HHV-8 protein), tax (HTLV-1 protein), LMP1 (EBV protein) and hepatitis C RNA. Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation, inhibition of apoptosis and induction of inflammation. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: HHV8GK18_gp80, tax, LMP1 shown in grey are viral proteins. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15102437 PS:PMID 16485028 PS:PMID 17072331 PS:PMID 17119127 PS:PMID 18056430 PS:PMID 20001209 PS:PMID 20066113 PS:PMID 23915189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Hyperhomocysteinemia is associated with increased risk of diseases associated with aging. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-670baac6-6b3d-44c6-895f-be1df0a20750 NodeType: Pathway Notes: Headnote: Hyperhomocysteinemia is elevated plasma level of homocysteine (Hcy) which is synthesized during methionine metabolism. Hyperhomocysteinemia is associated with increased risk of atherosclerosis and arterial and venous thrombosis and other diseases associated with aging. Hyperhomocysteinemia may be caused by mutation in the MTHFR gene, defects in metabolism of vitamin B12, folate, choline or pyridoxal 5'-phosphate. Signaling description: Transport of folate into the cell initiates the folate cycle in which MTHFR converts folate to its active form, 5-methyltetrahydrofolate. Human Mthfr C677T genotype is associated with mild MTHFR deficiency in the condition of high temperature stress and less production of 5-methyltetrahydrofolate. 5-methyltetrahydrofolate is a necessary co-factor in methionine cycle and play role in production of universal methyl donor S-adenosylmethionine. Less production of 5-methyltetrahydrofolate due altered MTHFR function may lead to accumulation of non-metabolized Hcy. The level of dietary intakes of methionine, folate, and B12 also influences on the physiological levels of Hcy. Outcome effects: Hyperhomocysteinemia affects DNA methylation and associated with hypo-methylation due to changes in S-adenosylmethionine/S-adenosylhomocysteine methylation ratio. Changing DNA methylation pattern is the documented process in aging. Accumulation of non-metabolized Hcy hurts the cell in different ways and may cause the cell senescence. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. Organ: generic Organ_System: generic PMID: 21571175 PMID: 25324876 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-670baac6-6b3d-44c6-895f-be1df0a20750 High Level of Homocystine Effects (Methylation Cycle) uuid-670baac6-6b3d-44c6-895f-be1df0a20750 PS:CellType generic PS:Description Hyperhomocysteinemia is associated with increased risk of diseases associated with aging. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-670baac6-6b3d-44c6-895f-be1df0a20750 PS:NodeType Pathway PS:Notes Headnote: Hyperhomocysteinemia is elevated plasma level of homocysteine (Hcy) which is synthesized during methionine metabolism. Hyperhomocysteinemia is associated with increased risk of atherosclerosis and arterial and venous thrombosis and other diseases associated with aging. Hyperhomocysteinemia may be caused by mutation in the MTHFR gene, defects in metabolism of vitamin B12, folate, choline or pyridoxal 5'-phosphate. Signaling description: Transport of folate into the cell initiates the folate cycle in which MTHFR converts folate to its active form, 5-methyltetrahydrofolate. Human Mthfr C677T genotype is associated with mild MTHFR deficiency in the condition of high temperature stress and less production of 5-methyltetrahydrofolate. 5-methyltetrahydrofolate is a necessary co-factor in methionine cycle and play role in production of universal methyl donor S-adenosylmethionine. Less production of 5-methyltetrahydrofolate due altered MTHFR function may lead to accumulation of non-metabolized Hcy. The level of dietary intakes of methionine, folate, and B12 also influences on the physiological levels of Hcy. Outcome effects: Hyperhomocysteinemia affects DNA methylation and associated with hypo-methylation due to changes in S-adenosylmethionine/S-adenosylhomocysteine methylation ratio. Changing DNA methylation pattern is the documented process in aging. Accumulation of non-metabolized Hcy hurts the cell in different ways and may cause the cell senescence. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 21571175 PS:PMID 25324876 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-671b1518-b743-4a73-b589-f5f4839c61b1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-671b1518-b743-4a73-b589-f5f4839c61b1 IL2 Expression Targets uuid-671b1518-b743-4a73-b589-f5f4839c61b1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-671b1518-b743-4a73-b589-f5f4839c61b1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-672d8cac-e59f-4b08-afed-da5e2b5bd710 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-672d8cac-e59f-4b08-afed-da5e2b5bd710 Arabinose degradation template uuid-672d8cac-e59f-4b08-afed-da5e2b5bd710 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-672d8cac-e59f-4b08-afed-da5e2b5bd710 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Obese men show decreased bioavailable levels of androgens and increased levels of estrogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67515dfe-0183-463a-8307-06551e97d1fe NodeType: Pathway Notes: Headnote: In normal conditions circulating androgens control adipocyte size, suppress adipose tissue accumulation and improve insulin sensitivity. Obese men show decreased bioavailable levels of androgens and increased levels of estrogens due to an increase in aromatase (CYP19A1) activity that mediates peripheral conversion of androgens to estrogens. Signaling description: Testosterone can act to androgen receptor (AR) directly or be converted to the more potent androgen 5-dihydrotestosterone by 5-alpha-reductase (SRD5A1/2). Increase in circulating estrogenes level lead to an inhibition of the hypothalamic gonadotropin-releasing hormone (GNRH1) secretion and luteinizing hormone pulse which results in a reduction of gonadal testosterone production. In obesity adipose tissue is also able to affect gonadotropin release through increased secretion of cytokines, in particular TNF and IL6. Insulin excess is known to inhibit hepatic synthesis and secretion of sex-hormone-binding globulin (SHBG), the testosterone transporter.Obesity is characterized by development leptin resistance and high level of leptin. Leptin affects testosterone production directly inhibiting Leydig cell function by blocking the steroidogenesis. Testosterone inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an adipose-specific glycolysis enzyme. It also suppresses lipoprotein lipase (LPL) activity and lipid uptake in adipocytes. Testosterone was shown to downregulate expression of lipolytic enzyme hormone-sensitive lipase (LIPE) and beta-2-adrenoreceptor (ADRB2), which normally drives the lipolysis in adipocytes (it was shown for subcutaneous fat tissue). Normally AR stimulation results in inhibition of adipogenic differentiation and proliferation by directly activating downstream Wnt effector molecules, including beta-catenin (CTNNB1), T-cell factor 4 (TCF4), and lymphoidenhancer factor 1 (LEF1). Inhibition of adipogenesis involves suppression of key adipogenic factors PPARG, CEBPA, and CEBPD. Outcome effects: In obesity low testosterone level leads to adipocytes hypertrophy and hyperplasia. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: endocrine system PMID: 16210377 PMID: 17977473 PMID: 21109497 PMID: 21709300 PMID: 22235202 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-67515dfe-0183-463a-8307-06551e97d1fe Androgen Deficiency in Male Obesity uuid-67515dfe-0183-463a-8307-06551e97d1fe PS:CellType adipocyte PS:Description Obese men show decreased bioavailable levels of androgens and increased levels of estrogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67515dfe-0183-463a-8307-06551e97d1fe PS:NodeType Pathway PS:Notes Headnote: In normal conditions circulating androgens control adipocyte size, suppress adipose tissue accumulation and improve insulin sensitivity. Obese men show decreased bioavailable levels of androgens and increased levels of estrogens due to an increase in aromatase (CYP19A1) activity that mediates peripheral conversion of androgens to estrogens. Signaling description: Testosterone can act to androgen receptor (AR) directly or be converted to the more potent androgen 5-dihydrotestosterone by 5-alpha-reductase (SRD5A1/2). Increase in circulating estrogenes level lead to an inhibition of the hypothalamic gonadotropin-releasing hormone (GNRH1) secretion and luteinizing hormone pulse which results in a reduction of gonadal testosterone production. In obesity adipose tissue is also able to affect gonadotropin release through increased secretion of cytokines, in particular TNF and IL6. Insulin excess is known to inhibit hepatic synthesis and secretion of sex-hormone-binding globulin (SHBG), the testosterone transporter.Obesity is characterized by development leptin resistance and high level of leptin. Leptin affects testosterone production directly inhibiting Leydig cell function by blocking the steroidogenesis. Testosterone inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an adipose-specific glycolysis enzyme. It also suppresses lipoprotein lipase (LPL) activity and lipid uptake in adipocytes. Testosterone was shown to downregulate expression of lipolytic enzyme hormone-sensitive lipase (LIPE) and beta-2-adrenoreceptor (ADRB2), which normally drives the lipolysis in adipocytes (it was shown for subcutaneous fat tissue). Normally AR stimulation results in inhibition of adipogenic differentiation and proliferation by directly activating downstream Wnt effector molecules, including beta-catenin (CTNNB1), T-cell factor 4 (TCF4), and lymphoidenhancer factor 1 (LEF1). Inhibition of adipogenesis involves suppression of key adipogenic factors PPARG, CEBPA, and CEBPD. Outcome effects: In obesity low testosterone level leads to adipocytes hypertrophy and hyperplasia. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System endocrine system PS:PMID 16210377 PS:PMID 17977473 PS:PMID 21109497 PS:PMID 21709300 PS:PMID 22235202 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-677f56a7-6f9b-469c-a8e2-4397a862d570 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-677f56a7-6f9b-469c-a8e2-4397a862d570 Granulocytes recruitment in the cornea uuid-677f56a7-6f9b-469c-a8e2-4397a862d570 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-677f56a7-6f9b-469c-a8e2-4397a862d570 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67a830ad-31d3-4d68-8d23-88248e7e46ce NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-67a830ad-31d3-4d68-8d23-88248e7e46ce 1_ab_Amyloid-beta in Alzheimer's disease uuid-67a830ad-31d3-4d68-8d23-88248e7e46ce PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67a830ad-31d3-4d68-8d23-88248e7e46ce PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67aa274a-2f9f-4066-9fd9-13bfa6ff48e1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-67aa274a-2f9f-4066-9fd9-13bfa6ff48e1 Gly/Thr metabolism template uuid-67aa274a-2f9f-4066-9fd9-13bfa6ff48e1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67aa274a-2f9f-4066-9fd9-13bfa6ff48e1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67b03d81-ead3-4e96-9fb3-75041c7b10e4 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-67b03d81-ead3-4e96-9fb3-75041c7b10e4 Migraine Molecular Biomarkers uuid-67b03d81-ead3-4e96-9fb3-75041c7b10e4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67b03d81-ead3-4e96-9fb3-75041c7b10e4 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67eb0fce-0a5f-43f6-921f-29843d2c72ca NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-67eb0fce-0a5f-43f6-921f-29843d2c72ca Glycerols metabolism template uuid-67eb0fce-0a5f-43f6-921f-29843d2c72ca PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-67eb0fce-0a5f-43f6-921f-29843d2c72ca PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Genetic factors are thought to account for approximately 70? of the risk of developing epilepsy. Most of the genes identified in the first group encode ion channels (channelopathies). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-680db651-c678-4dd0-b78e-d1dfdc0e1130 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Genetic factors are thought to account for approximately 70% of the risk of developing epilepsy. Signaling description: Epilepsy genetics has two broad categories: genes and loci discovered in association with primary epilepsy syndromes, in which the epilepsy is a principal presenting feature and genes discovered in association with disorders of brain development that are associated with epilepsy. Most of the genes identified in the latter group encode ion channels (channelopathies). Specifically, mutations in voltage-dependent Na+ channel genes including SCN1A, SCN2A, and SCN1B are found in epilepsy. SCN1A mutations are found in febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (Dravet syndrome/SMEI), and intractable childhood epilepsy with frequent generalized tonic-clonic seizures (ICEGTC). SCN2A mutations are associated with benign familial neonatal-infantile seizures (BFNIS), GEFS, and SMEI-like phenotype. SCN1B mutations are also reported in GEFS+. In addition, mutations of K channels including KCNA1, KCNQ2/3, KCNMA1, and KCNJ11 are found in epilepsy. KCNA1 mutations are associated with episodic ataxia type 1 (EA1). KCNQ2/3 mutations are found in benign familial neonatal convulsions (BFNC). KCNMA1 mutations are described in generalized epilepsy and paroxysmal dyskinesia. KCNJ11 mutations cause neonatal diabetes mellitus accompanied by developmental delay and seizures. Furthermore, hyperpolarization activated cyclic nucleotide-gated K channels 1 and 2 (HCN1/2) mutations may contribute to epilepsy development. LGI1 is a secreted non-ion channel protein that is mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTLE, also known as autosomal dominant partial epilepsy with auditory features, ADPEAF). LGI1 can modulate the function of K channels including KCNA1, KCNAB1, and KCNA4. Wild-type LGI1 has been reported to increase the surface expression of excitatory AMPA-type glutamate receptors, via an interaction with the transmembrane adhesion protein ADAM22. As mutant LGI1 appears unable to bind ADAM22, this mutation could result in a decrease in excitatory AMPA currents. Mutations of Ca2+ channels such as CACNA1A, CACNA1H, and CACNB4 are also described in epilepsy. CACNA1A mutations may be associated with familial hemiplegic migraine, spinocerebellar ataxia type 6, and episodic ataxia type 2 (EA2). Some patients with EA2 also suffer from absence seizures. CACNB4 mutations are associated with juvenile myoclonic epilepsy (JME). CACNA1H mutations occasionally occur in association with childhood absence epilepsy (CAE). EFHC1 is a protein associated with Ca2+ channel CACNA1E. Mutations of EFHC1 are associated with JME. In addition, Cl- channel CLCN2 mutations are associated with different forms of idiopathic generalized epilepsy including CAE, JME, juvenile absence epilepsy (JAE), and epilepsy with grand mal seizures on awakening (EGMA). Furthermore, nicotinic acetylcholine receptors are ligand-gated ion channels. Mutations in CHRNA and CHRNB2 genes are found in patients suffering from nocturnal frontal lobe epilepsy (NFLE), while CHRNA7 mutations are found in JME. Lastly, GABA-A receptor in the brain is most often composed of GABRA1, GABRB2, and GABRG2 subunits. GABRA1 mutations are associated with JME and CAE, while GABRG2 mutations are found in GEFS+, CAE, and febrile seizures. GABRD encodes the delta subunit that forms heteromeric extra- or peri-synaptic channels that differ from the synaptic GABA-A receptor channels. GABRD mutations are found in GEFS+ seizures. Outcome effects: Seizures may result from gain-of-function mutations of sodium (Na+) and calcium (Ca2+) channels or loss-of-function mutation Organ: brain Organ_System: nervous system PMID: 18952142 PMID: 21277190 PMID: 22178301 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-680db651-c678-4dd0-b78e-d1dfdc0e1130 Inherited Channelopathies uuid-680db651-c678-4dd0-b78e-d1dfdc0e1130 PS:CellType neuron PS:Description Genetic factors are thought to account for approximately 70? of the risk of developing epilepsy. Most of the genes identified in the first group encode ion channels (channelopathies). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-680db651-c678-4dd0-b78e-d1dfdc0e1130 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Genetic factors are thought to account for approximately 70% of the risk of developing epilepsy. Signaling description: Epilepsy genetics has two broad categories: genes and loci discovered in association with primary epilepsy syndromes, in which the epilepsy is a principal presenting feature and genes discovered in association with disorders of brain development that are associated with epilepsy. Most of the genes identified in the latter group encode ion channels (channelopathies). Specifically, mutations in voltage-dependent Na+ channel genes including SCN1A, SCN2A, and SCN1B are found in epilepsy. SCN1A mutations are found in febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (Dravet syndrome/SMEI), and intractable childhood epilepsy with frequent generalized tonic-clonic seizures (ICEGTC). SCN2A mutations are associated with benign familial neonatal-infantile seizures (BFNIS), GEFS, and SMEI-like phenotype. SCN1B mutations are also reported in GEFS+. In addition, mutations of K channels including KCNA1, KCNQ2/3, KCNMA1, and KCNJ11 are found in epilepsy. KCNA1 mutations are associated with episodic ataxia type 1 (EA1). KCNQ2/3 mutations are found in benign familial neonatal convulsions (BFNC). KCNMA1 mutations are described in generalized epilepsy and paroxysmal dyskinesia. KCNJ11 mutations cause neonatal diabetes mellitus accompanied by developmental delay and seizures. Furthermore, hyperpolarization activated cyclic nucleotide-gated K channels 1 and 2 (HCN1/2) mutations may contribute to epilepsy development. LGI1 is a secreted non-ion channel protein that is mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTLE, also known as autosomal dominant partial epilepsy with auditory features, ADPEAF). LGI1 can modulate the function of K channels including KCNA1, KCNAB1, and KCNA4. Wild-type LGI1 has been reported to increase the surface expression of excitatory AMPA-type glutamate receptors, via an interaction with the transmembrane adhesion protein ADAM22. As mutant LGI1 appears unable to bind ADAM22, this mutation could result in a decrease in excitatory AMPA currents. Mutations of Ca2+ channels such as CACNA1A, CACNA1H, and CACNB4 are also described in epilepsy. CACNA1A mutations may be associated with familial hemiplegic migraine, spinocerebellar ataxia type 6, and episodic ataxia type 2 (EA2). Some patients with EA2 also suffer from absence seizures. CACNB4 mutations are associated with juvenile myoclonic epilepsy (JME). CACNA1H mutations occasionally occur in association with childhood absence epilepsy (CAE). EFHC1 is a protein associated with Ca2+ channel CACNA1E. Mutations of EFHC1 are associated with JME. In addition, Cl- channel CLCN2 mutations are associated with different forms of idiopathic generalized epilepsy including CAE, JME, juvenile absence epilepsy (JAE), and epilepsy with grand mal seizures on awakening (EGMA). Furthermore, nicotinic acetylcholine receptors are ligand-gated ion channels. Mutations in CHRNA and CHRNB2 genes are found in patients suffering from nocturnal frontal lobe epilepsy (NFLE), while CHRNA7 mutations are found in JME. Lastly, GABA-A receptor in the brain is most often composed of GABRA1, GABRB2, and GABRG2 subunits. GABRA1 mutations are associated with JME and CAE, while GABRG2 mutations are found in GEFS+, CAE, and febrile seizures. GABRD encodes the delta subunit that forms heteromeric extra- or peri-synaptic channels that differ from the synaptic GABA-A receptor channels. GABRD mutations are found in GEFS+ seizures. Outcome effects: Seizures may result from gain-of-function mutations of sodium (Na+) and calcium (Ca2+) channels or loss-of-function mutation PS:Organ brain PS:Organ_System nervous system PS:PMID 18952142 PS:PMID 21277190 PS:PMID 22178301 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-682bf902-3b43-4e26-b570-c0e750324c03 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-682bf902-3b43-4e26-b570-c0e750324c03 CD86 -> NF-kB Expression Targets uuid-682bf902-3b43-4e26-b570-c0e750324c03 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-682bf902-3b43-4e26-b570-c0e750324c03 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68423c73-d79b-4cb0-b1c5-7465636a8448 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-68423c73-d79b-4cb0-b1c5-7465636a8448 CHRNA3-B4/A4-B2/A7 -> Ion Transport uuid-68423c73-d79b-4cb0-b1c5-7465636a8448 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68423c73-d79b-4cb0-b1c5-7465636a8448 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-684ee075-0120-462f-b116-374724dbadd3 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-684ee075-0120-462f-b116-374724dbadd3 GRM2-4/6-8 (Presynaptic) -> Glutamate Release Attenuation uuid-684ee075-0120-462f-b116-374724dbadd3 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-684ee075-0120-462f-b116-374724dbadd3 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: muscle cell Description: Hypoparathyroidism is a condition characterized by deficient PTH secretion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-685e741a-c5ae-48a0-a2c4-8f2dc9d21489 NodeType: Pathway Notes: Headnote: Hypoparathyroidism refers to an endocrine disorder characterized by hyposecretion of parathyroid hormone (PTH). Hyposecretion of PTH is associated with hypocalcemia and results in myocytes dysfunction. Clinical symptoms include myopathy, tetany and convulsions. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: musculoskeletal system PMID: 21176846 PMID: 21709182 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-685e741a-c5ae-48a0-a2c4-8f2dc9d21489 Myocyte Dysfunction in Hypoparathyroidism uuid-685e741a-c5ae-48a0-a2c4-8f2dc9d21489 PS:CellType muscle cell PS:Description Hypoparathyroidism is a condition characterized by deficient PTH secretion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-685e741a-c5ae-48a0-a2c4-8f2dc9d21489 PS:NodeType Pathway PS:Notes Headnote: Hypoparathyroidism refers to an endocrine disorder characterized by hyposecretion of parathyroid hormone (PTH). Hyposecretion of PTH is associated with hypocalcemia and results in myocytes dysfunction. Clinical symptoms include myopathy, tetany and convulsions. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System musculoskeletal system PS:PMID 21176846 PS:PMID 21709182 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Promoter-specific hypermethylation is commonly observed in neoplasias and leads to genomic instability. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-688a3ffd-5c20-4159-a463-b5dcceb5bbf9 NodeType: Pathway Notes: Headnote: Epigenetic changes including DNA methylation participate in the onset of genomic instability and progression of cancer in numerous tumor types. Global DNA hypomethylation and promoter-specific hypermethylation are commonly observed in neoplasias. Signaling description: The maintenance of appropriate DNA methylation within the CpG dinucleotide islands is involved in regulation of a wide variety of molecular processes including stability of chromosomal structure and control of gene expression. In general, DNA methylation in promoter regions results in gene silencing. Many hundreds of genes can be inactivated in a single cancer by promoter methylation. Tumor cell-specific promoter hypermethylation in genes which affects cell cycle, apoptosis, DNA repair, differentiation, and cell adhesion is often a hallmark of neoplasms.The proteins that mediate these changes are encoded by DNA methyltransferases (DNMT) and methyl-CpG-binding domain (MBD) proteins. DNMT1/3A/3B, MBD4 can be mutated in cancer. DNMT1 can be hyper-activated by PKC, PCNA, AKT1, KDM1A, H.pylori - activated NFkB signaling and other mechanisms. DNMT3A/3B can be activated due to down-regulation of certain MIRs. In turn, DNMTs and MBDs regulate the expression/function of target genes. Outcome effects: A large number of genes can be inactivated in a single cancer by promoter methylation resulting in their impaired function. We show only selected genes as examples: CDKN2A, CDKN1A (cell cycle), BRCA1 (DNA repair), CDH1 (cell adhesion), MGMT (DNA alkylation), histone H3 proteins (chromatin remodeling).Pharmacological targeting of DNA methylation is a promising therapeutic approach. A number of DNA methylation inhibitors are currently under investigation, including decitabine, 5-azacitidine, hydralazine and others. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Associated with Dysregulation of DNA Methylation in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Associated with Dysregulation of DNA Methylation in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17320506 PMID: 17613546 PMID: 19509247 PMID: 21074720 PMID: 26751963 PMID: 27717710 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-688a3ffd-5c20-4159-a463-b5dcceb5bbf9 DNMT and MBD Families Activation in DNA Methylation in Cancer uuid-688a3ffd-5c20-4159-a463-b5dcceb5bbf9 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Promoter-specific hypermethylation is commonly observed in neoplasias and leads to genomic instability. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-688a3ffd-5c20-4159-a463-b5dcceb5bbf9 PS:NodeType Pathway PS:Notes Headnote: Epigenetic changes including DNA methylation participate in the onset of genomic instability and progression of cancer in numerous tumor types. Global DNA hypomethylation and promoter-specific hypermethylation are commonly observed in neoplasias. Signaling description: The maintenance of appropriate DNA methylation within the CpG dinucleotide islands is involved in regulation of a wide variety of molecular processes including stability of chromosomal structure and control of gene expression. In general, DNA methylation in promoter regions results in gene silencing. Many hundreds of genes can be inactivated in a single cancer by promoter methylation. Tumor cell-specific promoter hypermethylation in genes which affects cell cycle, apoptosis, DNA repair, differentiation, and cell adhesion is often a hallmark of neoplasms.The proteins that mediate these changes are encoded by DNA methyltransferases (DNMT) and methyl-CpG-binding domain (MBD) proteins. DNMT1/3A/3B, MBD4 can be mutated in cancer. DNMT1 can be hyper-activated by PKC, PCNA, AKT1, KDM1A, H.pylori - activated NFkB signaling and other mechanisms. DNMT3A/3B can be activated due to down-regulation of certain MIRs. In turn, DNMTs and MBDs regulate the expression/function of target genes. Outcome effects: A large number of genes can be inactivated in a single cancer by promoter methylation resulting in their impaired function. We show only selected genes as examples: CDKN2A, CDKN1A (cell cycle), BRCA1 (DNA repair), CDH1 (cell adhesion), MGMT (DNA alkylation), histone H3 proteins (chromatin remodeling).Pharmacological targeting of DNA methylation is a promising therapeutic approach. A number of DNA methylation inhibitors are currently under investigation, including decitabine, 5-azacitidine, hydralazine and others. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Associated with Dysregulation of DNA Methylation in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Associated with Dysregulation of DNA Methylation in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17320506 PS:PMID 17613546 PS:PMID 19509247 PS:PMID 21074720 PS:PMID 26751963 PS:PMID 27717710 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68965af6-d45e-4756-a023-05df73489721 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-68965af6-d45e-4756-a023-05df73489721 TNFRSF5 -> STAT Signaling uuid-68965af6-d45e-4756-a023-05df73489721 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68965af6-d45e-4756-a023-05df73489721 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6897921e-f84e-447c-8146-efbe2de7b3a1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6897921e-f84e-447c-8146-efbe2de7b3a1 Ubiquinone-9 biosynthesis (eukaryotic) template uuid-6897921e-f84e-447c-8146-efbe2de7b3a1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6897921e-f84e-447c-8146-efbe2de7b3a1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top most studied anatomy and molecular biomarkers assotiated with disease Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68af5f11-bab8-4e77-9c22-629be7647989 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-68af5f11-bab8-4e77-9c22-629be7647989 Ovarian Cancer Anatomy and Molecular Biomarkers uuid-68af5f11-bab8-4e77-9c22-629be7647989 PS:Description Top most studied anatomy and molecular biomarkers assotiated with disease PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68af5f11-bab8-4e77-9c22-629be7647989 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Heme-derived molecules bilirubin and biliverdin act as endogenous AHR ligands. Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68c669e1-ea66-4eba-9df3-5bc6cb21f855 NodeType: Pathway Notes: Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Heme-derived molecules bilirubin and biliverdin act as endogenous AHR ligands. Because the bulk of bilirubin is conjugated to albumin and thereby unavailable as an AHR ligand, its effects may be local rather than systemic. It would be expected that they act in heme-rich organs such as liver and spleen. Outcome effects: CYP1A1 and CYP1A2 are regulated by AHR and contribute to bilirubin catabolism suggesting a negative feedback loop. PMID: 23908379 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-68c669e1-ea66-4eba-9df3-5bc6cb21f855 Aryl Hydrocarbon Receptor/Heme-Derived Molecules Signaling uuid-68c669e1-ea66-4eba-9df3-5bc6cb21f855 PS:Description Heme-derived molecules bilirubin and biliverdin act as endogenous AHR ligands. Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68c669e1-ea66-4eba-9df3-5bc6cb21f855 PS:NodeType Pathway PS:Notes Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Heme-derived molecules bilirubin and biliverdin act as endogenous AHR ligands. Because the bulk of bilirubin is conjugated to albumin and thereby unavailable as an AHR ligand, its effects may be local rather than systemic. It would be expected that they act in heme-rich organs such as liver and spleen. Outcome effects: CYP1A1 and CYP1A2 are regulated by AHR and contribute to bilirubin catabolism suggesting a negative feedback loop. PS:PMID 23908379 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68c763e4-e48b-479b-9509-9e8e863f8947 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-68c763e4-e48b-479b-9509-9e8e863f8947 Folate Biosynthesis uuid-68c763e4-e48b-479b-9509-9e8e863f8947 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68c763e4-e48b-479b-9509-9e8e863f8947 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Kinetochores are unique protein complexes assembled onto the single centromere DNA region of each sister chromatid during mitosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68cabaf1-2b9e-4af8-9442-ce237865ba2a NodeType: Pathway Notes: Headnote: Kinetochores are unique protein complexes assembled on a single centromere DNA region of each sister chromatid during mitosis. The primary function of kinetochores is to create attachments between chromosomes and microtubules in a dividing mother cell. The accurate partitioning of sister chromatids to the daughter cells relies on these attachments. Signaling description: In vertebrates, kinetochores have three the main subcomponents including the inner kinetochore which contributes a sturdy interface with centromeric chromatin, the outer kinetochore which contributes a microtubule-binding interface, and the spindle assembly checkpoint which is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. At the heart of the kinetochore is a specialized nucleosome that contains centromere protein CENPA, a histone H3 homologue. CENPB is required to establish centromeric chromatin, but is not necessary for its maintenance. OIP5 is crucial for chromatin incorporation of CENPA during the mitotic exit. CASC5, MIS12, and NDC80 have emerged as crucial components of the specialized machinery involved in microtubule binding. INCENP and AURKB are part of a complex that is commonly referred to as the chromosome passenger complex (CPC) which performs essential functions on chromosomes throughout mitosis. Cytoplasmic dynein, a minus-end directed motor, and CENPE, a plus-end directed motor, are needed for the congression of chromosomes to the metaphase plate. Several inner kinetochore components associate with kinetochores throughout the cell cycle. Many other proteins are recruited to the outer kinetochore specifically in mitosis. They provide a landing platform for the spindle-assembly checkpoint (SAC) proteins. At the attached kinetochore, MAD2L1/BUB1B complex binds to CDC20 and form the mitotic checkpoint complex (MCC), which binds to and inhibits the anaphase promoting complex (APC/C). Outcome effects: In the metaphase, APC/C-mediated CDC20 inhibition is released by SAC silencing. This event is followed by the onset of anaphase when sister chromatids are separated and pulled toward opposite poles of the cell. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-68cabaf1-2b9e-4af8-9442-ce237865ba2a Kinetochore Assembly uuid-68cabaf1-2b9e-4af8-9442-ce237865ba2a PS:CellType generic PS:Description Kinetochores are unique protein complexes assembled onto the single centromere DNA region of each sister chromatid during mitosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68cabaf1-2b9e-4af8-9442-ce237865ba2a PS:NodeType Pathway PS:Notes Headnote: Kinetochores are unique protein complexes assembled on a single centromere DNA region of each sister chromatid during mitosis. The primary function of kinetochores is to create attachments between chromosomes and microtubules in a dividing mother cell. The accurate partitioning of sister chromatids to the daughter cells relies on these attachments. Signaling description: In vertebrates, kinetochores have three the main subcomponents including the inner kinetochore which contributes a sturdy interface with centromeric chromatin, the outer kinetochore which contributes a microtubule-binding interface, and the spindle assembly checkpoint which is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. At the heart of the kinetochore is a specialized nucleosome that contains centromere protein CENPA, a histone H3 homologue. CENPB is required to establish centromeric chromatin, but is not necessary for its maintenance. OIP5 is crucial for chromatin incorporation of CENPA during the mitotic exit. CASC5, MIS12, and NDC80 have emerged as crucial components of the specialized machinery involved in microtubule binding. INCENP and AURKB are part of a complex that is commonly referred to as the chromosome passenger complex (CPC) which performs essential functions on chromosomes throughout mitosis. Cytoplasmic dynein, a minus-end directed motor, and CENPE, a plus-end directed motor, are needed for the congression of chromosomes to the metaphase plate. Several inner kinetochore components associate with kinetochores throughout the cell cycle. Many other proteins are recruited to the outer kinetochore specifically in mitosis. They provide a landing platform for the spindle-assembly checkpoint (SAC) proteins. At the attached kinetochore, MAD2L1/BUB1B complex binds to CDC20 and form the mitotic checkpoint complex (MCC), which binds to and inhibits the anaphase promoting complex (APC/C). Outcome effects: In the metaphase, APC/C-mediated CDC20 inhibition is released by SAC silencing. This event is followed by the onset of anaphase when sister chromatids are separated and pulled toward opposite poles of the cell. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68f035c3-3348-4fc3-829d-81d62b4e4488 NodeType: Pathway Notes: Alveolar macrophages localize at the boundary between the lungs and external environment. Macrophages are responsible for the removal of particles, such as dust or microorganisms, from the respiratory surfaces by phagocytosis. To be effective, they must maintain a high level of activity. Chronic lung inflammation and tissue remodeling by proteolytic enzymes are the consequence of sustained macrophage activation in COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-68f035c3-3348-4fc3-829d-81d62b4e4488 3_Role of alveolar macrophages in pulmonary tissue destruction in COPD uuid-68f035c3-3348-4fc3-829d-81d62b4e4488 PS:CellType macrophage PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-68f035c3-3348-4fc3-829d-81d62b4e4488 PS:NodeType Pathway PS:Notes Alveolar macrophages localize at the boundary between the lungs and external environment. Macrophages are responsible for the removal of particles, such as dust or microorganisms, from the respiratory surfaces by phagocytosis. To be effective, they must maintain a high level of activity. Chronic lung inflammation and tissue remodeling by proteolytic enzymes are the consequence of sustained macrophage activation in COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-690a0563-0c07-4dc7-a14a-cc8aa4077500 NodeType: Pathway Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-690a0563-0c07-4dc7-a14a-cc8aa4077500 Proteins Involved in Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy uuid-690a0563-0c07-4dc7-a14a-cc8aa4077500 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-690a0563-0c07-4dc7-a14a-cc8aa4077500 PS:NodeType Pathway PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-691dd3c6-bb75-4fb7-ab32-dc694a1c9f0c NodeType: Pathway Organ: brain Organ: spinal cord Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-691dd3c6-bb75-4fb7-ab32-dc694a1c9f0c Proteins Involved in Amyotrophic Lateral Sclerosis uuid-691dd3c6-bb75-4fb7-ab32-dc694a1c9f0c PS:CellType astrocyte PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-691dd3c6-bb75-4fb7-ab32-dc694a1c9f0c PS:NodeType Pathway PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-692a0142-ef0a-463a-aa08-5ee8447a853c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-692a0142-ef0a-463a-aa08-5ee8447a853c AREG -> FOXO3A Expression Target uuid-692a0142-ef0a-463a-aa08-5ee8447a853c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-692a0142-ef0a-463a-aa08-5ee8447a853c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-692fa851-02b5-4058-9b58-cd6057057a84 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-692fa851-02b5-4058-9b58-cd6057057a84 TGFA -> MEF/MYOD/NFATC Expression Targets uuid-692fa851-02b5-4058-9b58-cd6057057a84 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-692fa851-02b5-4058-9b58-cd6057057a84 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69404655-a3ec-4fee-a563-2f40d85652b2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-69404655-a3ec-4fee-a563-2f40d85652b2 BTC -> AP-1/ATF/CREB Expression Targets uuid-69404655-a3ec-4fee-a563-2f40d85652b2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69404655-a3ec-4fee-a563-2f40d85652b2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69478a00-be58-4a93-82b5-0d117e4a5784 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-69478a00-be58-4a93-82b5-0d117e4a5784 Histidine Metabolism uuid-69478a00-be58-4a93-82b5-0d117e4a5784 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69478a00-be58-4a93-82b5-0d117e4a5784 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The extracellular matrix (ECM), a complex meshwork of proteins and proteoglycans, provides structure and support for cells and tissues. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69536d51-79c2-4fae-8072-43c158b34569 NodeType: Pathway Notes: Headnote: The extracellular matrix (ECM), a complex meshwork of proteins and proteoglycans, provides structure and support for cells and tissues. ECM can have properties of a soft gel (eyes), a polymer fiber rope (ligaments), or a rock-hard composite (bones). Signaling description: ECM proteins are grouped as glycoproteins, proteoglycans, and collagens and the majority of them are collagen, fibronectin (FN1), and laminin. Glycosaminoglycans and polysaccharides can covalently attach to the core proteins. ECM polymerization is contingent on the synthesizing activity of fibroblasts and osteoblasts. The degradation of the ECM is a critical process during cell morphogenesis, differentiation, cell migration, and apoptosis. Matrix metalloproteinases (MMPs) are a group of 23 related proteinases that have a central role in the degradation of ECM. The activity of MMPs can be regulated by nitric oxide (NO) and by TIMPs which inhibit MMP activity. In addition, MMPs are nonspecifically inhibited by their association with A2M and once in a complex, MMPs can no longer bind to substrate and are readily cleared by endocytosis through LRP1. TFPI2 has also been described as an MMP binding agent. Outcome effects: RECK inhibits MMPs which suppresses the invasion of tissues, metastasis, and tumor angiogenesis. This interaction is required for normal development. ECM degradation is often accomplished via protrusions of the plasma membrane known as podosomes or invadopodia. These cellular structures are responsible for cell invasion by degradation of the ECM barriers. Podosomes are composed of an F-actin core, surrounded by actin-associated proteins, signal transduction proteins, and MMPs which include membrane-bound MMPs such as MMP14 and secreted MMPs such as MMP2 and MMP9. FAP, in association with DPP4, is involved in the pericellular proteolysis of the ECM as well as the migration and invasion of endothelial cells into the ECM. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-69536d51-79c2-4fae-8072-43c158b34569 Extracellular Matrix Turnover uuid-69536d51-79c2-4fae-8072-43c158b34569 PS:CellType generic PS:Description The extracellular matrix (ECM), a complex meshwork of proteins and proteoglycans, provides structure and support for cells and tissues. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69536d51-79c2-4fae-8072-43c158b34569 PS:NodeType Pathway PS:Notes Headnote: The extracellular matrix (ECM), a complex meshwork of proteins and proteoglycans, provides structure and support for cells and tissues. ECM can have properties of a soft gel (eyes), a polymer fiber rope (ligaments), or a rock-hard composite (bones). Signaling description: ECM proteins are grouped as glycoproteins, proteoglycans, and collagens and the majority of them are collagen, fibronectin (FN1), and laminin. Glycosaminoglycans and polysaccharides can covalently attach to the core proteins. ECM polymerization is contingent on the synthesizing activity of fibroblasts and osteoblasts. The degradation of the ECM is a critical process during cell morphogenesis, differentiation, cell migration, and apoptosis. Matrix metalloproteinases (MMPs) are a group of 23 related proteinases that have a central role in the degradation of ECM. The activity of MMPs can be regulated by nitric oxide (NO) and by TIMPs which inhibit MMP activity. In addition, MMPs are nonspecifically inhibited by their association with A2M and once in a complex, MMPs can no longer bind to substrate and are readily cleared by endocytosis through LRP1. TFPI2 has also been described as an MMP binding agent. Outcome effects: RECK inhibits MMPs which suppresses the invasion of tissues, metastasis, and tumor angiogenesis. This interaction is required for normal development. ECM degradation is often accomplished via protrusions of the plasma membrane known as podosomes or invadopodia. These cellular structures are responsible for cell invasion by degradation of the ECM barriers. Podosomes are composed of an F-actin core, surrounded by actin-associated proteins, signal transduction proteins, and MMPs which include membrane-bound MMPs such as MMP14 and secreted MMPs such as MMP2 and MMP9. FAP, in association with DPP4, is involved in the pericellular proteolysis of the ECM as well as the migration and invasion of endothelial cells into the ECM. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-695d5263-b1cf-4705-8c81-bb371ad2cfeb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-695d5263-b1cf-4705-8c81-bb371ad2cfeb Sympathetic Pathway->Lacrimation uuid-695d5263-b1cf-4705-8c81-bb371ad2cfeb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-695d5263-b1cf-4705-8c81-bb371ad2cfeb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-695ddad1-de94-46e8-a9c6-24322b4310ab NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-695ddad1-de94-46e8-a9c6-24322b4310ab TNFSF14 Expression Targets uuid-695ddad1-de94-46e8-a9c6-24322b4310ab PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-695ddad1-de94-46e8-a9c6-24322b4310ab PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6964bf75-7b0c-4aad-ab48-39c28472403b NodeType: Pathway Organ: joint Organ: kidney Organ_System: skeletal system Organ_System: urinary tract PathwayType: network Source: Diseases urn:agi-pathway:uuid-6964bf75-7b0c-4aad-ab48-39c28472403b Proteins Involved in Gout uuid-6964bf75-7b0c-4aad-ab48-39c28472403b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6964bf75-7b0c-4aad-ab48-39c28472403b PS:NodeType Pathway PS:Organ joint PS:Organ kidney PS:Organ_System skeletal system PS:Organ_System urinary tract PS:PathwayType network PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6965c348-1f1a-4b0b-8cbb-c8d24b55b755 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-6965c348-1f1a-4b0b-8cbb-c8d24b55b755 TLR3-|fibroblasts uuid-6965c348-1f1a-4b0b-8cbb-c8d24b55b755 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6965c348-1f1a-4b0b-8cbb-c8d24b55b755 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activating mutations in oncogenes and inactivating mutations in tumor suppressor genes drive metabolic deregulation in cancer cells. NodeType: Pathway Notes: Headnote: Activating mutations in oncogenes and inactivating mutations in tumor suppressor genes drive metabolic deregulation in cancer cells. Signaling description: A number of oncogenes mutated in cancer are implicated in deregulation of metabolism in such cells. They include components of the RAS/PI3K/AKT signaling (HRAS, NRAS, KRAS, PIK3CA, AKT1), CTNNB1, MYC, RELA and some other proteins. Tumor suppressor genes implicated in deregulation of metabolism include NF1, PTEN, TSC1/2, STK11, TP53, RB1 and some others. Outcome effects: Genes responsible for glucose import, glycolysis, amino acid transport and metabolism, as well as, fatty acid and triglyceride synthesis are activated providing metabolites necessary for cancer cell growth, division and spread. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details._ Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" for details. Organ: oncogenic Organ_System: oncogenic PMID: 23897900 PMID: 25878364 PMID: 28025559 PathwayType: signaling Tissue: oncogenic urn:agi-pathway:uuid-699d613d-9ebe-4a0c-9460-1fed804afdcf Metabolic effects of oncogenes and tumor suppressor in cancer cells uuid-699d613d-9ebe-4a0c-9460-1fed804afdcf PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activating mutations in oncogenes and inactivating mutations in tumor suppressor genes drive metabolic deregulation in cancer cells. PS:NodeType Pathway PS:Notes Headnote: Activating mutations in oncogenes and inactivating mutations in tumor suppressor genes drive metabolic deregulation in cancer cells. Signaling description: A number of oncogenes mutated in cancer are implicated in deregulation of metabolism in such cells. They include components of the RAS/PI3K/AKT signaling (HRAS, NRAS, KRAS, PIK3CA, AKT1), CTNNB1, MYC, RELA and some other proteins. Tumor suppressor genes implicated in deregulation of metabolism include NF1, PTEN, TSC1/2, STK11, TP53, RB1 and some others. Outcome effects: Genes responsible for glucose import, glycolysis, amino acid transport and metabolism, as well as, fatty acid and triglyceride synthesis are activated providing metabolites necessary for cancer cell growth, division and spread. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details._ Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 23897900 PS:PMID 25878364 PS:PMID 28025559 PS:PathwayType signaling PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69a2340e-cc61-4d08-95f7-a1714ef261d1 NodeType: Pathway Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-69a2340e-cc61-4d08-95f7-a1714ef261d1 P2RXs -> Synaptic Transmission uuid-69a2340e-cc61-4d08-95f7-a1714ef261d1 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69a2340e-cc61-4d08-95f7-a1714ef261d1 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Histamine plays a critical role in mediating wakefulness in mammals. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69a68e04-6ed4-4f0d-8e1f-dfcad34a0c5e NodeType: Pathway Notes: Headnote: Histamine plays a critical role in mediating wakefulness in mammals. Histamine release in the hypothalamus and other target regions is highest during wakefulness. Signaling description: The histaminergic neurons display maximal activity during the state of vigilance and cease their activity during NREM and REM sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. Histaminergic neurons are exclusively localized in the tuberomammillary nucleus (TMN) in the posterior hypothalamus and send widespread projections to various brain areas. Histaminergic neurons activate or facilitate large brain areas through postsynaptic H1 and H2 receptors, thus contributing to cortical activation. Outcome effects: The administration of histamine or H1 receptor (HRH1) agonists induces wakefulness, whereas administration of HRH1 antagonists promotes sleep. The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. The activation of HRH3 decreases histamine production and release, thus promoting sleep. Conversely, the blockade of HRH3 promotes wakefulness. Therefore, HRH3 constitutes a brain target for the treatment of sleep-wake disorders. Organ: brain Organ_System: nervous system PMID: 18626069 PMID: 20851648 PMID: 20864502 PMID: 21318261 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-69a68e04-6ed4-4f0d-8e1f-dfcad34a0c5e Histamine in Arousal Regulation uuid-69a68e04-6ed4-4f0d-8e1f-dfcad34a0c5e PS:CellType neuron PS:Description Histamine plays a critical role in mediating wakefulness in mammals. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69a68e04-6ed4-4f0d-8e1f-dfcad34a0c5e PS:NodeType Pathway PS:Notes Headnote: Histamine plays a critical role in mediating wakefulness in mammals. Histamine release in the hypothalamus and other target regions is highest during wakefulness. Signaling description: The histaminergic neurons display maximal activity during the state of vigilance and cease their activity during NREM and REM sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. Histaminergic neurons are exclusively localized in the tuberomammillary nucleus (TMN) in the posterior hypothalamus and send widespread projections to various brain areas. Histaminergic neurons activate or facilitate large brain areas through postsynaptic H1 and H2 receptors, thus contributing to cortical activation. Outcome effects: The administration of histamine or H1 receptor (HRH1) agonists induces wakefulness, whereas administration of HRH1 antagonists promotes sleep. The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. The activation of HRH3 decreases histamine production and release, thus promoting sleep. Conversely, the blockade of HRH3 promotes wakefulness. Therefore, HRH3 constitutes a brain target for the treatment of sleep-wake disorders. PS:Organ brain PS:Organ_System nervous system PS:PMID 18626069 PS:PMID 20851648 PS:PMID 20864502 PS:PMID 21318261 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69b80253-1939-4fcd-bf7b-f394617357d2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-69b80253-1939-4fcd-bf7b-f394617357d2 oxLDL+>apoptosis uuid-69b80253-1939-4fcd-bf7b-f394617357d2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69b80253-1939-4fcd-bf7b-f394617357d2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69bc3a0b-6bdf-4ad5-a746-7f3f2e5fd004 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-69bc3a0b-6bdf-4ad5-a746-7f3f2e5fd004 PTGER2/3 -> Inflammation-Related Expression Targets uuid-69bc3a0b-6bdf-4ad5-a746-7f3f2e5fd004 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69bc3a0b-6bdf-4ad5-a746-7f3f2e5fd004 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69fe1005-d1a7-40ff-83eb-ab5512959514 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-69fe1005-d1a7-40ff-83eb-ab5512959514 PTGIR -> IL6 Production uuid-69fe1005-d1a7-40ff-83eb-ab5512959514 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-69fe1005-d1a7-40ff-83eb-ab5512959514 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a2282d4-9574-4c7b-bb0e-86170ed741d3 NodeType: Pathway Organ: generic Organ_System: generic PMID: 20331961 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-6a2282d4-9574-4c7b-bb0e-86170ed741d3 Lysophosphatidic Acid/LPARs Signaling uuid-6a2282d4-9574-4c7b-bb0e-86170ed741d3 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a2282d4-9574-4c7b-bb0e-86170ed741d3 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 20331961 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Peroxisomes are ubiquitous cellular compartments or organelles with a single membrane involved in the metabolism of hydrogen peroxide and the beta-oxidation of fatty acids. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a39b744-4270-4c4a-9fdc-00a34472a4d8 NodeType: Pathway Notes: Headnote: Peroxisomes are ubiquitous cellular compartments or organelles with a single membrane involved in the metabolism of hydrogen peroxide and the beta-oxidation of fatty acids. All peroxisomal proteins are synthesized at free ribosomes and are post-translationally transferred to the cytosol and imported into peroxisomes. The main function in detoxifying peroxides or peroxide radicals into water belongs to catalase (CAT). Signaling description: The newly synthesized proteins contain peroxisomal targeting signals (PTSs). Almost all matrix proteins have a peroxisome targeting signal 1 (PTS1) which is a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). PTS1 is specifically recognized by receptor PEX5. Peroxisome targeting signal 2 (PTS2) is a non-peptide with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) located near the N-terminus (X can be any amino acid). PTS2 is specifically recognized by receptor PEX7. The import process involves three distinct steps. The import receptors, PEX5 and PEX7, bind proteins with PTS1 and PTS2 in the cytosol and direct them to the peroxisomal membrane-bound PEX13/PEX14 receptor complex. In mammals, an isoform of PEX5 (PEX5L) is required as an accessory protein for PEX7. This complex is part of a larger complex known as the peroxisomal importomer which includes the membrane proteins PEX2, PEX10, and PEX12. Cargoes are then translocated into the peroxisomal matrix in a manner that exposes the receptor to the matrix of the peroxisome. Whether the receptors translocate completely into the matrix or retain association with the translocation complex is still unknown. The docking and RING complexes (PEX2, PEX10, and PEX12) are involved in translocation. Cargoes are released on the matrix side of the membrane and receptors are recycled to the cytoplasm. The recycling of cargo-released PEX5 to the cytosol requires PEX1 and PEX6. Membrane assembly and insertion of peroxisomal membrane proteins (PMPs), containing targeting signals of PMPs (mPTS), requires PEX19 and PEX16 which may function as receptor/chaperone which binds the PMPs in the cytosol and interacts with PEX3 at the peroxisomal membrane. The ubiquitylation of the import receptor is emerging as an important aspect of import. Peroxisomes can evidently arise from the fission of preexisting peroxisomes. PEX11A, PEX11B, and PEX11G are the only peroxins known to be involved in the regulation of peroxisome size and number (proliferation) in mammals. The division of peroxisomes is mediated by DNM1L. It has been demonstrated that the fission of preexisting peroxisomes is coupled to the transfer of membrane material from the ER to peroxisomes through PEX3-containing vesicles. Mammalian peroxisomes move along microtubules and bind kinesin and dynein motors by a mechanism that is not clear. Organ: generic Organ_System: generic PMID: 27284042 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-6a39b744-4270-4c4a-9fdc-00a34472a4d8 Peroxisome Protein Import and Peroxisome Division uuid-6a39b744-4270-4c4a-9fdc-00a34472a4d8 PS:CellType generic PS:Description Peroxisomes are ubiquitous cellular compartments or organelles with a single membrane involved in the metabolism of hydrogen peroxide and the beta-oxidation of fatty acids. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a39b744-4270-4c4a-9fdc-00a34472a4d8 PS:NodeType Pathway PS:Notes Headnote: Peroxisomes are ubiquitous cellular compartments or organelles with a single membrane involved in the metabolism of hydrogen peroxide and the beta-oxidation of fatty acids. All peroxisomal proteins are synthesized at free ribosomes and are post-translationally transferred to the cytosol and imported into peroxisomes. The main function in detoxifying peroxides or peroxide radicals into water belongs to catalase (CAT). Signaling description: The newly synthesized proteins contain peroxisomal targeting signals (PTSs). Almost all matrix proteins have a peroxisome targeting signal 1 (PTS1) which is a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). PTS1 is specifically recognized by receptor PEX5. Peroxisome targeting signal 2 (PTS2) is a non-peptide with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) located near the N-terminus (X can be any amino acid). PTS2 is specifically recognized by receptor PEX7. The import process involves three distinct steps. The import receptors, PEX5 and PEX7, bind proteins with PTS1 and PTS2 in the cytosol and direct them to the peroxisomal membrane-bound PEX13/PEX14 receptor complex. In mammals, an isoform of PEX5 (PEX5L) is required as an accessory protein for PEX7. This complex is part of a larger complex known as the peroxisomal importomer which includes the membrane proteins PEX2, PEX10, and PEX12. Cargoes are then translocated into the peroxisomal matrix in a manner that exposes the receptor to the matrix of the peroxisome. Whether the receptors translocate completely into the matrix or retain association with the translocation complex is still unknown. The docking and RING complexes (PEX2, PEX10, and PEX12) are involved in translocation. Cargoes are released on the matrix side of the membrane and receptors are recycled to the cytoplasm. The recycling of cargo-released PEX5 to the cytosol requires PEX1 and PEX6. Membrane assembly and insertion of peroxisomal membrane proteins (PMPs), containing targeting signals of PMPs (mPTS), requires PEX19 and PEX16 which may function as receptor/chaperone which binds the PMPs in the cytosol and interacts with PEX3 at the peroxisomal membrane. The ubiquitylation of the import receptor is emerging as an important aspect of import. Peroxisomes can evidently arise from the fission of preexisting peroxisomes. PEX11A, PEX11B, and PEX11G are the only peroxins known to be involved in the regulation of peroxisome size and number (proliferation) in mammals. The division of peroxisomes is mediated by DNM1L. It has been demonstrated that the fission of preexisting peroxisomes is coupled to the transfer of membrane material from the ER to peroxisomes through PEX3-containing vesicles. Mammalian peroxisomes move along microtubules and bind kinesin and dynein motors by a mechanism that is not clear. PS:Organ generic PS:Organ_System generic PS:PMID 27284042 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a6eb5f4-b552-46ed-92a4-ffd0c4759a34 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6a6eb5f4-b552-46ed-92a4-ffd0c4759a34 NGF -> AP-1/TP53/MYC Expression Targets uuid-6a6eb5f4-b552-46ed-92a4-ffd0c4759a34 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a6eb5f4-b552-46ed-92a4-ffd0c4759a34 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a7b8ff9-4046-466e-bd2f-1adfbbaf6539 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-6a7b8ff9-4046-466e-bd2f-1adfbbaf6539 CD86 -> NFATC Expression Targets uuid-6a7b8ff9-4046-466e-bd2f-1adfbbaf6539 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a7b8ff9-4046-466e-bd2f-1adfbbaf6539 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a9ed64e-157a-4a72-a481-c9bc8723e216 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6a9ed64e-157a-4a72-a481-c9bc8723e216 Gluconeogenesis template uuid-6a9ed64e-157a-4a72-a481-c9bc8723e216 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6a9ed64e-157a-4a72-a481-c9bc8723e216 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aae5d22-19b0-455a-b4b4-4f9b5d9e5842 NodeType: Pathway Notes: Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: Several pathways are activated in this complication such as the accelerated formation of advanced glycation end products (AGEs), polyol, hexosamine, and protein kinase C (PKC) pathways. AGE, hexosamine, and PKC pathways provoke impairment in blood flow end exchange diffusion and result in PAI-1 (SERPINE1) transcription. SERPINE1 inhibits plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. The disruption of fibrinolysis is the underlying cause for vascular occlusion in diabetes. TGFB1 causes FN1, collagen IV, and collagen VI expression, thus increasing blood vessel permeability and thickening of capillary basement membranes. These processes are the origin of edema and cause of the exchange diffusion impairment (metabolites and oxygen) in the tissue. AGE-AGER interaction mediates NF-kB activation. The signal is transduced from AGER to KRAS which affects PI3K. Generated by PI3K, PIP3 initiates AKT1 activation by PDPK1. AKT1 provokes the release of NF-kB from its inhibitor, NFKBIA and free NF-kB promotes ICAM1, VCAM1, SERPINE1, and EDN1 transcription. Outcome effects: A critical consequence of VCAM1 and ICAM1 expression on the endothelial surface is the attraction of mononuclear phagocytes into the vessel wall that promotes inflammation. EDN1 causes vasoconstriction impairing blood flow in the tissue. Furthermore, the activation of the polyol pathway promotes reactive oxygen species (ROS) generation exposing cells to oxidative stress, AGE precursor formation (methylglyoxal) leading to vessel wall damage. Normally, ischemia (hypoxia) provokes the release of HIF1A from its inhibitor, EGLN2. Free HIF1A with its interacting proteins, EP300 and ARNT trigger the expression of vascularization factors including CXCL12, VEGFA, CXCR4, and NOS3. In the pathology, HIF1A and EP300 are inhibited by methylglyoxal preventing vascularization. Highlighted proteins: Entities with increased level or activity are highlighted in red and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PMID: 18230954 PMID: 18793542 PMID: 21739639 PMID: 8799700 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-6aae5d22-19b0-455a-b4b4-4f9b5d9e5842 Peripheral Tissue Microangiopathy uuid-6aae5d22-19b0-455a-b4b4-4f9b5d9e5842 PS:CellType vascular smooth muscle cell PS:Description Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aae5d22-19b0-455a-b4b4-4f9b5d9e5842 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: Several pathways are activated in this complication such as the accelerated formation of advanced glycation end products (AGEs), polyol, hexosamine, and protein kinase C (PKC) pathways. AGE, hexosamine, and PKC pathways provoke impairment in blood flow end exchange diffusion and result in PAI-1 (SERPINE1) transcription. SERPINE1 inhibits plasminogen activators (PLAT and PLAU) disrupting fibrinolysis. The disruption of fibrinolysis is the underlying cause for vascular occlusion in diabetes. TGFB1 causes FN1, collagen IV, and collagen VI expression, thus increasing blood vessel permeability and thickening of capillary basement membranes. These processes are the origin of edema and cause of the exchange diffusion impairment (metabolites and oxygen) in the tissue. AGE-AGER interaction mediates NF-kB activation. The signal is transduced from AGER to KRAS which affects PI3K. Generated by PI3K, PIP3 initiates AKT1 activation by PDPK1. AKT1 provokes the release of NF-kB from its inhibitor, NFKBIA and free NF-kB promotes ICAM1, VCAM1, SERPINE1, and EDN1 transcription. Outcome effects: A critical consequence of VCAM1 and ICAM1 expression on the endothelial surface is the attraction of mononuclear phagocytes into the vessel wall that promotes inflammation. EDN1 causes vasoconstriction impairing blood flow in the tissue. Furthermore, the activation of the polyol pathway promotes reactive oxygen species (ROS) generation exposing cells to oxidative stress, AGE precursor formation (methylglyoxal) leading to vessel wall damage. Normally, ischemia (hypoxia) provokes the release of HIF1A from its inhibitor, EGLN2. Free HIF1A with its interacting proteins, EP300 and ARNT trigger the expression of vascularization factors including CXCL12, VEGFA, CXCR4, and NOS3. In the pathology, HIF1A and EP300 are inhibited by methylglyoxal preventing vascularization. Highlighted proteins: Entities with increased level or activity are highlighted in red and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 18230954 PS:PMID 18793542 PS:PMID 21739639 PS:PMID 8799700 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aaf5c28-cd44-4462-8d09-b98240b6e633 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-6aaf5c28-cd44-4462-8d09-b98240b6e633 Proteins Involved in Muscular Dystrophy, Facioscapulohumeral uuid-6aaf5c28-cd44-4462-8d09-b98240b6e633 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aaf5c28-cd44-4462-8d09-b98240b6e633 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ab95669-587f-44a4-9ff4-3c5bcc768a26 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-6ab95669-587f-44a4-9ff4-3c5bcc768a26 Proteins with Altered Expression in Cancer Metabolic Reprogramming (Krebs Cycle) uuid-6ab95669-587f-44a4-9ff4-3c5bcc768a26 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ab95669-587f-44a4-9ff4-3c5bcc768a26 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases and may contribute to development of cancer. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ac7da26-af89-4db1-998b-dc709813fda4 NodeType: Pathway Notes: Headnote: TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases. They regulate a mix of processes, including cell proliferation/survival, cell adhesion and migration, regulation of inflammatory cytokine release and contribute to development of cancer. Signaling description: Signal-induced stimulation of TAM receptors by GAS6 or PROS1 activate PI3K/AKT, RAS-MAPK, PLCG as well as other pathways. TAM receptors also interplay with other oncogenic receptors such as MET, EGFR, ERBB2. Overexpression of GAS6, PROS1, AXL, MERTK is typical for different types of cancers. AXL may be up-regulated by multiple transcription factors: TP53, SP1/3, EZH2, ESR1 and others. Outcome effects: The activation of TAM signaling results in increased proliferation and survival, migration and invasiveness of cancer cells. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18620092 PMID: 20809868 PMID: 21933973 PMID: 22150307 PMID: 27834816 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-6ac7da26-af89-4db1-998b-dc709813fda4 TAM Receptor Signaling Activation in Cancer uuid-6ac7da26-af89-4db1-998b-dc709813fda4 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases and may contribute to development of cancer. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ac7da26-af89-4db1-998b-dc709813fda4 PS:NodeType Pathway PS:Notes Headnote: TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases. They regulate a mix of processes, including cell proliferation/survival, cell adhesion and migration, regulation of inflammatory cytokine release and contribute to development of cancer. Signaling description: Signal-induced stimulation of TAM receptors by GAS6 or PROS1 activate PI3K/AKT, RAS-MAPK, PLCG as well as other pathways. TAM receptors also interplay with other oncogenic receptors such as MET, EGFR, ERBB2. Overexpression of GAS6, PROS1, AXL, MERTK is typical for different types of cancers. AXL may be up-regulated by multiple transcription factors: TP53, SP1/3, EZH2, ESR1 and others. Outcome effects: The activation of TAM signaling results in increased proliferation and survival, migration and invasiveness of cancer cells. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18620092 PS:PMID 20809868 PS:PMID 21933973 PS:PMID 22150307 PS:PMID 27834816 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ad167f5-17eb-45ca-94d3-a2c676ebc597 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-6ad167f5-17eb-45ca-94d3-a2c676ebc597 Myoblast -> Neutrophil Surface Expression Markers uuid-6ad167f5-17eb-45ca-94d3-a2c676ebc597 PS:CellType neutrophil PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ad167f5-17eb-45ca-94d3-a2c676ebc597 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: Cold-induced vasoconstriction in the cutaneous circulation is normally a protective response that acts to reduce heat loss. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ad42f49-5722-4b6e-bb81-49f24fdd9759 NodeType: Pathway Notes: Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Cold-induced vasoconstriction in the cutaneous circulation is normally a protective response that acts to reduce the heat loss. Cold exposure initiates cutaneous vasoconstriction through a reflex increase in sympathetic nerve activity and through a direct action on the blood vessel, which enhances the sympathetic constriction. Norepinephrine is the major sympathetic neurotransmitter, which initiates cutaneous vasoconstriction by activating two distinct families of receptors, namely the alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle (VSM) cells. At the same time, cold exposure amplifies constriction mediated by alpha 2-adrenoceptors, while simultaneously reducing the activity of alpha 1-adrenoceptors. Although alpha 2-adrenoceptors represent a family of three distinct subtypes (a2A, a2B, and a2C), only one subtype, the a2C-adrenoceptor (ADRA2C), appears to be 'thermosensitive'. In contrast to the a2A-adrenoceptors and a2B-adrenoceptors, which are directed to the plasma membrane, ADRA2C is predominantly localized to the ER/Golgi compartments. Cold causes a remarkable functional and spatial rescue of ADRA2C from the trans-Golgi to the cell surface, where they can respond to stimulation. Immediately upon cooling, there is an increased generation of reactive oxygen species (ROS) from VSM mitochondria in cutaneous arteries. This represents the earliest detectable cold-induced response in cutaneous arteries, suggesting that the mitochondria may be the 'thermosensor' responsible for initiating cold-induced vasoconstriction in cutaneous blood vessels. These mitochondrial ROS do not appear to be pathogenic, but instead activate the novel REDOX signaling through the RhoA/Rho kinase (ROCK) pathway. Outcome effects: RHOA is a member of the Ras family of small GTP-binding proteins and has a central role in regulating actin myosin-dependent processes in VSMs including contractility and motility. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ: bone Organ_System: musculoskeletal system PMID: 17644575 PMID: 18329534 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage urn:agi-pathway:uuid-6ad42f49-5722-4b6e-bb81-49f24fdd9759 Cold Stress and Adrenoceptor alpha 2C Signaling in Raynaud Disease uuid-6ad42f49-5722-4b6e-bb81-49f24fdd9759 PS:CellType vascular smooth muscle cell PS:Description Cold-induced vasoconstriction in the cutaneous circulation is normally a protective response that acts to reduce heat loss. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ad42f49-5722-4b6e-bb81-49f24fdd9759 PS:NodeType Pathway PS:Notes Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Cold-induced vasoconstriction in the cutaneous circulation is normally a protective response that acts to reduce the heat loss. Cold exposure initiates cutaneous vasoconstriction through a reflex increase in sympathetic nerve activity and through a direct action on the blood vessel, which enhances the sympathetic constriction. Norepinephrine is the major sympathetic neurotransmitter, which initiates cutaneous vasoconstriction by activating two distinct families of receptors, namely the alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle (VSM) cells. At the same time, cold exposure amplifies constriction mediated by alpha 2-adrenoceptors, while simultaneously reducing the activity of alpha 1-adrenoceptors. Although alpha 2-adrenoceptors represent a family of three distinct subtypes (a2A, a2B, and a2C), only one subtype, the a2C-adrenoceptor (ADRA2C), appears to be 'thermosensitive'. In contrast to the a2A-adrenoceptors and a2B-adrenoceptors, which are directed to the plasma membrane, ADRA2C is predominantly localized to the ER/Golgi compartments. Cold causes a remarkable functional and spatial rescue of ADRA2C from the trans-Golgi to the cell surface, where they can respond to stimulation. Immediately upon cooling, there is an increased generation of reactive oxygen species (ROS) from VSM mitochondria in cutaneous arteries. This represents the earliest detectable cold-induced response in cutaneous arteries, suggesting that the mitochondria may be the 'thermosensor' responsible for initiating cold-induced vasoconstriction in cutaneous blood vessels. These mitochondrial ROS do not appear to be pathogenic, but instead activate the novel REDOX signaling through the RhoA/Rho kinase (ROCK) pathway. Outcome effects: RHOA is a member of the Ras family of small GTP-binding proteins and has a central role in regulating actin myosin-dependent processes in VSMs including contractility and motility. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ bone PS:Organ_System musculoskeletal system PS:PMID 17644575 PS:PMID 18329534 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ade8b09-d2be-44e6-8965-a61bf8ad68d7 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-6ade8b09-d2be-44e6-8965-a61bf8ad68d7 Fatty acid regulation of Circadian rhythm uuid-6ade8b09-d2be-44e6-8965-a61bf8ad68d7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ade8b09-d2be-44e6-8965-a61bf8ad68d7 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: corneocyte Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ae3cb75-93bf-47f8-9e6b-474c6c00b8ad NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together. Corneodesmosomes are formed by members of the cadherin family of extracellular transmembrane glycoproteins including desmoglein (DSG) and desmocollin (DSC). Within the corneocytes, DSG and DSC are linked to keratin filaments through corneodesmosomal plaque proteins including plakoglobin (JUP), desmoplakin (DSP), and plakophilin (PKP). DSG and DSC migrate from the corneocyte envelope into the lipid lamellae sandwiched between the corneocytes and bind to the corneodesmosomal plaque proteins on adjacent cells. Outcome effects: The human kallikrein (KLK)-related peptidases such as SC chymotryptic enzyme (KLK7) and SC tryptic enzyme (KLK5) are key proteases involved in desquamation. Their increased expression can lead to impaired epidermal barrier function in AD. KLK7, with chymotrypsin-like activity, has been shown to hydrolyze corneodesmosin (CDSN) and desmocollin 1 (DSC1); whereas, KLK5 can cleave desmoglein 1 (DSG1) with its trypsin-like activity. Enzymatically active KLK14, also exhibiting trypsin-like activity, is present in the SC where it cleaves DSG1. In addition, SPINK5 is a potent inhibitor of both KLK5 and KLK7, and thus, is critical for epidermal barrier function. As the pH becomes more acidic, the inhibitory potential of SPINK5 is reduced. The inhibition by SPINK5 in the superficial layers of the SC is sufficiently reduced to support localized desquamation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 19494826 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-6ae3cb75-93bf-47f8-9e6b-474c6c00b8ad Corneodesmosomes in Atopic Dermatitis uuid-6ae3cb75-93bf-47f8-9e6b-474c6c00b8ad PS:CellType corneocyte PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ae3cb75-93bf-47f8-9e6b-474c6c00b8ad PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. AD is associated impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together. Corneodesmosomes are formed by members of the cadherin family of extracellular transmembrane glycoproteins including desmoglein (DSG) and desmocollin (DSC). Within the corneocytes, DSG and DSC are linked to keratin filaments through corneodesmosomal plaque proteins including plakoglobin (JUP), desmoplakin (DSP), and plakophilin (PKP). DSG and DSC migrate from the corneocyte envelope into the lipid lamellae sandwiched between the corneocytes and bind to the corneodesmosomal plaque proteins on adjacent cells. Outcome effects: The human kallikrein (KLK)-related peptidases such as SC chymotryptic enzyme (KLK7) and SC tryptic enzyme (KLK5) are key proteases involved in desquamation. Their increased expression can lead to impaired epidermal barrier function in AD. KLK7, with chymotrypsin-like activity, has been shown to hydrolyze corneodesmosin (CDSN) and desmocollin 1 (DSC1); whereas, KLK5 can cleave desmoglein 1 (DSG1) with its trypsin-like activity. Enzymatically active KLK14, also exhibiting trypsin-like activity, is present in the SC where it cleaves DSG1. In addition, SPINK5 is a potent inhibitor of both KLK5 and KLK7, and thus, is critical for epidermal barrier function. As the pH becomes more acidic, the inhibitory potential of SPINK5 is reduced. The inhibition by SPINK5 in the superficial layers of the SC is sufficiently reduced to support localized desquamation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 19494826 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aebd620-eb7d-4f65-a807-8900a1b23b95 NodeType: Pathway Notes: The presence of neurotrophic factors (NTFs) supports cell survival, while NTF deprivation may lead to apoptosis. A range of NTFs, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophins (NTF3 and NTF4), and ciliary neurotrophic factor (CNTF), are implicated in this process. The interruption of axonal transport and NTF deprivation due to elevated intraocular pressure are believed to cause the apoptotic death of retinal ganglion cells (RGCs). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-6aebd620-eb7d-4f65-a807-8900a1b23b95 3_Role of neurotrophic factor deprivation in retinal ganglion cell death uuid-6aebd620-eb7d-4f65-a807-8900a1b23b95 PS:CellType retina cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6aebd620-eb7d-4f65-a807-8900a1b23b95 PS:NodeType Pathway PS:Notes The presence of neurotrophic factors (NTFs) supports cell survival, while NTF deprivation may lead to apoptosis. A range of NTFs, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophins (NTF3 and NTF4), and ciliary neurotrophic factor (CNTF), are implicated in this process. The interruption of axonal transport and NTF deprivation due to elevated intraocular pressure are believed to cause the apoptotic death of retinal ganglion cells (RGCs). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b1e8a22-e0cc-46b6-9e52-6a9547ebe2c9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-6b1e8a22-e0cc-46b6-9e52-6a9547ebe2c9 Mitotic spindle orientation uuid-6b1e8a22-e0cc-46b6-9e52-6a9547ebe2c9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b1e8a22-e0cc-46b6-9e52-6a9547ebe2c9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b31a53d-8e14-4d5b-9e5b-d6ef88f20ae1 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-6b31a53d-8e14-4d5b-9e5b-d6ef88f20ae1 Proteins Involved in Insulin Resistance uuid-6b31a53d-8e14-4d5b-9e5b-d6ef88f20ae1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b31a53d-8e14-4d5b-9e5b-d6ef88f20ae1 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: ameloblast CellType: odontoblast Description: Bloch-Sulzberger syndrome (BSS, Incontinentia pigmenti) is a genetic disorder that affects the skin, teeth, hair nails, and central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b55c4dd-f431-4b8d-8531-f0ebff8595a3 NodeType: Pathway Notes: Bloch-Sulzberger syndrome (BSS, Incontinentia pigmenti) is a genetic disorder that affects the skin, teeth, hair, nails, and central nervous system. BSS is inherited in an X-linked dominant manner, and is caused by mutations in IKBKG (NEMO). Mutated genes: Mutated genes are shown in white-out style. Organ: Tooth Organ: mouth Organ_System: digestive system PMID: 12140463 PMID: 17569396 PMID: 22453515 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: dental enamel Tissue: dentin urn:agi-pathway:uuid-6b55c4dd-f431-4b8d-8531-f0ebff8595a3 Dentin and Enamel Dysruprion in Bloch-Sulzberger Syndrome uuid-6b55c4dd-f431-4b8d-8531-f0ebff8595a3 PS:CellType ameloblast PS:CellType odontoblast PS:Description Bloch-Sulzberger syndrome (BSS, Incontinentia pigmenti) is a genetic disorder that affects the skin, teeth, hair nails, and central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b55c4dd-f431-4b8d-8531-f0ebff8595a3 PS:NodeType Pathway PS:Notes Bloch-Sulzberger syndrome (BSS, Incontinentia pigmenti) is a genetic disorder that affects the skin, teeth, hair, nails, and central nervous system. BSS is inherited in an X-linked dominant manner, and is caused by mutations in IKBKG (NEMO). Mutated genes: Mutated genes are shown in white-out style. PS:Organ Tooth PS:Organ mouth PS:Organ_System digestive system PS:PMID 12140463 PS:PMID 17569396 PS:PMID 22453515 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue dental enamel PS:Tissue dentin PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Several members of double strand DNA non-homologous DNA repair can be mutated in cancer Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b6fb252-f841-4dfc-8537-17b7293980be NodeType: Pathway Notes: Headnote: Several proteins involved in double strand DNA non-homologous repair can be mutated in cancer, including ATM, MRE11A, NBN, TP53BP1, RAD50, H2AFX, PRKDC, XRCC5/6, WRN, POLB, FEN1. Signaling description: Double strand DNA breaks are common in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). NHEJ double strand repair recovers two broken DNA ends without using a homologous template. XRCC6/XRCC5 heterodimer protein associates with free DNA ends and recruits other factors including DNA-dependent protein kinase (PRKDC). During DNA binding, PRKDC becomes activated and phosphorylates multiple proteins including DNA ligase IV (LIG4) cofactor XRCC4. The final step of NHEJ involves the ligation of DNA ends by LIG4. Microhomology-mediated end joining (MMEJ) is XRCC6/XRCC5-independent NHEJ and involves short homologous sequences called microhomologies, which exist in single-stranded overhangs on the ends of double-stranded gaps. MMEJ is based on ligating hung mismatched DNA ends that remove overhanging nucleotides and fill the gaps. MMEJ results in removal of mutations from the genetic code. In most cases, MMEJ is used only when NHEJ is impossible. Outcome effects: Deregulation of double strand DNA non-homologous repair machinery leads to genomic instability in cancer cells. Persistent DNA repair affects cell cycle regulation and may be associated with oncogenesis. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20177397 PMID: 20965415 PMID: 24947262 PMID: 25017190 PMID: 25579208 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-6b6fb252-f841-4dfc-8537-17b7293980be Persistent Double Strand DNA non-Homologous Repair in Cancer uuid-6b6fb252-f841-4dfc-8537-17b7293980be PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Several members of double strand DNA non-homologous DNA repair can be mutated in cancer PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b6fb252-f841-4dfc-8537-17b7293980be PS:NodeType Pathway PS:Notes Headnote: Several proteins involved in double strand DNA non-homologous repair can be mutated in cancer, including ATM, MRE11A, NBN, TP53BP1, RAD50, H2AFX, PRKDC, XRCC5/6, WRN, POLB, FEN1. Signaling description: Double strand DNA breaks are common in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). NHEJ double strand repair recovers two broken DNA ends without using a homologous template. XRCC6/XRCC5 heterodimer protein associates with free DNA ends and recruits other factors including DNA-dependent protein kinase (PRKDC). During DNA binding, PRKDC becomes activated and phosphorylates multiple proteins including DNA ligase IV (LIG4) cofactor XRCC4. The final step of NHEJ involves the ligation of DNA ends by LIG4. Microhomology-mediated end joining (MMEJ) is XRCC6/XRCC5-independent NHEJ and involves short homologous sequences called microhomologies, which exist in single-stranded overhangs on the ends of double-stranded gaps. MMEJ is based on ligating hung mismatched DNA ends that remove overhanging nucleotides and fill the gaps. MMEJ results in removal of mutations from the genetic code. In most cases, MMEJ is used only when NHEJ is impossible. Outcome effects: Deregulation of double strand DNA non-homologous repair machinery leads to genomic instability in cancer cells. Persistent DNA repair affects cell cycle regulation and may be associated with oncogenesis. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20177397 PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PMID 25579208 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b8f6e49-e155-4b06-8298-50d6a40728fb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6b8f6e49-e155-4b06-8298-50d6a40728fb Heme biosynthesis template uuid-6b8f6e49-e155-4b06-8298-50d6a40728fb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b8f6e49-e155-4b06-8298-50d6a40728fb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Trabecular meshwork (TM) and Schlemm's canal is the outflow system for aqueous humor (AH) in the eye. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b94c331-6bbb-4476-bbfb-bc0e8916bf7e NodeType: Pathway Notes: Headnote: Trabecular meshwork (TM) and Schlemm's canal is the outflow system for aqueous humor (AH) in the eye. TM is a network of beams covered with endothelial cells. The outflow resistance is dependent on the TM extracellular matrix state and on the size and volume of endothelial cells. Signaling description: Endothelial cell nitric oxide synthase (NOS3) has been shown to be activated, as a result of intraocular pressure (IOP) increase, and produce nitric oxide (NO). NO activates soluble guanylate cyclase (sGC), formation of cGMP, and activation of protein kinase G (PKG) with the subsequent phosphorylation of target proteins including BK channels and K+:Cl- symporters with subsequent K+ efflux. In addition, water efflux is mediated by AQP1. Outcome effects: As a result, cell volume decreases allowing easy outflow of AH leading to IOP decrease. TM is a contractile tissue itself with properties similar to those of smooth muscle. TM contractility is linked to RHOA, which inhibits myosin light chain phosphatase (MLCP), resulting in the accumulation of phosphorylated myosin light chain, which is then capable of interacting with actin to produce contraction. The contraction of TM cells decreases the permeability of the TM due to the reduced size of the intercellular spaces. Similarly, when TM cells relax, the opposite effect appears and the permeability of the tissue increases. Elevated concentrations of endothelin-1 (EDN1) have been documented in the AH of patients with glaucoma. EDN1 is capable of inducing the contraction of both TM cells and the cellular matrix. The contraction seems to be triggered by the activation of the RHOA/ROCK1 pathway which leads to the increase in outflow resistance and consequently to IOP elevation. Rho kinase (ROCK1) inhibitors are a novel potential class of glaucoma therapeutics, and endothelin receptor antagonists would be ideal to lower IOP. Highlighted proteins: Protein with increased expression or activity is highlighted in red. References: 1) Rocha-Sousa A, et al. (2013) New therapeutic targets for intraocular pressure lowering. ISRN Ophthalmol. Organ: eye Organ_System: sensory system PMID: 14500801 PMID: 18385281 PMID: 20484594 PMID: 21293732 PMID: 22179003 PMID: 24558600 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6b94c331-6bbb-4476-bbfb-bc0e8916bf7e Trabecular Meshwork and Schlemm's Canal Endothelial Cell Volume and Contractility uuid-6b94c331-6bbb-4476-bbfb-bc0e8916bf7e PS:CellType endothelial cell PS:Description Trabecular meshwork (TM) and Schlemm's canal is the outflow system for aqueous humor (AH) in the eye. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6b94c331-6bbb-4476-bbfb-bc0e8916bf7e PS:NodeType Pathway PS:Notes Headnote: Trabecular meshwork (TM) and Schlemm's canal is the outflow system for aqueous humor (AH) in the eye. TM is a network of beams covered with endothelial cells. The outflow resistance is dependent on the TM extracellular matrix state and on the size and volume of endothelial cells. Signaling description: Endothelial cell nitric oxide synthase (NOS3) has been shown to be activated, as a result of intraocular pressure (IOP) increase, and produce nitric oxide (NO). NO activates soluble guanylate cyclase (sGC), formation of cGMP, and activation of protein kinase G (PKG) with the subsequent phosphorylation of target proteins including BK channels and K+:Cl- symporters with subsequent K+ efflux. In addition, water efflux is mediated by AQP1. Outcome effects: As a result, cell volume decreases allowing easy outflow of AH leading to IOP decrease. TM is a contractile tissue itself with properties similar to those of smooth muscle. TM contractility is linked to RHOA, which inhibits myosin light chain phosphatase (MLCP), resulting in the accumulation of phosphorylated myosin light chain, which is then capable of interacting with actin to produce contraction. The contraction of TM cells decreases the permeability of the TM due to the reduced size of the intercellular spaces. Similarly, when TM cells relax, the opposite effect appears and the permeability of the tissue increases. Elevated concentrations of endothelin-1 (EDN1) have been documented in the AH of patients with glaucoma. EDN1 is capable of inducing the contraction of both TM cells and the cellular matrix. The contraction seems to be triggered by the activation of the RHOA/ROCK1 pathway which leads to the increase in outflow resistance and consequently to IOP elevation. Rho kinase (ROCK1) inhibitors are a novel potential class of glaucoma therapeutics, and endothelin receptor antagonists would be ideal to lower IOP. Highlighted proteins: Protein with increased expression or activity is highlighted in red. References: 1) Rocha-Sousa A, et al. (2013) New therapeutic targets for intraocular pressure lowering. ISRN Ophthalmol. PS:Organ eye PS:Organ_System sensory system PS:PMID 14500801 PS:PMID 18385281 PS:PMID 20484594 PS:PMID 21293732 PS:PMID 22179003 PS:PMID 24558600 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Epigenetic changes including histone methylation to play important roles in the onset and progression of cancer in numerous tumor types. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ba03de8-b5c2-4eae-95fc-9bd887d68d38 NodeType: Pathway Notes: Headnote: Epigenetic changes including histone methylation are now thought to participate in the onset and progression of cancer in numerous tumor types. Methylation of specific residues in the core histones H3 and H4 have been identified as a marker of tumor cells. Signaling description: Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. According to modern data, histone methylation can either repress or activate transcription. In general, methylation at H3K4, H3K36, and H3K79 is associated with transcriptional activation, whereas H3K9, H3K27, and H3K20 methylation is associated with transcriptional repression. Monomethylations at H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations at H3K27, H3K9, and H3K79 are linked to repression. A number of HMTs can be mutated in cancer, including KMT2A/C/D, NSD1, WHSC1, WHSC1L1, EZH2, PRDM1/2/12/16, MECOM. DOT1L may be activated by fusion proteins MLL-AF10, MLL-AF4, MLL-ELL. Outcome effects: Deregulation of HMT leads to the impairment of chromatin remodeling and makes impact to oncogenic progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Implicated in Histone Methylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations Implicated in Histone Methylation" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17613546 PMID: 19509247 PMID: 21074720 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-6ba03de8-b5c2-4eae-95fc-9bd887d68d38 Methylases in Histone Methylation Cancer uuid-6ba03de8-b5c2-4eae-95fc-9bd887d68d38 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Epigenetic changes including histone methylation to play important roles in the onset and progression of cancer in numerous tumor types. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ba03de8-b5c2-4eae-95fc-9bd887d68d38 PS:NodeType Pathway PS:Notes Headnote: Epigenetic changes including histone methylation are now thought to participate in the onset and progression of cancer in numerous tumor types. Methylation of specific residues in the core histones H3 and H4 have been identified as a marker of tumor cells. Signaling description: Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. According to modern data, histone methylation can either repress or activate transcription. In general, methylation at H3K4, H3K36, and H3K79 is associated with transcriptional activation, whereas H3K9, H3K27, and H3K20 methylation is associated with transcriptional repression. Monomethylations at H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations at H3K27, H3K9, and H3K79 are linked to repression. A number of HMTs can be mutated in cancer, including KMT2A/C/D, NSD1, WHSC1, WHSC1L1, EZH2, PRDM1/2/12/16, MECOM. DOT1L may be activated by fusion proteins MLL-AF10, MLL-AF4, MLL-ELL. Outcome effects: Deregulation of HMT leads to the impairment of chromatin remodeling and makes impact to oncogenic progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Implicated in Histone Methylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations Implicated in Histone Methylation" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17613546 PS:PMID 19509247 PS:PMID 21074720 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Recent studies suggest the role of Hedgehog pathway in mantle cell lymphoma (MCL). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bc6f910-4358-4de2-9fd2-f062acc3c710 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: Recent studies suggest the role of Hedgehog pathway in MCL. The binding of hedgehog protein (SHH) to Patched receptor prevents smoothened (SMO) receptor inhibition by Patched and SMO activation. Outcome effects: Target transcripts of SHH (GLI1 and GLI2) are overexpressed in MCL resulting in the activation of proliferation and block of apoptosis. SHH-GLI pathway is a potential therapeutic target in MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: lymph node Organ_System: lymphatic system PMID: 20940415 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6bc6f910-4358-4de2-9fd2-f062acc3c710 Hedgehog Signaling in Mantle Cell Lymphoma uuid-6bc6f910-4358-4de2-9fd2-f062acc3c710 PS:CellType B-cell PS:CellType cancer cell PS:Description Recent studies suggest the role of Hedgehog pathway in mantle cell lymphoma (MCL). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bc6f910-4358-4de2-9fd2-f062acc3c710 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: Recent studies suggest the role of Hedgehog pathway in MCL. The binding of hedgehog protein (SHH) to Patched receptor prevents smoothened (SMO) receptor inhibition by Patched and SMO activation. Outcome effects: Target transcripts of SHH (GLI1 and GLI2) are overexpressed in MCL resulting in the activation of proliferation and block of apoptosis. SHH-GLI pathway is a potential therapeutic target in MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 20940415 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bc92d77-b1ea-4f08-b4a2-3ef20d33cdd9 NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G1/S transition determines the whether the cell should divide or not. Many cells stop at this stage and reenter the resting state G0. The restriction point (R) is defined as a point of no return in G1, following which the cell is committed to enter the cell cycle (S phase). G1 ends when DNA synthesis begins and S phase starts with DNA synthesis. Signaling description: The CycE/CDK2 complex accumulates during late G1-phase and triggers the passage into S-phase. When CycE is abundant it interacts with the CDK2 and phosphorylates RB1. When dephosphorylated in G0, RB1 blocks the transcription via E2F transcription factors; however, when CycD - CDK4/6 and CycE - CDK2 complexes phosphorylate RB1, it dissociates from E2F, allowing E2F to activate the transcription of genes required for S-phase. One of the genes activated by E2F is CycE itself. CycE (and CycA) inactivates the cyclin-dependent kinase inhibitor 1B (CDKN1B) forming inactive trimmers with CDK2. At this stage, the cell is past the restriction point. Outcome effects: The decision by the cell to progress into S-phase is the result, in part of the balance between CycE production and its proteolytic degradation in the proteosome. Cyclin-dependent kinase inhibitor proteins (CKI, CDKN) are regulated both by internal and external signals. ATAD2, HELLS, RAD54B, RAD54L are consistently highly expressed in G1/S. They stimulate G1 to S phase transitions. HELLS and ATAD2 both co-activate E2F transcription factors and recruit DNA repair and chromatin-modifying proteins and DNA double strand break repair proteins. In Myc- dependent cancers ATAD2 stimulate cell cycle progression. FOXM1 promotes G1/S transition by releasing the inhibition of CDKN1B and by the transcriptional regulation of the CDC25A. BMyb also plays an important role during the late G1 and early S phases of the cell cycle. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-6bc92d77-b1ea-4f08-b4a2-3ef20d33cdd9 G1/S Damage Checkpoint uuid-6bc92d77-b1ea-4f08-b4a2-3ef20d33cdd9 PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bc92d77-b1ea-4f08-b4a2-3ef20d33cdd9 PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G1/S transition determines the whether the cell should divide or not. Many cells stop at this stage and reenter the resting state G0. The restriction point (R) is defined as a point of no return in G1, following which the cell is committed to enter the cell cycle (S phase). G1 ends when DNA synthesis begins and S phase starts with DNA synthesis. Signaling description: The CycE/CDK2 complex accumulates during late G1-phase and triggers the passage into S-phase. When CycE is abundant it interacts with the CDK2 and phosphorylates RB1. When dephosphorylated in G0, RB1 blocks the transcription via E2F transcription factors; however, when CycD - CDK4/6 and CycE - CDK2 complexes phosphorylate RB1, it dissociates from E2F, allowing E2F to activate the transcription of genes required for S-phase. One of the genes activated by E2F is CycE itself. CycE (and CycA) inactivates the cyclin-dependent kinase inhibitor 1B (CDKN1B) forming inactive trimmers with CDK2. At this stage, the cell is past the restriction point. Outcome effects: The decision by the cell to progress into S-phase is the result, in part of the balance between CycE production and its proteolytic degradation in the proteosome. Cyclin-dependent kinase inhibitor proteins (CKI, CDKN) are regulated both by internal and external signals. ATAD2, HELLS, RAD54B, RAD54L are consistently highly expressed in G1/S. They stimulate G1 to S phase transitions. HELLS and ATAD2 both co-activate E2F transcription factors and recruit DNA repair and chromatin-modifying proteins and DNA double strand break repair proteins. In Myc- dependent cancers ATAD2 stimulate cell cycle progression. FOXM1 promotes G1/S transition by releasing the inhibition of CDKN1B and by the transcriptional regulation of the CDC25A. BMyb also plays an important role during the late G1 and early S phases of the cell cycle. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Dopamine is produced by tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus of the hypothalamus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bdf033a-ff25-488b-a9a9-fbc379c3d52e NodeType: Pathway Notes: Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: Dopamine is produced by tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus of the hypothalamus. It has been shown that prolactin (PRL) stimulates activity and transcription of tyrosine hydroxylase (TH), which would increase the stores of dopamine available for release. Outcome effects: Dopanine is a well-known inhibitor of PRL production and release. Thereby, the high level of PRL promotes a negative feedback mechanism. Organ: brain Organ_System: nervous system PMID: 15388649 PMID: 22674282 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-6bdf033a-ff25-488b-a9a9-fbc379c3d52e Prolactin Induced Dopamin Synthesis by TIDA Neurons (Negative Feedback) uuid-6bdf033a-ff25-488b-a9a9-fbc379c3d52e PS:CellType neuron PS:Description Dopamine is produced by tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus of the hypothalamus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6bdf033a-ff25-488b-a9a9-fbc379c3d52e PS:NodeType Pathway PS:Notes Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: Dopamine is produced by tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus of the hypothalamus. It has been shown that prolactin (PRL) stimulates activity and transcription of tyrosine hydroxylase (TH), which would increase the stores of dopamine available for release. Outcome effects: Dopanine is a well-known inhibitor of PRL production and release. Thereby, the high level of PRL promotes a negative feedback mechanism. PS:Organ brain PS:Organ_System nervous system PS:PMID 15388649 PS:PMID 22674282 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c02ef0e-58c7-484f-b742-d1af27873076 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6c02ef0e-58c7-484f-b742-d1af27873076 Mevalonate degradation template uuid-6c02ef0e-58c7-484f-b742-d1af27873076 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c02ef0e-58c7-484f-b742-d1af27873076 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c2a9247-20c6-4141-a72b-44e1b97b505a NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-6c2a9247-20c6-4141-a72b-44e1b97b505a GALR1/2/3 -> Neurotransmitter Metabolism uuid-6c2a9247-20c6-4141-a72b-44e1b97b505a PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c2a9247-20c6-4141-a72b-44e1b97b505a PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c2b1b87-d1f7-458b-a8bb-c429ce20cba8 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-6c2b1b87-d1f7-458b-a8bb-c429ce20cba8 Amino Sugars Synthesis uuid-6c2b1b87-d1f7-458b-a8bb-c429ce20cba8 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c2b1b87-d1f7-458b-a8bb-c429ce20cba8 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Circadian rhythm is generated in the suprachiasmatic nucleus (SCN) in the hypothalamus, as well as in individual cells called peripheral oscillators. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c45d065-05db-4b6b-b58c-07aa6b3c7e32 NodeType: Pathway Notes: Headnote: Circadian rhythm is generated in the suprachiasmatic nucleus (SCN) in the hypothalamus, as well as in individual cells called peripheral oscillators. The SCN is known as the master clock and organizes the cycle of peripheral oscillators throughout the body. However, both the SCN and the peripheral oscillators are capable of affecting each other. Signaling description: The transcription factors that turn on the light-induced promoters are dimers of CLOCK-ARNTL or NPAS2-ARNTL. They activate the negative regulators of the circadian cycle such as period circadian proteins (PER1/2/3), cryptochrome (CRY1/2) genes, positive regulators such as retinoic acid-related orphan receptor A (RORA) gene, and hundreds of effector genes whose products control a wide variety of metabolic functions including cellular respiration, glycolysis, gluconeogenesis, and lipid metabolism. PER and CRY mRNAs are exported to the cytoplasm where they are translated. The PER and CRY proteins then enter the nucleus where they inhibit CLOCK-ARNTL or NPAS2-ARNTL thus turning off transcription of PER and CRY. The PER-CRY complex is then progressively removed by CSNK1D/CSNK1E-mediated phosphorylation and ubiquitin-proteasome-mediated degradation. Outcome effects: These described events allow CLOCK and ARNTL to once again stimulate transcription of PER and CRY. However, the negative feedback loop causes the level of ARNTL and PER/CRY to oscillate in opposite phases. A second autoregulatory feedback loop is induced by the transcription of NR1D1 and NR1D2. The NR1D1-NR1D2 complex represses ARNTL transcription. This pathway stabilizes CLOCK and can also directly drive circadian rhythms. Circadian rhythms are controlled by external cues, with light being the major contributor. Light is processed in the retina and via the retinohypothalamic tract leads to the synchronization of rhythms in hypothalamic SCN, which constitutes the master clock of the organism. SCN then projects to the subparaventricular zone and subsequently to the rest of the hypothalamus including ventrolateral preoptic nucleus (VLPO), the lateral hypothalamus, and the paraventricular nucleus to control hormone, temperature, feeding, and sleep-arousal cycles. VLPO also connects to tuberomammillary nucleus (TMN), which is important for sleep-wake rhythms. The exact connection between the sleep hormone, melatonin and circadian rhythm has yet to be determined, but there are two putative pathways. The first pathway is the repression of adenylate cyclase (ADCY) and protein kinase A (PKA), which influences CREB1 activation. The second pathway is the direct activation of nuclear receptors, RORA and RORB by melatonin. Organ: brain Organ_System: nervous system PMID: 17245414 PMID: 20664079 PMID: 22022309 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-6c45d065-05db-4b6b-b58c-07aa6b3c7e32 Circadian Clock and Sleep Regulation by Melatonin uuid-6c45d065-05db-4b6b-b58c-07aa6b3c7e32 PS:CellType neuron PS:Description Circadian rhythm is generated in the suprachiasmatic nucleus (SCN) in the hypothalamus, as well as in individual cells called peripheral oscillators. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c45d065-05db-4b6b-b58c-07aa6b3c7e32 PS:NodeType Pathway PS:Notes Headnote: Circadian rhythm is generated in the suprachiasmatic nucleus (SCN) in the hypothalamus, as well as in individual cells called peripheral oscillators. The SCN is known as the master clock and organizes the cycle of peripheral oscillators throughout the body. However, both the SCN and the peripheral oscillators are capable of affecting each other. Signaling description: The transcription factors that turn on the light-induced promoters are dimers of CLOCK-ARNTL or NPAS2-ARNTL. They activate the negative regulators of the circadian cycle such as period circadian proteins (PER1/2/3), cryptochrome (CRY1/2) genes, positive regulators such as retinoic acid-related orphan receptor A (RORA) gene, and hundreds of effector genes whose products control a wide variety of metabolic functions including cellular respiration, glycolysis, gluconeogenesis, and lipid metabolism. PER and CRY mRNAs are exported to the cytoplasm where they are translated. The PER and CRY proteins then enter the nucleus where they inhibit CLOCK-ARNTL or NPAS2-ARNTL thus turning off transcription of PER and CRY. The PER-CRY complex is then progressively removed by CSNK1D/CSNK1E-mediated phosphorylation and ubiquitin-proteasome-mediated degradation. Outcome effects: These described events allow CLOCK and ARNTL to once again stimulate transcription of PER and CRY. However, the negative feedback loop causes the level of ARNTL and PER/CRY to oscillate in opposite phases. A second autoregulatory feedback loop is induced by the transcription of NR1D1 and NR1D2. The NR1D1-NR1D2 complex represses ARNTL transcription. This pathway stabilizes CLOCK and can also directly drive circadian rhythms. Circadian rhythms are controlled by external cues, with light being the major contributor. Light is processed in the retina and via the retinohypothalamic tract leads to the synchronization of rhythms in hypothalamic SCN, which constitutes the master clock of the organism. SCN then projects to the subparaventricular zone and subsequently to the rest of the hypothalamus including ventrolateral preoptic nucleus (VLPO), the lateral hypothalamus, and the paraventricular nucleus to control hormone, temperature, feeding, and sleep-arousal cycles. VLPO also connects to tuberomammillary nucleus (TMN), which is important for sleep-wake rhythms. The exact connection between the sleep hormone, melatonin and circadian rhythm has yet to be determined, but there are two putative pathways. The first pathway is the repression of adenylate cyclase (ADCY) and protein kinase A (PKA), which influences CREB1 activation. The second pathway is the direct activation of nuclear receptors, RORA and RORB by melatonin. PS:Organ brain PS:Organ_System nervous system PS:PMID 17245414 PS:PMID 20664079 PS:PMID 22022309 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: The phagocytosis and degradation of pathogens is one of the main functions of neutrophils. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c98e9e2-39cc-44fa-9402-08de08c23201 NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. The phagocytosis and degradation of pathogens is one of the main functions of neutrophils. Signaling description: During phagocytosis, neutrophils engulf and take up microbes into specialized compartments known as phagosomes in a receptor-mediated, clathrin-independent process. Neutrophils absorb pathogens tagged with opsonins, which are molecules that attach to the cell surface and facilitate phagocytosis. Opsonin receptors initiate phagocytosis in neutrophils that are presented by FCGR3B, FCGR2A, and CR3. FCGR-mediated phagocytosis is associated with pseudopod extension. CR3-mediated phagocytosis occurs without pseudopod formation, but requires microtubules. Outcome effects: VAV1-related signaling is active in pseudopod formation and inactive in complement signaling. Complement-dependent phagocytosis in neutrophils is determined by the activation of RASGRF1 signaling. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-6c98e9e2-39cc-44fa-9402-08de08c23201 CR3 Mediated Phagocytosis in Neutrophils and Macrophages uuid-6c98e9e2-39cc-44fa-9402-08de08c23201 PS:CellType macrophage PS:Description The phagocytosis and degradation of pathogens is one of the main functions of neutrophils. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6c98e9e2-39cc-44fa-9402-08de08c23201 PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. The phagocytosis and degradation of pathogens is one of the main functions of neutrophils. Signaling description: During phagocytosis, neutrophils engulf and take up microbes into specialized compartments known as phagosomes in a receptor-mediated, clathrin-independent process. Neutrophils absorb pathogens tagged with opsonins, which are molecules that attach to the cell surface and facilitate phagocytosis. Opsonin receptors initiate phagocytosis in neutrophils that are presented by FCGR3B, FCGR2A, and CR3. FCGR-mediated phagocytosis is associated with pseudopod extension. CR3-mediated phagocytosis occurs without pseudopod formation, but requires microtubules. Outcome effects: VAV1-related signaling is active in pseudopod formation and inactive in complement signaling. Complement-dependent phagocytosis in neutrophils is determined by the activation of RASGRF1 signaling. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: natural killer cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cb44a76-8941-4ecc-ada5-6dae4cde8ef4 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-6cb44a76-8941-4ecc-ada5-6dae4cde8ef4 Natural Killer Cell Precursor -> Natural Killer Cell Surface Expression Markers uuid-6cb44a76-8941-4ecc-ada5-6dae4cde8ef4 PS:CellType natural killer cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cb44a76-8941-4ecc-ada5-6dae4cde8ef4 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cbdc3a9-9e6b-4882-9bd6-853cf7e4ebe1 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-6cbdc3a9-9e6b-4882-9bd6-853cf7e4ebe1 IL23R -> STAT3/NF-kB Signaling uuid-6cbdc3a9-9e6b-4882-9bd6-853cf7e4ebe1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cbdc3a9-9e6b-4882-9bd6-853cf7e4ebe1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cd1ae57-7e0e-46cd-b66e-206a16a0a177 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6cd1ae57-7e0e-46cd-b66e-206a16a0a177 F2 -> STAT1/NF-kB Expression Targets uuid-6cd1ae57-7e0e-46cd-b66e-206a16a0a177 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cd1ae57-7e0e-46cd-b66e-206a16a0a177 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell CellType: stem cell Description: Hematopoietic stem cells (HSCs) are progenitor cells which differentiate to all blood cell types in hematopoiesis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cdb8148-853d-413b-877c-6977a21b5735 NodeType: Pathway Notes: Headnote: Hematopoietic stem cells (HSCs) are progenitor cells that differentiate into all other blood cell types via the process of hematopoiesis. Signaling description: Classically, HSCs are thought to differentiate into two distinct leneages, i.e. lymphoid and myelo-erythroid cells. Hematopoetic lineage cell can be identified by the expression of specific cell surface lineage markers. In mice common lymphoid progenitor cells are the earliest lymphoid progenitor cells, and give rise to T-lineage cells, B-lineage cells, natural killer (NK) cells. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-6cdb8148-853d-413b-877c-6977a21b5735 Hematopoietic Cell Lineage: B-cell (mouse) uuid-6cdb8148-853d-413b-877c-6977a21b5735 PS:CellType B-cell PS:CellType stem cell PS:Description Hematopoietic stem cells (HSCs) are progenitor cells which differentiate to all blood cell types in hematopoiesis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cdb8148-853d-413b-877c-6977a21b5735 PS:NodeType Pathway PS:Notes Headnote: Hematopoietic stem cells (HSCs) are progenitor cells that differentiate into all other blood cell types via the process of hematopoiesis. Signaling description: Classically, HSCs are thought to differentiate into two distinct leneages, i.e. lymphoid and myelo-erythroid cells. Hematopoetic lineage cell can be identified by the expression of specific cell surface lineage markers. In mice common lymphoid progenitor cells are the earliest lymphoid progenitor cells, and give rise to T-lineage cells, B-lineage cells, natural killer (NK) cells. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: lactotroph Description: Prolactinoma is a benign tumor of the pituitary that produces prolactin (PRL), it is the most common type of pituitary tumor (about 40? of all pituitary tumors). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cdde45f-751a-4173-8e3c-5382da392a1c NodeType: Pathway Notes: Headnote: Prolactinoma is a benign tumor of the pituitary that produces prolactin (PRL), it is the most common type of pituitary tumor (about 40% of all pituitary tumors). Prolactinomas are more common in women, with a peak incidence during the childbearing years, but they can also appear in men. Rarely prolactinomas may be malign and metastatic. Prolactinoma symptoms include galactorrhea and amenorrhea in women, gynecomastia, decreased libido an erectile dysfunction in men. In both sexes it may lead to infertility. Signaling description: A number of genes may be mutated in prolacinoma, including GNAS1, HRAS, PIK3CA, AIP, MEN1. Gain-of-function GNAS1 mutation leads to constitutive activation of the cAMP pathway and PRL hyperproduction. Menin (MEN1) is a tumor suppressor protein that regulates transcription of cyclin kinase inhibitors. Loss-of-function mutations in MEN1 leads to development multiple endocrine neoplasia syndrome type I, including prolactinoma. Aryl hydrocarbon interacting protein (AIP) associates with the cytoplasmic aryl hydrocarbon receptor (AHR), which is a transcription factor that interacts with proteins which regulate cell cycle such as retinoblastoma protein (RB1). AIP also regulates the localization and activity of phosphodiesterase 4A (PDE4A), an enzyme responsible for the hydrolysis of intracellular cAMP. Loss-of-function AIP mutation leads to decreased PDE4A5 activity resulting in persistent cAMP signaling. A number of factors may be overexpressed in prolactinoma including PTTG1 and HMGA2. Overexpression of PTTG1 leads to high expression of FGF2 and VEGF with subsequent lactotroph hyperplasia and increased angiogenesis. Overexpression of the HMGA2 may be responsible for POU1F1 upregulation. HMGA2 also interacts with RB1 and facilitates the expression of E2F1 target genes through histone modifications and acetylation of E2F1 itself, thereby promoting the G1/S cell phase transition. Recently, HRAS and PIK3CA mutations have been reported in invasive prolactinomas. Outcome effects: The large majority of patients with prolactinomas can be successfully treated with dopamine D2 receptor (DRD2) agonists as first-line treatment, with normalization of prolactin secretion and gonadal function. However, about 20% of prolactinomas may exhibit either dopamine agonist resistance or high recurrence rates after surgery. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 17287403 PMID: 19401448 PMID: 21214334 PMID: 22635680 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6cdde45f-751a-4173-8e3c-5382da392a1c Prolactinoma Overiew uuid-6cdde45f-751a-4173-8e3c-5382da392a1c PS:CellType lactotroph PS:Description Prolactinoma is a benign tumor of the pituitary that produces prolactin (PRL), it is the most common type of pituitary tumor (about 40? of all pituitary tumors). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6cdde45f-751a-4173-8e3c-5382da392a1c PS:NodeType Pathway PS:Notes Headnote: Prolactinoma is a benign tumor of the pituitary that produces prolactin (PRL), it is the most common type of pituitary tumor (about 40% of all pituitary tumors). Prolactinomas are more common in women, with a peak incidence during the childbearing years, but they can also appear in men. Rarely prolactinomas may be malign and metastatic. Prolactinoma symptoms include galactorrhea and amenorrhea in women, gynecomastia, decreased libido an erectile dysfunction in men. In both sexes it may lead to infertility. Signaling description: A number of genes may be mutated in prolacinoma, including GNAS1, HRAS, PIK3CA, AIP, MEN1. Gain-of-function GNAS1 mutation leads to constitutive activation of the cAMP pathway and PRL hyperproduction. Menin (MEN1) is a tumor suppressor protein that regulates transcription of cyclin kinase inhibitors. Loss-of-function mutations in MEN1 leads to development multiple endocrine neoplasia syndrome type I, including prolactinoma. Aryl hydrocarbon interacting protein (AIP) associates with the cytoplasmic aryl hydrocarbon receptor (AHR), which is a transcription factor that interacts with proteins which regulate cell cycle such as retinoblastoma protein (RB1). AIP also regulates the localization and activity of phosphodiesterase 4A (PDE4A), an enzyme responsible for the hydrolysis of intracellular cAMP. Loss-of-function AIP mutation leads to decreased PDE4A5 activity resulting in persistent cAMP signaling. A number of factors may be overexpressed in prolactinoma including PTTG1 and HMGA2. Overexpression of PTTG1 leads to high expression of FGF2 and VEGF with subsequent lactotroph hyperplasia and increased angiogenesis. Overexpression of the HMGA2 may be responsible for POU1F1 upregulation. HMGA2 also interacts with RB1 and facilitates the expression of E2F1 target genes through histone modifications and acetylation of E2F1 itself, thereby promoting the G1/S cell phase transition. Recently, HRAS and PIK3CA mutations have been reported in invasive prolactinomas. Outcome effects: The large majority of patients with prolactinomas can be successfully treated with dopamine D2 receptor (DRD2) agonists as first-line treatment, with normalization of prolactin secretion and gonadal function. However, about 20% of prolactinomas may exhibit either dopamine agonist resistance or high recurrence rates after surgery. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 17287403 PS:PMID 19401448 PS:PMID 21214334 PS:PMID 22635680 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: Impaired osteoblast function occurs in postmenopausal osteoporosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d03f957-c181-49f4-9867-3f1dfd1d80b5 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Following the menopause, risk of bone loss is increased due to lower levels of estrogen. Postmenopausal osteoporosis is characterized by impaired osteoblast function. Signaling description: Normally, estrogen acts via the estrogen receptor ESR1 to promote bone mineral density. Estrogen binding to ESR1 activates intracellular signaling through IGF1R stabilization in the cell membrane and CTNNB1 translocation to the nucleus. The first route involves IGF1 signaling and the second affects the WNT pathway. Outcome effects: IGF1R signaling includes downstream activation of two axes: AKT1 pathway and MAPK pathway providing cell proliferation and cell survival. Further, canonical WNT pathway is responsible for osteoblast differentiation involving RUNX2 transcription factor. Estrogen deficiency and/or polymorphisms in the ESR1 lead to impaired osteoblast functioning and bone biomineralization. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Bikle DD, Wang Y (2011) Insulin-like growth factor-I and bone. IBMS BoneKEy.8:328-41. Organ: bone Organ_System: skeletal system PMID: 16322775 PMID: 19171108 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6d03f957-c181-49f4-9867-3f1dfd1d80b5 Osteoblast Function Decline in Osteoporosis uuid-6d03f957-c181-49f4-9867-3f1dfd1d80b5 PS:CellType osteoblast PS:Description Impaired osteoblast function occurs in postmenopausal osteoporosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d03f957-c181-49f4-9867-3f1dfd1d80b5 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Following the menopause, risk of bone loss is increased due to lower levels of estrogen. Postmenopausal osteoporosis is characterized by impaired osteoblast function. Signaling description: Normally, estrogen acts via the estrogen receptor ESR1 to promote bone mineral density. Estrogen binding to ESR1 activates intracellular signaling through IGF1R stabilization in the cell membrane and CTNNB1 translocation to the nucleus. The first route involves IGF1 signaling and the second affects the WNT pathway. Outcome effects: IGF1R signaling includes downstream activation of two axes: AKT1 pathway and MAPK pathway providing cell proliferation and cell survival. Further, canonical WNT pathway is responsible for osteoblast differentiation involving RUNX2 transcription factor. Estrogen deficiency and/or polymorphisms in the ESR1 lead to impaired osteoblast functioning and bone biomineralization. Highlighted proteins: Entities with reduced level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Bikle DD, Wang Y (2011) Insulin-like growth factor-I and bone. IBMS BoneKEy.8:328-41. PS:Organ bone PS:Organ_System skeletal system PS:PMID 16322775 PS:PMID 19171108 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d10769d-add0-429d-b1ca-5ff39b77f4b2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-6d10769d-add0-429d-b1ca-5ff39b77f4b2 Vg9Vd2 cells-|SARS uuid-6d10769d-add0-429d-b1ca-5ff39b77f4b2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d10769d-add0-429d-b1ca-5ff39b77f4b2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Primary Hypoparathyroidism (PH) is a heterogeneous group of conditions characterized by deficient or absent of PTH secretion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d45b5cd-d10a-4a23-bbfe-308cee4259e9 NodeType: Pathway Notes: Headnote: Primary Hypoparathyroidism (PH) refers to a heterogeneous group of conditions characterized by deficient or absent of parathyroid hormone (PTH) secretion. Loss-of-function mutations in GCM2, GATA3 and heterozygous activating mutations in CASR result in different forms of PH. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: Parathyroid gland Organ_System: endocrine system PMID: 11994364 PMID: 18712808 PMID: 20032048 PMID: 20729338 PMID: 25917456 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-6d45b5cd-d10a-4a23-bbfe-308cee4259e9 Hypoparathyroidism, Primary uuid-6d45b5cd-d10a-4a23-bbfe-308cee4259e9 PS:CellType parathyroid cell PS:Description Primary Hypoparathyroidism (PH) is a heterogeneous group of conditions characterized by deficient or absent of PTH secretion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d45b5cd-d10a-4a23-bbfe-308cee4259e9 PS:NodeType Pathway PS:Notes Headnote: Primary Hypoparathyroidism (PH) refers to a heterogeneous group of conditions characterized by deficient or absent of parathyroid hormone (PTH) secretion. Loss-of-function mutations in GCM2, GATA3 and heterozygous activating mutations in CASR result in different forms of PH. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 11994364 PS:PMID 18712808 PS:PMID 20032048 PS:PMID 20729338 PS:PMID 25917456 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d5fa80d-0921-467d-88db-2459857cff5e NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-6d5fa80d-0921-467d-88db-2459857cff5e Proteins Involved in Epilepsy uuid-6d5fa80d-0921-467d-88db-2459857cff5e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d5fa80d-0921-467d-88db-2459857cff5e PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d8cddc1-b484-4cb0-bf6b-86da5e81c7ff NodeType: Pathway Notes: Fat breakdown (lipolysis/fatty acid oxidation) is stimulated by a high carbohydrate diet, whereas it is inhibited by polyunsaturated fatty acids. Hormones may inhibit (growth hormone, leptin) or stimulate (insulin) lipogenesis. Organ: generic Organ_System: generic PMID: 11306547 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: adipose tissue urn:agi-pathway:uuid-6d8cddc1-b484-4cb0-bf6b-86da5e81c7ff Lipogenesis Regulation in Adipocyte uuid-6d8cddc1-b484-4cb0-bf6b-86da5e81c7ff PS:CellType adipocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d8cddc1-b484-4cb0-bf6b-86da5e81c7ff PS:NodeType Pathway PS:Notes Fat breakdown (lipolysis/fatty acid oxidation) is stimulated by a high carbohydrate diet, whereas it is inhibited by polyunsaturated fatty acids. Hormones may inhibit (growth hormone, leptin) or stimulate (insulin) lipogenesis. PS:Organ generic PS:Organ_System generic PS:PMID 11306547 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue adipose tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d9dc49f-19d0-45ce-8561-7a87555be04a NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. Under physiological conditions, a major source of synaptic adenosine is the vesicular release of ATP from astrocytes and neurons followed by its extracellular degradation to adenosine. Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. The transient downregulation of ADK and elevated levels of adenosine following acute brain injury protects the brain from seizures. Outcome effects: Adenosine inhibits synaptic transmission via ADORA1 and induces neuroinflammation via ADORA2A. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 17056128 PMID: 18249058 PMID: 22700220 PMID: 23385089 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-6d9dc49f-19d0-45ce-8561-7a87555be04a ADK Expression Downregulation after Acute Seizures uuid-6d9dc49f-19d0-45ce-8561-7a87555be04a PS:CellType astrocyte PS:CellType neuron PS:Description ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6d9dc49f-19d0-45ce-8561-7a87555be04a PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. Under physiological conditions, a major source of synaptic adenosine is the vesicular release of ATP from astrocytes and neurons followed by its extracellular degradation to adenosine. Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. The transient downregulation of ADK and elevated levels of adenosine following acute brain injury protects the brain from seizures. Outcome effects: Adenosine inhibits synaptic transmission via ADORA1 and induces neuroinflammation via ADORA2A. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 17056128 PS:PMID 18249058 PS:PMID 22700220 PS:PMID 23385089 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6da47c0a-005b-4bd3-83a7-8440fd98bc51 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6da47c0a-005b-4bd3-83a7-8440fd98bc51 PDGF -> FOXO3A Expression Targets uuid-6da47c0a-005b-4bd3-83a7-8440fd98bc51 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6da47c0a-005b-4bd3-83a7-8440fd98bc51 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dae32f9-8ea4-46cd-907e-8563feb7cd41 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-6dae32f9-8ea4-46cd-907e-8563feb7cd41 AMPK activates autophagy uuid-6dae32f9-8ea4-46cd-907e-8563feb7cd41 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dae32f9-8ea4-46cd-907e-8563feb7cd41 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dc07ef1-f4dc-415e-ad25-cc6335278b5d NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-6dc07ef1-f4dc-415e-ad25-cc6335278b5d H3 Tyrosine and Threonine Modification Sites uuid-6dc07ef1-f4dc-415e-ad25-cc6335278b5d PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dc07ef1-f4dc-415e-ad25-cc6335278b5d PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd2b5a3-e95d-4294-8793-1c3e8d743103 NodeType: Pathway Organ: joint Organ: kidney Organ_System: skeletal system Organ_System: urinary tract PathwayType: network Source: Diseases urn:agi-pathway:uuid-6dd2b5a3-e95d-4294-8793-1c3e8d743103 Proteins with Altered Expression in Gout uuid-6dd2b5a3-e95d-4294-8793-1c3e8d743103 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd2b5a3-e95d-4294-8793-1c3e8d743103 PS:NodeType Pathway PS:Organ joint PS:Organ kidney PS:Organ_System skeletal system PS:Organ_System urinary tract PS:PathwayType network PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd66c49-7de7-4a1a-b473-ded97200716d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6dd66c49-7de7-4a1a-b473-ded97200716d KITLG -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-6dd66c49-7de7-4a1a-b473-ded97200716d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd66c49-7de7-4a1a-b473-ded97200716d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd7f23e-7a0b-4e4f-a26a-0b0319d0324c NodeType: Pathway Notes: In the absence of prosurvival factors, neutrophils, eosinophils, and basophils die by intrinsic apoptosis within a short time after maturation. The apoptosis and clearance of eosinophils by macrophages are attenuated in asthma. TGFB1 and other ligands bind to the death receptor FAS to stimulate eosinophil apoptosis and apoptosis of other cells (not shown). Sialic acid–binding Ig-like lectin 8 (SIGLEC8) is an important target for asthma-related drug target research. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-6dd7f23e-7a0b-4e4f-a26a-0b0319d0324c 2_2_Eosinophilia and neutrophilia in asthma: eosinophil apoptosis uuid-6dd7f23e-7a0b-4e4f-a26a-0b0319d0324c PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd7f23e-7a0b-4e4f-a26a-0b0319d0324c PS:NodeType Pathway PS:Notes In the absence of prosurvival factors, neutrophils, eosinophils, and basophils die by intrinsic apoptosis within a short time after maturation. The apoptosis and clearance of eosinophils by macrophages are attenuated in asthma. TGFB1 and other ligands bind to the death receptor FAS to stimulate eosinophil apoptosis and apoptosis of other cells (not shown). Sialic acid–binding Ig-like lectin 8 (SIGLEC8) is an important target for asthma-related drug target research. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd8a9b9-d952-497c-ab48-6e6d9459bc61 NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6dd8a9b9-d952-497c-ab48-6e6d9459bc61 Proteins Involved in Chronic Bronchitis uuid-6dd8a9b9-d952-497c-ab48-6e6d9459bc61 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dd8a9b9-d952-497c-ab48-6e6d9459bc61 PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6de737e0-c3a2-4ba2-bba9-b72faafa61da NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6de737e0-c3a2-4ba2-bba9-b72faafa61da TGFA -> TP53 Expression Targets uuid-6de737e0-c3a2-4ba2-bba9-b72faafa61da PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6de737e0-c3a2-4ba2-bba9-b72faafa61da PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: eosinophil Description: Patients with asthma show high levels of IL33 in serum and in the lungs. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dee5fdf-68be-4b7d-8202-cda3eca4c235 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Patients with asthma exhibit high levels of IL33 in the serum and lungs. IL33 signaling pathway enhances the expression of CCR3 in dendritic cells (or macrophages and mast cells), which has a central role in facilitating eosinophil mobilization to the inflammatory lung in asthma. IL33 binds to its plasma membrane receptor inducing NFkB and MAPK activation. Outcome effects; IL33 can trigger the production of IL13 from eosinophil, dendritic cells and mast cells. IL33 could be an important driver for CCL17 production by eosinophils, leading to the accumulation of lymphocytes in the airways. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 21469105 PMID: 21618506 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-6dee5fdf-68be-4b7d-8202-cda3eca4c235 IL33 Signaling Related Eosinophilia in Asthma uuid-6dee5fdf-68be-4b7d-8202-cda3eca4c235 PS:CellType eosinophil PS:Description Patients with asthma show high levels of IL33 in serum and in the lungs. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dee5fdf-68be-4b7d-8202-cda3eca4c235 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Patients with asthma exhibit high levels of IL33 in the serum and lungs. IL33 signaling pathway enhances the expression of CCR3 in dendritic cells (or macrophages and mast cells), which has a central role in facilitating eosinophil mobilization to the inflammatory lung in asthma. IL33 binds to its plasma membrane receptor inducing NFkB and MAPK activation. Outcome effects; IL33 can trigger the production of IL13 from eosinophil, dendritic cells and mast cells. IL33 could be an important driver for CCL17 production by eosinophils, leading to the accumulation of lymphocytes in the airways. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 21469105 PS:PMID 21618506 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dfc4b88-e827-4bbc-a545-f5b2102cad17 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6dfc4b88-e827-4bbc-a545-f5b2102cad17 TGFB1-ACVRL1 Expression Targets uuid-6dfc4b88-e827-4bbc-a545-f5b2102cad17 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6dfc4b88-e827-4bbc-a545-f5b2102cad17 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e0445b4-5e29-45ff-a18d-ad1256d56874 NodeType: Pathway Organ: brain Organ: pituitary gland Organ_System: endocrine system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6e0445b4-5e29-45ff-a18d-ad1256d56874 Proteins Involved in Hyperprolactinemia uuid-6e0445b4-5e29-45ff-a18d-ad1256d56874 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e0445b4-5e29-45ff-a18d-ad1256d56874 PS:NodeType Pathway PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e045d28-0f33-47db-a5a4-ede51ddeef54 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-6e045d28-0f33-47db-a5a4-ede51ddeef54 Receptor Tyrosine Kinase Family -> Expression Targets in Lymphoid System and Blood uuid-6e045d28-0f33-47db-a5a4-ede51ddeef54 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e045d28-0f33-47db-a5a4-ede51ddeef54 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: Acute myeloid leukemia is a hematological malignancy that is characterized by uncontrolled increase in the amount of myeloid progenitors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e106fb8-15f5-4249-a658-98d4fdff8631 NodeType: Pathway Notes: Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. According to the French-American-British (FAB) classification, AML is divided into eight subtypes, M0 through M7, based on the type of cell from which the leukemia developed and its degree of maturity. A block of differentiation may happen at any stage of myeloblast development in the different subtypes. Mutations and translocations of genes responsible for myeloid differentiation and development are the molecular basis of AML development. Signaling description: The most frequent mutations affect FLT3, KIT, and RAS. FLT3 and KIT are hematopoietic growth factor receptors of the family of tyrosine kinases (RTKs). Major signal transduction pathways leading from FLT3 and KIT include PI3K and RAS/MAPK. The expression of target genes leads to the inhibition of myeloblast differentiation and apoptosis while activating cell cycle and proliferation. RAS oncogenes are key molecules in signal transduction pathways through RTKs. Activating mutations of RAS are found in approximately 25% of AML cases and occur most frequently in NRAS. The hematopoietic factors, CEBPA, SPI1, and RUNX1 may be inactivated due to mutations in AML. The inactivation of CEBPA leads to block of differentiation of blasts in M1, 2, and 4 variants of AML. The inactivation of SPI1 plays the same role in AML M0, 4, 5, and 6 while the inactivation of RUNX1 occurs in AML M0 and 2. Nucleophosmin (NPM1) mutations are common in karyotypically normal AML, occurring in 50-60% of such cases. NPM1 acts as a cellular p53 negative regulator to protect hematopoietic cells from apoptosis. About 50-55% of AML cases are characterized by the presence of specific balanced chromosome abnormalities involved in the formation of specific fusion genes that code for fusion proteins which play a key role in the development of leukemia. The retinoic acid receptor (RARA) chimeric proteins, PML-RAR, PLZF-RAR and NPM-RAR are typical for AML M3 and have been associated with acute promyelocytic leukemia. Translocations involving MLL gene are typical for AML M5, with the most frequent being MLL-AF10. Chromosomal translocation products, AML-ETO1, AML1-MTG16, and AML1-MDS1-EVI1 act as activated oncogenes in AML M2. The chromosomal translocation product, CBFB-MYH11 acts as an oncogene in AML M4. Outcome effects: The aforementioned genetic events cause block of differentiation, inhibition of apoptosis, and increased cell proliferation which are the main mechanisms of AML development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. References: 1). Delwel R (2012) Molecular biology of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.6:23-32. 2). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.5:27-35. Organ_System: hematological system PMID: 17229639 PMID: 21245861 PMID: 22096254 PMID: 22778276 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-6e106fb8-15f5-4249-a658-98d4fdff8631 Acute Myeloid Leukemia uuid-6e106fb8-15f5-4249-a658-98d4fdff8631 PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description Acute myeloid leukemia is a hematological malignancy that is characterized by uncontrolled increase in the amount of myeloid progenitors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e106fb8-15f5-4249-a658-98d4fdff8631 PS:NodeType Pathway PS:Notes Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. According to the French-American-British (FAB) classification, AML is divided into eight subtypes, M0 through M7, based on the type of cell from which the leukemia developed and its degree of maturity. A block of differentiation may happen at any stage of myeloblast development in the different subtypes. Mutations and translocations of genes responsible for myeloid differentiation and development are the molecular basis of AML development. Signaling description: The most frequent mutations affect FLT3, KIT, and RAS. FLT3 and KIT are hematopoietic growth factor receptors of the family of tyrosine kinases (RTKs). Major signal transduction pathways leading from FLT3 and KIT include PI3K and RAS/MAPK. The expression of target genes leads to the inhibition of myeloblast differentiation and apoptosis while activating cell cycle and proliferation. RAS oncogenes are key molecules in signal transduction pathways through RTKs. Activating mutations of RAS are found in approximately 25% of AML cases and occur most frequently in NRAS. The hematopoietic factors, CEBPA, SPI1, and RUNX1 may be inactivated due to mutations in AML. The inactivation of CEBPA leads to block of differentiation of blasts in M1, 2, and 4 variants of AML. The inactivation of SPI1 plays the same role in AML M0, 4, 5, and 6 while the inactivation of RUNX1 occurs in AML M0 and 2. Nucleophosmin (NPM1) mutations are common in karyotypically normal AML, occurring in 50-60% of such cases. NPM1 acts as a cellular p53 negative regulator to protect hematopoietic cells from apoptosis. About 50-55% of AML cases are characterized by the presence of specific balanced chromosome abnormalities involved in the formation of specific fusion genes that code for fusion proteins which play a key role in the development of leukemia. The retinoic acid receptor (RARA) chimeric proteins, PML-RAR, PLZF-RAR and NPM-RAR are typical for AML M3 and have been associated with acute promyelocytic leukemia. Translocations involving MLL gene are typical for AML M5, with the most frequent being MLL-AF10. Chromosomal translocation products, AML-ETO1, AML1-MTG16, and AML1-MDS1-EVI1 act as activated oncogenes in AML M2. The chromosomal translocation product, CBFB-MYH11 acts as an oncogene in AML M4. Outcome effects: The aforementioned genetic events cause block of differentiation, inhibition of apoptosis, and increased cell proliferation which are the main mechanisms of AML development. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. References: 1). Delwel R (2012) Molecular biology of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.6:23-32. 2). Rice K., Buzzai M., Altman J., Licht J (2011) The molecular basis of acute myeloid leukemia.Hematology Education: the education program for the annual congress of the European Hematology Association.5:27-35. PS:Organ_System hematological system PS:PMID 17229639 PS:PMID 21245861 PS:PMID 22096254 PS:PMID 22778276 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e24c5af-561a-4689-9375-17599fa1fd03 NodeType: Pathway Organ: kidney Organ_System: endocrine system Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-6e24c5af-561a-4689-9375-17599fa1fd03 Proteins Involved in Diabetic Nephropathy uuid-6e24c5af-561a-4689-9375-17599fa1fd03 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e24c5af-561a-4689-9375-17599fa1fd03 PS:NodeType Pathway PS:Organ kidney PS:Organ_System endocrine system PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Arterial Hypertension (AH) is a medical condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e2dacbe-5a9b-4f55-973e-efce5712f321 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Na+/Cl-/K+ homeostasis disorder have a key role in the development of arterial hypertension. Non-voltage gated sodium (Na ) channels including amiloride-sensitive Na channels, epithelial Na channel (ENaC), and Na channel non-neuronal 1 (SCNN1) control Na transport across epithelia in nephron collecting ducts. This channel is a heterotrimeric complex consisting of alpha (SCNN1A), beta (SCNN1B) and gamma (SCNN1G) subunits. It plays a major role in Na homeostasis by reabsorption of Na ions. The activity of ENaC in kidney is modulated by the mineralocorticoid aldosterone. A kidney-specific SLC12A1 plays a key role in Na , Cl-, and K ion balance. KCNJ1 is activated by internal ATP and plays an important role in K homeostasis. SLC12A3 mediates Na and Cl- reabsorption in the distal renal tubule. These channels control electrolyte transport across epithelia in nephrons which are responsible for Na and Cl- reabsorption into plasma and K excretion. The transport of Na and K plays a dominant role in blood pressure and the overproduction of Na in plasma is the cause of arterial hypertension. Aldosterone binds to NR3C2, which interacts with NR3C1, and they both function as transcription factors that bind to corticoid response elements in the promoters of corticoid responsive genes to activate their transcription. NR3C1 promotes TSC22D3 which increases the transcription of SGK1. Subsequently, SGK1 phosphorylates NEDD4L. NEDD4L mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial Na transport by regulating the cell surface expression of ENaC. WNK1/4 regulate blood pressure by controlling the transport of Na and Cl- ions via activation of STK39 and OXSR1. STK39 and OXSR1 stimulate SLC12A1 and SLC12A3. Mutations in SCNN1B/SCNN1G cause Liddle syndrome while excessive levels of aldosterone is the cause of hyperaldosteronism. In addition, mutations in WNK1/4, NR3C2 and excessive levels of dietary sodium cause pseudohyperaldosteronism that are characterized by high blood pressure. Highlighted proteins: Entities with increased levels are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 18300843 PMID: 19690383 PMID: 21436285 PMID: 22058154 PMID: 23378101 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-6e2dacbe-5a9b-4f55-973e-efce5712f321 Aldosterone Signaling in Arterial Hypertension uuid-6e2dacbe-5a9b-4f55-973e-efce5712f321 PS:CellType epithelial cell PS:Description Arterial Hypertension (AH) is a medical condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e2dacbe-5a9b-4f55-973e-efce5712f321 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Na+/Cl-/K+ homeostasis disorder have a key role in the development of arterial hypertension. Non-voltage gated sodium (Na ) channels including amiloride-sensitive Na channels, epithelial Na channel (ENaC), and Na channel non-neuronal 1 (SCNN1) control Na transport across epithelia in nephron collecting ducts. This channel is a heterotrimeric complex consisting of alpha (SCNN1A), beta (SCNN1B) and gamma (SCNN1G) subunits. It plays a major role in Na homeostasis by reabsorption of Na ions. The activity of ENaC in kidney is modulated by the mineralocorticoid aldosterone. A kidney-specific SLC12A1 plays a key role in Na , Cl-, and K ion balance. KCNJ1 is activated by internal ATP and plays an important role in K homeostasis. SLC12A3 mediates Na and Cl- reabsorption in the distal renal tubule. These channels control electrolyte transport across epithelia in nephrons which are responsible for Na and Cl- reabsorption into plasma and K excretion. The transport of Na and K plays a dominant role in blood pressure and the overproduction of Na in plasma is the cause of arterial hypertension. Aldosterone binds to NR3C2, which interacts with NR3C1, and they both function as transcription factors that bind to corticoid response elements in the promoters of corticoid responsive genes to activate their transcription. NR3C1 promotes TSC22D3 which increases the transcription of SGK1. Subsequently, SGK1 phosphorylates NEDD4L. NEDD4L mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial Na transport by regulating the cell surface expression of ENaC. WNK1/4 regulate blood pressure by controlling the transport of Na and Cl- ions via activation of STK39 and OXSR1. STK39 and OXSR1 stimulate SLC12A1 and SLC12A3. Mutations in SCNN1B/SCNN1G cause Liddle syndrome while excessive levels of aldosterone is the cause of hyperaldosteronism. In addition, mutations in WNK1/4, NR3C2 and excessive levels of dietary sodium cause pseudohyperaldosteronism that are characterized by high blood pressure. Highlighted proteins: Entities with increased levels are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 18300843 PS:PMID 19690383 PS:PMID 21436285 PS:PMID 22058154 PS:PMID 23378101 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e4e17d2-0774-49ae-b3f6-f1cf77595912 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: pancreas Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-6e4e17d2-0774-49ae-b3f6-f1cf77595912 Elevated Receptors -> Expression Targets in Pancreas uuid-6e4e17d2-0774-49ae-b3f6-f1cf77595912 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e4e17d2-0774-49ae-b3f6-f1cf77595912 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ pancreas PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e5adddf-632f-47a5-bc5d-42ca6d1d8ff5 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6e5adddf-632f-47a5-bc5d-42ca6d1d8ff5 Nicotinate and NAD metabolism template uuid-6e5adddf-632f-47a5-bc5d-42ca6d1d8ff5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e5adddf-632f-47a5-bc5d-42ca6d1d8ff5 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Cryopyrin-associated periodic syndromes (CAPS) encompasses three diseases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e6f629c-e425-46a0-b812-acf952b723e6 NodeType: Pathway Notes: Headnote: Cryopyrin-associated periodic syndromes (CAPS) include three diseases, namely familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic cutaneous articular [CINCA] syndrome). Among the three syndromes, FCAS is the mildest in the clinical spectrum. It is characterized by cold-induced episodes of inflammation, associated with fever, chills, urticarial, and joint symptoms. Patients with MWS present with fever, urticarial rash, and arthritis, as well as subsequent hearing loss, and often have eye manifestations, namely conjunctivitis and episcleritis. In addition, amyloidosis develops in many patients with MWS. NOMID is one of the most severe monogenic autoinflammatory diseases. It has a more chronic and persistent course than FCAS and MWS, rather than clear-cut episodes. Patients display ongoing fever, continuous rash, optic disc edema, uveitis, abnormal bony overgrowth of the knees, and a variety of central nervous system manifestations. The common symptoms observed in patients with CAPS are fever, urticarial rash, musculoskeletal symptoms, high levels of acute-phase reactants, and conjunctivitis. Signaling description: All three syndromes are associated with mutations in NLRP3 gene, which codes for a key protein of the NLRP3 inflammasome which activates caspase 1 (CASP1). Activated NLRP3 oligomerizes and interacts with PYCARD and pro-caspase 1, resulting in the enzymatic activation of CASP1. Outcome effects: Activated CASP1 can convert pro-IL-1beta to its mature form (IL1B). IL-1beta maturation and secretion activates inflammatory response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 24247370 PMID: 24282415 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone tissue Tissue: epidermis urn:agi-pathway:uuid-6e6f629c-e425-46a0-b812-acf952b723e6 Cryopyrin (NLPR3) Associated Periodic Syndromes uuid-6e6f629c-e425-46a0-b812-acf952b723e6 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Cryopyrin-associated periodic syndromes (CAPS) encompasses three diseases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e6f629c-e425-46a0-b812-acf952b723e6 PS:NodeType Pathway PS:Notes Headnote: Cryopyrin-associated periodic syndromes (CAPS) include three diseases, namely familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic cutaneous articular [CINCA] syndrome). Among the three syndromes, FCAS is the mildest in the clinical spectrum. It is characterized by cold-induced episodes of inflammation, associated with fever, chills, urticarial, and joint symptoms. Patients with MWS present with fever, urticarial rash, and arthritis, as well as subsequent hearing loss, and often have eye manifestations, namely conjunctivitis and episcleritis. In addition, amyloidosis develops in many patients with MWS. NOMID is one of the most severe monogenic autoinflammatory diseases. It has a more chronic and persistent course than FCAS and MWS, rather than clear-cut episodes. Patients display ongoing fever, continuous rash, optic disc edema, uveitis, abnormal bony overgrowth of the knees, and a variety of central nervous system manifestations. The common symptoms observed in patients with CAPS are fever, urticarial rash, musculoskeletal symptoms, high levels of acute-phase reactants, and conjunctivitis. Signaling description: All three syndromes are associated with mutations in NLRP3 gene, which codes for a key protein of the NLRP3 inflammasome which activates caspase 1 (CASP1). Activated NLRP3 oligomerizes and interacts with PYCARD and pro-caspase 1, resulting in the enzymatic activation of CASP1. Outcome effects: Activated CASP1 can convert pro-IL-1beta to its mature form (IL1B). IL-1beta maturation and secretion activates inflammatory response. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 24247370 PS:PMID 24282415 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone tissue PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e9518c6-dae1-410b-a1c2-4e72fe25c672 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-6e9518c6-dae1-410b-a1c2-4e72fe25c672 Elevated Receptors -> Expression Targets in Lymphoid System and Blood uuid-6e9518c6-dae1-410b-a1c2-4e72fe25c672 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6e9518c6-dae1-410b-a1c2-4e72fe25c672 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6eb0dc37-6f7f-4f24-8a5a-3351a87e3dcf NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-6eb0dc37-6f7f-4f24-8a5a-3351a87e3dcf Eat me Signal: Apoptotic Cell Induces Phagocytosis uuid-6eb0dc37-6f7f-4f24-8a5a-3351a87e3dcf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6eb0dc37-6f7f-4f24-8a5a-3351a87e3dcf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6eb8c8bc-cc39-4f2a-8b3d-4eadee9575b4 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-6eb8c8bc-cc39-4f2a-8b3d-4eadee9575b4 H1 Modification Sites uuid-6eb8c8bc-cc39-4f2a-8b3d-4eadee9575b4 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6eb8c8bc-cc39-4f2a-8b3d-4eadee9575b4 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ec0e370-52a8-4d35-a593-dd0d75d576a0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6ec0e370-52a8-4d35-a593-dd0d75d576a0 AREG -> HIF1A Expression Targets uuid-6ec0e370-52a8-4d35-a593-dd0d75d576a0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ec0e370-52a8-4d35-a593-dd0d75d576a0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Clear cell ovarian carcinoma (CCOC) is also known as clear cell mesonephroma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ecd5c7d-7e73-4f3f-a39d-0be7a5aae6bf NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Clear cell ovarian carcinoma (CCOC) is also known as clear cell adenocarcinoma and clear cell mesonephroma. Approximately 6% of ovarian cancers are clear cell carcinoma, and this histological subtype is one of the most aggressive forms of ovarian cancer. CCOC is generally resistant to standard therapy. Signaling description: CGOC is characterized by mutations in KRAS, BRAF, PTEN, and ARID1A genes. In addition, the overexpression of PDGFA/B, MET, HGF, PPM1D, and FBXO5 are also associated with CCOC. The platelet-derived growth factor receptors (PDGFR alpha/beta) are transmembrane receptor tyrosine kinases that are activated by platelet-derived growth factors (PDGFs). The met proto-oncogene (MET) is a transmembrane hepatocyte growth factor receptor. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound MET activates PIK3CA, which activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses the AKT-mediated signaling, and mutations in PTEN gene lead to the constitutive activation of AKT1. In addition, PDGFRs and MET mediate Janus kinases 1/2 (JAK1/2), which regulate cell growth. PDGFRs and MET also interact with SHC1/GRB2/SOS1 and activate BRAF which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the CTNNB1 stabilization. CTNNB1 protein then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD, whuch leads to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and apoptotic caspase cascade activation. Further, the oncogenic PPM1D protein is an important regulator in the DNA damage pathway. PPM1D dephosphorylates and inactivates ATM, which then phosphorylates CHEK1 and CHEK2, required for checkpoint mediated cell cycle arrest. CHEK1 and CHEK2 regulate TP53 and BRCA1 activity, and BRCA1 plays a central role in DNA repair. Anaphase promoting complex (APC/C) is required to exit from mitosis, as it induces proteolysis of different cell cycle regulators. The activation of APC/C is mediated by CDC20, while FBXO5 is a negative regulator of CDC20. The overexpression of FBXO5 inhibits the activation of APC/C and induces cell proliferation. AT rich interactive domain 1A (ARID1A) is a component of SWI/SNF chromatin remodeling complex which also includes SMARCA4, ACTB, ACTL6A, ACTL6B, ARID1B, and SMARCD1/SMARCD2/SMARCD3/SMARCC1/SMARCC2/SMARCB1. Mutations in ARID1A result in the dysfunction of chromatin remodeling. Highlighted proteins: Proteins with increased expression are highlighted in red an Organ: ovary Organ_System: reproductive system PMID: 18204430 PMID: 18317228 PMID: 19221485 PMID: 19578761 PMID: 22525820 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-6ecd5c7d-7e73-4f3f-a39d-0be7a5aae6bf Clear Cell Ovarian Carcinoma uuid-6ecd5c7d-7e73-4f3f-a39d-0be7a5aae6bf PS:CellType cancer cell PS:CellType epithelial cell PS:Description Clear cell ovarian carcinoma (CCOC) is also known as clear cell mesonephroma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6ecd5c7d-7e73-4f3f-a39d-0be7a5aae6bf PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Clear cell ovarian carcinoma (CCOC) is also known as clear cell adenocarcinoma and clear cell mesonephroma. Approximately 6% of ovarian cancers are clear cell carcinoma, and this histological subtype is one of the most aggressive forms of ovarian cancer. CCOC is generally resistant to standard therapy. Signaling description: CGOC is characterized by mutations in KRAS, BRAF, PTEN, and ARID1A genes. In addition, the overexpression of PDGFA/B, MET, HGF, PPM1D, and FBXO5 are also associated with CCOC. The platelet-derived growth factor receptors (PDGFR alpha/beta) are transmembrane receptor tyrosine kinases that are activated by platelet-derived growth factors (PDGFs). The met proto-oncogene (MET) is a transmembrane hepatocyte growth factor receptor. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound MET activates PIK3CA, which activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses the AKT-mediated signaling, and mutations in PTEN gene lead to the constitutive activation of AKT1. In addition, PDGFRs and MET mediate Janus kinases 1/2 (JAK1/2), which regulate cell growth. PDGFRs and MET also interact with SHC1/GRB2/SOS1 and activate BRAF which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the CTNNB1 stabilization. CTNNB1 protein then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD, whuch leads to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and apoptotic caspase cascade activation. Further, the oncogenic PPM1D protein is an important regulator in the DNA damage pathway. PPM1D dephosphorylates and inactivates ATM, which then phosphorylates CHEK1 and CHEK2, required for checkpoint mediated cell cycle arrest. CHEK1 and CHEK2 regulate TP53 and BRCA1 activity, and BRCA1 plays a central role in DNA repair. Anaphase promoting complex (APC/C) is required to exit from mitosis, as it induces proteolysis of different cell cycle regulators. The activation of APC/C is mediated by CDC20, while FBXO5 is a negative regulator of CDC20. The overexpression of FBXO5 inhibits the activation of APC/C and induces cell proliferation. AT rich interactive domain 1A (ARID1A) is a component of SWI/SNF chromatin remodeling complex which also includes SMARCA4, ACTB, ACTL6A, ACTL6B, ARID1B, and SMARCD1/SMARCD2/SMARCD3/SMARCC1/SMARCC2/SMARCB1. Mutations in ARID1A result in the dysfunction of chromatin remodeling. Highlighted proteins: Proteins with increased expression are highlighted in red an PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18204430 PS:PMID 18317228 PS:PMID 19221485 PS:PMID 19578761 PS:PMID 22525820 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: Cone cells, or cones, are photoreceptor cells that are in the retina of the eye which are responsible for color vision. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f0126fe-f221-43d6-ac9b-f8ee790849e5 NodeType: Pathway Notes: Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Cone cells, or cones, are photoreceptor cells in the retina of the eye, which are responsible for color vision. They function best in relatively bright light, as opposed to rod cells that work better in dim light. Signaling description: Humans normally have three kinds of cones. The first type of cones peak at the long-wave red color and contain long-wave-sensitive opsin 1 (OPN1LW). Cones of the second type peak at the green part of the spectrum and contain medium-wave-sensitive opsins 1 (OPN1MW and OPN1MW2). The third type of cones peak at the blue part of the spectrum and contain short-wave-sensitive opsin 1 (OPN1SW). As their visual pigment is destroyed in the process of photoactivation, the continuous function of cones imposes the need for rapid recycling of their chromophore. Cones recycle chromophore and restore their activity much faster than rods do. This is why the visual cycle in rods includes an alternative visual cycle in addition to the canonical one (the canonical visual cycle is the same for rods). Following photolysis, all-trans-retinal is reduced to all-trans-retinol (vitamin A) by retinol dehydrogenase RDH8 and DHRS3. Vitamin A is then released and transported across the interphotoreceptor matrix (IPM) to Muller cells, with the help of RBP3. Outcome effects: In Muller cells, vitamin A is isomerized directly to 11-cis-retinol by retinol isomerase following binding with RBP1. 11-cis-retinol is released from Muller cells to the IPM and transported to the cone. 11-cis retinol is oxidized to 11-cis retinal by an unidentified 11-cis RDH retinol dehydrogenase. Organ: Retina Organ: eye Organ_System: sensory system PMID: 16706600 PMID: 16968212 PMID: 21111842 PMID: 23905688 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-6f0126fe-f221-43d6-ac9b-f8ee790849e5 Visual Cycle in Retinal Cones uuid-6f0126fe-f221-43d6-ac9b-f8ee790849e5 PS:CellType retina cell PS:Description Cone cells, or cones, are photoreceptor cells that are in the retina of the eye which are responsible for color vision. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f0126fe-f221-43d6-ac9b-f8ee790849e5 PS:NodeType Pathway PS:Notes Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Cone cells, or cones, are photoreceptor cells in the retina of the eye, which are responsible for color vision. They function best in relatively bright light, as opposed to rod cells that work better in dim light. Signaling description: Humans normally have three kinds of cones. The first type of cones peak at the long-wave red color and contain long-wave-sensitive opsin 1 (OPN1LW). Cones of the second type peak at the green part of the spectrum and contain medium-wave-sensitive opsins 1 (OPN1MW and OPN1MW2). The third type of cones peak at the blue part of the spectrum and contain short-wave-sensitive opsin 1 (OPN1SW). As their visual pigment is destroyed in the process of photoactivation, the continuous function of cones imposes the need for rapid recycling of their chromophore. Cones recycle chromophore and restore their activity much faster than rods do. This is why the visual cycle in rods includes an alternative visual cycle in addition to the canonical one (the canonical visual cycle is the same for rods). Following photolysis, all-trans-retinal is reduced to all-trans-retinol (vitamin A) by retinol dehydrogenase RDH8 and DHRS3. Vitamin A is then released and transported across the interphotoreceptor matrix (IPM) to Muller cells, with the help of RBP3. Outcome effects: In Muller cells, vitamin A is isomerized directly to 11-cis-retinol by retinol isomerase following binding with RBP1. 11-cis-retinol is released from Muller cells to the IPM and transported to the cone. 11-cis retinol is oxidized to 11-cis retinal by an unidentified 11-cis RDH retinol dehydrogenase. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 16706600 PS:PMID 16968212 PS:PMID 21111842 PS:PMID 23905688 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f087897-a9ce-4a5f-b7ae-23b8dfb89fe0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-6f087897-a9ce-4a5f-b7ae-23b8dfb89fe0 INHBB/ACVR2 Expression Target uuid-6f087897-a9ce-4a5f-b7ae-23b8dfb89fe0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f087897-a9ce-4a5f-b7ae-23b8dfb89fe0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f097b0e-d868-4a11-a6db-fb000918a772 NodeType: Pathway Notes: In macrophage, inflammatory mediators upregulate the synthesis of the major intracellular iron storage protein ferritin and stimulate the ferritin-bound deposition of iron. In AI/ACD the levels of HAMP secreted from hepatocytes is higher than normal. HAMP can inhibit iron export by binding to the iron transporter ferroportin (SLC40A1), which is present on macrophages to trigger its degradation. Bacterial infection may also cause the downregulation of SLC40A1 synthesis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-6f097b0e-d868-4a11-a6db-fb000918a772 3_Impairment of iron release from splenic macrophages uuid-6f097b0e-d868-4a11-a6db-fb000918a772 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f097b0e-d868-4a11-a6db-fb000918a772 PS:NodeType Pathway PS:Notes In macrophage, inflammatory mediators upregulate the synthesis of the major intracellular iron storage protein ferritin and stimulate the ferritin-bound deposition of iron. In AI/ACD the levels of HAMP secreted from hepatocytes is higher than normal. HAMP can inhibit iron export by binding to the iron transporter ferroportin (SLC40A1), which is present on macrophages to trigger its degradation. Bacterial infection may also cause the downregulation of SLC40A1 synthesis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f5d94b2-dc31-49e9-9c40-1ae2cdbdac53 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-6f5d94b2-dc31-49e9-9c40-1ae2cdbdac53 CD247 Expression Targets uuid-6f5d94b2-dc31-49e9-9c40-1ae2cdbdac53 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f5d94b2-dc31-49e9-9c40-1ae2cdbdac53 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Approximately 4? of cases of adult-onset primary open-angle glaucoma and more than 10? of juvenile-onset cases are associated with myocilin (MYOC) mutations. The exact function of MYOC is unknown. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f76f633-5201-478c-8061-f14601550dbb NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Approximately 4% of adult-onset primary open-angle glaucoma cases and more than 10% of juvenile-onset cases are associated with myocilin (MYOC) mutations. Signaling description: The exact function of MYOC is unknown. Elevated amounts of wild-type MYOC in the aqueous humor of transgenic mice produce significant changes in the expression of genes involved in cell adhesion and cell-matrix interactions. Outcome effects: Therefore, MYOC is suggested to have a role in modulating cellular adhesion. Among the genes that were found to be differentially regulatedby MYOC are WASL, CEACAM1, and SPON2. All of these genes are involved in cell adhesion and cell-matrix interactions. Animal data: Experimental data obtained from transgenic mice. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ: trabecular meshwork Organ_System: sensory system PMID: 18602390 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-6f76f633-5201-478c-8061-f14601550dbb MYOC in Cell Adhesion in Glaucoma uuid-6f76f633-5201-478c-8061-f14601550dbb PS:Description Approximately 4? of cases of adult-onset primary open-angle glaucoma and more than 10? of juvenile-onset cases are associated with myocilin (MYOC) mutations. The exact function of MYOC is unknown. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f76f633-5201-478c-8061-f14601550dbb PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Approximately 4% of adult-onset primary open-angle glaucoma cases and more than 10% of juvenile-onset cases are associated with myocilin (MYOC) mutations. Signaling description: The exact function of MYOC is unknown. Elevated amounts of wild-type MYOC in the aqueous humor of transgenic mice produce significant changes in the expression of genes involved in cell adhesion and cell-matrix interactions. Outcome effects: Therefore, MYOC is suggested to have a role in modulating cellular adhesion. Among the genes that were found to be differentially regulatedby MYOC are WASL, CEACAM1, and SPON2. All of these genes are involved in cell adhesion and cell-matrix interactions. Animal data: Experimental data obtained from transgenic mice. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ trabecular meshwork PS:Organ_System sensory system PS:PMID 18602390 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f7b9e62-daaf-4ea8-a35d-325877311c05 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-6f7b9e62-daaf-4ea8-a35d-325877311c05 Macrophage activation in corneal injury uuid-6f7b9e62-daaf-4ea8-a35d-325877311c05 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f7b9e62-daaf-4ea8-a35d-325877311c05 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f7f2799-3136-406d-a9eb-2c005a1ffdab NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-6f7f2799-3136-406d-a9eb-2c005a1ffdab Fatty acid biosynthesis (plastids) template uuid-6f7f2799-3136-406d-a9eb-2c005a1ffdab PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6f7f2799-3136-406d-a9eb-2c005a1ffdab PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fba01a3-d7b6-469a-9206-ae0d40880b83 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-6fba01a3-d7b6-469a-9206-ae0d40880b83 H2AK119 Ubiquitination uuid-6fba01a3-d7b6-469a-9206-ae0d40880b83 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fba01a3-d7b6-469a-9206-ae0d40880b83 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: neuroglia Description: Microglia is a type of glial cell that acts as the first and main form of active immune defense in the central nervous system (CNS). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fc73f22-4eb4-4f8d-bf14-0f17b4e30a0e NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Microglia is a type of glial cells that act as the first and main form of active immune defense in the central nervous system (CNS). Microglia activation and the subsequent increase in proinflammatory molecules are observed in Parkinson's disease (PD). Microglia activation occurs when aggregates of alpha-synuclein (SNCA) form intermediate-state oligomers (protofibrils) which upon release from neurons are taken up by microglial cells. Subsequently, SNCA protofibrils activate microglia by triggering NF-kB-dependent production of proinflammatory mediators. Mutations in the transcription factor, NR4A2 are associated with a rare familial form of PD. NR4A2 acts as a transrepressor in microglia and astrocytes attenuating inflammatory gene transcription by NF-kB. Outcome effects: Proinflammatory mediators act directly on dopaminergic neurons of the substantia nigra, leading to cell death in PD. The positive feedback loop between proinflammatory mediators and microglia further amplify the inflammatory response. Lipopolysaccharides (LPS) of dead neurons, acting primarily through toll-like receptor 4 (TLR4), also induce an inflammatory response in the substantia nigra resulting in the loss of dopaminergic neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17956294 PMID: 19296921 PMID: 20234358 PMID: 20303880 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-6fc73f22-4eb4-4f8d-bf14-0f17b4e30a0e Microglia Activation in Parkinson's Disease uuid-6fc73f22-4eb4-4f8d-bf14-0f17b4e30a0e PS:CellType neuroglia PS:Description Microglia is a type of glial cell that acts as the first and main form of active immune defense in the central nervous system (CNS). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fc73f22-4eb4-4f8d-bf14-0f17b4e30a0e PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Microglia is a type of glial cells that act as the first and main form of active immune defense in the central nervous system (CNS). Microglia activation and the subsequent increase in proinflammatory molecules are observed in Parkinson's disease (PD). Microglia activation occurs when aggregates of alpha-synuclein (SNCA) form intermediate-state oligomers (protofibrils) which upon release from neurons are taken up by microglial cells. Subsequently, SNCA protofibrils activate microglia by triggering NF-kB-dependent production of proinflammatory mediators. Mutations in the transcription factor, NR4A2 are associated with a rare familial form of PD. NR4A2 acts as a transrepressor in microglia and astrocytes attenuating inflammatory gene transcription by NF-kB. Outcome effects: Proinflammatory mediators act directly on dopaminergic neurons of the substantia nigra, leading to cell death in PD. The positive feedback loop between proinflammatory mediators and microglia further amplify the inflammatory response. Lipopolysaccharides (LPS) of dead neurons, acting primarily through toll-like receptor 4 (TLR4), also induce an inflammatory response in the substantia nigra resulting in the loss of dopaminergic neurons. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17956294 PS:PMID 19296921 PS:PMID 20234358 PS:PMID 20303880 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fd09da9-1802-47a0-aa8c-e7db687209ef NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-6fd09da9-1802-47a0-aa8c-e7db687209ef NSP9 interactions uuid-6fd09da9-1802-47a0-aa8c-e7db687209ef PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fd09da9-1802-47a0-aa8c-e7db687209ef PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fe19ed7-990b-48b8-97ff-734872baff8f NodeType: Pathway urn:agi-pathway:uuid-6fe19ed7-990b-48b8-97ff-734872baff8f TORC1-|Apoptosis uuid-6fe19ed7-990b-48b8-97ff-734872baff8f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-6fe19ed7-990b-48b8-97ff-734872baff8f PS:NodeType Pathway PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70015438-9c7a-429d-9955-9d6a33b7f7cf NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-70015438-9c7a-429d-9955-9d6a33b7f7cf Starch solubilization(cloroplast stroma) template uuid-70015438-9c7a-429d-9955-9d6a33b7f7cf PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70015438-9c7a-429d-9955-9d6a33b7f7cf PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using iPTMnet database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70198ebf-341a-4ae5-bd5c-4674f4d672b2 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-70198ebf-341a-4ae5-bd5c-4674f4d672b2 Proteins Involved in Histone 1 Modification Sites uuid-70198ebf-341a-4ae5-bd5c-4674f4d672b2 PS:Description Pathway is build using iPTMnet database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70198ebf-341a-4ae5-bd5c-4674f4d672b2 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Link PS:NodeType PS:Pathway_Author PS:Tissue Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7028cece-ee01-45d7-96f6-76064501a7f1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: endothelium urn:agi-pathway:uuid-7028cece-ee01-45d7-96f6-76064501a7f1 ITG+>cell survival uuid-7028cece-ee01-45d7-96f6-76064501a7f1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7028cece-ee01-45d7-96f6-76064501a7f1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue endothelium PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70319624-0b19-4f0a-bda0-f37af18f2a28 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-70319624-0b19-4f0a-bda0-f37af18f2a28 Genes with Mutations Associated with Vitiligo uuid-70319624-0b19-4f0a-bda0-f37af18f2a28 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70319624-0b19-4f0a-bda0-f37af18f2a28 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7045cf80-97d2-4306-8cb6-e6757360a99a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7045cf80-97d2-4306-8cb6-e6757360a99a Xyloglucan remodelling template uuid-7045cf80-97d2-4306-8cb6-e6757360a99a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7045cf80-97d2-4306-8cb6-e6757360a99a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70593f37-8280-46cb-aea1-297e95318f16 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-70593f37-8280-46cb-aea1-297e95318f16 Nitroxyl and CGRP in Migraine Pain Activation uuid-70593f37-8280-46cb-aea1-297e95318f16 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70593f37-8280-46cb-aea1-297e95318f16 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Desmosomes are molecular complexes that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7076be25-f12d-442e-8639-f360f087be65 NodeType: Pathway Notes: Headnote: Desmosomes are molecular complexes that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments. Desmosomes are the most common type of intercellular junction in vertebrate epithelial cells that link the intermediate filament network of one cell to its neighbors. Signaling description: The cell adhesion proteins of the desmosome, desmoglein (DSG) and desmocollin (DSC), are members of the cadherin family that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmosomal cadherins on the adjacent cell. Both of them have five extracellular domains and calcium-binding motifs. The extracellular domain of the desmosome is called the extracellular core domain (ECD) and contains DSG and DSC proteins bound to each other. Outcome effects: There are two dense structures on the cytoplasmic side of the plasma membrane, the outer dense plaque (ODP) and the inner dense plaque (IDP). At the ODP, the cytoplasmic domains of the cadherins attach to desmoplakin (DSP) via plakoglobin (JUP) and plakophilin (PKP). The IDP is where DSP attaches to the intermediate filaments of the cell. JUP and PKP may bind to other members of the plakin family of cytolinkers which also includes plectin (PLEC), envoplakin (EVPL), and periplakin (PPL). Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7076be25-f12d-442e-8639-f360f087be65 Desmosome Assembly uuid-7076be25-f12d-442e-8639-f360f087be65 PS:CellType generic PS:Description Desmosomes are molecular complexes that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7076be25-f12d-442e-8639-f360f087be65 PS:NodeType Pathway PS:Notes Headnote: Desmosomes are molecular complexes that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments. Desmosomes are the most common type of intercellular junction in vertebrate epithelial cells that link the intermediate filament network of one cell to its neighbors. Signaling description: The cell adhesion proteins of the desmosome, desmoglein (DSG) and desmocollin (DSC), are members of the cadherin family that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmosomal cadherins on the adjacent cell. Both of them have five extracellular domains and calcium-binding motifs. The extracellular domain of the desmosome is called the extracellular core domain (ECD) and contains DSG and DSC proteins bound to each other. Outcome effects: There are two dense structures on the cytoplasmic side of the plasma membrane, the outer dense plaque (ODP) and the inner dense plaque (IDP). At the ODP, the cytoplasmic domains of the cadherins attach to desmoplakin (DSP) via plakoglobin (JUP) and plakophilin (PKP). The IDP is where DSP attaches to the intermediate filaments of the cell. JUP and PKP may bind to other members of the plakin family of cytolinkers which also includes plectin (PLEC), envoplakin (EVPL), and periplakin (PPL). PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Direct DNA repair may be impaired in cancer due to MGMT inhibition Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7078d855-146a-4136-91af-faafeae8fba2 NodeType: Pathway Notes: Headnote: Direct DNA repair includes single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. In humans, the main type of direct DNA damage reversal systems repair alkylating damage via the action of alkyltransferases and dioxygenases. Biologically important lesions formed in double-stranded DNA (dsDNA) are 6-methoxyguanine, 3-methylcytosine, and 1-methyladenine. Dioxygenases ALKBH2 and ALKBH3 preferentially repair 1-methyladenine and 3-methylcytosine lesions by oxidative demethylation. MGMT (Methylguanine-DNA methyltransferase or O-6-methylguanine-DNA-alkyltransferase) directly dealkylates mutagenic 6-methoxyguanine lesions within DNA.Methylation of MGMT promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma.DNMT1 and MECP2 are inhibitors of MGMT. They can be mutated in cancer and exhibit an increased inhibitory activity. MGMT also can be down-regulated by MIR181D in glioma, glioblastoma and other neoplasms. Outcome effects: silencing of MGMT impairs direct DNA repair and promotes genomic instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20965415 PMID: 24947262 PMID: 25017190 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-7078d855-146a-4136-91af-faafeae8fba2 Direct DNA Repair Supression in Cancer uuid-7078d855-146a-4136-91af-faafeae8fba2 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Direct DNA repair may be impaired in cancer due to MGMT inhibition PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7078d855-146a-4136-91af-faafeae8fba2 PS:NodeType Pathway PS:Notes Headnote: Direct DNA repair includes single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. In humans, the main type of direct DNA damage reversal systems repair alkylating damage via the action of alkyltransferases and dioxygenases. Biologically important lesions formed in double-stranded DNA (dsDNA) are 6-methoxyguanine, 3-methylcytosine, and 1-methyladenine. Dioxygenases ALKBH2 and ALKBH3 preferentially repair 1-methyladenine and 3-methylcytosine lesions by oxidative demethylation. MGMT (Methylguanine-DNA methyltransferase or O-6-methylguanine-DNA-alkyltransferase) directly dealkylates mutagenic 6-methoxyguanine lesions within DNA.Methylation of MGMT promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma.DNMT1 and MECP2 are inhibitors of MGMT. They can be mutated in cancer and exhibit an increased inhibitory activity. MGMT also can be down-regulated by MIR181D in glioma, glioblastoma and other neoplasms. Outcome effects: silencing of MGMT impairs direct DNA repair and promotes genomic instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70811771-4144-4675-9e8b-4405fdfcaa3b NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-70811771-4144-4675-9e8b-4405fdfcaa3b HTR1 -> Vascular Motility uuid-70811771-4144-4675-9e8b-4405fdfcaa3b PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70811771-4144-4675-9e8b-4405fdfcaa3b PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70888663-6ada-4ed3-9454-2f90f9ae28a2 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-70888663-6ada-4ed3-9454-2f90f9ae28a2 P2RY11/13/14 -> IL8/10 Production uuid-70888663-6ada-4ed3-9454-2f90f9ae28a2 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70888663-6ada-4ed3-9454-2f90f9ae28a2 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70888a19-2888-437b-8fd0-760e7566556f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-70888a19-2888-437b-8fd0-760e7566556f FibronectinR -> ICAP-1A/MYC Signaling uuid-70888a19-2888-437b-8fd0-760e7566556f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70888a19-2888-437b-8fd0-760e7566556f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-708db1ba-e8b3-4b18-b3b1-e89e3e4a653f NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-708db1ba-e8b3-4b18-b3b1-e89e3e4a653f Achondroplasia uuid-708db1ba-e8b3-4b18-b3b1-e89e3e4a653f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-708db1ba-e8b3-4b18-b3b1-e89e3e4a653f PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70927bec-a643-4680-87b9-0e0fa679a019 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-70927bec-a643-4680-87b9-0e0fa679a019 AREG -> CTNN Expression Targets uuid-70927bec-a643-4680-87b9-0e0fa679a019 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70927bec-a643-4680-87b9-0e0fa679a019 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7096cfb4-3da8-43d1-9529-cf120076c5d6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-7096cfb4-3da8-43d1-9529-cf120076c5d6 TGFb+>Cornea opacity uuid-7096cfb4-3da8-43d1-9529-cf120076c5d6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7096cfb4-3da8-43d1-9529-cf120076c5d6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SIRT4 is a mitochondrial protein more efficiently works as an ADP-ribosyltransferase than deacetylase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70a1c761-a0fa-4468-b090-ff7b0d1271d0 NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT4 is a mitochondrial protein more efficiently works as an ADP-ribosyltransferase than deacetylase. Signaling description: SIRT4 controls glutamate metabolism through GLUD1 and may participate in insulin secretion regulation. SIRT4 may regulate mitochondrial ATP homeostasis via the ANT2 feedback loop involving AMPK. Outcome effects: SIRT4 is considered as a regulator of glucose and lipid homeostasis during pancreas and hepatic aging or synaptic activity regulator during brain aging. Organ: generic Organ_System: generic PMID: 17079682 PMID: 23746352 PMID: 24296486 PMID: 28380376 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-70a1c761-a0fa-4468-b090-ff7b0d1271d0 SIRT4 Signaling in Aging uuid-70a1c761-a0fa-4468-b090-ff7b0d1271d0 PS:CellType generic PS:Description SIRT4 is a mitochondrial protein more efficiently works as an ADP-ribosyltransferase than deacetylase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70a1c761-a0fa-4468-b090-ff7b0d1271d0 PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT4 is a mitochondrial protein more efficiently works as an ADP-ribosyltransferase than deacetylase. Signaling description: SIRT4 controls glutamate metabolism through GLUD1 and may participate in insulin secretion regulation. SIRT4 may regulate mitochondrial ATP homeostasis via the ANT2 feedback loop involving AMPK. Outcome effects: SIRT4 is considered as a regulator of glucose and lipid homeostasis during pancreas and hepatic aging or synaptic activity regulator during brain aging. PS:Organ generic PS:Organ_System generic PS:PMID 17079682 PS:PMID 23746352 PS:PMID 24296486 PS:PMID 28380376 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70ab3c8c-87c6-4167-a513-1e1ed40e2cd4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-70ab3c8c-87c6-4167-a513-1e1ed40e2cd4 Insulin -> MEF/MYOD Expression Targets uuid-70ab3c8c-87c6-4167-a513-1e1ed40e2cd4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70ab3c8c-87c6-4167-a513-1e1ed40e2cd4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70d9fbb4-ab25-4438-9a69-93ba2f5fa7eb NodeType: Pathway Organ: generic Organ_System: generic PMID: 18313409 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-70d9fbb4-ab25-4438-9a69-93ba2f5fa7eb TGF-beta Signaling uuid-70d9fbb4-ab25-4438-9a69-93ba2f5fa7eb PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70d9fbb4-ab25-4438-9a69-93ba2f5fa7eb PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 18313409 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70ffda9b-ce38-4486-ba2b-39195987ae09 NodeType: Pathway Notes: Ichthyosis is one of the most frequent monogenic disorders in humans. It caused by mutations in one of several genes including the filaggrin gene (FLG). Filaggrin (FLG) is a key protein of the keratohyalin granules in the stratum granulosum. Keratohyalin granules are important in the formation of the protective skin barrier and the terminal differentiation of the epidermis. FLG is associated with keratin intermediate filaments in the outer granular layer of the epidermis, and it supports their packing into bundles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-70ffda9b-ce38-4486-ba2b-39195987ae09 1_Ichthyosis vulgaris overview uuid-70ffda9b-ce38-4486-ba2b-39195987ae09 PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-70ffda9b-ce38-4486-ba2b-39195987ae09 PS:NodeType Pathway PS:Notes Ichthyosis is one of the most frequent monogenic disorders in humans. It caused by mutations in one of several genes including the filaggrin gene (FLG). Filaggrin (FLG) is a key protein of the keratohyalin granules in the stratum granulosum. Keratohyalin granules are important in the formation of the protective skin barrier and the terminal differentiation of the epidermis. FLG is associated with keratin intermediate filaments in the outer granular layer of the epidermis, and it supports their packing into bundles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-710c56bd-9896-46d5-895c-49de4fe671f1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-710c56bd-9896-46d5-895c-49de4fe671f1 Propionoate metabolism template uuid-710c56bd-9896-46d5-895c-49de4fe671f1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-710c56bd-9896-46d5-895c-49de4fe671f1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Pyelonephritis is a type of urinary tract infection. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71306f18-43fe-4d93-8080-8ea52cffb96a NodeType: Pathway Notes: Pyelonephritis is a type of urinary tract infection. Endothelial dysfunction is a major mechanism for renal diseases. Upon injury, the endothelial cells lose its ability to regulate vascular tone, perfusion and permeability. Organ: blood vessel Organ_System: urinary tract PMID: 14752242 PMID: 16339963 PMID: 24198613 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endothelium urn:agi-pathway:uuid-71306f18-43fe-4d93-8080-8ea52cffb96a Endothelial Cell Dysfunction in Pyelonephritis uuid-71306f18-43fe-4d93-8080-8ea52cffb96a PS:CellType endothelial cell PS:Description Pyelonephritis is a type of urinary tract infection. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71306f18-43fe-4d93-8080-8ea52cffb96a PS:NodeType Pathway PS:Notes Pyelonephritis is a type of urinary tract infection. Endothelial dysfunction is a major mechanism for renal diseases. Upon injury, the endothelial cells lose its ability to regulate vascular tone, perfusion and permeability. PS:Organ blood vessel PS:Organ_System urinary tract PS:PMID 14752242 PS:PMID 16339963 PS:PMID 24198613 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endothelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7142ec7c-d6ad-46d8-8bc8-65de9ad8f670 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7142ec7c-d6ad-46d8-8bc8-65de9ad8f670 Maltose metabolism template uuid-7142ec7c-d6ad-46d8-8bc8-65de9ad8f670 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7142ec7c-d6ad-46d8-8bc8-65de9ad8f670 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-714e9a86-a612-4f9b-8699-89022dc1b20f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-714e9a86-a612-4f9b-8699-89022dc1b20f Myelin sphingolipids biosynthesis template uuid-714e9a86-a612-4f9b-8699-89022dc1b20f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-714e9a86-a612-4f9b-8699-89022dc1b20f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: dendritic cell Description: IL6, IL10 and VEGFA induce STAT3 activation in dendritic cells and inhibition of their antitumor function. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71633b19-7036-427b-aaa9-1ff0766e3ac2 NodeType: Pathway Notes: Headnote: IL-6, IL-10 and VEGFA are produced at the site of inflammation by immune cells and may act on dendritic cells. Signaling description: IL-6, IL-10 and VEGFA, through their receptors, induce STAT3 activation via JAK1/2, TYK2 and SRC. STAT3 inhibits the expression of MHC class II molecules, CD80, CD86 and IL12A by dendritic cells. Outcome effects: MHC class II molecules, CD80, CD86 are required for normal differentiation and maturation of dendritic cells. Thus, when MHC II are downregulated, dendritic cells cannot perform as an antigen-presenting cells and stimulate the anti-tumor effects of CD8+ T cells and natural killer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ_System: lymphatic system PMID: 15356132 PMID: 16177074 PMID: 17186030 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-71633b19-7036-427b-aaa9-1ff0766e3ac2 STAT3 Inhibits Maturation of Dendritic Cells and Facilitates Cancer Progression uuid-71633b19-7036-427b-aaa9-1ff0766e3ac2 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType dendritic cell PS:Description IL6, IL10 and VEGFA induce STAT3 activation in dendritic cells and inhibition of their antitumor function. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71633b19-7036-427b-aaa9-1ff0766e3ac2 PS:NodeType Pathway PS:Notes Headnote: IL-6, IL-10 and VEGFA are produced at the site of inflammation by immune cells and may act on dendritic cells. Signaling description: IL-6, IL-10 and VEGFA, through their receptors, induce STAT3 activation via JAK1/2, TYK2 and SRC. STAT3 inhibits the expression of MHC class II molecules, CD80, CD86 and IL12A by dendritic cells. Outcome effects: MHC class II molecules, CD80, CD86 are required for normal differentiation and maturation of dendritic cells. Thus, when MHC II are downregulated, dendritic cells cannot perform as an antigen-presenting cells and stimulate the anti-tumor effects of CD8+ T cells and natural killer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ_System lymphatic system PS:PMID 15356132 PS:PMID 16177074 PS:PMID 17186030 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Spindle fibers separate the chromosomes into daughter cells during cell division. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-716adde8-1e2e-4c5c-96a3-34438cb71e6f NodeType: Pathway Notes: Headnote: The spindle fibers help separate the chromosomes into daughter cells during the process of cell division. The cellular spindle apparatus consists of the spindle microtubules, centrosomes or asters present at the spindle poles, and associated proteins. Signaling description: Spindle poles are the pointed ends of the spindle where spindle microtubules are nucleated by the centrosomes. In the wide middle portion, known as the spindle midzone, antiparallel microtubules are bundled by the minus-end-directed kinesin ATPase proteins. The two ends of the microtubule differ in growth rate and chromosomes attach to the spindle by binding the faster growing (plus) ends of microtubules. The centrosome is held to the minus ends of microtubules by additional proteins. Dynein-dependent transport of free microtubule bundles from the cytoplasm into the forming spindle continues through prometaphase and metaphase stages of mitosis. Microtubules are stabilized by dynein/dynactin associated with the nuclear envelope and facilitate breakup of the envelope. The major function of the centrosome is to dominate spindle assembly by nucleating microtubules. Outcome effects: Once spindle assembly has progressed to anaphase, centrosomes are no longer required for spindle maintenance. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-716adde8-1e2e-4c5c-96a3-34438cb71e6f Spindle Assembly uuid-716adde8-1e2e-4c5c-96a3-34438cb71e6f PS:CellType generic PS:Description Spindle fibers separate the chromosomes into daughter cells during cell division. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-716adde8-1e2e-4c5c-96a3-34438cb71e6f PS:NodeType Pathway PS:Notes Headnote: The spindle fibers help separate the chromosomes into daughter cells during the process of cell division. The cellular spindle apparatus consists of the spindle microtubules, centrosomes or asters present at the spindle poles, and associated proteins. Signaling description: Spindle poles are the pointed ends of the spindle where spindle microtubules are nucleated by the centrosomes. In the wide middle portion, known as the spindle midzone, antiparallel microtubules are bundled by the minus-end-directed kinesin ATPase proteins. The two ends of the microtubule differ in growth rate and chromosomes attach to the spindle by binding the faster growing (plus) ends of microtubules. The centrosome is held to the minus ends of microtubules by additional proteins. Dynein-dependent transport of free microtubule bundles from the cytoplasm into the forming spindle continues through prometaphase and metaphase stages of mitosis. Microtubules are stabilized by dynein/dynactin associated with the nuclear envelope and facilitate breakup of the envelope. The major function of the centrosome is to dominate spindle assembly by nucleating microtubules. Outcome effects: Once spindle assembly has progressed to anaphase, centrosomes are no longer required for spindle maintenance. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-716d0e68-e1f0-4518-8941-b4736f185444 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-716d0e68-e1f0-4518-8941-b4736f185444 PDGF -> STAT Expression Targets uuid-716d0e68-e1f0-4518-8941-b4736f185444 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-716d0e68-e1f0-4518-8941-b4736f185444 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7192b020-de79-4406-a39e-f210c9fc67c0 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7192b020-de79-4406-a39e-f210c9fc67c0 Elevated Receptors -> Expression Targets in Breast uuid-7192b020-de79-4406-a39e-f210c9fc67c0 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7192b020-de79-4406-a39e-f210c9fc67c0 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71c0738f-45cb-4c85-a7c5-7adef9c5cdce NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-71c0738f-45cb-4c85-a7c5-7adef9c5cdce H2B Modification Sites uuid-71c0738f-45cb-4c85-a7c5-7adef9c5cdce PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71c0738f-45cb-4c85-a7c5-7adef9c5cdce PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71d6058b-2c4b-4933-a2db-f481f38248cf NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-71d6058b-2c4b-4933-a2db-f481f38248cf PTPRU -> CTNNB Signaling uuid-71d6058b-2c4b-4933-a2db-f481f38248cf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-71d6058b-2c4b-4933-a2db-f481f38248cf PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-720ba484-d2fe-4cb0-b346-97d556587013 NodeType: Pathway Notes: Headnote: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT), which encodes an abnormally long polyglutamine repeat in the huntingtin protein. It is monogenic, inherited in an autosomal dominant manner with age-dependent penetrance. Clinical features of Huntington's disease include progressive motor dysfunction (chorea, dystonia, bradykinesia, or incoordination), cognitive decline, and psychiatric disturbance caused by both neuronal dysfunction and neuronal cell death. Within the brain, there is massive striatal neuronal cell death with up to 95% loss of GABAergic medium spiny projection neurons; other affected neuronal populations include the pyramidal neurons of layers III and V of the cortex. HTT is widely expressed in neuronal and non-neuronal tissues and is particularly abundant in neurons of the striatum and layers III and V of the cortex. The lack of neurotrophic action of BDNF is regarded to be one of the main reasons of selected striatal neurons damage in HD. Signaling description: Munatant HTT (mHTT) interacts with many proteins leading to impairment of multiple cellular functions. mHTT infracts with transcription factors SP1, CREB1, REST, SIN3A, NCOR1, and TP53. Interaction of mHTT with CREB1 and REST is responsible for decreased synthesis of neurotrophic factor BDNF, and CREB1. Interaction of mHTT with REST, SIN3A, and NCOR1 impairs chromatin remodeling. mHTT impairs DNA transcription and RNA processing via interaction with TFIIF, TFIID, TBP, TCERG1, PRPF40A and PRPF40B, all these factors make impact in regulation of RNA polymerase II function. mHTT interaction with TORC1 impairs translation and may induce autophagy. Activation of TP53 and induction of caspases via HIPPI (IFT57) may induce apoptosis.Proteins with decreased expression or activity are highlighted in blue. Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17184144 PMID: 21163446 PMID: 21882412 PMID: 22200539 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-720ba484-d2fe-4cb0-b346-97d556587013 Huntingtin Gene Mutation in Striatal Neuron uuid-720ba484-d2fe-4cb0-b346-97d556587013 PS:CellType neuron PS:Description Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-720ba484-d2fe-4cb0-b346-97d556587013 PS:NodeType Pathway PS:Notes Headnote: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT), which encodes an abnormally long polyglutamine repeat in the huntingtin protein. It is monogenic, inherited in an autosomal dominant manner with age-dependent penetrance. Clinical features of Huntington's disease include progressive motor dysfunction (chorea, dystonia, bradykinesia, or incoordination), cognitive decline, and psychiatric disturbance caused by both neuronal dysfunction and neuronal cell death. Within the brain, there is massive striatal neuronal cell death with up to 95% loss of GABAergic medium spiny projection neurons; other affected neuronal populations include the pyramidal neurons of layers III and V of the cortex. HTT is widely expressed in neuronal and non-neuronal tissues and is particularly abundant in neurons of the striatum and layers III and V of the cortex. The lack of neurotrophic action of BDNF is regarded to be one of the main reasons of selected striatal neurons damage in HD. Signaling description: Munatant HTT (mHTT) interacts with many proteins leading to impairment of multiple cellular functions. mHTT infracts with transcription factors SP1, CREB1, REST, SIN3A, NCOR1, and TP53. Interaction of mHTT with CREB1 and REST is responsible for decreased synthesis of neurotrophic factor BDNF, and CREB1. Interaction of mHTT with REST, SIN3A, and NCOR1 impairs chromatin remodeling. mHTT impairs DNA transcription and RNA processing via interaction with TFIIF, TFIID, TBP, TCERG1, PRPF40A and PRPF40B, all these factors make impact in regulation of RNA polymerase II function. mHTT interaction with TORC1 impairs translation and may induce autophagy. Activation of TP53 and induction of caspases via HIPPI (IFT57) may induce apoptosis.Proteins with decreased expression or activity are highlighted in blue. Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17184144 PS:PMID 21163446 PS:PMID 21882412 PS:PMID 22200539 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72139469-7d70-422e-b6a2-385751724945 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-72139469-7d70-422e-b6a2-385751724945 Overview. Endocrine and metabolic diseases (chapter 4) uuid-72139469-7d70-422e-b6a2-385751724945 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72139469-7d70-422e-b6a2-385751724945 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: All cellular layers of hair develop from the niche of dermal papilla (DP) cells, which is the lower part of the hair follicle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-723321d6-e5c0-4738-828e-67eea54cdab8 NodeType: Pathway Notes: Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss and is due to the shortening or absence of the anagen phase of hair growth. Signaling description: All cellular layers of hair develop from the niche of dermal papilla (DP) cells, which is the lower part of the hair follicle adjacent to the dermis that provides the induction of hair keratinocyte differentiation. The signaling which follows at the DP and hair follicle interface in a balding individual with androgenetic alopecia (AGA) results in premature termination of anagen associated with premature entry into catagen. The anagen-to-catagen transition is characterized by apoptotic cell death in hair bulb epithelial cells, including outer root sheath (ORS) cells. Androgen receptor (AR)-overexpressing human DP cells from AGA express androgen-inducible TGFB1, DKK1, and IL6 which suppress hair keratinocyte growth derived from DP cells. DKK1 is an inhibitor of canonical WNT/CTNNB1 signaling and hair follicle growth. DKK1 induces the proapoptotic protein, BAX which results in the apoptosis of ORS keratinocytes. An increased expression of cytokines, such as TGFB1 promotes apoptosis. Outcome effects: IL6 is expressed in the DP of human hair follicles, whereas IL6R and IL6ST are expressed in the inner and ORS of human hair follicles. IL6 promotes anagen-to-catagen transition in vivo. PTGDS is elevated at the mRNA and protein levels in bald scalp compared with haired scalp of men with AGA. Prostaglandin D2 (PGD2) is similarly elevated in the bald scalp. PGD2 is a potent vessel contractor and may contribute to AGA development through the deterioration of blood supply of the hair follicle. PGD2 inhibits hair follicle regeneration through PTGDR2 which suggests that the inhibition of PGD2 production or PTGDR2 signaling may promote skin regeneration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 12015971 PMID: 12894996 PMID: 22358062 PMID: 22440736 PMID: 23974579 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-723321d6-e5c0-4738-828e-67eea54cdab8 Hair Follicle Keratinocyte Apoptosis uuid-723321d6-e5c0-4738-828e-67eea54cdab8 PS:CellType keratinocyte PS:Description All cellular layers of hair develop from the niche of dermal papilla (DP) cells, which is the lower part of the hair follicle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-723321d6-e5c0-4738-828e-67eea54cdab8 PS:NodeType Pathway PS:Notes Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss and is due to the shortening or absence of the anagen phase of hair growth. Signaling description: All cellular layers of hair develop from the niche of dermal papilla (DP) cells, which is the lower part of the hair follicle adjacent to the dermis that provides the induction of hair keratinocyte differentiation. The signaling which follows at the DP and hair follicle interface in a balding individual with androgenetic alopecia (AGA) results in premature termination of anagen associated with premature entry into catagen. The anagen-to-catagen transition is characterized by apoptotic cell death in hair bulb epithelial cells, including outer root sheath (ORS) cells. Androgen receptor (AR)-overexpressing human DP cells from AGA express androgen-inducible TGFB1, DKK1, and IL6 which suppress hair keratinocyte growth derived from DP cells. DKK1 is an inhibitor of canonical WNT/CTNNB1 signaling and hair follicle growth. DKK1 induces the proapoptotic protein, BAX which results in the apoptosis of ORS keratinocytes. An increased expression of cytokines, such as TGFB1 promotes apoptosis. Outcome effects: IL6 is expressed in the DP of human hair follicles, whereas IL6R and IL6ST are expressed in the inner and ORS of human hair follicles. IL6 promotes anagen-to-catagen transition in vivo. PTGDS is elevated at the mRNA and protein levels in bald scalp compared with haired scalp of men with AGA. Prostaglandin D2 (PGD2) is similarly elevated in the bald scalp. PGD2 is a potent vessel contractor and may contribute to AGA development through the deterioration of blood supply of the hair follicle. PGD2 inhibits hair follicle regeneration through PTGDR2 which suggests that the inhibition of PGD2 production or PTGDR2 signaling may promote skin regeneration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 12015971 PS:PMID 12894996 PS:PMID 22358062 PS:PMID 22440736 PS:PMID 23974579 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-727f08d6-c074-4009-b092-673e1a8bb678 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-727f08d6-c074-4009-b092-673e1a8bb678 Ketonogenesis uuid-727f08d6-c074-4009-b092-673e1a8bb678 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-727f08d6-c074-4009-b092-673e1a8bb678 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72846a8d-ee43-4f18-9339-009bc57ebb2e NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: placenta Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-72846a8d-ee43-4f18-9339-009bc57ebb2e Elevated Receptors -> Expression Targets in Placenta uuid-72846a8d-ee43-4f18-9339-009bc57ebb2e PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72846a8d-ee43-4f18-9339-009bc57ebb2e PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ placenta PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72848bf0-6eeb-4161-b82c-0240bb65c544 NodeType: Pathway Notes: It is estimated that 2%–3% of patients with the Z-type of alpha-1-antitrypsin deficiency develop liver cirrhosis during childhood. The rest of the patients are at an elevated risk for developing liver function abnormalities. Alpha-1-antitrypsin (AAT) is synthesized by hepatocytes and monocytes, and it is passively transported through normal circulation into the lungs. Approximately 80%–90% of mutant AAT (SERPINA1) protein is retained in the endoplasmic reticulum (ER) of hepatocytes. Retention of the mutant protein within the ER is thought to be the basis for the pathogenesis of hepatic disease. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: liver Organ_System: digestive system Organelle: endoplasmic reticulum PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-72848bf0-6eeb-4161-b82c-0240bb65c544 2_SERPINA1-associated liver damage uuid-72848bf0-6eeb-4161-b82c-0240bb65c544 PS:CellType hepatocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72848bf0-6eeb-4161-b82c-0240bb65c544 PS:NodeType Pathway PS:Notes It is estimated that 2%–3% of patients with the Z-type of alpha-1-antitrypsin deficiency develop liver cirrhosis during childhood. The rest of the patients are at an elevated risk for developing liver function abnormalities. Alpha-1-antitrypsin (AAT) is synthesized by hepatocytes and monocytes, and it is passively transported through normal circulation into the lungs. Approximately 80%–90% of mutant AAT (SERPINA1) protein is retained in the endoplasmic reticulum (ER) of hepatocytes. Retention of the mutant protein within the ER is thought to be the basis for the pathogenesis of hepatic disease. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ liver PS:Organ_System digestive system PS:Organelle endoplasmic reticulum PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-728d7077-23d4-454b-98e8-c2c7277802c6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-728d7077-23d4-454b-98e8-c2c7277802c6 HBEGF -> EP300/ETS/ETV/SP1 Expression Targets uuid-728d7077-23d4-454b-98e8-c2c7277802c6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-728d7077-23d4-454b-98e8-c2c7277802c6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-729dbc76-57eb-407a-97b2-6117dde74e66 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-729dbc76-57eb-407a-97b2-6117dde74e66 ERBB2/3 -> EP300/ETS/ETV/SP1 Signaling uuid-729dbc76-57eb-407a-97b2-6117dde74e66 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-729dbc76-57eb-407a-97b2-6117dde74e66 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Actin, which is exclusively found in eukaryotes, is a highly conserved protein family that consists of three broad classes including alpha-, beta-, and gamma-isoforms. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72bd848a-01c2-478c-a8b5-a79ee8f363a8 NodeType: Pathway Notes: Headnote: Actin belongs to a highly conserved eukaryotic protein family which consists of three broad classes including alpha-, beta-, and gamma-isoforms. The highest concentrations of actin are in striated muscles; however, there are significant quantities of actin present in nonmuscle cells where it has a variety of functions including myosin-independent changes of cell shape, motor-based organelle transport, regulation of ion transport, and receptor-mediated responses of the cell to external signals. Signaling description: Actin exists in two principal forms: globular monomeric (G-actin) and filamentous polymeric (F-actin). G-actin contains an ATP binding site in the center of the molecule and can form dimers or trimers that serve as sites for nucleation and growth of F-actin. Actin binds to a significant number of proteins collectively known as actin-binding proteins (ABPs) which bind to actin filaments and modulate their properties and functions. ABPs can be classified into several groups depending upon their activity towards actin. Cross-linking proteins, such as actin related protein 2/3 complex, ACTN1, FSCN1, and filamin, force the elongation of filament bundles, branching of filaments, and formation of three-dimensional networks. Actin related protein 2/3 complex binds to the side of ATP-F-actin near the growing, or barbed end, of the filament and causes nucleation of a new F-actin branch. In addition, WASP-family proteins, including WASF1, bring G-actin and actin related protein 2/3 complex together to regulate elongation while monomer-binding proteins bind to and prevent the polymerization of G-actin. Some examples of monomer-binding proteins include profilin, thymosin, and ABP-50. Outcome effects: The filament-severing proteins such as GSN and CFL1/2 shorten the average length of filaments by binding to the side of F-actin and cutting it into two pieces. Filament end-binding proteins, such as CAPZA1, cap the ends of F-actin and prevent the exchange of monomers. Lastly, stabilizing proteins, including tropomyosin and tropomodulin, prevent actin depolymerization by binding to the sides of F-actin. The actin cytoskeleton may be rearranged in response to the activation of CDC42 and Rac signal transduction pathways which leads to the formation of filopodia and lamellipodia, respectively. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-72bd848a-01c2-478c-a8b5-a79ee8f363a8 Actin Cytoskeleton uuid-72bd848a-01c2-478c-a8b5-a79ee8f363a8 PS:CellType generic PS:Description Actin, which is exclusively found in eukaryotes, is a highly conserved protein family that consists of three broad classes including alpha-, beta-, and gamma-isoforms. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72bd848a-01c2-478c-a8b5-a79ee8f363a8 PS:NodeType Pathway PS:Notes Headnote: Actin belongs to a highly conserved eukaryotic protein family which consists of three broad classes including alpha-, beta-, and gamma-isoforms. The highest concentrations of actin are in striated muscles; however, there are significant quantities of actin present in nonmuscle cells where it has a variety of functions including myosin-independent changes of cell shape, motor-based organelle transport, regulation of ion transport, and receptor-mediated responses of the cell to external signals. Signaling description: Actin exists in two principal forms: globular monomeric (G-actin) and filamentous polymeric (F-actin). G-actin contains an ATP binding site in the center of the molecule and can form dimers or trimers that serve as sites for nucleation and growth of F-actin. Actin binds to a significant number of proteins collectively known as actin-binding proteins (ABPs) which bind to actin filaments and modulate their properties and functions. ABPs can be classified into several groups depending upon their activity towards actin. Cross-linking proteins, such as actin related protein 2/3 complex, ACTN1, FSCN1, and filamin, force the elongation of filament bundles, branching of filaments, and formation of three-dimensional networks. Actin related protein 2/3 complex binds to the side of ATP-F-actin near the growing, or barbed end, of the filament and causes nucleation of a new F-actin branch. In addition, WASP-family proteins, including WASF1, bring G-actin and actin related protein 2/3 complex together to regulate elongation while monomer-binding proteins bind to and prevent the polymerization of G-actin. Some examples of monomer-binding proteins include profilin, thymosin, and ABP-50. Outcome effects: The filament-severing proteins such as GSN and CFL1/2 shorten the average length of filaments by binding to the side of F-actin and cutting it into two pieces. Filament end-binding proteins, such as CAPZA1, cap the ends of F-actin and prevent the exchange of monomers. Lastly, stabilizing proteins, including tropomyosin and tropomodulin, prevent actin depolymerization by binding to the sides of F-actin. The actin cytoskeleton may be rearranged in response to the activation of CDC42 and Rac signal transduction pathways which leads to the formation of filopodia and lamellipodia, respectively. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: Fibulin 5 (FBLN5) is downregulated in some tumors and potentiates angiogenesis through re-activation of migration and proliferation of endothelial cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72d05f1b-374d-4722-a90d-4ec8a4a4f77d NodeType: Pathway Notes: Headnote: Fibulin 5 (FBLN5) is an extracellular matrix (ECM) protein prominently expressed in developing arteries. FBLN5's function is the stabilization of basement membrane and elastic fibers. FBLN5 enhances attachment of endothelial cell (ECs) to the basement membrane (BM) and inhibits migration and proliferation of ECs in a context-dependent manner. Signaling description: Generally, FBLN5 blocks angiogenesis by inducing the anti-angiogenic protein THBS1 and by antagonizing pro-angiogenic VEGF and TEK signaling. The precise mechanism of interaction of FBLN5 with THBS1, VEGFA and TEK signaling pathways is not clear. The down-regulation of FBLN5 potentiates angiogenesis in the opposite manner. Normally, FBLN5 enhances the attachment of ECs to BM through binding to ECM proteins (ELN, EMILIN1 and others) and integrins on the cell surface; whereas, down-regulation of FBLN5 potentiates the release of ECs from BM and their migration. FBLN5 may regulate ECs migration and proliferation through integrins, but the exact mechanism of this regulatory action of FBLN5 is yet to be determined. Outcome effects: The detachment of ECs from BM, their migration and proliferation promoted by down-regulation of FBLN5 signaling leads to activation of angiogenesis. Animal data: The majority of the data concerning the FBLN5 role in angiogenesis were revealed from animal model experiments. Some data were obtained from human cancer cell experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 16510581 PMID: 16555973 PMID: 17607303 PMID: 19798595 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-72d05f1b-374d-4722-a90d-4ec8a4a4f77d FBLN5 Potentiates Migration and Proliferation of Endothelial Cells in Cancer uuid-72d05f1b-374d-4722-a90d-4ec8a4a4f77d PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description Fibulin 5 (FBLN5) is downregulated in some tumors and potentiates angiogenesis through re-activation of migration and proliferation of endothelial cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72d05f1b-374d-4722-a90d-4ec8a4a4f77d PS:NodeType Pathway PS:Notes Headnote: Fibulin 5 (FBLN5) is an extracellular matrix (ECM) protein prominently expressed in developing arteries. FBLN5's function is the stabilization of basement membrane and elastic fibers. FBLN5 enhances attachment of endothelial cell (ECs) to the basement membrane (BM) and inhibits migration and proliferation of ECs in a context-dependent manner. Signaling description: Generally, FBLN5 blocks angiogenesis by inducing the anti-angiogenic protein THBS1 and by antagonizing pro-angiogenic VEGF and TEK signaling. The precise mechanism of interaction of FBLN5 with THBS1, VEGFA and TEK signaling pathways is not clear. The down-regulation of FBLN5 potentiates angiogenesis in the opposite manner. Normally, FBLN5 enhances the attachment of ECs to BM through binding to ECM proteins (ELN, EMILIN1 and others) and integrins on the cell surface; whereas, down-regulation of FBLN5 potentiates the release of ECs from BM and their migration. FBLN5 may regulate ECs migration and proliferation through integrins, but the exact mechanism of this regulatory action of FBLN5 is yet to be determined. Outcome effects: The detachment of ECs from BM, their migration and proliferation promoted by down-regulation of FBLN5 signaling leads to activation of angiogenesis. Animal data: The majority of the data concerning the FBLN5 role in angiogenesis were revealed from animal model experiments. Some data were obtained from human cancer cell experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 16510581 PS:PMID 16555973 PS:PMID 17607303 PS:PMID 19798595 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Profound innate antiviral defense mechanism exists within the cardiac myocyte. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72e4c2b7-b69f-45af-b56d-47c6f0a8e184 NodeType: Pathway Notes: Profound innate antiviral defense mechanism exists within the cardiac myocyte that can be inhibited by suppressor of cytokine signaling (SOCS) 1 or SOCS3. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 12588885 PMID: 19451363 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-72e4c2b7-b69f-45af-b56d-47c6f0a8e184 SOCS in Negative Feedback Regulation in Myocarditis uuid-72e4c2b7-b69f-45af-b56d-47c6f0a8e184 PS:CellType cardiac myocyte PS:Description Profound innate antiviral defense mechanism exists within the cardiac myocyte. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72e4c2b7-b69f-45af-b56d-47c6f0a8e184 PS:NodeType Pathway PS:Notes Profound innate antiviral defense mechanism exists within the cardiac myocyte that can be inhibited by suppressor of cytokine signaling (SOCS) 1 or SOCS3. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 12588885 PS:PMID 19451363 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72e8f8f9-d493-402b-a9bd-c2f8903d2e7f NodeType: Pathway Notes: Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in the DUOX2, SLC5A5, TG, TPO, and TSHB genes prevent or reduce the production of thyroid hormones. In iodine sufficient countries, 85% of congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis called dyshormonogenesis. Thyroglobulin (TG) is a precursor protein used by the thyroid gland to produce thyroxine (T4) and triiodothyronine (T3). Outcome effects: TG gene autosomal recessive mutations cause dysmorphogenesis with a wide phenotype variation and is characterized usually by the presence of congenital goiter or goiter appearing shortly after birth, high I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T4 and low, normal or high serum T3. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: thyroid gland Organ_System: endocrine system PMID: 23455760 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-72e8f8f9-d493-402b-a9bd-c2f8903d2e7f Thyroglobulin Related Thyroid Dyshormonogenesis uuid-72e8f8f9-d493-402b-a9bd-c2f8903d2e7f PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72e8f8f9-d493-402b-a9bd-c2f8903d2e7f PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in the DUOX2, SLC5A5, TG, TPO, and TSHB genes prevent or reduce the production of thyroid hormones. In iodine sufficient countries, 85% of congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis called dyshormonogenesis. Thyroglobulin (TG) is a precursor protein used by the thyroid gland to produce thyroxine (T4) and triiodothyronine (T3). Outcome effects: TG gene autosomal recessive mutations cause dysmorphogenesis with a wide phenotype variation and is characterized usually by the presence of congenital goiter or goiter appearing shortly after birth, high I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T4 and low, normal or high serum T3. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 23455760 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72ebc95e-d2cc-4b8e-8848-e2bc3bbf33c1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-72ebc95e-d2cc-4b8e-8848-e2bc3bbf33c1 NSP8 interactions uuid-72ebc95e-d2cc-4b8e-8848-e2bc3bbf33c1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72ebc95e-d2cc-4b8e-8848-e2bc3bbf33c1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Eicosanoids (or icosanoids) are a family of lipophilic small molecules derived from the twenty carbon fatty acid-arachidonic acid (omega-6 fatty acid) and possess mostly proinflammatory properties. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72f1f28b-79ea-4bf0-845c-d29fc4915bae NodeType: Pathway Notes: Headnote: Eicosanoids (or icosanoids) are a family of lipophilic small molecules derived from the twenty carbon fatty acid-arachidonic acid (omega-6 fatty acid) and possess mostly proinflammatory properties. These molecules include leukotrienes (LTA4, LTE4, LTD4, LTC4, and LTB4), prostaglandins (PGD2, PGF2, and PGE2), prostacyclins (PGI2), and thromboxanes (TXA2). In addition, eicosanoids also include derivatives of eicosapentaenoic acid (EPA, omega-3 fatty acid), PGG3, PGH2, PGI2, TXA2, and LTB4, and the derivatives of dihomo-gamma-linolenic acid (DGLA, omega-6 fatty acid), PGE1, and TXA1. Signaling description: The synthesis of these molecules proceeds simultaneously. Eicosapentaenoic acid-derived eicosanoids participate in similar reactions during inflammation as omega-6 fatty acid-derived ones, but with lower efficiency. This is most likely due to omega-3 fatty acid derivatives competing with omega-6 fatty acid derivatives for receptors; they may be natural inhibitors of inflammation in an organism. Low dietary intake of omega-3 fatty acids has been linked to several inflammation-related diseases. Most eicosanoids act locally on neighboring cells instead of on distant parts of the body. They are not stored in cells so the regulation of their synthesis is the main way to control their activity. Membrane-bound phospholipase A2 in response to extracellular stimuli releases arachidonic acid phospholipids. PTGS2 synthase converts arachidonic acid to PGG2. PTGS2 increases prostaglandin levels in inflammation. ALOX5 acts with the membrane-bound protein ALOX5AP to produce LTA4 which is hydrolyzed to produce LTB4 or LTC4 and LTD4. The most frequently used non-steroidal anti-inflammatory drugs (NSAIDS) including aspirin, acetaminophen, and ibuprofen inhibit PTGS2. Leukotrienes, produced by mast cells and leukocytes, are primarily known for their role in chemotaxis and vascular permeability activation. LTB4, in response to inflammatory mediators, is able to induce the chemotaxis of leukocytes to the injured endothelium. LTB4 stimulates production by leukocytes IL1/IL2 and IFNG. LTB4 is a powerful chemoattractant for neutrophils where it is able to induce the formation of reactive oxygen species. Leukotrienes LTC4, LTD4, and LTE4 induce endothelial vascular permeability. In airway smooth muscle cells, they cause constriction that signal via the CYSLT1 receptor. In alveoli, this function leads to bronchospasm. Outcome effects: Local inflammatory symtoms produced by prostaglandins include vasoconstriction or vasodilation, coagulation (platelet aggregation), pain, and fever. PGD2 is produced by mast cells and decreases platelet and leukocyte aggregation, T-cell proliferation, and lymphocyte migration. PGD2 induces vasodilation but causes bronchoconstriction. PGD2 is commonly known as a sleep promoter, reduces fever, and acts in an opposite manner as PGE2. PGE2 and PGF2alpha are produced in kidney, spleen, heart, and brain. PGE2 is one of the main prostaglandins involved in inflammation. PGE2 sensitizes pain neurons and causes fever or the heat of localized inflammation. PGE2 increases vasodilation and platelet aggregation induction of uterine contractions. Conversely, it plays an anti-inflammatory role via inhibition of granulocyte functions and decreases T-cell proliferation. PGF2alpha increases vasoconstriction, bronchoconstriction, and smooth muscle contraction. Prostacyclin PGI2, produced in heart and vascular endothelial cells, inhibits coagulation (platelet aggregation) and provokes vasodilation. Thromboxane (TXA2) is produced by platelets and acts as a fast vasoconstrictor and stimulator of coagulation (platelet aggregation). It also causes constriction of blood vessels and bronchioles. All small eicosanoids act through G-protein related signaling pathways. The specificity of eicosanoid action is reached due to cell-specific expression of their receptors and due to the interaction with other active signaling pathways. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-72f1f28b-79ea-4bf0-845c-d29fc4915bae Eicosanoids in Inflammation uuid-72f1f28b-79ea-4bf0-845c-d29fc4915bae PS:CellType generic PS:Description Eicosanoids (or icosanoids) are a family of lipophilic small molecules derived from the twenty carbon fatty acid-arachidonic acid (omega-6 fatty acid) and possess mostly proinflammatory properties. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-72f1f28b-79ea-4bf0-845c-d29fc4915bae PS:NodeType Pathway PS:Notes Headnote: Eicosanoids (or icosanoids) are a family of lipophilic small molecules derived from the twenty carbon fatty acid-arachidonic acid (omega-6 fatty acid) and possess mostly proinflammatory properties. These molecules include leukotrienes (LTA4, LTE4, LTD4, LTC4, and LTB4), prostaglandins (PGD2, PGF2, and PGE2), prostacyclins (PGI2), and thromboxanes (TXA2). In addition, eicosanoids also include derivatives of eicosapentaenoic acid (EPA, omega-3 fatty acid), PGG3, PGH2, PGI2, TXA2, and LTB4, and the derivatives of dihomo-gamma-linolenic acid (DGLA, omega-6 fatty acid), PGE1, and TXA1. Signaling description: The synthesis of these molecules proceeds simultaneously. Eicosapentaenoic acid-derived eicosanoids participate in similar reactions during inflammation as omega-6 fatty acid-derived ones, but with lower efficiency. This is most likely due to omega-3 fatty acid derivatives competing with omega-6 fatty acid derivatives for receptors; they may be natural inhibitors of inflammation in an organism. Low dietary intake of omega-3 fatty acids has been linked to several inflammation-related diseases. Most eicosanoids act locally on neighboring cells instead of on distant parts of the body. They are not stored in cells so the regulation of their synthesis is the main way to control their activity. Membrane-bound phospholipase A2 in response to extracellular stimuli releases arachidonic acid phospholipids. PTGS2 synthase converts arachidonic acid to PGG2. PTGS2 increases prostaglandin levels in inflammation. ALOX5 acts with the membrane-bound protein ALOX5AP to produce LTA4 which is hydrolyzed to produce LTB4 or LTC4 and LTD4. The most frequently used non-steroidal anti-inflammatory drugs (NSAIDS) including aspirin, acetaminophen, and ibuprofen inhibit PTGS2. Leukotrienes, produced by mast cells and leukocytes, are primarily known for their role in chemotaxis and vascular permeability activation. LTB4, in response to inflammatory mediators, is able to induce the chemotaxis of leukocytes to the injured endothelium. LTB4 stimulates production by leukocytes IL1/IL2 and IFNG. LTB4 is a powerful chemoattractant for neutrophils where it is able to induce the formation of reactive oxygen species. Leukotrienes LTC4, LTD4, and LTE4 induce endothelial vascular permeability. In airway smooth muscle cells, they cause constriction that signal via the CYSLT1 receptor. In alveoli, this function leads to bronchospasm. Outcome effects: Local inflammatory symtoms produced by prostaglandins include vasoconstriction or vasodilation, coagulation (platelet aggregation), pain, and fever. PGD2 is produced by mast cells and decreases platelet and leukocyte aggregation, T-cell proliferation, and lymphocyte migration. PGD2 induces vasodilation but causes bronchoconstriction. PGD2 is commonly known as a sleep promoter, reduces fever, and acts in an opposite manner as PGE2. PGE2 and PGF2alpha are produced in kidney, spleen, heart, and brain. PGE2 is one of the main prostaglandins involved in inflammation. PGE2 sensitizes pain neurons and causes fever or the heat of localized inflammation. PGE2 increases vasodilation and platelet aggregation induction of uterine contractions. Conversely, it plays an anti-inflammatory role via inhibition of granulocyte functions and decreases T-cell proliferation. PGF2alpha increases vasoconstriction, bronchoconstriction, and smooth muscle contraction. Prostacyclin PGI2, produced in heart and vascular endothelial cells, inhibits coagulation (platelet aggregation) and provokes vasodilation. Thromboxane (TXA2) is produced by platelets and acts as a fast vasoconstrictor and stimulator of coagulation (platelet aggregation). It also causes constriction of blood vessels and bronchioles. All small eicosanoids act through G-protein related signaling pathways. The specificity of eicosanoid action is reached due to cell-specific expression of their receptors and due to the interaction with other active signaling pathways. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7319331e-f2bd-4624-b3a2-0659ea9bd9b1 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7319331e-f2bd-4624-b3a2-0659ea9bd9b1 CXCL6 Expression Targets uuid-7319331e-f2bd-4624-b3a2-0659ea9bd9b1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7319331e-f2bd-4624-b3a2-0659ea9bd9b1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-731f7d0a-885d-49db-8a86-da1dce972839 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-731f7d0a-885d-49db-8a86-da1dce972839 FGF19 signaling pathway uuid-731f7d0a-885d-49db-8a86-da1dce972839 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-731f7d0a-885d-49db-8a86-da1dce972839 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: The pituitary secretes thyroid-stimulating hormone (TSH) which stimulates the thyroid gland to secrete hormones that affect body metabolism. TSH resistance can cause hypothyroidism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-733fe971-4c0b-477f-bb69-e3e0704d28c2 NodeType: Pathway Notes: Headnote: Hypothyroidism is a pathological state characterized by the deficiency of thyroid hormones. The pituitary secretes thyroid-stimulating hormone (TSH) which stimulates the thyroid gland to secrete thyroid hormones. TSH resistance can cause hypothyroidism and is characterized by high levels of serum TSH, normal or reduced levels of serum thyroid hormone, and a normal/hypoplastic thyroid gland. Depending on the degree of TSH insensitivity, the presentations may be extremely variable, ranging from severe congenital hypothyroidism to mild elevations of TSH in the absence of hypothyroidism. The defect may affect any step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes.The pathway describes the three major signaling routes up-regulated by TSHR: via G proteins to cAMP, G proteins to Ca2, and STAT3 activation. Outcome effects: There exist several forms of TSH resistance with the most common being a hereditary syndrome of congenital TSH resistance due to mutations in the TSH receptor gene leading to thyroid hypoplasia. Twenty three different TSHR loss-of-function mutations have been shown to be responsible for TSH resistance. Mutations in Gs alpha (GNAS) can lead to pseudohypoparathyroidism type 1a and defective TSH signaling. Mutations and polymorphisms in other genes, such as PDE-8B may be involved in TSH resistance. The reduced function of mutated genes may lead to a down-regulation of thyroid hormone synthesis and a diminished rate of thyroid cell proliferation. Low levels of thyroid hormones can cause thyroid dysgenesis. . Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 21513912 PMID: 23154162 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-733fe971-4c0b-477f-bb69-e3e0704d28c2 Thyroid Stimulating Hormone (TSH) Resistance in Congenital Hypothyroidism uuid-733fe971-4c0b-477f-bb69-e3e0704d28c2 PS:CellType thyroid cell PS:Description The pituitary secretes thyroid-stimulating hormone (TSH) which stimulates the thyroid gland to secrete hormones that affect body metabolism. TSH resistance can cause hypothyroidism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-733fe971-4c0b-477f-bb69-e3e0704d28c2 PS:NodeType Pathway PS:Notes Headnote: Hypothyroidism is a pathological state characterized by the deficiency of thyroid hormones. The pituitary secretes thyroid-stimulating hormone (TSH) which stimulates the thyroid gland to secrete thyroid hormones. TSH resistance can cause hypothyroidism and is characterized by high levels of serum TSH, normal or reduced levels of serum thyroid hormone, and a normal/hypoplastic thyroid gland. Depending on the degree of TSH insensitivity, the presentations may be extremely variable, ranging from severe congenital hypothyroidism to mild elevations of TSH in the absence of hypothyroidism. The defect may affect any step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes.The pathway describes the three major signaling routes up-regulated by TSHR: via G proteins to cAMP, G proteins to Ca2, and STAT3 activation. Outcome effects: There exist several forms of TSH resistance with the most common being a hereditary syndrome of congenital TSH resistance due to mutations in the TSH receptor gene leading to thyroid hypoplasia. Twenty three different TSHR loss-of-function mutations have been shown to be responsible for TSH resistance. Mutations in Gs alpha (GNAS) can lead to pseudohypoparathyroidism type 1a and defective TSH signaling. Mutations and polymorphisms in other genes, such as PDE-8B may be involved in TSH resistance. The reduced function of mutated genes may lead to a down-regulation of thyroid hormone synthesis and a diminished rate of thyroid cell proliferation. Low levels of thyroid hormones can cause thyroid dysgenesis. . Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 21513912 PS:PMID 23154162 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-736643ac-8193-4d94-9925-75b727add622 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-736643ac-8193-4d94-9925-75b727add622 CCKBR -> Neurotransmitter Uptake uuid-736643ac-8193-4d94-9925-75b727add622 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-736643ac-8193-4d94-9925-75b727add622 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: Leptin is found at elevated levels in the peritoneal fluid and serum of patients with endometriosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-738d94eb-0915-4235-98d0-56c09d6a6a94 NodeType: Pathway Notes: Headnote: Leptin is primarily known as the protein released by fat cells. However, leptin is also found at elevated levels in the peritoneal fluid and serum of patients with endometriosis. Signaling description: Leptin expression can be stimulated by pro-inflammatory cytokines such as TNFa and IL-1B and can, in turn, stimulate proliferation of ectopic endometriotic cells. Leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Organ: uterus Organ_System: reproductive system PMID: 20825374 PMID: 23184927 PMID: 24927773 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-738d94eb-0915-4235-98d0-56c09d6a6a94 Leptin Role in Endometriosis uuid-738d94eb-0915-4235-98d0-56c09d6a6a94 PS:CellType endometrium cell PS:Description Leptin is found at elevated levels in the peritoneal fluid and serum of patients with endometriosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-738d94eb-0915-4235-98d0-56c09d6a6a94 PS:NodeType Pathway PS:Notes Headnote: Leptin is primarily known as the protein released by fat cells. However, leptin is also found at elevated levels in the peritoneal fluid and serum of patients with endometriosis. Signaling description: Leptin expression can be stimulated by pro-inflammatory cytokines such as TNFa and IL-1B and can, in turn, stimulate proliferation of ectopic endometriotic cells. Leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 20825374 PS:PMID 23184927 PS:PMID 24927773 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-738f1a82-e72c-4e16-800e-42f577e40d2f NodeType: Pathway Organ: kidney Organ: lung Organ: skin Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-738f1a82-e72c-4e16-800e-42f577e40d2f Proteins Involved in Cystic Fibrosis uuid-738f1a82-e72c-4e16-800e-42f577e40d2f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-738f1a82-e72c-4e16-800e-42f577e40d2f PS:NodeType Pathway PS:Organ kidney PS:Organ lung PS:Organ skin PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-739c091c-2dc8-41a8-bef8-1c4b77258520 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-739c091c-2dc8-41a8-bef8-1c4b77258520 TGFB1-TGFBR1 Expression Targets uuid-739c091c-2dc8-41a8-bef8-1c4b77258520 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-739c091c-2dc8-41a8-bef8-1c4b77258520 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73aea6b9-9f23-4894-b752-9bef3fd5aabe NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-73aea6b9-9f23-4894-b752-9bef3fd5aabe EGF -> HIF1A Expression Targets uuid-73aea6b9-9f23-4894-b752-9bef3fd5aabe PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73aea6b9-9f23-4894-b752-9bef3fd5aabe PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73d8137a-9d44-473d-911c-390fa73c6bdb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-73d8137a-9d44-473d-911c-390fa73c6bdb Conjuctival epithelium Induce Goblet cells and Lacrimation uuid-73d8137a-9d44-473d-911c-390fa73c6bdb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73d8137a-9d44-473d-911c-390fa73c6bdb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: granulosa cell CellType: theca cell Description: Loss of function mutations affecting FSHR and LHCGR cause gonadotropin resistance with hypergonadotropic hypogonadism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73dc9688-340a-4b69-95e8-62fc77d1e51e NodeType: Pathway Notes: Headnote: Follicle stimulating hormone (FSH) and lutenising hormone (LH) are produced in the anterior lobe of pituitary gland and their function in gonads is mediated over distinct FSH and LH receptors (FSHR and LHCGR), respectively. LH receptors are found on both granulosa and thecal cells; the expression of FSH receptors is restricted to the granulose cells. Loss of function mutations in these receptors cause gonadotropin resistance with hypergonadotropic hypogonadism. Mutations of beta subunits of FSH or LH (FSHB and LHB respectively) also cause hypogonadism and infertility. Signaling description: LH stimulates female progesterone synthesis and ovulation and also theca cell androgen production. FSH is required for follicle maturation and stimulation of ovarian estrogen production. During the process of folliculogenesis, the conversion of cholesterol into ovarian hormones takes place. Conversion of steroids to androgens occurs within the theca cells. Androgens and are converted to estrogens by aromatase enzyme (CYP19A1) in the granulosa cells. NR5A1 is a key transcriptional regulator involved in production of key steroidogenic enzymes and transporters, including STAR, CYP11A1, CYP17A1, and CYP19A. Mutations in the NR5A1 have also been associated with impairment of ovarian development and function. CYP19A1 mutation causes follicle maturation arrest and subsequently ovarian dysgenesis. FOXL2 is involved in the development of granulosa cells and controls CYP19A. If mutated, it may cause female infertility. Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 18703422 PMID: 20362963 PMID: 20364094 PMID: 20382564 PMID: 24365330 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-73dc9688-340a-4b69-95e8-62fc77d1e51e LH and FSH Signaling Impairment in Primary Ovarian Insufficiency uuid-73dc9688-340a-4b69-95e8-62fc77d1e51e PS:CellType granulosa cell PS:CellType theca cell PS:Description Loss of function mutations affecting FSHR and LHCGR cause gonadotropin resistance with hypergonadotropic hypogonadism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73dc9688-340a-4b69-95e8-62fc77d1e51e PS:NodeType Pathway PS:Notes Headnote: Follicle stimulating hormone (FSH) and lutenising hormone (LH) are produced in the anterior lobe of pituitary gland and their function in gonads is mediated over distinct FSH and LH receptors (FSHR and LHCGR), respectively. LH receptors are found on both granulosa and thecal cells; the expression of FSH receptors is restricted to the granulose cells. Loss of function mutations in these receptors cause gonadotropin resistance with hypergonadotropic hypogonadism. Mutations of beta subunits of FSH or LH (FSHB and LHB respectively) also cause hypogonadism and infertility. Signaling description: LH stimulates female progesterone synthesis and ovulation and also theca cell androgen production. FSH is required for follicle maturation and stimulation of ovarian estrogen production. During the process of folliculogenesis, the conversion of cholesterol into ovarian hormones takes place. Conversion of steroids to androgens occurs within the theca cells. Androgens and are converted to estrogens by aromatase enzyme (CYP19A1) in the granulosa cells. NR5A1 is a key transcriptional regulator involved in production of key steroidogenic enzymes and transporters, including STAR, CYP11A1, CYP17A1, and CYP19A. Mutations in the NR5A1 have also been associated with impairment of ovarian development and function. CYP19A1 mutation causes follicle maturation arrest and subsequently ovarian dysgenesis. FOXL2 is involved in the development of granulosa cells and controls CYP19A. If mutated, it may cause female infertility. Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18703422 PS:PMID 20362963 PS:PMID 20364094 PS:PMID 20382564 PS:PMID 24365330 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73de598d-7fcf-42e1-8b08-6d760b8ec75e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-73de598d-7fcf-42e1-8b08-6d760b8ec75e CSF1 -> STAT Expression Targets uuid-73de598d-7fcf-42e1-8b08-6d760b8ec75e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73de598d-7fcf-42e1-8b08-6d760b8ec75e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73e9c016-5900-4372-ac3d-08854c5e6004 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-73e9c016-5900-4372-ac3d-08854c5e6004 Proteins Involved in Ichthyosis uuid-73e9c016-5900-4372-ac3d-08854c5e6004 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73e9c016-5900-4372-ac3d-08854c5e6004 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: leukocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73ea99c4-cab5-4dc8-9487-9dca1346655d NodeType: Pathway Organ_System: digestive system PMID: 14755326 PMID: 20938460 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-73ea99c4-cab5-4dc8-9487-9dca1346655d DupA Induced IL12 Production in Helicobacter Pylori Infection uuid-73ea99c4-cab5-4dc8-9487-9dca1346655d PS:CellType leukocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73ea99c4-cab5-4dc8-9487-9dca1346655d PS:NodeType Pathway PS:Organ_System digestive system PS:PMID 14755326 PS:PMID 20938460 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73f09608-2be7-49f5-9b89-fb9b60463f2a NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-73f09608-2be7-49f5-9b89-fb9b60463f2a Proteins Involved in Autistic Disorder and Aggression uuid-73f09608-2be7-49f5-9b89-fb9b60463f2a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73f09608-2be7-49f5-9b89-fb9b60463f2a PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Duchenne muscular dystrophy (DMD) is caused by mutations in the gene coding for dystrophin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73fafc3e-f5a4-4246-a7dc-db6fdc321cd1 NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. Several channel types were reported as possible points of Ca2+ entry in DMD. Stretch-activated Ca2+ channels respond to increased susceptibility to stretch. Store-operated and leak channels were characterized by their physiological parameters, and it was hypothesized that their major molecular components are TRPC1 and TRPV2. Membrane tears that may occur in fragile membranes may also allow Ca2+ to enter the cell. Outcome effects: An increase in Ca2+ levels has several unfavorable consequences. Ca2+ activates calpains, Ca2+ -dependent proteases, which leads to increased proteolysis of the structural proteins of muscle. Calpains also activate Ca2+ leak channels creating a positive feedback loop of Ca2+ entry. Ca2+ -induced activation of phospholipase A2 resulting in changes in membrane composition is another positive feedback loop in Ca2 overload. Increased Ca2+ affects Ca2+ buffering and storage as well as the excitation-contraction coupling process. As Ca2+ serves as a signaling molecule, its increase causes aberrant activation of intracellular signaling cascades. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-73fafc3e-f5a4-4246-a7dc-db6fdc321cd1 Ca2+ Overload in Muscular Dystrophies uuid-73fafc3e-f5a4-4246-a7dc-db6fdc321cd1 PS:CellType muscle cell PS:Description Duchenne muscular dystrophy (DMD) is caused by mutations in the gene coding for dystrophin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-73fafc3e-f5a4-4246-a7dc-db6fdc321cd1 PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. Several channel types were reported as possible points of Ca2+ entry in DMD. Stretch-activated Ca2+ channels respond to increased susceptibility to stretch. Store-operated and leak channels were characterized by their physiological parameters, and it was hypothesized that their major molecular components are TRPC1 and TRPV2. Membrane tears that may occur in fragile membranes may also allow Ca2+ to enter the cell. Outcome effects: An increase in Ca2+ levels has several unfavorable consequences. Ca2+ activates calpains, Ca2+ -dependent proteases, which leads to increased proteolysis of the structural proteins of muscle. Calpains also activate Ca2+ leak channels creating a positive feedback loop of Ca2+ entry. Ca2+ -induced activation of phospholipase A2 resulting in changes in membrane composition is another positive feedback loop in Ca2 overload. Increased Ca2+ affects Ca2+ buffering and storage as well as the excitation-contraction coupling process. As Ca2+ serves as a signaling molecule, its increase causes aberrant activation of intracellular signaling cascades. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Myocarditis is defined as inflammation of the heart muscle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7407aaf4-918c-4f79-b9df-6760c6e6682e NodeType: Pathway Notes: Headnote: Myocarditis is defined as inflammation of the heart muscle. Many viruses have been implicated as causative agents in the development of myocarditis. These most commonly include adenoviruses and enteroviruses, such as the coxsackieviruses. Signaling description: Recently, parvovirus B19 has been detected in a significant percentage of patients diagnosed with myocarditis and dilated cardiomyopathy (DCM). At the same time, a growing body of data indicates that parvovirus is present in many patients who do not develop myocarditis. In epithelial cells, coxsackievirus initially attaches to DAF on the apical surface of the cell. This facilitates the interaction of the virus with CAR localized at the tight junction of epithelial cells, an area not normally accessible to viral particles. Outcome effects: The binding of coxsackievirus to DAF triggers actin rearrangement through the AbI kinase activation and permits movement of virus particle into the tight junction. CAR is a transmembrane protein with 2 extracellular immunoglobulin domains. The extracellular region of CAR is thought to bind to another CAR molecule on an adjacent cell as an antiparallel homodimer. Organ: heart Organ_System: cardiovascular system PMID: 16413486 PMID: 19451363 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-7407aaf4-918c-4f79-b9df-6760c6e6682e Myocarditis, Acute Viral Overiew uuid-7407aaf4-918c-4f79-b9df-6760c6e6682e PS:CellType cardiac myocyte PS:Description Myocarditis is defined as inflammation of the heart muscle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7407aaf4-918c-4f79-b9df-6760c6e6682e PS:NodeType Pathway PS:Notes Headnote: Myocarditis is defined as inflammation of the heart muscle. Many viruses have been implicated as causative agents in the development of myocarditis. These most commonly include adenoviruses and enteroviruses, such as the coxsackieviruses. Signaling description: Recently, parvovirus B19 has been detected in a significant percentage of patients diagnosed with myocarditis and dilated cardiomyopathy (DCM). At the same time, a growing body of data indicates that parvovirus is present in many patients who do not develop myocarditis. In epithelial cells, coxsackievirus initially attaches to DAF on the apical surface of the cell. This facilitates the interaction of the virus with CAR localized at the tight junction of epithelial cells, an area not normally accessible to viral particles. Outcome effects: The binding of coxsackievirus to DAF triggers actin rearrangement through the AbI kinase activation and permits movement of virus particle into the tight junction. CAR is a transmembrane protein with 2 extracellular immunoglobulin domains. The extracellular region of CAR is thought to bind to another CAR molecule on an adjacent cell as an antiparallel homodimer. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 16413486 PS:PMID 19451363 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author CellType: endothelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-740ba766-0c92-4522-aaba-6654a192338b NodeType: Pathway Organ: Blood Vessels PMID: 19217422 PMID: 20627076 PMID: 21860391 PMID: 22020130 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-740ba766-0c92-4522-aaba-6654a192338b VEGFA/NOTCH1/WNT Cross-talk in Blood Vessel Sprouting and Branching uuid-740ba766-0c92-4522-aaba-6654a192338b PS:CellType endothelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-740ba766-0c92-4522-aaba-6654a192338b PS:NodeType Pathway PS:Organ Blood Vessels PS:PMID 19217422 PS:PMID 20627076 PS:PMID 21860391 PS:PMID 22020130 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7427c0ca-b2df-4529-b605-9c644d14a114 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7427c0ca-b2df-4529-b605-9c644d14a114 HBEGF -> AP-1/ATF Expression Targets uuid-7427c0ca-b2df-4529-b605-9c644d14a114 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7427c0ca-b2df-4529-b605-9c644d14a114 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7435cbe5-5716-4f6e-b93f-7c41265b7348 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7435cbe5-5716-4f6e-b93f-7c41265b7348 CD72 -> NFATC Expression Targets uuid-7435cbe5-5716-4f6e-b93f-7c41265b7348 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7435cbe5-5716-4f6e-b93f-7c41265b7348 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: Rod cells, or rods, are photoreceptor cells in the retina of the eye that are very sensitive to light (can be induced by a single photon) and support vision at low light levels. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74405c12-6fac-46e6-b487-028295a02f7f NodeType: Pathway Notes: Headnote: Rod cells, or rods, are photoreceptor cells in the retina of the eye that are very sensitive to light (can be induced by a single photon) and support vision at low light levels. Signaling description: Rods are concentrated at the outer edges of the retina and are used in peripheral vision. As their visual pigment is destroyed in the process of photoactivation, the continuous function of rods imposes the need for rapid recycling of their chromophore and regeneration of their pigment. The visual cycle is the biological conversion of a photon into an electrical signal in the retina. The absorption of a photon by a rhodopsin (RHO) pigment molecule induces the isomerization of 11-cis-retinal to all-trans-retinal resulting in activated metarhodopsin II. Outcome effects: The decay of metarhodopsin II yields apo-opsin and free all-trans-retinal. The translocation of all-trans-retinal from the disc membrane to the cytoplasmic space is facilitated by an ATP-binding cassette transporter ABCA4. All-trans-retinal is reduced to all-trans-retinol (vitamin A) by retinol dehydrogenases (RDH). Vitamin A is transported from rods to retinal pigment epithelial cells (RPEs) by RBP3. Vitamin A also may come to RPE from the blood stream through STRA6. In RPEs, vitamin A is esterified to a fatty acid by lecithin retinol acyltransferase (LRAT). The isomerase, RPE-specific 65 kDa protein (RPE65) uses an all-trans-retinyl ester as a substrate to form 11-cis-retinol. 11-cis-retinol binds to the cellular retinaldehyde-binding protein (RLBP1). 11-cis-retinol is oxidized to 11-cis-retinal by retinol dehydrogenases (RDH). Non-photoreceptor RGR opsin also takes part in this process. 11-cis- retinol is released by the RPE and taken up by the rod, where it is incorporated into RHO. Organ: Retina Organ: eye Organ_System: sensory system PMID: 16968212 PMID: 20435355 PMID: 21447403 PMID: 23857173 PMID: 23905688 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-74405c12-6fac-46e6-b487-028295a02f7f Visual Cycle in Retinal Rods uuid-74405c12-6fac-46e6-b487-028295a02f7f PS:CellType retina cell PS:Description Rod cells, or rods, are photoreceptor cells in the retina of the eye that are very sensitive to light (can be induced by a single photon) and support vision at low light levels. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74405c12-6fac-46e6-b487-028295a02f7f PS:NodeType Pathway PS:Notes Headnote: Rod cells, or rods, are photoreceptor cells in the retina of the eye that are very sensitive to light (can be induced by a single photon) and support vision at low light levels. Signaling description: Rods are concentrated at the outer edges of the retina and are used in peripheral vision. As their visual pigment is destroyed in the process of photoactivation, the continuous function of rods imposes the need for rapid recycling of their chromophore and regeneration of their pigment. The visual cycle is the biological conversion of a photon into an electrical signal in the retina. The absorption of a photon by a rhodopsin (RHO) pigment molecule induces the isomerization of 11-cis-retinal to all-trans-retinal resulting in activated metarhodopsin II. Outcome effects: The decay of metarhodopsin II yields apo-opsin and free all-trans-retinal. The translocation of all-trans-retinal from the disc membrane to the cytoplasmic space is facilitated by an ATP-binding cassette transporter ABCA4. All-trans-retinal is reduced to all-trans-retinol (vitamin A) by retinol dehydrogenases (RDH). Vitamin A is transported from rods to retinal pigment epithelial cells (RPEs) by RBP3. Vitamin A also may come to RPE from the blood stream through STRA6. In RPEs, vitamin A is esterified to a fatty acid by lecithin retinol acyltransferase (LRAT). The isomerase, RPE-specific 65 kDa protein (RPE65) uses an all-trans-retinyl ester as a substrate to form 11-cis-retinol. 11-cis-retinol binds to the cellular retinaldehyde-binding protein (RLBP1). 11-cis-retinol is oxidized to 11-cis-retinal by retinol dehydrogenases (RDH). Non-photoreceptor RGR opsin also takes part in this process. 11-cis- retinol is released by the RPE and taken up by the rod, where it is incorporated into RHO. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 16968212 PS:PMID 20435355 PS:PMID 21447403 PS:PMID 23857173 PS:PMID 23905688 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-744fa0e1-6d45-4483-b8ce-87d63c002b3b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-744fa0e1-6d45-4483-b8ce-87d63c002b3b PTPRJ Expression Targets uuid-744fa0e1-6d45-4483-b8ce-87d63c002b3b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-744fa0e1-6d45-4483-b8ce-87d63c002b3b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74616904-9659-4482-b1f6-a3eeaec0ce0c NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-74616904-9659-4482-b1f6-a3eeaec0ce0c Cervical Cancer Clinical Trials uuid-74616904-9659-4482-b1f6-a3eeaec0ce0c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74616904-9659-4482-b1f6-a3eeaec0ce0c PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: macrophage Description: The exposure of neurotoxins, such as rotenone and Cyperquat, can cause symptoms that are similar to those seen in Parkinson's disease (PD). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7467ad1c-ea8c-4d98-96b5-f2da76b0503d NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: The exposure of neurotoxins, such as rotenone and Cyperquat, can cause symptoms that are similar to those seen in Parkinson's disease (PD). These neurotoxins are commonly used in toxin-induced animal models of the disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a by-product of the recreational drug, 1-methyl-4-phenyl-4-propionoxypiperidine (desmethylprodine), while rotenone is a broad-spectrum pesticide. MPTP itself is non-toxic and as a lipophilic compound, it can penetrate the blood-brain barrier. Once inside the brain, it is converted by monoamine oxidase B (MAOB) into Cyperquat, which is toxic. Cyperquat and rotenone attack dopaminergic neurons and inhibit NADH dehydrogenase-respiratory chain complex I, resulting in ATP depletion. Respiratory chain disruption leads to a massive superoxide radical burst resulting in the generation of reactive oxygen species (ROS). One of the initial events triggered by ATP depletion is loss of energy required for dopamine trafficking. With regards to energy, a lack of ATP diminishes the capability of intracellular ATPase pumps to sequester dopamine into synaptic vesicles. In addition, Cyperquat can cause further insult due to its ability to bind directly to a vesicular monoamine transporter, VMAT2 (SLC18A2), gain entrance into the synaptic vesicles, and release dopamine back into the cytoplasmic compartment. Outcome effects: In the cytoplasm, dopamine is oxidized by tyrosinase (TYR) and xanthine dehydrogenase (XDH) to dopaminoquinone which in turn is oxidized to aminochrome. The oxidation of dopamine in the cytoplasm causes the formation of oxidopamine that also inhibits NADH dehydrogenase. Free radicals which are formed in the dopamine oxidation reaction then contribute to alpha-synuclein (SNCA) aggregation. Peroxinitrite also inhibits glutathione synthesis which disrupts ROS detoxification in mitochondria. Animal data: Rotenone and Cyperquat are neurotoxins commonly used in toxin-induced animal models of PD. Highlighted proteins: Entities with incresed level or activity is highlighted in red and entities with decresed level or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 15790530 PMID: 21340000 PMID: 21785590 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-7467ad1c-ea8c-4d98-96b5-f2da76b0503d Neurotoxin Effects in Parkinson's Disease uuid-7467ad1c-ea8c-4d98-96b5-f2da76b0503d PS:CellType macrophage PS:Description The exposure of neurotoxins, such as rotenone and Cyperquat, can cause symptoms that are similar to those seen in Parkinson's disease (PD). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7467ad1c-ea8c-4d98-96b5-f2da76b0503d PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: The exposure of neurotoxins, such as rotenone and Cyperquat, can cause symptoms that are similar to those seen in Parkinson's disease (PD). These neurotoxins are commonly used in toxin-induced animal models of the disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a by-product of the recreational drug, 1-methyl-4-phenyl-4-propionoxypiperidine (desmethylprodine), while rotenone is a broad-spectrum pesticide. MPTP itself is non-toxic and as a lipophilic compound, it can penetrate the blood-brain barrier. Once inside the brain, it is converted by monoamine oxidase B (MAOB) into Cyperquat, which is toxic. Cyperquat and rotenone attack dopaminergic neurons and inhibit NADH dehydrogenase-respiratory chain complex I, resulting in ATP depletion. Respiratory chain disruption leads to a massive superoxide radical burst resulting in the generation of reactive oxygen species (ROS). One of the initial events triggered by ATP depletion is loss of energy required for dopamine trafficking. With regards to energy, a lack of ATP diminishes the capability of intracellular ATPase pumps to sequester dopamine into synaptic vesicles. In addition, Cyperquat can cause further insult due to its ability to bind directly to a vesicular monoamine transporter, VMAT2 (SLC18A2), gain entrance into the synaptic vesicles, and release dopamine back into the cytoplasmic compartment. Outcome effects: In the cytoplasm, dopamine is oxidized by tyrosinase (TYR) and xanthine dehydrogenase (XDH) to dopaminoquinone which in turn is oxidized to aminochrome. The oxidation of dopamine in the cytoplasm causes the formation of oxidopamine that also inhibits NADH dehydrogenase. Free radicals which are formed in the dopamine oxidation reaction then contribute to alpha-synuclein (SNCA) aggregation. Peroxinitrite also inhibits glutathione synthesis which disrupts ROS detoxification in mitochondria. Animal data: Rotenone and Cyperquat are neurotoxins commonly used in toxin-induced animal models of PD. Highlighted proteins: Entities with incresed level or activity is highlighted in red and entities with decresed level or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 15790530 PS:PMID 21340000 PS:PMID 21785590 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74700d2d-985f-457c-a3f3-8383ad314be5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-74700d2d-985f-457c-a3f3-8383ad314be5 TANs antitumor activity uuid-74700d2d-985f-457c-a3f3-8383ad314be5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74700d2d-985f-457c-a3f3-8383ad314be5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74769a1e-18a6-4f30-98df-c87c02847537 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-74769a1e-18a6-4f30-98df-c87c02847537 IFNLR1-> STAT/NFKB Signaling uuid-74769a1e-18a6-4f30-98df-c87c02847537 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74769a1e-18a6-4f30-98df-c87c02847537 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of NFKB non-canonical signaling pathway in cancer contributes to uncontrolled cell proliferation and inhibition of apoptosis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7476f1b6-fc9c-4af2-b729-1a937b1a085f NodeType: Pathway Notes: Headnote: The non-canonical NFKB pathway is an important arm of NFKB signaling that predominantly targets activation of the NFKB2/RELB NFKB complex and may be activated in cancers. Signaling description: At the core of non-canonical pathway is NFKB-inducing kinase (MAP3K14), which mediates signals from certain TNF receptor family members and positively-regulates CHUK, the downstream kinase, which induces NFKB2 phosphorylation and processing. The basal level of MAP3K14 is low due to the action of the TRAF-BIRC destruction complex, and activation of non-canonical NFKB signaling includes MAP3K14 stabilization. Activating mutations of CD40, MAP3K14, NFKB2 or inactivating mutations of natural inhibitors BIRC2/3 and TRAF3 may activate non-canonical NFKB pathway in cancers. It also may be activated by viral proteins LMP1 (EBV protein) and tax (HTLV-1 protein). Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation and inhibition of apoptosis. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: Tax and LMP1 shown in grey are viral proteins. Organ: oncogenic Organ_System: oncogenic PMID: 17119127 PMID: 21173796 PMID: 23915189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-7476f1b6-fc9c-4af2-b729-1a937b1a085f NFKB Non-Canonical Signaling Activation in Cancer uuid-7476f1b6-fc9c-4af2-b729-1a937b1a085f PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of NFKB non-canonical signaling pathway in cancer contributes to uncontrolled cell proliferation and inhibition of apoptosis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7476f1b6-fc9c-4af2-b729-1a937b1a085f PS:NodeType Pathway PS:Notes Headnote: The non-canonical NFKB pathway is an important arm of NFKB signaling that predominantly targets activation of the NFKB2/RELB NFKB complex and may be activated in cancers. Signaling description: At the core of non-canonical pathway is NFKB-inducing kinase (MAP3K14), which mediates signals from certain TNF receptor family members and positively-regulates CHUK, the downstream kinase, which induces NFKB2 phosphorylation and processing. The basal level of MAP3K14 is low due to the action of the TRAF-BIRC destruction complex, and activation of non-canonical NFKB signaling includes MAP3K14 stabilization. Activating mutations of CD40, MAP3K14, NFKB2 or inactivating mutations of natural inhibitors BIRC2/3 and TRAF3 may activate non-canonical NFKB pathway in cancers. It also may be activated by viral proteins LMP1 (EBV protein) and tax (HTLV-1 protein). Outcome effects: Constant NFKB activation leads to uncontrolled cellular proliferation and inhibition of apoptosis. Animal data: Some data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: Tax and LMP1 shown in grey are viral proteins. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17119127 PS:PMID 21173796 PS:PMID 23915189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Oxidized low-density lipoprotein (oxLDL) induces platelet activation and increases the ability of platelets to adhere to endothelial vascular cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74aa422a-7e31-402d-9c86-17d6b37fac4c NodeType: Pathway Notes: Headnote: Oxidized low-density lipoprotein (oxLDL) induces platelet activation and increases the ability of platelets to adhere to endothelial vascular cells which induces an inflammatory response and leads to platelet accumulation following vascular injury. Signaling description: OxLDL induces platelet activation via class B scavenger receptor CD36 signaling. OLR1 (also known as LOX-1) is a class E scavenger receptor that is exposed on the surface of platelets following activation. Activated platelets internalize significant amounts of oxLDL compared to resting platelets. CD36 mediates oxLDL binding to platelets in resting platelets, however in activated platelets; the binding of oxLDL is mediated by both CD36 and OLR1. OxLDL-positive platelets induce platelet aggregation following vascular injury since OLR1can recognize and bind activated platelets. Moreover, oxLDL-positive platelets induce adhesion molecule expression on vascular endothelial cells, reduce regeneration of endothelial cells, and induce foam cell formation. The exact mechanism of intracellular OLR1 signaling in platelets remains unknown. In the plasma membrane, OLR1 is mainly localized in caveolae/lipid rafts, which are cholesterol-enriched membrane microdomains, so its function is modulated by the cholesterol content of the membrane. OxLDL is rapidly internalized by the cell following interaction with OLR1. Outcome effects: Following the endocytosis of oxLDL-OLR1 complex, the receptor is uncoupled from oxLDL and both are positioned in separate compartments within the cytosol. OxLDL is trafficked through the early endosome and onto the lysosome for degradation. It is believed that the majority of OLR1 is targeted back to the plasma membrane by a recycling pathway from endosome-to-plasma membrane. Cytosolic factors that mediate recognition, endocytosis, and/or recycling of OLR1 have yet to be identified. OxLDL/OLR1 signaling may influence ADP-induced platelet aggregation. OLR1 is important for ADP-stimulated activation of platelet ITGA2B and ITGB3 integrins (fibrinogen receptors). In platelets, ADP/P2RY1 signaling activates PLCB1 and leads to calcium (Ca2+) mobilization and PKC activation which are necessary for shape change and initiation of aggregation. OLR1 is important for ADP-mediated platelet integrin activation, which possibly occurs via PKC. The manner in which OLR1 influences PKC function is currently unknown. Lastly, CD68 is exposed on the surface of activated platelets in parallel with the lysosome membrane. CD68 has been shown to bind oxLDL, although it is unclear whether this plays any role in platelet recognition of oxLDL. Organ: generic Organ_System: hematological system PMID: 16712941 PMID: 21292024 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-74aa422a-7e31-402d-9c86-17d6b37fac4c Scavenger Receptors in Platelet Aggregation uuid-74aa422a-7e31-402d-9c86-17d6b37fac4c PS:CellType blood platelet PS:Description Oxidized low-density lipoprotein (oxLDL) induces platelet activation and increases the ability of platelets to adhere to endothelial vascular cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74aa422a-7e31-402d-9c86-17d6b37fac4c PS:NodeType Pathway PS:Notes Headnote: Oxidized low-density lipoprotein (oxLDL) induces platelet activation and increases the ability of platelets to adhere to endothelial vascular cells which induces an inflammatory response and leads to platelet accumulation following vascular injury. Signaling description: OxLDL induces platelet activation via class B scavenger receptor CD36 signaling. OLR1 (also known as LOX-1) is a class E scavenger receptor that is exposed on the surface of platelets following activation. Activated platelets internalize significant amounts of oxLDL compared to resting platelets. CD36 mediates oxLDL binding to platelets in resting platelets, however in activated platelets; the binding of oxLDL is mediated by both CD36 and OLR1. OxLDL-positive platelets induce platelet aggregation following vascular injury since OLR1can recognize and bind activated platelets. Moreover, oxLDL-positive platelets induce adhesion molecule expression on vascular endothelial cells, reduce regeneration of endothelial cells, and induce foam cell formation. The exact mechanism of intracellular OLR1 signaling in platelets remains unknown. In the plasma membrane, OLR1 is mainly localized in caveolae/lipid rafts, which are cholesterol-enriched membrane microdomains, so its function is modulated by the cholesterol content of the membrane. OxLDL is rapidly internalized by the cell following interaction with OLR1. Outcome effects: Following the endocytosis of oxLDL-OLR1 complex, the receptor is uncoupled from oxLDL and both are positioned in separate compartments within the cytosol. OxLDL is trafficked through the early endosome and onto the lysosome for degradation. It is believed that the majority of OLR1 is targeted back to the plasma membrane by a recycling pathway from endosome-to-plasma membrane. Cytosolic factors that mediate recognition, endocytosis, and/or recycling of OLR1 have yet to be identified. OxLDL/OLR1 signaling may influence ADP-induced platelet aggregation. OLR1 is important for ADP-stimulated activation of platelet ITGA2B and ITGB3 integrins (fibrinogen receptors). In platelets, ADP/P2RY1 signaling activates PLCB1 and leads to calcium (Ca2+) mobilization and PKC activation which are necessary for shape change and initiation of aggregation. OLR1 is important for ADP-mediated platelet integrin activation, which possibly occurs via PKC. The manner in which OLR1 influences PKC function is currently unknown. Lastly, CD68 is exposed on the surface of activated platelets in parallel with the lysosome membrane. CD68 has been shown to bind oxLDL, although it is unclear whether this plays any role in platelet recognition of oxLDL. PS:Organ generic PS:Organ_System hematological system PS:PMID 16712941 PS:PMID 21292024 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74af106f-efb4-47bf-8434-6c0fc7827a72 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-74af106f-efb4-47bf-8434-6c0fc7827a72 Rosmarinate biosynthesis template uuid-74af106f-efb4-47bf-8434-6c0fc7827a72 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74af106f-efb4-47bf-8434-6c0fc7827a72 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74bc32d2-6c87-423d-9e5d-7514ad7eb85d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-74bc32d2-6c87-423d-9e5d-7514ad7eb85d Chondroitin biosynthesis template uuid-74bc32d2-6c87-423d-9e5d-7514ad7eb85d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74bc32d2-6c87-423d-9e5d-7514ad7eb85d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74dfc719-7fbf-41b8-a49b-6703e5903971 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-74dfc719-7fbf-41b8-a49b-6703e5903971 CTGF -> NCOR2 Expression Target uuid-74dfc719-7fbf-41b8-a49b-6703e5903971 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74dfc719-7fbf-41b8-a49b-6703e5903971 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: hepatocyte Description: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease in Western countries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74ea5fa0-c108-442b-b5e3-a826e943c80b NodeType: Pathway Notes: Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. NAFLD was shown to be associated with mutations in the PNPLA3 gene. Signaling description: PNPLA3 plays an important role in hepatocyte lipogenesis. Insulin resistance and disordered lipid metabolism contribute to the development of NAFLD. Normally, insulin (INS) inhibits triglyceride storage via the following mechanism. Activated INSR and IGF1R stimulate PDPK1 via IRS2/PIK3R1 and the formation of PIP3. In turn, PDPK1 activates AKT1 which inhibits FOXO1. Outcome effects: FOXO1 is the activator of CEBPA and, consequently SREBF1, which is in turn the activator of PNPLA3 via MLXIPL. PNPLA3 is a triacylglycerol lipase which mediates triacylglycerol hydrolysis in hepatocytes. In the liver4, fatty acids induce SREBF1 which promotes PNPLA3 via MLXIPL. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: PNPLA3 mutated in NAFLD is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 23394097 PMID: 25045276 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-74ea5fa0-c108-442b-b5e3-a826e943c80b PNPLA3 in non-Alcoholic Fatty Liver Disease uuid-74ea5fa0-c108-442b-b5e3-a826e943c80b PS:CellType adipocyte PS:CellType hepatocyte PS:Description Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease in Western countries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-74ea5fa0-c108-442b-b5e3-a826e943c80b PS:NodeType Pathway PS:Notes Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. NAFLD was shown to be associated with mutations in the PNPLA3 gene. Signaling description: PNPLA3 plays an important role in hepatocyte lipogenesis. Insulin resistance and disordered lipid metabolism contribute to the development of NAFLD. Normally, insulin (INS) inhibits triglyceride storage via the following mechanism. Activated INSR and IGF1R stimulate PDPK1 via IRS2/PIK3R1 and the formation of PIP3. In turn, PDPK1 activates AKT1 which inhibits FOXO1. Outcome effects: FOXO1 is the activator of CEBPA and, consequently SREBF1, which is in turn the activator of PNPLA3 via MLXIPL. PNPLA3 is a triacylglycerol lipase which mediates triacylglycerol hydrolysis in hepatocytes. In the liver4, fatty acids induce SREBF1 which promotes PNPLA3 via MLXIPL. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: PNPLA3 mutated in NAFLD is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 23394097 PS:PMID 25045276 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-750083f8-2b44-4125-abe7-af4cda942129 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-750083f8-2b44-4125-abe7-af4cda942129 SARS PLpro (NSP3) inhibitors uuid-750083f8-2b44-4125-abe7-af4cda942129 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-750083f8-2b44-4125-abe7-af4cda942129 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or binding proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-751e1983-7ca1-48b4-bda1-4634dfa0d90a NodeType: Pathway Notes: Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The alternative complement pathway can operate without antibody participation. A variety of activators of this pathway have been described such as certain particulate polysaccharides including bacterial LPS and a number of immunoglobulins. The first step in the alternative pathway is the binding of a thioester bond of C3 to an activator, -OH or -NH2 groups. C3, in the free state, is rapidly inactivated by the serum protein factors CFH and CFI. Bound C3, which is protected from such inactivation, interacts with CFB to form magnesium (Mg2+)-dependent complex C3-CFB. This complex is cleaved by CFD and the resultant cleavage causes the initial alternative complement pathway C3/C5 convertase to form which is confined to the fluid phase. The initial C3/C5 convertase is under positive regulation by CFP, whose function in the alternative pathway is to bind to cell-bound C3 and to stabilize the C3/C5 convertase. At this point, the alternative pathway proceeds in the same manner as the classical pathway and recruits additional complement factors including C6, C7, C8A, and C9 to ultimately form MAC and the lysis of the associated cell. Outcome effects: The major consequence of activation of the complement system is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-751e1983-7ca1-48b4-bda1-4634dfa0d90a Complement Alternative Pathway uuid-751e1983-7ca1-48b4-bda1-4634dfa0d90a PS:CellType generic PS:Description The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or binding proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-751e1983-7ca1-48b4-bda1-4634dfa0d90a PS:NodeType Pathway PS:Notes Headnote: The complement system is a component of innate immunity that consists of multiple plasma proteins that function either as enzymes or binding proteins. Signaling description: Most complement proteins are present in plasma in the form of inactive precursors called zymogens. The activation of the complement system initiates a series of enzymatic reactions in which zymogens covalently bind to or fix on the pathogen surface and form the membrane attack complex (MAC). The formation of MAC leads to the lysis of pathogenic cells. There are three categories of complement pathway according to the type of activation including classical pathway, alternative pathway, and lectin pathway. The alternative complement pathway can operate without antibody participation. A variety of activators of this pathway have been described such as certain particulate polysaccharides including bacterial LPS and a number of immunoglobulins. The first step in the alternative pathway is the binding of a thioester bond of C3 to an activator, -OH or -NH2 groups. C3, in the free state, is rapidly inactivated by the serum protein factors CFH and CFI. Bound C3, which is protected from such inactivation, interacts with CFB to form magnesium (Mg2+)-dependent complex C3-CFB. This complex is cleaved by CFD and the resultant cleavage causes the initial alternative complement pathway C3/C5 convertase to form which is confined to the fluid phase. The initial C3/C5 convertase is under positive regulation by CFP, whose function in the alternative pathway is to bind to cell-bound C3 and to stabilize the C3/C5 convertase. At this point, the alternative pathway proceeds in the same manner as the classical pathway and recruits additional complement factors including C6, C7, C8A, and C9 to ultimately form MAC and the lysis of the associated cell. Outcome effects: The major consequence of activation of the complement system is the uptake and destruction of complement-coated microbes by phagocytes that bear receptors for these complement fragments. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-754ce9e2-8174-46fe-8551-fd49616d86fd NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-754ce9e2-8174-46fe-8551-fd49616d86fd IL7R -> STAT Signaling uuid-754ce9e2-8174-46fe-8551-fd49616d86fd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-754ce9e2-8174-46fe-8551-fd49616d86fd PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-755ebaec-11ab-450b-a026-78d86fb2900d NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-755ebaec-11ab-450b-a026-78d86fb2900d TGFB+>temporary ECM at wounded edge uuid-755ebaec-11ab-450b-a026-78d86fb2900d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-755ebaec-11ab-450b-a026-78d86fb2900d PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-755ecb2a-c679-4449-9cba-54e3f46f0dda NodeType: Pathway Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-755ecb2a-c679-4449-9cba-54e3f46f0dda Proteins Involved in Noise-Induced Hearing Loss uuid-755ecb2a-c679-4449-9cba-54e3f46f0dda PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-755ecb2a-c679-4449-9cba-54e3f46f0dda PS:NodeType Pathway PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Norepinephrine, epinephrine, orexin A and substance P regulate norepinephrine release from noradrenergic neuron. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75669f82-ea29-4b2c-8ae8-4bc6314fc366 NodeType: Pathway Notes: Headnote: Norepinephrine release is regulated by neuronal and extraneuronal norepinephrine uptake, neuropeptides and via adrenoceptors. Presynaptic adrenoceptors are neuronal norepinephrine uptake sites at which transmitters inhibit or facilitate the release of norepinephrine from its terminals by principles of feedback. Signaling description: Norepinephrine and epinephrine regulate ADCY/cAMP/PKA/MAPKs/CREB1 signaling via ADRA2A and ADRB2. CREB1 promotes tyrosine hydroxylase (TH) expression involved in the conversion of tyrosine to norepinephrine. Also, CREB1 promotes the expression of neurotransmitter transporter (SLC6A2) that regulates the neuronal norepinephrine level and its uptake. Neuropeptides, orexin A and substance P bind to HCRTR1 and TACR1 which mediate PLCB1/DAG/PKC signaling. Activated PKC stimulates voltage-dependent calcium channel required for secretory vesicle fusion and norepinephrine release. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Norepinephrine and epinephrine regulate norepinephrine release from neuroendocrine terminal. Animal data: Some of the data was revealed from animal model experiments. Organ: brain Organ_System: nervous system PMID: 20144684 PMID: 22408604 PMID: 24054156 PMID: 27902931 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-75669f82-ea29-4b2c-8ae8-4bc6314fc366 Norepinephrine Release Regulation uuid-75669f82-ea29-4b2c-8ae8-4bc6314fc366 PS:CellType neuron PS:Description Norepinephrine, epinephrine, orexin A and substance P regulate norepinephrine release from noradrenergic neuron. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75669f82-ea29-4b2c-8ae8-4bc6314fc366 PS:NodeType Pathway PS:Notes Headnote: Norepinephrine release is regulated by neuronal and extraneuronal norepinephrine uptake, neuropeptides and via adrenoceptors. Presynaptic adrenoceptors are neuronal norepinephrine uptake sites at which transmitters inhibit or facilitate the release of norepinephrine from its terminals by principles of feedback. Signaling description: Norepinephrine and epinephrine regulate ADCY/cAMP/PKA/MAPKs/CREB1 signaling via ADRA2A and ADRB2. CREB1 promotes tyrosine hydroxylase (TH) expression involved in the conversion of tyrosine to norepinephrine. Also, CREB1 promotes the expression of neurotransmitter transporter (SLC6A2) that regulates the neuronal norepinephrine level and its uptake. Neuropeptides, orexin A and substance P bind to HCRTR1 and TACR1 which mediate PLCB1/DAG/PKC signaling. Activated PKC stimulates voltage-dependent calcium channel required for secretory vesicle fusion and norepinephrine release. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Norepinephrine and epinephrine regulate norepinephrine release from neuroendocrine terminal. Animal data: Some of the data was revealed from animal model experiments. PS:Organ brain PS:Organ_System nervous system PS:PMID 20144684 PS:PMID 22408604 PS:PMID 24054156 PS:PMID 27902931 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: regulatory T-cell Description: The role of toll-like receptors (TLRs) in the pathogenesis of type 1 diabetes has been extensively studied. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-759199a9-41b2-4dc7-8d7b-6256065b58b5 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: The role of toll-like receptors (TLRs) in the pathogenesis of type 1 diabetes has been extensively studied. As key receptors of the innate immune system, TLRs trigger inflammatory immune responses upon binding to cognate ligands. On a predisposed genetic background, this event may initiate islet inflammation followed by progressive beta-cell destruction and finally overt type 1 diabetes. The accumulation of apoptotic beta-cells, which may undergo secondary necrosis may result in the activation of antigen-presenting cells (APC) via TLR engagement by released endogenous molecules and thereby contributing to the induction of diabetogenic T-cells. Regulatory T-cells (Treg) are TLR-expressing adaptive immune cells. In the presence of beta-cell antigens, TLR2 signaling may, while inducing a pro-inflammatory immune response simultaneously promote suppressive Treg functions. Outcome effects: Upon their induction, diabetogenic T-cells are recruited to the pancreatic islets by chemokines such as CCL2, CCL5, CXCL9, and CXCL10 which can be released from beta-cells upon TLR ligation. Consistent with this (Hypothesis) is the fact that TLR2 induces apoptosis and promotes diabetes in a mouse model following activation via the synthetic ligand Pam3CSK4. The observation of delayed or reduced diabetes onset in TLR9-deficient mice further supports the theory. With regard to Treg cells, it has been demonstrated that TLR2 stimulation results in a temporary abrogation of the regulatory capacity of Treg. In addition to TLR2, other TLRs also modulate Treg functions. TLR4 and TLR5 ligands are capable of boosting the suppressive function of Treg on T-effector cells. Taken together, TLRs act as important modulators of Treg proliferation and function. Treg function can either be enhanced or attenuated depending on the concentration of TLR ligands and the anatomical site of TLR engagement. Animal data: TLR2 induces apoptosis and promotes diabetes in mouse model. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PMID: 23898332 PMID: 24715890 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-759199a9-41b2-4dc7-8d7b-6256065b58b5 TLR2 Signaling in Treg-Cell in Type 1 Diabetes (Animal Model) uuid-759199a9-41b2-4dc7-8d7b-6256065b58b5 PS:CellType T-cell PS:CellType regulatory T-cell PS:Description The role of toll-like receptors (TLRs) in the pathogenesis of type 1 diabetes has been extensively studied. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-759199a9-41b2-4dc7-8d7b-6256065b58b5 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: The role of toll-like receptors (TLRs) in the pathogenesis of type 1 diabetes has been extensively studied. As key receptors of the innate immune system, TLRs trigger inflammatory immune responses upon binding to cognate ligands. On a predisposed genetic background, this event may initiate islet inflammation followed by progressive beta-cell destruction and finally overt type 1 diabetes. The accumulation of apoptotic beta-cells, which may undergo secondary necrosis may result in the activation of antigen-presenting cells (APC) via TLR engagement by released endogenous molecules and thereby contributing to the induction of diabetogenic T-cells. Regulatory T-cells (Treg) are TLR-expressing adaptive immune cells. In the presence of beta-cell antigens, TLR2 signaling may, while inducing a pro-inflammatory immune response simultaneously promote suppressive Treg functions. Outcome effects: Upon their induction, diabetogenic T-cells are recruited to the pancreatic islets by chemokines such as CCL2, CCL5, CXCL9, and CXCL10 which can be released from beta-cells upon TLR ligation. Consistent with this (Hypothesis) is the fact that TLR2 induces apoptosis and promotes diabetes in a mouse model following activation via the synthetic ligand Pam3CSK4. The observation of delayed or reduced diabetes onset in TLR9-deficient mice further supports the theory. With regard to Treg cells, it has been demonstrated that TLR2 stimulation results in a temporary abrogation of the regulatory capacity of Treg. In addition to TLR2, other TLRs also modulate Treg functions. TLR4 and TLR5 ligands are capable of boosting the suppressive function of Treg on T-effector cells. Taken together, TLRs act as important modulators of Treg proliferation and function. Treg function can either be enhanced or attenuated depending on the concentration of TLR ligands and the anatomical site of TLR engagement. Animal data: TLR2 induces apoptosis and promotes diabetes in mouse model. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:PMID 23898332 PS:PMID 24715890 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: The survival of myelin-specific T cells is one of the most important factors in the pathogenic process in multiple sclerosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75c8ba57-f1d9-4a23-93fd-7838d08fecc5 NodeType: Pathway Notes: The survival of myelin-specific T cells is one of the most important factors in the pathogenic process in multiple sclerosis. This process is activated by osteopontin, encoded by SSP1 gene. Organ_System: lymphatic system PMID: 19444308 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-75c8ba57-f1d9-4a23-93fd-7838d08fecc5 SPP1 Induced Survival of Myelin Specific T-Cells in Multiple Sclerosis uuid-75c8ba57-f1d9-4a23-93fd-7838d08fecc5 PS:CellType T-cell PS:Description The survival of myelin-specific T cells is one of the most important factors in the pathogenic process in multiple sclerosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75c8ba57-f1d9-4a23-93fd-7838d08fecc5 PS:NodeType Pathway PS:Notes The survival of myelin-specific T cells is one of the most important factors in the pathogenic process in multiple sclerosis. This process is activated by osteopontin, encoded by SSP1 gene. PS:Organ_System lymphatic system PS:PMID 19444308 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75e24696-7e4e-40bc-ab9a-0d06f84939d6 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-75e24696-7e4e-40bc-ab9a-0d06f84939d6 Xylan degradation template uuid-75e24696-7e4e-40bc-ab9a-0d06f84939d6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75e24696-7e4e-40bc-ab9a-0d06f84939d6 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75e9adf4-6d60-4752-9d5d-daa6afdb8642 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Signaling description: The exact mechanism of anticonvulsant action for KD remains unknown, and several hypotheses have been suggested. KD decreases insulin levels, and thus is expected to inhibit MTOR activity indirectly by decreasing the PI3K/AKT1/MTOR signaling. Energy and nutrient deprivation may also lead to the inhibition of MTOR via the STK11/AMPK/TSC1/TSC2 activation. In addition, polyunsaturated fatty acids (PUFAs) boost the activity of PPARA, which in turn activates brain-specific uncoupling protein UCP2 and downregulates NF-kB. Further, reduced glucose levels activate PANX1, which releases ATP into the extracellular space. ATP is converted into adenosine which subsequently activates adenosine receptor ADORA1. Lastly, leptin (LEP) inhibits seizures possibly through the blockade of AMPA receptor-mediated synaptic transmission. Chronic ketosis is predicted to cause increased levels of acetone which may activate KCNK2 channels. Outcome effects: MTOR inhibition has been shown to prevent epileptogenesis. Further, UCP2 activation results in limited ROS generation and inhibition of neurodegeneration, whereas reduction of IL1B, TNF, and IL6 expression via NF-kB inhibition leads to reduced neuroinflammation. ADORA1 activation is coupled to ATP-activated inward rectifier potassium (K+) channels. Ultimately, the opening of these K channels hyperpolarizes neurons and diminishes neuronal excitability and contributes to the anticonvulsant actions of KD. Activation of KCNK2 channels results in hyperpolarizion of neurons and limits their excitability. Acting directly, PUFAs may inhibit both voltage-gated Na and Ca2+ channels, activate a lipid-sensitive class of KCNK2 K channels, and enhance the activity of Na /K -exchanging ATPase to limit neuronal excitability and dampen seizure activity. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Masino SA, Rho JM (2012) Mechanisms of Ketogenic Diet Action. Jasper's basic Mechanisms of the Epilepsies. 4th edition. 2).Wong M (2010) Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia.51(1):27-36. Organ: brain Organ_System: nervous system PMID: 17241207 PMID: 19049610 PMID: 19817806 PMID: 21354266 PMID: 22787591 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-75e9adf4-6d60-4752-9d5d-daa6afdb8642 Ketogenic Diet Mechanism (Hypothesis) uuid-75e9adf4-6d60-4752-9d5d-daa6afdb8642 PS:CellType neuron PS:Description A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75e9adf4-6d60-4752-9d5d-daa6afdb8642 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet used to treat refractory epilepsy in children. Signaling description: The exact mechanism of anticonvulsant action for KD remains unknown, and several hypotheses have been suggested. KD decreases insulin levels, and thus is expected to inhibit MTOR activity indirectly by decreasing the PI3K/AKT1/MTOR signaling. Energy and nutrient deprivation may also lead to the inhibition of MTOR via the STK11/AMPK/TSC1/TSC2 activation. In addition, polyunsaturated fatty acids (PUFAs) boost the activity of PPARA, which in turn activates brain-specific uncoupling protein UCP2 and downregulates NF-kB. Further, reduced glucose levels activate PANX1, which releases ATP into the extracellular space. ATP is converted into adenosine which subsequently activates adenosine receptor ADORA1. Lastly, leptin (LEP) inhibits seizures possibly through the blockade of AMPA receptor-mediated synaptic transmission. Chronic ketosis is predicted to cause increased levels of acetone which may activate KCNK2 channels. Outcome effects: MTOR inhibition has been shown to prevent epileptogenesis. Further, UCP2 activation results in limited ROS generation and inhibition of neurodegeneration, whereas reduction of IL1B, TNF, and IL6 expression via NF-kB inhibition leads to reduced neuroinflammation. ADORA1 activation is coupled to ATP-activated inward rectifier potassium (K+) channels. Ultimately, the opening of these K channels hyperpolarizes neurons and diminishes neuronal excitability and contributes to the anticonvulsant actions of KD. Activation of KCNK2 channels results in hyperpolarizion of neurons and limits their excitability. Acting directly, PUFAs may inhibit both voltage-gated Na and Ca2+ channels, activate a lipid-sensitive class of KCNK2 K channels, and enhance the activity of Na /K -exchanging ATPase to limit neuronal excitability and dampen seizure activity. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. References: 1). Masino SA, Rho JM (2012) Mechanisms of Ketogenic Diet Action. Jasper's basic Mechanisms of the Epilepsies. 4th edition. 2).Wong M (2010) Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia.51(1):27-36. PS:Organ brain PS:Organ_System nervous system PS:PMID 17241207 PS:PMID 19049610 PS:PMID 19817806 PS:PMID 21354266 PS:PMID 22787591 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75ec06fa-630a-4a13-a2a5-a1ecbc1452ea NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-75ec06fa-630a-4a13-a2a5-a1ecbc1452ea NOTCH -> MEF/MYOD Signaling uuid-75ec06fa-630a-4a13-a2a5-a1ecbc1452ea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75ec06fa-630a-4a13-a2a5-a1ecbc1452ea PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: TLR signaling is activated by a variety of ligands that are generally associated with infectious pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75ed7eaf-ff92-44db-9a67-1ca5f9a8e4e6 NodeType: Pathway Notes: TLR signaling is activated by a variety of ligands that are generally associated with infectious pathogens. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 19451363 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-75ed7eaf-ff92-44db-9a67-1ca5f9a8e4e6 Toll-like Receptors (TLR) in Antiviral Innate Immune Response uuid-75ed7eaf-ff92-44db-9a67-1ca5f9a8e4e6 PS:CellType cardiac myocyte PS:Description TLR signaling is activated by a variety of ligands that are generally associated with infectious pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75ed7eaf-ff92-44db-9a67-1ca5f9a8e4e6 PS:NodeType Pathway PS:Notes TLR signaling is activated by a variety of ligands that are generally associated with infectious pathogens. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 19451363 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75fe4f8b-7c25-4e8e-8632-1897f8ddfc3e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-75fe4f8b-7c25-4e8e-8632-1897f8ddfc3e Vitamin K biosynthesis template uuid-75fe4f8b-7c25-4e8e-8632-1897f8ddfc3e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-75fe4f8b-7c25-4e8e-8632-1897f8ddfc3e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-760d375e-9501-4161-b271-7999b20fa08b NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-760d375e-9501-4161-b271-7999b20fa08b Genes with Mutations in Cancer Metabolic Reprogramming uuid-760d375e-9501-4161-b271-7999b20fa08b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-760d375e-9501-4161-b271-7999b20fa08b PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7612d48d-f240-4e29-a2a6-4e0f08eaa69c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7612d48d-f240-4e29-a2a6-4e0f08eaa69c CSH1/GHR Expression Targets uuid-7612d48d-f240-4e29-a2a6-4e0f08eaa69c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7612d48d-f240-4e29-a2a6-4e0f08eaa69c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuroglia CellType: neuron Description: Oxidative stress (OS) is proven to be one of the mechanisms of ALS pathogenesis. About 20-25? of family ALS cases arise from mutations in superoxide dismutase 1 (SOD1). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76198d6d-827b-47bd-ac73-28c61d876901 NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Oxidative stress (OS) is proven to be one of the mechanisms for ALS pathogenesis. OS is caused by an imbalance between the generation and removal of reactive oxygen and nitrogen species (ROS/RNS) and causes structural damage and changes in redox-sensitive signaling. About 20-25% of family ALS cases arise from mutations in the superoxide dismutase 1 (SOD1) gene. Normally, SOD1 converts the superoxide anion to hydrogen peroxide (H2O2) and protects the cell from OS. This enzyme plays an important role as a cellular antioxidant, and mutant SOD1 (mSOD1) can selectively kill motor neurons due to loss of dismutase function. At the same time, mSOD1 can impair multiple cellular functions including the disruption of CYBB regulation via direct interaction with RAC1. CYBB is a superoxide anion producer, and its dysregulation allows persistent superoxide production. NFE2L2 antioxidant response pathway is the primary cellular defense against the cytotoxic effects of OS. Outcome effects: NFE2L2 normally elevates the expression of several antioxidant enzymes such as GSTA2, NQO1, GSR, GCLM, GCLC, and HMOX1. NFE2L2 is retained in the cytoplasm by KEAP1 and CUL3 which degrade NFE2L2 by ubiquitylation. KPNA6 has been identified as a protein which facilitates nuclear import and attenuates NFE2L2 signaling. NFE2L2 has been found to be downregulated in ALS. In addition, PPARG is an important neuroprotective factor in ALS and is upregulated in ALS. PPARG is activated by lipid peroxidation end product 4-hydroxynonenal, whose levels are elevated in the cerebrospinal fluid and spinal cord from ALS patients. PPARG triggers GSTA2 and HMOX1 production. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 19457088 PMID: 22051914 PMID: 22482452 PMID: 22910911 PMID: 23050144 PMID: 23533690 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-76198d6d-827b-47bd-ac73-28c61d876901 Oxidative Stress in Amyotrophic Lateral Sclerosis uuid-76198d6d-827b-47bd-ac73-28c61d876901 PS:CellType neuroglia PS:CellType neuron PS:Description Oxidative stress (OS) is proven to be one of the mechanisms of ALS pathogenesis. About 20-25? of family ALS cases arise from mutations in superoxide dismutase 1 (SOD1). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76198d6d-827b-47bd-ac73-28c61d876901 PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Oxidative stress (OS) is proven to be one of the mechanisms for ALS pathogenesis. OS is caused by an imbalance between the generation and removal of reactive oxygen and nitrogen species (ROS/RNS) and causes structural damage and changes in redox-sensitive signaling. About 20-25% of family ALS cases arise from mutations in the superoxide dismutase 1 (SOD1) gene. Normally, SOD1 converts the superoxide anion to hydrogen peroxide (H2O2) and protects the cell from OS. This enzyme plays an important role as a cellular antioxidant, and mutant SOD1 (mSOD1) can selectively kill motor neurons due to loss of dismutase function. At the same time, mSOD1 can impair multiple cellular functions including the disruption of CYBB regulation via direct interaction with RAC1. CYBB is a superoxide anion producer, and its dysregulation allows persistent superoxide production. NFE2L2 antioxidant response pathway is the primary cellular defense against the cytotoxic effects of OS. Outcome effects: NFE2L2 normally elevates the expression of several antioxidant enzymes such as GSTA2, NQO1, GSR, GCLM, GCLC, and HMOX1. NFE2L2 is retained in the cytoplasm by KEAP1 and CUL3 which degrade NFE2L2 by ubiquitylation. KPNA6 has been identified as a protein which facilitates nuclear import and attenuates NFE2L2 signaling. NFE2L2 has been found to be downregulated in ALS. In addition, PPARG is an important neuroprotective factor in ALS and is upregulated in ALS. PPARG is activated by lipid peroxidation end product 4-hydroxynonenal, whose levels are elevated in the cerebrospinal fluid and spinal cord from ALS patients. PPARG triggers GSTA2 and HMOX1 production. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 19457088 PS:PMID 22051914 PS:PMID 22482452 PS:PMID 22910911 PS:PMID 23050144 PS:PMID 23533690 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-762cafd7-2198-487b-b877-6099597fc53a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-762cafd7-2198-487b-b877-6099597fc53a CD72 -> NF-kB Expression Targets uuid-762cafd7-2198-487b-b877-6099597fc53a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-762cafd7-2198-487b-b877-6099597fc53a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76415504-47bb-4854-be7e-7b66936a917b NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-76415504-47bb-4854-be7e-7b66936a917b Panic Disorder: Posible Role of NMDA-R uuid-76415504-47bb-4854-be7e-7b66936a917b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76415504-47bb-4854-be7e-7b66936a917b PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Missense mutations in the carbonic anhydrase IV (CA4) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76436736-0b2b-4a9d-a59d-89eafd9c6583 NodeType: Pathway Notes: Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Missense mutations in the carbonic anhydrase IV (CA4) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP). CA4 is synthesized in the endoplasmic reticulum (ER) as a precursor. Following post-translational modifications, the mature form is expressed in the plasma membranes of epithelial and endothelial cells of different organs including the choriocapillaris of the eye. Outcome effects: Mutated CA4 has been shown to elevate levels of ER stress markers including HSPA5 and DDIT3, which can lead to cell death through apoptosis. Since CA4 is highly expressed in the choriocapillaris of the eye, but not in the retina, it has been proposed that ER stress-induced apoptosis of endothelial cells in the choriocapillaris may cause secondary damage in the overlying retina, which eventually leads to RP. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 19211803 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-76436736-0b2b-4a9d-a59d-89eafd9c6583 CA4 Induces Apoptosis of Choriocapillaris Endothelial Cells in RP uuid-76436736-0b2b-4a9d-a59d-89eafd9c6583 PS:CellType endothelial cell PS:Description Missense mutations in the carbonic anhydrase IV (CA4) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76436736-0b2b-4a9d-a59d-89eafd9c6583 PS:NodeType Pathway PS:Notes Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Missense mutations in the carbonic anhydrase IV (CA4) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP). CA4 is synthesized in the endoplasmic reticulum (ER) as a precursor. Following post-translational modifications, the mature form is expressed in the plasma membranes of epithelial and endothelial cells of different organs including the choriocapillaris of the eye. Outcome effects: Mutated CA4 has been shown to elevate levels of ER stress markers including HSPA5 and DDIT3, which can lead to cell death through apoptosis. Since CA4 is highly expressed in the choriocapillaris of the eye, but not in the retina, it has been proposed that ER stress-induced apoptosis of endothelial cells in the choriocapillaris may cause secondary damage in the overlying retina, which eventually leads to RP. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 19211803 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7643c1a6-04e1-4112-95a2-3e05be2372a8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7643c1a6-04e1-4112-95a2-3e05be2372a8 matairesinol biosynthesis template uuid-7643c1a6-04e1-4112-95a2-3e05be2372a8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7643c1a6-04e1-4112-95a2-3e05be2372a8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-764adf07-ad7f-475d-bd07-e38753580e7c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-764adf07-ad7f-475d-bd07-e38753580e7c GAST Expression Targets in GAST Expression Targets uuid-764adf07-ad7f-475d-bd07-e38753580e7c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-764adf07-ad7f-475d-bd07-e38753580e7c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-766df1b7-8a1d-4d92-bbbc-376cf2a10538 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-766df1b7-8a1d-4d92-bbbc-376cf2a10538 MVA biosynthesis template uuid-766df1b7-8a1d-4d92-bbbc-376cf2a10538 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-766df1b7-8a1d-4d92-bbbc-376cf2a10538 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: goblet cell Description: Mucus overproduction is a main feature of bronchial asthma, contributing to mortality in the disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76730c28-48c6-4cd0-ae35-478aa684e1fc NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Mucus overproduction is an important feature of bronchial asthma, contributing to mortality in the disease, and goblet cells are major mucus-producing cells. Signaling description: Airway mucus is a heterogeneous mixture of secreted polypeptides, cells, and cellular debris that are tethered together at the fluid surface by oligomeric mucin complexes. MUC5AC is probably the dominant mucin gene induced in the asthma mouse model. Following their synthesis and post-translational processing, mucins are stored within the intracellular secretory granules until stimulated for release by regulated exocytosis. EGF-R and Th2 cytokine pathways offer the greatest potential for inhibition of excessive mucus production. MARCKS has been shown to be a major regulator of the airway granule exocytosis of mucins, but the precise regulatory mechanism remains unknown. Under normal conditions, intracellular MARCKS is attached to the plasma membrane. Outcome effects: After being phosphorylated by activated PKC, MARCKS translocates from the plasma membrane to the cytoplasm. HSP70 and cysteine string protein (DNAJC5) associate with MARCKS during mucin secretion. VAMP8 is one of the SNAREs regulating mucin granule exocytosis in the goblet cells. Synaptotagmin 2 is essential for regulated excocytic mucin release from goblet cells. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 17716382 PMID: 21281703 PMID: 22144578 PMID: 23288845 PMID: 23377348 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-76730c28-48c6-4cd0-ae35-478aa684e1fc Goblet-Cell Exocytosis in Asthma uuid-76730c28-48c6-4cd0-ae35-478aa684e1fc PS:CellType goblet cell PS:Description Mucus overproduction is a main feature of bronchial asthma, contributing to mortality in the disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76730c28-48c6-4cd0-ae35-478aa684e1fc PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Mucus overproduction is an important feature of bronchial asthma, contributing to mortality in the disease, and goblet cells are major mucus-producing cells. Signaling description: Airway mucus is a heterogeneous mixture of secreted polypeptides, cells, and cellular debris that are tethered together at the fluid surface by oligomeric mucin complexes. MUC5AC is probably the dominant mucin gene induced in the asthma mouse model. Following their synthesis and post-translational processing, mucins are stored within the intracellular secretory granules until stimulated for release by regulated exocytosis. EGF-R and Th2 cytokine pathways offer the greatest potential for inhibition of excessive mucus production. MARCKS has been shown to be a major regulator of the airway granule exocytosis of mucins, but the precise regulatory mechanism remains unknown. Under normal conditions, intracellular MARCKS is attached to the plasma membrane. Outcome effects: After being phosphorylated by activated PKC, MARCKS translocates from the plasma membrane to the cytoplasm. HSP70 and cysteine string protein (DNAJC5) associate with MARCKS during mucin secretion. VAMP8 is one of the SNAREs regulating mucin granule exocytosis in the goblet cells. Synaptotagmin 2 is essential for regulated excocytic mucin release from goblet cells. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17716382 PS:PMID 21281703 PS:PMID 22144578 PS:PMID 23288845 PS:PMID 23377348 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-768510a7-fa5d-41dd-b9d1-aea39e2e12fa NodeType: Pathway Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-768510a7-fa5d-41dd-b9d1-aea39e2e12fa IFN suppression by COVID19 prevents pulmonary edema uuid-768510a7-fa5d-41dd-b9d1-aea39e2e12fa PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-768510a7-fa5d-41dd-b9d1-aea39e2e12fa PS:NodeType Pathway PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a048d5-fd5e-4c7d-8bc6-037cb3547b1a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-76a048d5-fd5e-4c7d-8bc6-037cb3547b1a RASs-RAFs-MAPK1/3 uuid-76a048d5-fd5e-4c7d-8bc6-037cb3547b1a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a048d5-fd5e-4c7d-8bc6-037cb3547b1a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a3e534-b076-4638-9794-cea0d2728988 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-76a3e534-b076-4638-9794-cea0d2728988 Metabolism of Estrogens and Androgens uuid-76a3e534-b076-4638-9794-cea0d2728988 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a3e534-b076-4638-9794-cea0d2728988 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a70324-e492-459f-9d98-dfdd8dc9e004 NodeType: Pathway Notes: Headnote: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Signaling description: In OA, cartilage homeostasis is disrupted by mechanisms driven by a combination of biophysical and biochemical factors. OA involves the re-initiation of a process that normally occurs in the embryo and children and ceases in adulthood. This process starts with hypertrophic differentiation of chondrocytes characterized by type X collagen (COL10A1) expression, followed by the conversion of nonvascularized and hypoxic cartilage tissue into highly vascularized bone tissue via the degradation of the cartilage matrix and vascular invasion. The signals to induce endochondral ossification cause cartilage degradation at the center of the joint and osteophyte formation at the periphery. The key chondrocyte signaling pathways include, but are not limited to, WNT/CTNNB1, EPAS1, TGFB2, TNF, and IL1B pathways. The degradation of extracellular matrix (ECM) caused by TNF, IL1B, DDR2, and advanced glycosylation end products are impaired due to mutations in FRZB gene. The loss of FRZB may contribute to cartilage damage by increasing the expression and activity of MMPs, in a WNT-dependent and WNT-independent manner. Excessive mechanical loading causes TNF and IL1B synthesis in cartilage. The cytokines bind to their receptors on the chondrocyte surface and through MAPK8, MAPK p38, and MAPK1 pathways lead to JUN-FOS activation. The release of NF-kB from its inhibitor, NFKBIA is also provoked by these cytokines. In addition, JUN, FOS, and NF-kB bind to the promoter regions of metalloproteinases including MMP1, MMP3, and MMP13 and cause their synthesis. In addition, TNF induces the expression of syndecan 4 (SDC4) in OA. Outcome effects: The metalloproteinases released into the ECM cleave collagens and aggrecan (ACAN), thereby provoking cartilage erosion. SDC4 directly activates ADAMTS5 which cleaves ACAN, which normally interacts with hyaluronic acid to form large proteoglycan aggregates (not shown). Proteoglycans provide COL2A1 fibrillar formation in articular cartilage; however, decreased proteoglycan aggregates due to the cleavage of ACAN are the reason for nonfibrillar COL2A1 presence. The latter binds to DDR2 receptor and through SHC1/TRAF6/TAB1/MAPK14 causes RUNX2 activation. RUNX2 and EPAS1 induce VEGFA and COL10A1 expression. These proteins are specific for hypertrophic chondrocytes and promote endochondral ossification and osteophyte formation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: bone Organ_System: skeletal system PMID: 12082286 PMID: 12110122 PMID: 21638205 PMID: 22172041 PMID: 22178514 PMID: 22179031 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-76a70324-e492-459f-9d98-dfdd8dc9e004 Osteoarthritis uuid-76a70324-e492-459f-9d98-dfdd8dc9e004 PS:CellType chondrocyte PS:Description Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76a70324-e492-459f-9d98-dfdd8dc9e004 PS:NodeType Pathway PS:Notes Headnote: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Signaling description: In OA, cartilage homeostasis is disrupted by mechanisms driven by a combination of biophysical and biochemical factors. OA involves the re-initiation of a process that normally occurs in the embryo and children and ceases in adulthood. This process starts with hypertrophic differentiation of chondrocytes characterized by type X collagen (COL10A1) expression, followed by the conversion of nonvascularized and hypoxic cartilage tissue into highly vascularized bone tissue via the degradation of the cartilage matrix and vascular invasion. The signals to induce endochondral ossification cause cartilage degradation at the center of the joint and osteophyte formation at the periphery. The key chondrocyte signaling pathways include, but are not limited to, WNT/CTNNB1, EPAS1, TGFB2, TNF, and IL1B pathways. The degradation of extracellular matrix (ECM) caused by TNF, IL1B, DDR2, and advanced glycosylation end products are impaired due to mutations in FRZB gene. The loss of FRZB may contribute to cartilage damage by increasing the expression and activity of MMPs, in a WNT-dependent and WNT-independent manner. Excessive mechanical loading causes TNF and IL1B synthesis in cartilage. The cytokines bind to their receptors on the chondrocyte surface and through MAPK8, MAPK p38, and MAPK1 pathways lead to JUN-FOS activation. The release of NF-kB from its inhibitor, NFKBIA is also provoked by these cytokines. In addition, JUN, FOS, and NF-kB bind to the promoter regions of metalloproteinases including MMP1, MMP3, and MMP13 and cause their synthesis. In addition, TNF induces the expression of syndecan 4 (SDC4) in OA. Outcome effects: The metalloproteinases released into the ECM cleave collagens and aggrecan (ACAN), thereby provoking cartilage erosion. SDC4 directly activates ADAMTS5 which cleaves ACAN, which normally interacts with hyaluronic acid to form large proteoglycan aggregates (not shown). Proteoglycans provide COL2A1 fibrillar formation in articular cartilage; however, decreased proteoglycan aggregates due to the cleavage of ACAN are the reason for nonfibrillar COL2A1 presence. The latter binds to DDR2 receptor and through SHC1/TRAF6/TAB1/MAPK14 causes RUNX2 activation. RUNX2 and EPAS1 induce VEGFA and COL10A1 expression. These proteins are specific for hypertrophic chondrocytes and promote endochondral ossification and osteophyte formation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ bone PS:Organ_System skeletal system PS:PMID 12082286 PS:PMID 12110122 PS:PMID 21638205 PS:PMID 22172041 PS:PMID 22178514 PS:PMID 22179031 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76ca6066-3a5d-4e9b-bf29-2193ee811c43 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-76ca6066-3a5d-4e9b-bf29-2193ee811c43 Dopamine Action in CSD Progression uuid-76ca6066-3a5d-4e9b-bf29-2193ee811c43 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-76ca6066-3a5d-4e9b-bf29-2193ee811c43 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77133745-7539-4490-a904-15cdaf55e3e3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-77133745-7539-4490-a904-15cdaf55e3e3 NSP1 inhibitors uuid-77133745-7539-4490-a904-15cdaf55e3e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77133745-7539-4490-a904-15cdaf55e3e3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77221dc5-0673-41a7-a744-a87368766253 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-77221dc5-0673-41a7-a744-a87368766253 Lysine degradation template uuid-77221dc5-0673-41a7-a744-a87368766253 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77221dc5-0673-41a7-a744-a87368766253 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7726b48f-fb3b-41b5-aafb-eb0c7e7376f2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7726b48f-fb3b-41b5-aafb-eb0c7e7376f2 2-Carboxyarabinitol 1-P biosynthesis template uuid-7726b48f-fb3b-41b5-aafb-eb0c7e7376f2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7726b48f-fb3b-41b5-aafb-eb0c7e7376f2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7741db10-0402-44e9-917d-14aec6202479 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7741db10-0402-44e9-917d-14aec6202479 Indole alkaloid biosynthesis template uuid-7741db10-0402-44e9-917d-14aec6202479 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7741db10-0402-44e9-917d-14aec6202479 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-776d2914-14fb-40b7-bc41-eb9eb6db1558 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: LTD4/CYSLTR1/CYSLTR2 activation in mast cells results in IL8 production and mast cell proliferation. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-776d2914-14fb-40b7-bc41-eb9eb6db1558 Mast-Cell Activation without Degranulation through CYSLTR1/CYSLTR2 Signaling uuid-776d2914-14fb-40b7-bc41-eb9eb6db1558 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-776d2914-14fb-40b7-bc41-eb9eb6db1558 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: LTD4/CYSLTR1/CYSLTR2 activation in mast cells results in IL8 production and mast cell proliferation. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77824242-471a-4449-bb2b-c7885bacda20 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-77824242-471a-4449-bb2b-c7885bacda20 Wiskott-Aldrich Syndrome Mutated Genes uuid-77824242-471a-4449-bb2b-c7885bacda20 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77824242-471a-4449-bb2b-c7885bacda20 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: Deficiency of inhibitory neuromediator GABA is regarded as on of the pathogenesis mechanisms of epilepsy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-778805e9-1e35-4a11-9bb6-605dfb305662 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: At an excitatory glutamatergic synapse, the neurotransmitter glutamate is released from presynaptic terminal vesicles. Glutamate binds to AMPA and N-methyl-D-aspartate (NMDA) selective glutamate receptors on the postsynaptic membrane and opens ion channels allowing the inward flow of calcium (Ca2+) and sodium (Na+) leading to action potential generation. Astrocytes are known to aid in homeostatic functions including the clearance of neuronally-released potassium (K+) and glutamate from the synapse. The propagation of action potentials and synaptic activity after local depolarization lead to fast fluctuations of the extracellular K+ concentration. If increases in K+ remain uncorrected, the resting potential may become more positive and affect activation of transmembrane ion channels, receptors, and transporters and may generate epileptiform activity. Two different mechanisms are thought to balance K+ including K+ uptake and spatial K+ buffering. Spatial buffering is dependent on proper distribution and function of astrocytic K+ channels, water channels, and gap junctions. In astrocytes, the inward rectifying K+ channel Kir4.1 (KCNJ10) allows K+ influx at negative membrane potentials. Elevated levels of K are taken up by perisynaptic astrocytes along with water by KCNJ10 and AQP4 channels, respectively. The loss or redistribution of AQP4 and KCNJ10 away from astrocytic endfeet observed in epilepsy would exacerbate astrocyte swelling since water flux into astrocytes at synapses would be increased while efflux via endfeet into the blood vessels would be decreased. GJA1 and GJB6 comprise the main connexins forming gap junctions of astrocytes. The lack of these gap junction proteins observed in epilepsy leads to the generation of spontaneous epileptiform activity due to impaired ion special buffering. Outcome effects: Astrocytes are responsible for glutamate uptake. The reduced excitatory amino acid transporter 1/2 (SLC1A3/SLC1A2) expression in epilepsy may lead to delayed clearance of glutamate from the synapse. Glutamate is converted into glutamine through glutamine synthetase (GLUL). The reduced expression of GLUL in epilepsy elevates the concentration of glutamate in astrocytes, providing more glutamate to be released. Elevated extracellular glutamate decreases the threshold for seizure induction. In addition, glutamine is used as a precursor for the synthesis of GABA in GABAergic neurons. The loss of GLUL in reactive astrocytes leads to a decrease in glutamine and GABA levels in GABAergic terminals. Consequently, GABAergic inhibition is reduced which leads to a reduction in the seizure threshold. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. References: 1). Clasadonte J, Haydon PG (2012) Astrocytes and Epilepsy. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. 2). Coulter DA (2009). Neurotransmitter function. Consequences of Diminished Function of the Glutamine Cycle on Inhibitory Function in the Epileptic Brain. Encyclopedia of Basic Epilepsy Research. pp 877-882.Avialable from: http://www.sciencedirect.com/science/article/pii/B9780123739612003453 Hubbard JA, Hsu MS, 3). 23376026 Organ: brain Organ_System: nervous system PMID: 23376026 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-778805e9-1e35-4a11-9bb6-605dfb305662 Astrocyte Dysfunction and GABA Signaling Deficiency uuid-778805e9-1e35-4a11-9bb6-605dfb305662 PS:CellType astrocyte PS:CellType neuron PS:Description Deficiency of inhibitory neuromediator GABA is regarded as on of the pathogenesis mechanisms of epilepsy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-778805e9-1e35-4a11-9bb6-605dfb305662 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: At an excitatory glutamatergic synapse, the neurotransmitter glutamate is released from presynaptic terminal vesicles. Glutamate binds to AMPA and N-methyl-D-aspartate (NMDA) selective glutamate receptors on the postsynaptic membrane and opens ion channels allowing the inward flow of calcium (Ca2+) and sodium (Na+) leading to action potential generation. Astrocytes are known to aid in homeostatic functions including the clearance of neuronally-released potassium (K+) and glutamate from the synapse. The propagation of action potentials and synaptic activity after local depolarization lead to fast fluctuations of the extracellular K+ concentration. If increases in K+ remain uncorrected, the resting potential may become more positive and affect activation of transmembrane ion channels, receptors, and transporters and may generate epileptiform activity. Two different mechanisms are thought to balance K+ including K+ uptake and spatial K+ buffering. Spatial buffering is dependent on proper distribution and function of astrocytic K+ channels, water channels, and gap junctions. In astrocytes, the inward rectifying K+ channel Kir4.1 (KCNJ10) allows K+ influx at negative membrane potentials. Elevated levels of K are taken up by perisynaptic astrocytes along with water by KCNJ10 and AQP4 channels, respectively. The loss or redistribution of AQP4 and KCNJ10 away from astrocytic endfeet observed in epilepsy would exacerbate astrocyte swelling since water flux into astrocytes at synapses would be increased while efflux via endfeet into the blood vessels would be decreased. GJA1 and GJB6 comprise the main connexins forming gap junctions of astrocytes. The lack of these gap junction proteins observed in epilepsy leads to the generation of spontaneous epileptiform activity due to impaired ion special buffering. Outcome effects: Astrocytes are responsible for glutamate uptake. The reduced excitatory amino acid transporter 1/2 (SLC1A3/SLC1A2) expression in epilepsy may lead to delayed clearance of glutamate from the synapse. Glutamate is converted into glutamine through glutamine synthetase (GLUL). The reduced expression of GLUL in epilepsy elevates the concentration of glutamate in astrocytes, providing more glutamate to be released. Elevated extracellular glutamate decreases the threshold for seizure induction. In addition, glutamine is used as a precursor for the synthesis of GABA in GABAergic neurons. The loss of GLUL in reactive astrocytes leads to a decrease in glutamine and GABA levels in GABAergic terminals. Consequently, GABAergic inhibition is reduced which leads to a reduction in the seizure threshold. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. References: 1). Clasadonte J, Haydon PG (2012) Astrocytes and Epilepsy. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. 2). Coulter DA (2009). Neurotransmitter function. Consequences of Diminished Function of the Glutamine Cycle on Inhibitory Function in the Epileptic Brain. Encyclopedia of Basic Epilepsy Research. pp 877-882.Avialable from: http://www.sciencedirect.com/science/article/pii/B9780123739612003453 Hubbard JA, Hsu MS, 3). 23376026 PS:Organ brain PS:Organ_System nervous system PS:PMID 23376026 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sebocyte Description: Androgenetic alopecia (AGA), like other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-778c8625-09e8-44e5-bcf4-87b1355c0089 NodeType: Pathway Notes: Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: Androgens are steroid hormones that are derived from cholesterol and differ only in the ring structure and side chains attached to it. Dehydroepiandrosterone sulfate (DHEA-sulfate) and androstenedione are the earlier compounds in the synthesis of androgen which are mainly produced in the adrenal gland. The later compounds such as testosterone and dihydrotestosterone (DHT) are mainly produced in the gonads. Free testosterone is the most potent circulating androgen. Skin cells and hair follicles express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens. Testosterone in women and DHT in both genders are synthesized in the skin. Sebaceous glands and sweat glands are major contributors to the synthesis of androgens by the skin. In addition, sebocytes are capable of de novo synthesis of cholesterol which can be utilized for the production of androgens. Cholesterol can be made within the cell from acetyl-CoA (de novo synthesis) by HMGCR. There is negative feedback regulation of HMGCR activity by cholesterol, so that high intracellular cholesterol inhibits de novo synthesis. Cholesterol is also taken up by the cell in the form of low density lipoprotein (LDL). LDL is taken into cells via CD36, and broken down into esterified cholesterol, and then free cholesterol. Five major enzymes are involved in androgen synthesis in the skin. The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone by CYP11A1 in the inner mitochondrial membrane. An additional cytochrome, CYP17A1 is necessary for the synthesis of DHEA and androstenedione. However, sebocytes express low levels of CYP17A1. Steroid sulfatase STS hydrolyzes DHEA-sulfate to DHEA in sebaceous glands. HSD3B1 converts DHEA to androstenedione. Human skin (sebaceous glands) exclusively expresses HSD3B1 isoform. Androstenedione is activated by the conversion to testosterone through HSD17B. HSD17B3 and HSD17B5 form the active androgen, testosterone from androstenedione, whereas the oxidative reaction of HSD17B2 types and HSD17B4 is in the reverse direction, inactivating the potent sexual steroids. SRD5A1 irreversibly converts testosterone to DHT, the most potent naturally occurring androgen in tissue. SRD5A1 isoforms dominate in the skin sebaceous and sweat glands, with lesser activity in epidermal cells and hair follicles. Outcome effects: Even though sebocytes are known to be the main source of androgen synthesis in the skin, their involvement in the progression of AGA is still unclear. There is no conclusive evidence regarding statistically significant alteration of the expression of steroidogenic enzymes in sebocytes of balding scalp. Some patients with AGA have significantly higher levels of STAR in the basal layer of sebaceous glands in bald parieto-frontal scalp as compared to the occipital scalp. The regulation of STAR expression may be associated with cAMP-PKA pathway, which includes PKA phosphorylation of CREB1, recruitment of CREB binding protein (CREBBP), retinoid X receptor alpha, and RARA to the STAR promoter. If AGA patients have no increase in endogenous androgen synthesis in sebocytes, levels of androgens in the skin may increase due to intensified proliferation or differentiation of sebocytes. Recent studies suggest that androgens are the positive signal for sebocyte proliferation and the factor that limits their differentiation. Nevertheless, the mechanism that provides the influence of androgens and androgen receptors (ARs) Organ: skin Organ_System: integumentary system PMID: 16778788 PMID: 17326004 PMID: 20032992 PMID: 20224689 PMID: 21519409 PMID: 24265455 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-778c8625-09e8-44e5-bcf4-87b1355c0089 Androgens Synthesis in Sebocytes uuid-778c8625-09e8-44e5-bcf4-87b1355c0089 PS:CellType sebocyte PS:Description Androgenetic alopecia (AGA), like other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-778c8625-09e8-44e5-bcf4-87b1355c0089 PS:NodeType Pathway PS:Notes Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: Androgens are steroid hormones that are derived from cholesterol and differ only in the ring structure and side chains attached to it. Dehydroepiandrosterone sulfate (DHEA-sulfate) and androstenedione are the earlier compounds in the synthesis of androgen which are mainly produced in the adrenal gland. The later compounds such as testosterone and dihydrotestosterone (DHT) are mainly produced in the gonads. Free testosterone is the most potent circulating androgen. Skin cells and hair follicles express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens. Testosterone in women and DHT in both genders are synthesized in the skin. Sebaceous glands and sweat glands are major contributors to the synthesis of androgens by the skin. In addition, sebocytes are capable of de novo synthesis of cholesterol which can be utilized for the production of androgens. Cholesterol can be made within the cell from acetyl-CoA (de novo synthesis) by HMGCR. There is negative feedback regulation of HMGCR activity by cholesterol, so that high intracellular cholesterol inhibits de novo synthesis. Cholesterol is also taken up by the cell in the form of low density lipoprotein (LDL). LDL is taken into cells via CD36, and broken down into esterified cholesterol, and then free cholesterol. Five major enzymes are involved in androgen synthesis in the skin. The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone by CYP11A1 in the inner mitochondrial membrane. An additional cytochrome, CYP17A1 is necessary for the synthesis of DHEA and androstenedione. However, sebocytes express low levels of CYP17A1. Steroid sulfatase STS hydrolyzes DHEA-sulfate to DHEA in sebaceous glands. HSD3B1 converts DHEA to androstenedione. Human skin (sebaceous glands) exclusively expresses HSD3B1 isoform. Androstenedione is activated by the conversion to testosterone through HSD17B. HSD17B3 and HSD17B5 form the active androgen, testosterone from androstenedione, whereas the oxidative reaction of HSD17B2 types and HSD17B4 is in the reverse direction, inactivating the potent sexual steroids. SRD5A1 irreversibly converts testosterone to DHT, the most potent naturally occurring androgen in tissue. SRD5A1 isoforms dominate in the skin sebaceous and sweat glands, with lesser activity in epidermal cells and hair follicles. Outcome effects: Even though sebocytes are known to be the main source of androgen synthesis in the skin, their involvement in the progression of AGA is still unclear. There is no conclusive evidence regarding statistically significant alteration of the expression of steroidogenic enzymes in sebocytes of balding scalp. Some patients with AGA have significantly higher levels of STAR in the basal layer of sebaceous glands in bald parieto-frontal scalp as compared to the occipital scalp. The regulation of STAR expression may be associated with cAMP-PKA pathway, which includes PKA phosphorylation of CREB1, recruitment of CREB binding protein (CREBBP), retinoid X receptor alpha, and RARA to the STAR promoter. If AGA patients have no increase in endogenous androgen synthesis in sebocytes, levels of androgens in the skin may increase due to intensified proliferation or differentiation of sebocytes. Recent studies suggest that androgens are the positive signal for sebocyte proliferation and the factor that limits their differentiation. Nevertheless, the mechanism that provides the influence of androgens and androgen receptors (ARs) PS:Organ skin PS:Organ_System integumentary system PS:PMID 16778788 PS:PMID 17326004 PS:PMID 20032992 PS:PMID 20224689 PS:PMID 21519409 PS:PMID 24265455 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7798bbac-b9fe-458c-9bf8-ac5431ec79ce NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7798bbac-b9fe-458c-9bf8-ac5431ec79ce GDF5/BMPR2/ACVR2 Expression Targets uuid-7798bbac-b9fe-458c-9bf8-ac5431ec79ce PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7798bbac-b9fe-458c-9bf8-ac5431ec79ce PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: T-cell Description: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77b0dd56-bfaf-4bc9-8fcc-d954f4c9769a NodeType: Pathway Notes: Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Tissue transglutaminase deamidates or crosslinks 33 mer gliadin which is then recognized by human leukocyte antigen (HLA)-DQ2 or -DQ8 molecules of antigen presenting cell (APC). Activated gluten-reactive CD4+ T-cells produce high levels of pro-infl ammatory cytokines, thus inducing a T-helper cell-type-(Th)1 pattern dominated by interferon gamma. Gluten peptides can be transported across the intestinal epithelium either paracellularly as a consequence of impaired mucosal integrity attributable to increased release of zonulin, or via transcytosis, or retrotranscytosis of secretory IgA through transferrin receptor CD71. Outcome effects: CD4+ gluten-specific T-helper (Th) cells recognize the deamidated gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 and respond by expressing high levels of interleukin 21 and interferon gamma. These cytokines affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. This response leads directly to tissue remodeling and flattening of the intestinal mucosa. Gluten peptides also trigger innate immune response characterized by an elevated expression of interleukin (IL)-15 by intestinal enterocytes. IL21 is critical for Th-cell-driven antibody responses and thus provides a link to B-cells.Description of Highlighted proteins: IL21, IL15, IFN-gamma and HP highlighted in red in order to emphasize violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease.Description of Mutated genes: CTLA4, HLA DQ2 and HLA DQ8 genes in whiteout style have genetic variants which increase susceptibility to Celiac disease. Organ: colon Organ: small intestine Organ_System: digestive system PMID: 20348961 PMID: 20947431 PMID: 23917697 PMID: 26972670 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-77b0dd56-bfaf-4bc9-8fcc-d954f4c9769a Celiac Disease uuid-77b0dd56-bfaf-4bc9-8fcc-d954f4c9769a PS:CellType B-cell PS:CellType T-cell PS:Description Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77b0dd56-bfaf-4bc9-8fcc-d954f4c9769a PS:NodeType Pathway PS:Notes Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Tissue transglutaminase deamidates or crosslinks 33 mer gliadin which is then recognized by human leukocyte antigen (HLA)-DQ2 or -DQ8 molecules of antigen presenting cell (APC). Activated gluten-reactive CD4+ T-cells produce high levels of pro-infl ammatory cytokines, thus inducing a T-helper cell-type-(Th)1 pattern dominated by interferon gamma. Gluten peptides can be transported across the intestinal epithelium either paracellularly as a consequence of impaired mucosal integrity attributable to increased release of zonulin, or via transcytosis, or retrotranscytosis of secretory IgA through transferrin receptor CD71. Outcome effects: CD4+ gluten-specific T-helper (Th) cells recognize the deamidated gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 and respond by expressing high levels of interleukin 21 and interferon gamma. These cytokines affect the epithelial cells and activate intraepithelial lymphocytes, ultimately leading to villous atrophy. This response leads directly to tissue remodeling and flattening of the intestinal mucosa. Gluten peptides also trigger innate immune response characterized by an elevated expression of interleukin (IL)-15 by intestinal enterocytes. IL21 is critical for Th-cell-driven antibody responses and thus provides a link to B-cells.Description of Highlighted proteins: IL21, IL15, IFN-gamma and HP highlighted in red in order to emphasize violation of mucosal integrity, epithelial damage and immune response, resulting in Celiac disease.Description of Mutated genes: CTLA4, HLA DQ2 and HLA DQ8 genes in whiteout style have genetic variants which increase susceptibility to Celiac disease. PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:PMID 20348961 PS:PMID 20947431 PS:PMID 23917697 PS:PMID 26972670 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77c45375-b48f-4fe8-a707-46e4bff1db3f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-77c45375-b48f-4fe8-a707-46e4bff1db3f IL21R -> STAT Signaling uuid-77c45375-b48f-4fe8-a707-46e4bff1db3f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77c45375-b48f-4fe8-a707-46e4bff1db3f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77cde7c8-3ade-456a-9b85-c09c09353aed NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-77cde7c8-3ade-456a-9b85-c09c09353aed Tumor acidification induces cancer-associated fibroblast differentiation uuid-77cde7c8-3ade-456a-9b85-c09c09353aed PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77cde7c8-3ade-456a-9b85-c09c09353aed PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: Leukotrienes LTC4 and LTD4 are powerful mediators of asthma, allergies, and airway hypersensitivity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77dd5a1d-b361-45f5-8dab-1d158c859ba0 NodeType: Pathway Notes: Headnote: Leukotrienes LTC4 and LTD4 are powerful mediators of asthma, allergies, and airway hypersensitivity. They induce bronchoconstriction, increase microvascular permeability, and enhance mucus secretion. Signaling description: LTC4, LTD4, and LTE4 are endothelial and airway smooth muscle constrictors, which act via CYSLTR1 and CYSLTR2 receptors. LTD4 is the preferred ligand for CYSLTR1, while LTC4 and LTE4 bind the receptor with progressively lower affinities. The rank order of affinity for binding CYSLTR2 is LTC4 = LTD4 > LTE4. A portion of CYSLT receptors are constitutively present as heterodimer pairs, thus the interplay of signaling between the two subtypes may regulate immune responses. Despite the clear evidence that leukotrienes are critical mediators of vascular constriction, the exact molecular mechanism by which CYSLTR1 and CYSLTR2 mediate these effects are unknown. CYSLTR1 and CYSLTR2 are G-protein receptors that induce an intracellular Ca2+ signal. CYSLTR1 receptor-induced intracellular mobilization of Ca2+ has been shown to be mediated by a pertussis toxin (PTX)-insensitive G-protein, while the influx is mediated by a PTX-sensitive G-protein (GNAI1 protein family). It is recognized that an increase in procontractile stimuli in the asthmatic airway promotes greater activation of GPCRs (Gq- and Gi-coupled receptors) mediating contraction. CYSLTR1 appears to be the preferred receptor for Ca2+ influx in epithelial and inflammatory cells. Intracellular Ca2+ plays a major role in airway smooth muscle contraction and relaxation. Phospholipase C beta (PLCB1) is the principal effector of Gq-mediated signaling. Activated PLCB1 hydrolyzes PIP2 into diacylglycerol and IP3. Increased IP3 and diacylglycerol levels lead to increased intracellular Ca2+ through its release from internal stores and influx from membrane bound channels. Outcome effects: The rise in intracellular Ca2+ promotes the formation of Ca2+-calmodulin complexes that activate myosin light chain kinase (MYLK). MYLK phosphorylates myosin light chains and enables actin to activate the myosin ATPase activity required for cross-bridge cycling and contraction. Additional effects shown to involve Gq activation by G-protein receptors in airway smooth muscle cells include Rho-dependent mechanism of contraction. RHOA activates ROCK1, which in turn phosphorylates the myosin light chain phosphatase (MLCP), resulting in increased phosphorylation of myosin light chain. GNAI1 family expressed in airway smooth muscle cells appears capable of activating RHOA through the activation of GEF. Furthermore, leukotrienes in airway smooth muscle cells activate the cell contractile machinery through both Ca2+ and protein kinase C (PKC)-dependent mechanisms. Diacylglycerol promotes the translocation of PKC from the cytoplasm to the membrane and its subsequent activation. Activated PKC is capable of phosphorylating a number of substrates including calponin (CNN1). PKC also phosphorylates intermediates of MAPK signaling pathways, which activate various gene transcription factors involved in promoting airway smooth muscle cell growth. MAPK1/MAPK3 phosphorylate and stimulate the catalytic activity of phospholipase A2. The binding of Ca2+ to phospholipase A2 triggers its association with the plasma or nuclear membrane and the subsequent cleaving and release of arachidonic acid, a precursor in the production of eicosanoids and leukotrienes. Organ: generic Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-77dd5a1d-b361-45f5-8dab-1d158c859ba0 Leukotriene Effect on Airway Smooth Muscle Response uuid-77dd5a1d-b361-45f5-8dab-1d158c859ba0 PS:CellType vascular smooth muscle cell PS:Description Leukotrienes LTC4 and LTD4 are powerful mediators of asthma, allergies, and airway hypersensitivity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77dd5a1d-b361-45f5-8dab-1d158c859ba0 PS:NodeType Pathway PS:Notes Headnote: Leukotrienes LTC4 and LTD4 are powerful mediators of asthma, allergies, and airway hypersensitivity. They induce bronchoconstriction, increase microvascular permeability, and enhance mucus secretion. Signaling description: LTC4, LTD4, and LTE4 are endothelial and airway smooth muscle constrictors, which act via CYSLTR1 and CYSLTR2 receptors. LTD4 is the preferred ligand for CYSLTR1, while LTC4 and LTE4 bind the receptor with progressively lower affinities. The rank order of affinity for binding CYSLTR2 is LTC4 = LTD4 > LTE4. A portion of CYSLT receptors are constitutively present as heterodimer pairs, thus the interplay of signaling between the two subtypes may regulate immune responses. Despite the clear evidence that leukotrienes are critical mediators of vascular constriction, the exact molecular mechanism by which CYSLTR1 and CYSLTR2 mediate these effects are unknown. CYSLTR1 and CYSLTR2 are G-protein receptors that induce an intracellular Ca2+ signal. CYSLTR1 receptor-induced intracellular mobilization of Ca2+ has been shown to be mediated by a pertussis toxin (PTX)-insensitive G-protein, while the influx is mediated by a PTX-sensitive G-protein (GNAI1 protein family). It is recognized that an increase in procontractile stimuli in the asthmatic airway promotes greater activation of GPCRs (Gq- and Gi-coupled receptors) mediating contraction. CYSLTR1 appears to be the preferred receptor for Ca2+ influx in epithelial and inflammatory cells. Intracellular Ca2+ plays a major role in airway smooth muscle contraction and relaxation. Phospholipase C beta (PLCB1) is the principal effector of Gq-mediated signaling. Activated PLCB1 hydrolyzes PIP2 into diacylglycerol and IP3. Increased IP3 and diacylglycerol levels lead to increased intracellular Ca2+ through its release from internal stores and influx from membrane bound channels. Outcome effects: The rise in intracellular Ca2+ promotes the formation of Ca2+-calmodulin complexes that activate myosin light chain kinase (MYLK). MYLK phosphorylates myosin light chains and enables actin to activate the myosin ATPase activity required for cross-bridge cycling and contraction. Additional effects shown to involve Gq activation by G-protein receptors in airway smooth muscle cells include Rho-dependent mechanism of contraction. RHOA activates ROCK1, which in turn phosphorylates the myosin light chain phosphatase (MLCP), resulting in increased phosphorylation of myosin light chain. GNAI1 family expressed in airway smooth muscle cells appears capable of activating RHOA through the activation of GEF. Furthermore, leukotrienes in airway smooth muscle cells activate the cell contractile machinery through both Ca2+ and protein kinase C (PKC)-dependent mechanisms. Diacylglycerol promotes the translocation of PKC from the cytoplasm to the membrane and its subsequent activation. Activated PKC is capable of phosphorylating a number of substrates including calponin (CNN1). PKC also phosphorylates intermediates of MAPK signaling pathways, which activate various gene transcription factors involved in promoting airway smooth muscle cell growth. MAPK1/MAPK3 phosphorylate and stimulate the catalytic activity of phospholipase A2. The binding of Ca2+ to phospholipase A2 triggers its association with the plasma or nuclear membrane and the subsequent cleaving and release of arachidonic acid, a precursor in the production of eicosanoids and leukotrienes. PS:Organ generic PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77e5ee7f-8d81-472f-ba68-c52402253ca8 NodeType: Pathway Notes: As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Recovery (Fig. 6). Details of the regulation of beta-cell renewal are still poorly understood. Instead of one single theory, various facts from different studies have been described here. Further, almost all facts about beta-cell proliferation or neogenesis originate from animal models and may not be entirely applicable to humans. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-77e5ee7f-8d81-472f-ba68-c52402253ca8 3_3_Beta-cell proliferation and compensation: recovery uuid-77e5ee7f-8d81-472f-ba68-c52402253ca8 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77e5ee7f-8d81-472f-ba68-c52402253ca8 PS:NodeType Pathway PS:Notes As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Recovery (Fig. 6). Details of the regulation of beta-cell renewal are still poorly understood. Instead of one single theory, various facts from different studies have been described here. Further, almost all facts about beta-cell proliferation or neogenesis originate from animal models and may not be entirely applicable to humans. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77f33f62-8249-4da0-a82d-3eed1cf1e463 NodeType: Pathway Notes: In the central nervous system, serotonin (5-hydroxytryptamine, 5-HT) regulates behavior and thermoregulation among other functions. Serotonin acts via the 5-HT receptors coupled to G proteins. Organ_System: generic Organ_System: nervous system PMID: 18676031 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-77f33f62-8249-4da0-a82d-3eed1cf1e463 Serotonin Receptors Signaling uuid-77f33f62-8249-4da0-a82d-3eed1cf1e463 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77f33f62-8249-4da0-a82d-3eed1cf1e463 PS:NodeType Pathway PS:Notes In the central nervous system, serotonin (5-hydroxytryptamine, 5-HT) regulates behavior and thermoregulation among other functions. Serotonin acts via the 5-HT receptors coupled to G proteins. PS:Organ_System generic PS:Organ_System nervous system PS:PMID 18676031 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77f79db5-e818-46f7-bfd2-2ebc12dcc8d1 NodeType: Pathway PMID: 25183867 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-77f79db5-e818-46f7-bfd2-2ebc12dcc8d1 SHH+>fibroblasts uuid-77f79db5-e818-46f7-bfd2-2ebc12dcc8d1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77f79db5-e818-46f7-bfd2-2ebc12dcc8d1 PS:NodeType Pathway PS:PMID 25183867 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: Calcium toxicity in lens cells is one of the main pathological mechanisms in cataract. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77fbf800-6d61-4b02-a1de-a942cbb981fc NodeType: Pathway Notes: Headnote: Cataract is clouding of the eye's lens that affects vision and is the leading cause of blindness in older individuals. The pathology generally develops due to the gradual accumulation of molecular modifications in crystallins, the major proteins in the lens, which changes crystallin structure and function and leads to clouding of the lens. Calcium (Ca2+) - mediated toxicity in the lens cells is one of the major pathological mechanisms leading to different forms of cataract including congenital, age-related, and diabetes-induced cataract. Signaling description: The disease develops as a result of the disruption of Ca2+ efflux due to the impairment of Ca2+ ATPases by reactive oxygen species (ROS). Normally, a high Ca2+ concentration is observed in the human aqueous humor. Therefore, the ions constantly enter the cell in an inwardly directed gradient across the plasma membrane. There are several mechanisms which help maintain a low Ca2+ concentration in lens cells. Na+/Ca2+ exchanger (SLC8A1) and Ca2+ ATPases including ATP2B1, ATP2B2, and ATP2B4 in healthy lenses are activated by Ca2+-dependent calmodulin and promote Ca2+ efflux from the cell. In contrast, ATP2A2 and ATP2A3 sequester Ca2+ in the endoplasmic reticulum Ca2+ store. Also, lipids bind ions on the outer membrane and decrease the ion concentration in the cell vicinity. ROS are accumulated in lens cells due to a number of factors in diabetic, age-related, and congenital forms of cataract and attack the membrane lipids causing their peroxidation. Outcome effects: Lipids peroxidation results in the dysfunction of Ca2+ ATPases and Ca2+ release from lipids. CASR and voltage-gated Ca2+ channels promote free Ca2+ entrance into the cell. Increased intracellular Ca2+ binds crystallins leading to their aggregation; and in addition, activates calpains, preferentially CAPN2, which cleave VIM and CRYAA. This leads to cytoskeleton disorganization and block of chaperone activity in the cell causing light scattering and lens opacities. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Organ: eye Organ_System: sensory system PMID: 10892870 PMID: 15456524 PMID: 19061888 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-77fbf800-6d61-4b02-a1de-a942cbb981fc Ca2+ Toxicity in Lens Cells uuid-77fbf800-6d61-4b02-a1de-a942cbb981fc PS:CellType epithelial cell PS:Description Calcium toxicity in lens cells is one of the main pathological mechanisms in cataract. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-77fbf800-6d61-4b02-a1de-a942cbb981fc PS:NodeType Pathway PS:Notes Headnote: Cataract is clouding of the eye's lens that affects vision and is the leading cause of blindness in older individuals. The pathology generally develops due to the gradual accumulation of molecular modifications in crystallins, the major proteins in the lens, which changes crystallin structure and function and leads to clouding of the lens. Calcium (Ca2+) - mediated toxicity in the lens cells is one of the major pathological mechanisms leading to different forms of cataract including congenital, age-related, and diabetes-induced cataract. Signaling description: The disease develops as a result of the disruption of Ca2+ efflux due to the impairment of Ca2+ ATPases by reactive oxygen species (ROS). Normally, a high Ca2+ concentration is observed in the human aqueous humor. Therefore, the ions constantly enter the cell in an inwardly directed gradient across the plasma membrane. There are several mechanisms which help maintain a low Ca2+ concentration in lens cells. Na+/Ca2+ exchanger (SLC8A1) and Ca2+ ATPases including ATP2B1, ATP2B2, and ATP2B4 in healthy lenses are activated by Ca2+-dependent calmodulin and promote Ca2+ efflux from the cell. In contrast, ATP2A2 and ATP2A3 sequester Ca2+ in the endoplasmic reticulum Ca2+ store. Also, lipids bind ions on the outer membrane and decrease the ion concentration in the cell vicinity. ROS are accumulated in lens cells due to a number of factors in diabetic, age-related, and congenital forms of cataract and attack the membrane lipids causing their peroxidation. Outcome effects: Lipids peroxidation results in the dysfunction of Ca2+ ATPases and Ca2+ release from lipids. CASR and voltage-gated Ca2+ channels promote free Ca2+ entrance into the cell. Increased intracellular Ca2+ binds crystallins leading to their aggregation; and in addition, activates calpains, preferentially CAPN2, which cleave VIM and CRYAA. This leads to cytoskeleton disorganization and block of chaperone activity in the cell causing light scattering and lens opacities. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. PS:Organ eye PS:Organ_System sensory system PS:PMID 10892870 PS:PMID 15456524 PS:PMID 19061888 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-781e0830-dd25-416a-923b-001c72e3b871 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-781e0830-dd25-416a-923b-001c72e3b871 IGF1R -> CEBPA/FOXO1A Signaling uuid-781e0830-dd25-416a-923b-001c72e3b871 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-781e0830-dd25-416a-923b-001c72e3b871 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Several arachidonic acid metabolites act as endogenous AHR ligands. Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78241141-df2e-425f-b5e9-5b07a8b879b4 NodeType: Pathway Notes: Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Several arachidonic acid metabolites act as endogenous AHR ligands. Prostaglandins (PGF3alpha, PGG2, PGH1, PGB2, PGD2, PGD3, and PGH2), hydroxyeicosatrienoic acid (12-HETE) and lipoxin A4 are AHR inducers. Of these compounds, PGG2 and 12-HETE are the most potent and efficacious AHR activators and are capable of inducing AhR activity at nanomolar concentrations and, in some cases, inducing a 3- to 4-fold greater level of AHR-dependent reporter activity than dioxin. PMID: 23908379 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-78241141-df2e-425f-b5e9-5b07a8b879b4 Aryl Hydrocarbon Receptor/Arachidonic Acid Metabolites Signaling uuid-78241141-df2e-425f-b5e9-5b07a8b879b4 PS:Description Several arachidonic acid metabolites act as endogenous AHR ligands. Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78241141-df2e-425f-b5e9-5b07a8b879b4 PS:NodeType Pathway PS:Notes Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Several arachidonic acid metabolites act as endogenous AHR ligands. Prostaglandins (PGF3alpha, PGG2, PGH1, PGB2, PGD2, PGD3, and PGH2), hydroxyeicosatrienoic acid (12-HETE) and lipoxin A4 are AHR inducers. Of these compounds, PGG2 and 12-HETE are the most potent and efficacious AHR activators and are capable of inducing AhR activity at nanomolar concentrations and, in some cases, inducing a 3- to 4-fold greater level of AHR-dependent reporter activity than dioxin. PS:PMID 23908379 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B cells and accounts for 30-40? of all adult non-Hodgkin lymphomas, making it the most common type. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7831e948-099a-4ee0-a4a0-baccd7c42891 NodeType: Pathway Notes: Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization.Gene-expression profiling divides DLBCL into three histologically indistinguishable molecular subtypes: activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). The process of malignant transformation differs for each subtype and the three subtypes vary in clinical presentation and cure rates. Signaling description: ABC DLBCLs characteristically express several genes that are normally expressed in plasma cells. The pathogenetic hallmark of ABC DLBCL is the constitutive activation of the NF-kB signaling pathway due to mutations/deletions of TNFAIP3 and activating mutations in NFKBIZ, MYD88, and CARD11. About 20% of ABC lymphomas have mutations in CD79A or CD79B leading to chronic active B-cell receptor signaling. ABC DLBCLs are characterized by amplifications and consecutive overexpression of BCL2 as well as deletions affecting CDKN2A and CDKN2B. ABC DLBCL has an unfavorable prognosis and remains the least curable form of this malignancy despite recent advances in therapy. GCB DLBCL has an expression profile typical for germinal center cells and does not seem to be influenced by NF-kB signaling. A significant fraction of GCB DLBCL cases have a t(14;18) (q32; q21) activating BCL2. In addition, PTEN deletions and PTEN suppression by miR-17-92 microRNA (miRNA) cluster leads to the constitutive activation of PI3K/Akt signaling. GCB DLBCLs are characterized by activating mutations of MDM2 and BCL-6 and inactivating mutations of TP53, CREBBP, EP300, and ING1. GCB DLBCL has a more favorable prognosis compared to ABC DLBCL. PMBL is characterized by the constitutive activation of NF-kB signaling resulting from TNFAIP3 and REL mutations. The gain or amplification of JAK2 and deletion of SOCS1 contribute to continuous JAK2/STAT signaling. CIITA translocations or CD274 and PDCD1LG2 activating mutations lead to the suppression of antitumor T-cell response. The role of Epstein Barr Virus (EBV) in DLBCL is restricted to a rare subset called Epstein Barr Virus-Positive Diffuse Large B-cell Lymphoma of the Elderly. EBV proteins such as LMP1, LMP-2A, and EBNA-1 play a major role in its pathogenesis. Furthermore, anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL) is another rare subtype which is characterized by translocations t(2;17)(p23;q23) and t(2;5)(p23;q35) leading to CLTC-ALK and NPM-ALK fusion protein formation, respectively. In addition, intravascular large B-cell lymphoma (IVLBCL) is a rare type of large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of small blood vessels, particularly capillaries, but not larger arteries and veins due to the lack of ITGB1 and ICAM-1 expression, which are molecules important for transvascular lymphocyte migration. The combination of chemotherapeutic agents (vincristine, cytoxan, doxorubicin, and prednisolone) and anti-CD20 antibodies (rituximab) can cure approximately 505 of DLBCL cases. Outcome effects: In conclusion, the resulting signaling inhibits plasma cell differentiation and leads to increased proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 19577170 PMID: 19642739 PMID: 20393178 PMID: 20582737 PMID: 22224767 PMID: 22409819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-7831e948-099a-4ee0-a4a0-baccd7c42891 Diffuse Large-B-Cell Lymphoma uuid-7831e948-099a-4ee0-a4a0-baccd7c42891 PS:CellType B-cell PS:CellType cancer cell PS:Description Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B cells and accounts for 30-40? of all adult non-Hodgkin lymphomas, making it the most common type. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7831e948-099a-4ee0-a4a0-baccd7c42891 PS:NodeType Pathway PS:Notes Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization.Gene-expression profiling divides DLBCL into three histologically indistinguishable molecular subtypes: activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). The process of malignant transformation differs for each subtype and the three subtypes vary in clinical presentation and cure rates. Signaling description: ABC DLBCLs characteristically express several genes that are normally expressed in plasma cells. The pathogenetic hallmark of ABC DLBCL is the constitutive activation of the NF-kB signaling pathway due to mutations/deletions of TNFAIP3 and activating mutations in NFKBIZ, MYD88, and CARD11. About 20% of ABC lymphomas have mutations in CD79A or CD79B leading to chronic active B-cell receptor signaling. ABC DLBCLs are characterized by amplifications and consecutive overexpression of BCL2 as well as deletions affecting CDKN2A and CDKN2B. ABC DLBCL has an unfavorable prognosis and remains the least curable form of this malignancy despite recent advances in therapy. GCB DLBCL has an expression profile typical for germinal center cells and does not seem to be influenced by NF-kB signaling. A significant fraction of GCB DLBCL cases have a t(14;18) (q32; q21) activating BCL2. In addition, PTEN deletions and PTEN suppression by miR-17-92 microRNA (miRNA) cluster leads to the constitutive activation of PI3K/Akt signaling. GCB DLBCLs are characterized by activating mutations of MDM2 and BCL-6 and inactivating mutations of TP53, CREBBP, EP300, and ING1. GCB DLBCL has a more favorable prognosis compared to ABC DLBCL. PMBL is characterized by the constitutive activation of NF-kB signaling resulting from TNFAIP3 and REL mutations. The gain or amplification of JAK2 and deletion of SOCS1 contribute to continuous JAK2/STAT signaling. CIITA translocations or CD274 and PDCD1LG2 activating mutations lead to the suppression of antitumor T-cell response. The role of Epstein Barr Virus (EBV) in DLBCL is restricted to a rare subset called Epstein Barr Virus-Positive Diffuse Large B-cell Lymphoma of the Elderly. EBV proteins such as LMP1, LMP-2A, and EBNA-1 play a major role in its pathogenesis. Furthermore, anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL) is another rare subtype which is characterized by translocations t(2;17)(p23;q23) and t(2;5)(p23;q35) leading to CLTC-ALK and NPM-ALK fusion protein formation, respectively. In addition, intravascular large B-cell lymphoma (IVLBCL) is a rare type of large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of small blood vessels, particularly capillaries, but not larger arteries and veins due to the lack of ITGB1 and ICAM-1 expression, which are molecules important for transvascular lymphocyte migration. The combination of chemotherapeutic agents (vincristine, cytoxan, doxorubicin, and prednisolone) and anti-CD20 antibodies (rituximab) can cure approximately 505 of DLBCL cases. Outcome effects: In conclusion, the resulting signaling inhibits plasma cell differentiation and leads to increased proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Viral proteins are shown in grey. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 19577170 PS:PMID 19642739 PS:PMID 20393178 PS:PMID 20582737 PS:PMID 22224767 PS:PMID 22409819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78383b2a-5242-4e88-808b-b67d8c4ef6f9 NodeType: Pathway Notes: As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Neogenesis/dedifferentiation (Fig. 5). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-78383b2a-5242-4e88-808b-b67d8c4ef6f9 3_2_Beta-cell proliferation and compensation: neogenesis/dedifferentiation uuid-78383b2a-5242-4e88-808b-b67d8c4ef6f9 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78383b2a-5242-4e88-808b-b67d8c4ef6f9 PS:NodeType Pathway PS:Notes As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Neogenesis/dedifferentiation (Fig. 5). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78433f6d-15e9-4fb5-8f54-b8d8ba28abae NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-78433f6d-15e9-4fb5-8f54-b8d8ba28abae FGF2 -> AP-1/CREB/CREBBP/ELK/SRF/MYC Expression Targets uuid-78433f6d-15e9-4fb5-8f54-b8d8ba28abae PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78433f6d-15e9-4fb5-8f54-b8d8ba28abae PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-784aa626-414e-406a-b370-923fd6df8784 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-784aa626-414e-406a-b370-923fd6df8784 MSTN/ACVR2/BMPR Expression Targets uuid-784aa626-414e-406a-b370-923fd6df8784 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-784aa626-414e-406a-b370-923fd6df8784 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Th17 are a subset of T-helper cells that primarily produce two main members of the IL17 family, IL17A and IL17F, which are involved in the recruitment, activation, and migration of neutrophils. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-785ee7d6-e699-4ac1-ba61-affb783e2d58 NodeType: Pathway Notes: Headnote: Th17 are a subset of T-helper cells that primarily produce two major members of the IL17 family, IL17A and IL17F involved in the recruitment, activation, and migration of neutrophils. Signaling description: In addition, Th17-cells secrete IL21 and IL22. In humans, a combination of TGFB1, IL1B, and IL23 induces Th17 differentiation from naive T-cells. Outcome effects: Interleukin (IL) receptor, T-cell receptor (TCR), and co-activator receptor (such as CD28) pathways activate transcription factors NF-kB, STAT3, RORA, and RORC for specific Th17-related cytokine expression. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-785ee7d6-e699-4ac1-ba61-affb783e2d58 Th17-Cell Differentiation uuid-785ee7d6-e699-4ac1-ba61-affb783e2d58 PS:CellType T-cell PS:Description Th17 are a subset of T-helper cells that primarily produce two main members of the IL17 family, IL17A and IL17F, which are involved in the recruitment, activation, and migration of neutrophils. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-785ee7d6-e699-4ac1-ba61-affb783e2d58 PS:NodeType Pathway PS:Notes Headnote: Th17 are a subset of T-helper cells that primarily produce two major members of the IL17 family, IL17A and IL17F involved in the recruitment, activation, and migration of neutrophils. Signaling description: In addition, Th17-cells secrete IL21 and IL22. In humans, a combination of TGFB1, IL1B, and IL23 induces Th17 differentiation from naive T-cells. Outcome effects: Interleukin (IL) receptor, T-cell receptor (TCR), and co-activator receptor (such as CD28) pathways activate transcription factors NF-kB, STAT3, RORA, and RORC for specific Th17-related cytokine expression. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Central tolerance is a process of T-cell clonal deletion and occurs during lymphocyte development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-786ca22b-8931-4ef1-9690-4a0a54ae7522 NodeType: Pathway Notes: Headnote: Central tolerance is a process of T-cell clonal deletion and occurs during lymphocyte development. Signaling description: The key factor determining the choice between positive and negative selection is the degree of binding strength between T-cell receptor (TCR) and antigen. The response to an antigen at this stage also depends on the properties of the antigen, the cell type, and the developmental stage. This may lead to the T-cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), or further differentiation. High-avidity binding of antigen to the TCR complex induces negative selection. High-avidity binding may occur due to a defect in TCR maturation or from a large number of antigens. According to one (Hypothesis), the mechanism of negative selection due to the over-activation of TCRs by antigens occurs when over-phosphorylated LAT is incapable of activating the PLCG1-dependent release of calcium ions. This results in the reduced activity of transcription factors such as NR4A1 which is required for T-cell proliferation. Conversely, completely phosphorylated LAT strengthens signaling, which leads to the activation of caspases and triggers apoptosis. Outcome effects: Finally, the activation of PDCD1 receptor on the surface of T-cells has also been shown to be necessary for the process of T-cell clonal deletion. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-786ca22b-8931-4ef1-9690-4a0a54ae7522 T-Cell Central Tolerance uuid-786ca22b-8931-4ef1-9690-4a0a54ae7522 PS:CellType T-cell PS:Description Central tolerance is a process of T-cell clonal deletion and occurs during lymphocyte development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-786ca22b-8931-4ef1-9690-4a0a54ae7522 PS:NodeType Pathway PS:Notes Headnote: Central tolerance is a process of T-cell clonal deletion and occurs during lymphocyte development. Signaling description: The key factor determining the choice between positive and negative selection is the degree of binding strength between T-cell receptor (TCR) and antigen. The response to an antigen at this stage also depends on the properties of the antigen, the cell type, and the developmental stage. This may lead to the T-cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), or further differentiation. High-avidity binding of antigen to the TCR complex induces negative selection. High-avidity binding may occur due to a defect in TCR maturation or from a large number of antigens. According to one (Hypothesis), the mechanism of negative selection due to the over-activation of TCRs by antigens occurs when over-phosphorylated LAT is incapable of activating the PLCG1-dependent release of calcium ions. This results in the reduced activity of transcription factors such as NR4A1 which is required for T-cell proliferation. Conversely, completely phosphorylated LAT strengthens signaling, which leads to the activation of caspases and triggers apoptosis. Outcome effects: Finally, the activation of PDCD1 receptor on the surface of T-cells has also been shown to be necessary for the process of T-cell clonal deletion. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue bone marrow PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-787c7285-e13b-469c-964f-81ced7cd0750 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-787c7285-e13b-469c-964f-81ced7cd0750 HCN mobilisation template uuid-787c7285-e13b-469c-964f-81ced7cd0750 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-787c7285-e13b-469c-964f-81ced7cd0750 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78849b41-9cca-446b-aea1-5934172487f2 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-78849b41-9cca-446b-aea1-5934172487f2 Cell Adhesion Receptors -> Expression Targets in Lymphoid System and Blood uuid-78849b41-9cca-446b-aea1-5934172487f2 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78849b41-9cca-446b-aea1-5934172487f2 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-789ff42c-a58b-4b73-a87e-e4c470083b5e NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-789ff42c-a58b-4b73-a87e-e4c470083b5e PPARG signaling before laser treatment uuid-789ff42c-a58b-4b73-a87e-e4c470083b5e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-789ff42c-a58b-4b73-a87e-e4c470083b5e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78b1ac2c-57c0-413d-9edf-625aa90aff07 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-78b1ac2c-57c0-413d-9edf-625aa90aff07 TNF -> TP53/ATF Expression Targets uuid-78b1ac2c-57c0-413d-9edf-625aa90aff07 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78b1ac2c-57c0-413d-9edf-625aa90aff07 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78bfc971-480e-47ec-9913-35adc7e747e2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-78bfc971-480e-47ec-9913-35adc7e747e2 TLR4 -> AP-1/EGR1/HIF1A Expression Targets uuid-78bfc971-480e-47ec-9913-35adc7e747e2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78bfc971-480e-47ec-9913-35adc7e747e2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Diabetes mellitus type 2 is characterized by impaired insulin sensitivity (insulin resistance) and decreased insulin secretion in the final stages of disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78c1c65b-8e0e-4899-bce7-f324011f476a NodeType: Pathway Notes: Headnote: Type 2 diabetes is a chronic metabolic disease characterized by abnormally high blood sugar levels and insulin resistance. Early symptoms include frequent urination, increased thirst, weight loss, increased hunger and fatigue. Long-term symptoms include heart disease, strokes, diabetic retinopathy, and kidney failure. Diabetes mellitus type 2 involves impaired insulin sensitivity (insulin resistance) and decreased insulin secretion at the final stages of disease. The origin of the pathology is complex and has various triggers such as a high-fat diet and obesity with a genetic predisposition to hypertension. Signaling description: There is no strong association between exact mutations and disease, and only the presence of single nucleotide polymorphisms (SNPs) in several genes in one person could lead to the disease. The disease originates when insulin-dependent tissues suffer from a lack of glucose due to insulin resistance. There is a compensation mechanism that occurs in which insulin secretion increases to maintain normoglycemia. The disease progression is accompanied by endocrine pancreatic cell exhaust resulting in beta-cell destruction. The destruction of pancreatic beta-cells in type 2 diabetes mellitus occurs gradually. The first stage is characterized by the maintenance of differentiated function with intact acute glucose-stimulated insulin. In normal cases, intracellular glucose is metabolized to ATP in glycolysis. The elevation in the ATP/ADP ratio induces the closure of cell-surface ATP-sensitive K channels (KCNJ11) leading to cell membrane depolarization. Cell-surface voltage-dependent calcium (Ca2+) channels open facilitating extracellular Ca2+ influx into the beta-cell. Ca2 activates phospholipase C (PLC) and the additional Ca2+ portion is released from intracellular storage. Outcome effects: Normally, a rise in free cytosolic Ca2+ triggers the exocytosis of insulin but constant glucose intake through GLUT2 (SLC2A2) leads to a permanent cell membrane depolarization and Ca2+ influx. An excessive amount of intracellular Ca2+ triggers CYCS release and cell apoptosis. The products of glycolysis (NADPH) are involved in the following stages of energy metabolism. NADHP is used in tricarboxylic acid cycle where NADH is formed. NADH is a substrate for ATP production during oxidative phosphorylation. Intensive oxidative phosphorylation in mitochondria generates reactive oxygen species (ROS) which are not eliminated due to their abundant amount. ROS trigger oxidative stress in cells. Under physiological conditions, glucose triggers the expression of insulin transcription factors, PDX1 and MAFA which positively regulate islet amyloid polypeptide (IAPP). Therefore, elevated intracellular glucose triggers their synthesis and insulin transcription occurs. IAPP then accumulates in the cell disrupting cell metabolism. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: pancreas Organ_System: endocrine system PMID: 16306327 PMID: 16306347 PMID: 19273118 PMID: 20217509 PMID: 20217512 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-78c1c65b-8e0e-4899-bce7-f324011f476a beta-Cell Death in Diabetes Mellitus Type 2 uuid-78c1c65b-8e0e-4899-bce7-f324011f476a PS:CellType insulin-secreting cell PS:Description Diabetes mellitus type 2 is characterized by impaired insulin sensitivity (insulin resistance) and decreased insulin secretion in the final stages of disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78c1c65b-8e0e-4899-bce7-f324011f476a PS:NodeType Pathway PS:Notes Headnote: Type 2 diabetes is a chronic metabolic disease characterized by abnormally high blood sugar levels and insulin resistance. Early symptoms include frequent urination, increased thirst, weight loss, increased hunger and fatigue. Long-term symptoms include heart disease, strokes, diabetic retinopathy, and kidney failure. Diabetes mellitus type 2 involves impaired insulin sensitivity (insulin resistance) and decreased insulin secretion at the final stages of disease. The origin of the pathology is complex and has various triggers such as a high-fat diet and obesity with a genetic predisposition to hypertension. Signaling description: There is no strong association between exact mutations and disease, and only the presence of single nucleotide polymorphisms (SNPs) in several genes in one person could lead to the disease. The disease originates when insulin-dependent tissues suffer from a lack of glucose due to insulin resistance. There is a compensation mechanism that occurs in which insulin secretion increases to maintain normoglycemia. The disease progression is accompanied by endocrine pancreatic cell exhaust resulting in beta-cell destruction. The destruction of pancreatic beta-cells in type 2 diabetes mellitus occurs gradually. The first stage is characterized by the maintenance of differentiated function with intact acute glucose-stimulated insulin. In normal cases, intracellular glucose is metabolized to ATP in glycolysis. The elevation in the ATP/ADP ratio induces the closure of cell-surface ATP-sensitive K channels (KCNJ11) leading to cell membrane depolarization. Cell-surface voltage-dependent calcium (Ca2+) channels open facilitating extracellular Ca2+ influx into the beta-cell. Ca2 activates phospholipase C (PLC) and the additional Ca2+ portion is released from intracellular storage. Outcome effects: Normally, a rise in free cytosolic Ca2+ triggers the exocytosis of insulin but constant glucose intake through GLUT2 (SLC2A2) leads to a permanent cell membrane depolarization and Ca2+ influx. An excessive amount of intracellular Ca2+ triggers CYCS release and cell apoptosis. The products of glycolysis (NADPH) are involved in the following stages of energy metabolism. NADHP is used in tricarboxylic acid cycle where NADH is formed. NADH is a substrate for ATP production during oxidative phosphorylation. Intensive oxidative phosphorylation in mitochondria generates reactive oxygen species (ROS) which are not eliminated due to their abundant amount. ROS trigger oxidative stress in cells. Under physiological conditions, glucose triggers the expression of insulin transcription factors, PDX1 and MAFA which positively regulate islet amyloid polypeptide (IAPP). Therefore, elevated intracellular glucose triggers their synthesis and insulin transcription occurs. IAPP then accumulates in the cell disrupting cell metabolism. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 16306327 PS:PMID 16306347 PS:PMID 19273118 PS:PMID 20217509 PS:PMID 20217512 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78cc872c-32d9-4f79-bd70-4af1adaffa5c NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-78cc872c-32d9-4f79-bd70-4af1adaffa5c TGFBR -> MEF/MYOD/MYOG Signaling uuid-78cc872c-32d9-4f79-bd70-4af1adaffa5c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78cc872c-32d9-4f79-bd70-4af1adaffa5c PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78d34efa-46d8-4dd0-81a2-058e003ee884 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-78d34efa-46d8-4dd0-81a2-058e003ee884 NFkB -> EMT uuid-78d34efa-46d8-4dd0-81a2-058e003ee884 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78d34efa-46d8-4dd0-81a2-058e003ee884 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78d3ceec-5ed8-4eaa-81c0-819af10f492c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-78d3ceec-5ed8-4eaa-81c0-819af10f492c TAC1 Expression Targets uuid-78d3ceec-5ed8-4eaa-81c0-819af10f492c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78d3ceec-5ed8-4eaa-81c0-819af10f492c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78e7424f-d414-4025-860d-40fb8c1ddee6 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-78e7424f-d414-4025-860d-40fb8c1ddee6 IMP purine precursor biosynthesis template uuid-78e7424f-d414-4025-860d-40fb8c1ddee6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78e7424f-d414-4025-860d-40fb8c1ddee6 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Arterial Hypertension (AH) is a condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78f51a7d-0306-4a49-92ce-ca6b1ab4bdcb NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction. Signaling description: The endothelium plays a crucial role in the regulation of vasoconstriction through the synthesis and release of vasodilator substances including nitric oxide (NO) and PGI2. NO and PGI2 are secreted by endothelial cells in response to specific stimuli such as bradykinin (KNG1) and hypoxia and act as local regulators of vascular tone. KNG1 is an endothelium-dependent vasodilator and is produced by kallikrein. Reduced levels of NO, PGI2, and KNG1 elevate vascular tone and promote endothelial cell proliferation. PGI2 binds PTGIR, while KNG1 acts through BDKRB2. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum and the activation of PRKCD. Outcome effects: PRKCD activates AKT1 pathway via PTK2B/SRC. Normally, AKT1 activates NOS3, which produces the main vasodilator, NO, which activates PTGS1/2. However, the lack of constitutional activation of NOS3 leads to the deficiency of NO and PGI2 production and impaired vasodilation. SRC transactivates EGFR that stimulates the MAPK cascade and promotes endothelial cell proliferation. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PMID: 19630832 PMID: 23227009 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endothelium urn:agi-pathway:uuid-78f51a7d-0306-4a49-92ce-ca6b1ab4bdcb Endothelial Cell Dysfunction in Arterial Hypertension uuid-78f51a7d-0306-4a49-92ce-ca6b1ab4bdcb PS:CellType endothelial cell PS:Description Arterial Hypertension (AH) is a condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-78f51a7d-0306-4a49-92ce-ca6b1ab4bdcb PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction. Signaling description: The endothelium plays a crucial role in the regulation of vasoconstriction through the synthesis and release of vasodilator substances including nitric oxide (NO) and PGI2. NO and PGI2 are secreted by endothelial cells in response to specific stimuli such as bradykinin (KNG1) and hypoxia and act as local regulators of vascular tone. KNG1 is an endothelium-dependent vasodilator and is produced by kallikrein. Reduced levels of NO, PGI2, and KNG1 elevate vascular tone and promote endothelial cell proliferation. PGI2 binds PTGIR, while KNG1 acts through BDKRB2. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum and the activation of PRKCD. Outcome effects: PRKCD activates AKT1 pathway via PTK2B/SRC. Normally, AKT1 activates NOS3, which produces the main vasodilator, NO, which activates PTGS1/2. However, the lack of constitutional activation of NOS3 leads to the deficiency of NO and PGI2 production and impaired vasodilation. SRC transactivates EGFR that stimulates the MAPK cascade and promotes endothelial cell proliferation. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 19630832 PS:PMID 23227009 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endothelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-790a6606-5260-45e8-b02a-c54a1360b4ee NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-790a6606-5260-45e8-b02a-c54a1360b4ee PAF/Gq -> NF-kB Expression Targets uuid-790a6606-5260-45e8-b02a-c54a1360b4ee PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-790a6606-5260-45e8-b02a-c54a1360b4ee PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7928a79c-0ca1-4eba-a92d-f68d1fc8e679 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7928a79c-0ca1-4eba-a92d-f68d1fc8e679 UDP-L-rhamnose biosynthesis template uuid-7928a79c-0ca1-4eba-a92d-f68d1fc8e679 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7928a79c-0ca1-4eba-a92d-f68d1fc8e679 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-793be9f2-0378-42e3-9020-d3735d8726ef NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-793be9f2-0378-42e3-9020-d3735d8726ef Immunoglobulin Superfamily -> Expression Targets in Lymphoid System and Blood uuid-793be9f2-0378-42e3-9020-d3735d8726ef PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-793be9f2-0378-42e3-9020-d3735d8726ef PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79769a3c-ded2-4e67-8e14-560312418cce NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-79769a3c-ded2-4e67-8e14-560312418cce TGFBR3 -> ARRB2 Signaling uuid-79769a3c-ded2-4e67-8e14-560312418cce PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79769a3c-ded2-4e67-8e14-560312418cce PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79e03f1e-9e37-4a4d-ad41-34fe050d36bb NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-79e03f1e-9e37-4a4d-ad41-34fe050d36bb PDGFR -> STAT Signaling uuid-79e03f1e-9e37-4a4d-ad41-34fe050d36bb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79e03f1e-9e37-4a4d-ad41-34fe050d36bb PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Argininemia (ICD10 - E72.21) is an autosomal-recessive disease that caused by a mutation in the ARG gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79effc5a-89e1-44f5-80ce-b3058fe37524 NodeType: Pathway Notes: Argininemia (ICD10 - E72.21) is an autosomal-recessive disease that caused by a mutation in the ARG gene. Organ: liver PMID: 15694174 PMID: 17513443 PMID: 20301396 PMID: 24772957 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-79effc5a-89e1-44f5-80ce-b3058fe37524 Argininemia uuid-79effc5a-89e1-44f5-80ce-b3058fe37524 PS:CellType hepatocyte PS:Description Argininemia (ICD10 - E72.21) is an autosomal-recessive disease that caused by a mutation in the ARG gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-79effc5a-89e1-44f5-80ce-b3058fe37524 PS:NodeType Pathway PS:Notes Argininemia (ICD10 - E72.21) is an autosomal-recessive disease that caused by a mutation in the ARG gene. PS:Organ liver PS:PMID 15694174 PS:PMID 17513443 PS:PMID 20301396 PS:PMID 24772957 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The CC chemokine proteins have two adjacent cysteine residues near their amino terminus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a05793a-30d8-4e9d-9482-c609473347dd NodeType: Pathway Notes: Headnote: The CC chemokine proteins have two adjacent cysteine residues near their amino terminus. There have been at least 27 distinct members of this subgroup reported in mammals called CC chemokine ligands (CCL)-1 to -28, where CCL10 is the same as CCL9. The chemokines of this subfamily usually contain four cysteine residues (C4-CC chemokines), but a small number of CC chemokines possess six cysteine residues (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23, and CCL28. Signaling description: CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. In different cellular environments, chemokines can regulate distinct second messengers or even positively or negatively regulate the same signal transduction pathway. All of the CC chemokine receptors work by activating the G-protein G alpha I (GNAI1). GNAI1 directly activates protein tyrosine kinase (PTK), which phosphorylates serine and threonine residues in the tail of the chemokine receptor, causing its desensitization or inactivation. In addition, this protein is part of a complex that inhibits adenylate cyclase (ADCY). Outcome effects: Chemokine receptor ligation ultimately leads to cell signaling events via PI3K, MAPK/Jun/Fos, and the NF-kB pathways. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7a05793a-30d8-4e9d-9482-c609473347dd CC Chemokine Receptor Signaling uuid-7a05793a-30d8-4e9d-9482-c609473347dd PS:CellType generic PS:Description The CC chemokine proteins have two adjacent cysteine residues near their amino terminus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a05793a-30d8-4e9d-9482-c609473347dd PS:NodeType Pathway PS:Notes Headnote: The CC chemokine proteins have two adjacent cysteine residues near their amino terminus. There have been at least 27 distinct members of this subgroup reported in mammals called CC chemokine ligands (CCL)-1 to -28, where CCL10 is the same as CCL9. The chemokines of this subfamily usually contain four cysteine residues (C4-CC chemokines), but a small number of CC chemokines possess six cysteine residues (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23, and CCL28. Signaling description: CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. In different cellular environments, chemokines can regulate distinct second messengers or even positively or negatively regulate the same signal transduction pathway. All of the CC chemokine receptors work by activating the G-protein G alpha I (GNAI1). GNAI1 directly activates protein tyrosine kinase (PTK), which phosphorylates serine and threonine residues in the tail of the chemokine receptor, causing its desensitization or inactivation. In addition, this protein is part of a complex that inhibits adenylate cyclase (ADCY). Outcome effects: Chemokine receptor ligation ultimately leads to cell signaling events via PI3K, MAPK/Jun/Fos, and the NF-kB pathways. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a355cfc-7066-456b-ad22-ccee03036e0c NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7a355cfc-7066-456b-ad22-ccee03036e0c Elevated Receptors -> Expression Targets in Endocrine Gands uuid-7a355cfc-7066-456b-ad22-ccee03036e0c PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a355cfc-7066-456b-ad22-ccee03036e0c PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: Paneth cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a47a932-7cbd-4ffc-82a5-e619d2895acf NodeType: Pathway Notes: Failed autophagy and a decline in the synthesis of defensins by antigen-presenting cells and Paneth cells are thought to lead to high levels of bacterial penetration to intestine tissue. Entry of pathogenic organisms or their component parts into the lamina propria and the migration of antigen-presenting cells to Peyer’s patches with antigens then stimulate the T-helper cell response and Crohn’s-like inflammation in the intestine Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: intestines Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-7a47a932-7cbd-4ffc-82a5-e619d2895acf 2_Paneth cell dysfunction in Crohn's disease uuid-7a47a932-7cbd-4ffc-82a5-e619d2895acf PS:CellType Paneth cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a47a932-7cbd-4ffc-82a5-e619d2895acf PS:NodeType Pathway PS:Notes Failed autophagy and a decline in the synthesis of defensins by antigen-presenting cells and Paneth cells are thought to lead to high levels of bacterial penetration to intestine tissue. Entry of pathogenic organisms or their component parts into the lamina propria and the migration of antigen-presenting cells to Peyer’s patches with antigens then stimulate the T-helper cell response and Crohn’s-like inflammation in the intestine Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ intestines PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a4979ba-cdd6-4be9-9225-c10dd10017d7 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: liver Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7a4979ba-cdd6-4be9-9225-c10dd10017d7 Elevated Receptors -> Expression Targets in Liver uuid-7a4979ba-cdd6-4be9-9225-c10dd10017d7 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a4979ba-cdd6-4be9-9225-c10dd10017d7 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ liver PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a5b97e6-dbf8-4efa-8f2e-5b02e2c152b7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7a5b97e6-dbf8-4efa-8f2e-5b02e2c152b7 NCAM1 Expression Targets uuid-7a5b97e6-dbf8-4efa-8f2e-5b02e2c152b7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a5b97e6-dbf8-4efa-8f2e-5b02e2c152b7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a7fe037-ec4f-4fc8-92d0-c0f785279371 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7a7fe037-ec4f-4fc8-92d0-c0f785279371 OXT Expression Targets uuid-7a7fe037-ec4f-4fc8-92d0-c0f785279371 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7a7fe037-ec4f-4fc8-92d0-c0f785279371 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Age-related cataract (ARC) is the leading cause of blindness in older individuals. Crystallins are the main cause of the disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac4bccd-c5ed-4f19-aea5-eaa8d8fa1eb4 NodeType: Pathway Notes: Headnote: Age-related cataract (ARC) is the leading cause of blindness in older individuals. The pathology develops due to the gradual accumulation of molecular modifications in crystallins, the major proteins in the lens, which changes crystallin structure and function and leads to clouding of the lens. To date, the widely accepted theory for the origin of ARC is related to the excessive production of reactive oxygen species (ROS). ROS are formed as a result of external and internal exposure. The external factors include UV, radiation, and smoking, while the internal factors include a decrease in intracellular antioxidant defenses which involve glutathione, SOD1, and ascorbate. Signaling description: The main molecular mechanism of the pathology is the disruption of ion transport leading to the elevation of intracellular calcium (Ca2+) and sodium (Na+). This leads to H2O efflux caused by ROS-induced membrane lipid peroxidation and direct impairment of structural proteins, crystallins, by ROS. Several mechanisms are responsible for the accumulation of ROS, which include oxygen (O2), hydrogen peroxide (H2O2), and hydroxyl radical. Elevated levels of Fe3+ and Cu2+ observed in older individuals, interact with ascorbate resulting in dehydroascorbate, H2O2, Fe2+, and Cu+ formation. Subsequently, H2O2, Fe2+, and Cu+ produce hydroxyl radicals. In addition, smoking, which is another risk factor for cataracts, also participates in ROS formation. Cd2+, present in tobacco smoke, enters the lens cells and replaces Zn2+ in the active center of SOD1 protein. As a result, SOD1 fails to detoxify O2. Further, growing evidence points to a decreased concentration of glutathione, a molecule involved in ROS detoxification, in most types of cataracts. Outcome effects: There are numerous consequences of ROS accumulation. H2O2 inhibits ATP1A1, a Na+/K ATPase, which prevents Na+ efflux. The increase in intracellular Na+ causes H2O influx, thereby provoking the separation of molecules and light scattering. ROS attack membrane lipids promoting peroxidation, which leads to the disruption of Ca2+ channels and Ca+ overload resulting in direct as well as calpain-mediated protein damage. ROS also attack and damage crystallins. In addition, oxygen radicals induce the degradation of intrinsic lens L-tryptophan to N-formylkynurenine, which increases yellow to brown coloration of the lens nucleus. Yellow-brown pigment together with the disruption of the normal architecture of the lens fibers cause the reduced transmission of light which in turn leads to visual problems. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Organ: eye Organ_System: sensory system PMID: 10657747 PMID: 16765571 PMID: 23222480 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-7ac4bccd-c5ed-4f19-aea5-eaa8d8fa1eb4 Age-Related Cataract uuid-7ac4bccd-c5ed-4f19-aea5-eaa8d8fa1eb4 PS:CellType epithelial cell PS:Description Age-related cataract (ARC) is the leading cause of blindness in older individuals. Crystallins are the main cause of the disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac4bccd-c5ed-4f19-aea5-eaa8d8fa1eb4 PS:NodeType Pathway PS:Notes Headnote: Age-related cataract (ARC) is the leading cause of blindness in older individuals. The pathology develops due to the gradual accumulation of molecular modifications in crystallins, the major proteins in the lens, which changes crystallin structure and function and leads to clouding of the lens. To date, the widely accepted theory for the origin of ARC is related to the excessive production of reactive oxygen species (ROS). ROS are formed as a result of external and internal exposure. The external factors include UV, radiation, and smoking, while the internal factors include a decrease in intracellular antioxidant defenses which involve glutathione, SOD1, and ascorbate. Signaling description: The main molecular mechanism of the pathology is the disruption of ion transport leading to the elevation of intracellular calcium (Ca2+) and sodium (Na+). This leads to H2O efflux caused by ROS-induced membrane lipid peroxidation and direct impairment of structural proteins, crystallins, by ROS. Several mechanisms are responsible for the accumulation of ROS, which include oxygen (O2), hydrogen peroxide (H2O2), and hydroxyl radical. Elevated levels of Fe3+ and Cu2+ observed in older individuals, interact with ascorbate resulting in dehydroascorbate, H2O2, Fe2+, and Cu+ formation. Subsequently, H2O2, Fe2+, and Cu+ produce hydroxyl radicals. In addition, smoking, which is another risk factor for cataracts, also participates in ROS formation. Cd2+, present in tobacco smoke, enters the lens cells and replaces Zn2+ in the active center of SOD1 protein. As a result, SOD1 fails to detoxify O2. Further, growing evidence points to a decreased concentration of glutathione, a molecule involved in ROS detoxification, in most types of cataracts. Outcome effects: There are numerous consequences of ROS accumulation. H2O2 inhibits ATP1A1, a Na+/K ATPase, which prevents Na+ efflux. The increase in intracellular Na+ causes H2O influx, thereby provoking the separation of molecules and light scattering. ROS attack membrane lipids promoting peroxidation, which leads to the disruption of Ca2+ channels and Ca+ overload resulting in direct as well as calpain-mediated protein damage. ROS also attack and damage crystallins. In addition, oxygen radicals induce the degradation of intrinsic lens L-tryptophan to N-formylkynurenine, which increases yellow to brown coloration of the lens nucleus. Yellow-brown pigment together with the disruption of the normal architecture of the lens fibers cause the reduced transmission of light which in turn leads to visual problems. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. PS:Organ eye PS:Organ_System sensory system PS:PMID 10657747 PS:PMID 16765571 PS:PMID 23222480 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac8899d-c708-4b88-b597-b38588df2d42 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7ac8899d-c708-4b88-b597-b38588df2d42 VEGFA -> CTNNB/CTNND Expression Targets uuid-7ac8899d-c708-4b88-b597-b38588df2d42 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac8899d-c708-4b88-b597-b38588df2d42 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: KISS1 is a peptide that stimulate GNRH1 release form hypothalamus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac97629-c494-4dd2-b7bc-1ca9b12c79eb NodeType: Pathway Notes: Headnote: Hypogonadotropic hypogonadism refers to the disruption of gonadal function caused by deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect. Signaling description: Loss-of-function mutations in KISS1, TAC3, TACR3, LEP, LEPR are associated with hypogonadotrophic hypogonadism. KISS1 is a peptide which stimulates GNRH1 release form hypothalamus; whereas TAC3 and PDYN regulate KISS1 production. In addition, expression of KISS1 may be induced by LEP. Outcome effects: As a result of mutations in genes encoding KISS1, TAC3, and LEPR, KISS1 production may be impaired. Mutated genes: Mutated genes are shown in white-out style Organ: brain Organ_System: endocrine system PMID: 19740674 PMID: 19854659 PMID: 20194706 PMID: 20699467 PMID: 20800582 PMID: 22229029 PMID: 22811428 PMID: 23550013 PMID: 24615662 PMID: 25071724 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-7ac97629-c494-4dd2-b7bc-1ca9b12c79eb KISS1 Production Impairment in Hypogonadotropic hypogonadism uuid-7ac97629-c494-4dd2-b7bc-1ca9b12c79eb PS:CellType neuron PS:Description KISS1 is a peptide that stimulate GNRH1 release form hypothalamus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ac97629-c494-4dd2-b7bc-1ca9b12c79eb PS:NodeType Pathway PS:Notes Headnote: Hypogonadotropic hypogonadism refers to the disruption of gonadal function caused by deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect. Signaling description: Loss-of-function mutations in KISS1, TAC3, TACR3, LEP, LEPR are associated with hypogonadotrophic hypogonadism. KISS1 is a peptide which stimulates GNRH1 release form hypothalamus; whereas TAC3 and PDYN regulate KISS1 production. In addition, expression of KISS1 may be induced by LEP. Outcome effects: As a result of mutations in genes encoding KISS1, TAC3, and LEPR, KISS1 production may be impaired. Mutated genes: Mutated genes are shown in white-out style PS:Organ brain PS:Organ_System endocrine system PS:PMID 19740674 PS:PMID 19854659 PS:PMID 20194706 PS:PMID 20699467 PS:PMID 20800582 PS:PMID 22229029 PS:PMID 22811428 PS:PMID 23550013 PS:PMID 24615662 PS:PMID 25071724 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Downregulation of pro-apoptotic and upregulation of anti-apoptotic BCL2 family proteins leads to cancer cell immortalization. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b3234ac-33a6-4342-ac3c-17db7fa58f7d NodeType: Pathway Notes: Headnote: The BCL2 family of proteins is comprised of pro-apoptotic and anti-apoptotic proteins that play a pivotal role in the regulation of apoptosis. These proteins act upstream of irreversible cellular damage mainly at the level of mitochondria. Signaling description: Over-expression of pro-apoptotitc proteins BCL2, BCL2L1, MCL1, BCL2L2, BCL2A1, BCL2L10 and under-expression/inactivation mutations of anti-apoptotic proteins BID, BCL2L11, BBC3, PMAIP1, BAD, BMF, HRK, BAX, BAK1 lead to impairment of apoptosis. Inactivation of some tumor suppressors (TP53, TP73, WWOX, FOXO3 and others) regulating the expression of BCL2 family proteins also have a role in apoptosis inactivation. Outcome effects: Caspases are not activated and apoptosis is not induced. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21453675 PMID: 21943236 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-7b3234ac-33a6-4342-ac3c-17db7fa58f7d Apoptosis Block by BCL2 Family Proteins in Cancer uuid-7b3234ac-33a6-4342-ac3c-17db7fa58f7d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Downregulation of pro-apoptotic and upregulation of anti-apoptotic BCL2 family proteins leads to cancer cell immortalization. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b3234ac-33a6-4342-ac3c-17db7fa58f7d PS:NodeType Pathway PS:Notes Headnote: The BCL2 family of proteins is comprised of pro-apoptotic and anti-apoptotic proteins that play a pivotal role in the regulation of apoptosis. These proteins act upstream of irreversible cellular damage mainly at the level of mitochondria. Signaling description: Over-expression of pro-apoptotitc proteins BCL2, BCL2L1, MCL1, BCL2L2, BCL2A1, BCL2L10 and under-expression/inactivation mutations of anti-apoptotic proteins BID, BCL2L11, BBC3, PMAIP1, BAD, BMF, HRK, BAX, BAK1 lead to impairment of apoptosis. Inactivation of some tumor suppressors (TP53, TP73, WWOX, FOXO3 and others) regulating the expression of BCL2 family proteins also have a role in apoptosis inactivation. Outcome effects: Caspases are not activated and apoptosis is not induced. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21453675 PS:PMID 21943236 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: muscle cell CellType: neuron Description: Myasthenia gravis (MG) is an autoimmune neuromuscular disease leading to muscle weakness and fatigue. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b38565f-f2e5-4266-b692-982db6857f20 NodeType: Pathway Notes: Headnote: Myasthenia gravis (MG) is an autoimmune neuromuscular disease leading to muscle weakness and fatigue. In most cases, the first noticeable symptom is weakness of the extrinsic ocular muscles (EOMs) called ocular myasthenia. Signaling description: Muscle weakness is caused by circulating self-antibodies that block the postsynaptic neuromuscular junction. In 80-85% of MG patients, auto-antibodies block the acetylcholine receptor (AChR), whereas in the remaining of MG patients, they block MUSK or LRP4. Thymic hyperplasia is observed in about 65% of MG patients and thymomas are present in about 10% of MG patients with anti-AChR antibodies. According to the nature of the antibodies, MG can be divided into several subtypes that differ by the age at onset, gender predominance, and thymus pathology. The neuromuscular junction is a structure of motoneurones in the presynaptic zone, containing synaptic vesicles filled with acetylcholine and the postsynaptic muscle. Normally, the cumulative activation of nicotinic acetylcholine receptor (nAChR) on the postsynaptic muscle membrane leads to the influx of Na or calcium Ca2+ ions into the muscle cell, which causes membrane depolarization. In addition, nAChR aggregation leads to the release of Ca2+ from the sarcoplasmic reticulum. When the levels of Ca2+ inside the muscle cell are sufficiently high, it will contract. The neuromuscular junction is initiated by the release of acetylcholine and agrin (AGRN) by motor neurons, which eventually leads to the clustering of nAChR, MUSK, and the dystrophin glycoprotein complex. Rapsyn (RAPSN) is a peripheral membrane protein associated with nAChRs and appears to be a central component of the clustering process. Outcome effects: The neuromuscular junction of the extraocular muscle (EOM) in MG patients contains intrinsic complement regulators C3, C9, and the membrane attack complex. In rodents, anti-nAChR antibodies activate the complement cascade, resulting in the destruction of the postsynaptic neuromuscular junction membrane. The neuromuscular junctions of EOM express fewer intrinsic complement regulators (CD55, CD46, and CD59) which make them more susceptible to complement-mediated injury. In addition, they have less postsynaptic nAChRs and Na channels than skeletal muscle. In skeletal muscles, fast-twitch fibers have neuromuscular junctions with greater quantal contents. These properties make fast-twitch skeletal muscle fibers less susceptible to myasthenic failure than slow-twitch fibers in EOM. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: eye Organ_System: sensory system PMID: 10166551 PMID: 17080188 PMID: 21019906 PMID: 24294607 PMID: 24389034 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-7b38565f-f2e5-4266-b692-982db6857f20 Extraocular Muscles Weakness in Myasthenia Gravis uuid-7b38565f-f2e5-4266-b692-982db6857f20 PS:CellType muscle cell PS:CellType neuron PS:Description Myasthenia gravis (MG) is an autoimmune neuromuscular disease leading to muscle weakness and fatigue. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b38565f-f2e5-4266-b692-982db6857f20 PS:NodeType Pathway PS:Notes Headnote: Myasthenia gravis (MG) is an autoimmune neuromuscular disease leading to muscle weakness and fatigue. In most cases, the first noticeable symptom is weakness of the extrinsic ocular muscles (EOMs) called ocular myasthenia. Signaling description: Muscle weakness is caused by circulating self-antibodies that block the postsynaptic neuromuscular junction. In 80-85% of MG patients, auto-antibodies block the acetylcholine receptor (AChR), whereas in the remaining of MG patients, they block MUSK or LRP4. Thymic hyperplasia is observed in about 65% of MG patients and thymomas are present in about 10% of MG patients with anti-AChR antibodies. According to the nature of the antibodies, MG can be divided into several subtypes that differ by the age at onset, gender predominance, and thymus pathology. The neuromuscular junction is a structure of motoneurones in the presynaptic zone, containing synaptic vesicles filled with acetylcholine and the postsynaptic muscle. Normally, the cumulative activation of nicotinic acetylcholine receptor (nAChR) on the postsynaptic muscle membrane leads to the influx of Na or calcium Ca2+ ions into the muscle cell, which causes membrane depolarization. In addition, nAChR aggregation leads to the release of Ca2+ from the sarcoplasmic reticulum. When the levels of Ca2+ inside the muscle cell are sufficiently high, it will contract. The neuromuscular junction is initiated by the release of acetylcholine and agrin (AGRN) by motor neurons, which eventually leads to the clustering of nAChR, MUSK, and the dystrophin glycoprotein complex. Rapsyn (RAPSN) is a peripheral membrane protein associated with nAChRs and appears to be a central component of the clustering process. Outcome effects: The neuromuscular junction of the extraocular muscle (EOM) in MG patients contains intrinsic complement regulators C3, C9, and the membrane attack complex. In rodents, anti-nAChR antibodies activate the complement cascade, resulting in the destruction of the postsynaptic neuromuscular junction membrane. The neuromuscular junctions of EOM express fewer intrinsic complement regulators (CD55, CD46, and CD59) which make them more susceptible to complement-mediated injury. In addition, they have less postsynaptic nAChRs and Na channels than skeletal muscle. In skeletal muscles, fast-twitch fibers have neuromuscular junctions with greater quantal contents. These properties make fast-twitch skeletal muscle fibers less susceptible to myasthenic failure than slow-twitch fibers in EOM. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ eye PS:Organ_System sensory system PS:PMID 10166551 PS:PMID 17080188 PS:PMID 21019906 PS:PMID 24294607 PS:PMID 24389034 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b4a4810-c507-454c-afae-25e39f0997be NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-7b4a4810-c507-454c-afae-25e39f0997be CNR1/2 -> Vascular Motility uuid-7b4a4810-c507-454c-afae-25e39f0997be PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b4a4810-c507-454c-afae-25e39f0997be PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: antigen-presenting cell CellType: cancer cell CellType: cancer stem cell CellType: effector T-cell Description: Effector T-cells may be inactivated in cancer due to increased negative co-stimulation and decreased positive co-stimulation. These changes along with FASLG signaling from cancer cells may lead to T-cell apoptosis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b57015b-c20f-42f3-b48f-baf693602e44 NodeType: Pathway Notes: Headnote: According to the "two signal" paradigm, full activation of T-cells in response to antigens requires two separate but complementary signals. Specifically, upon antigen encounter, naive T-cells receive one signal through the interaction of their T-cell receptor with the MHC/antigenic peptide complex on an antigen presenting cell (APC) and another signal through the interaction of a pair of positive costimulatory molecules expressed on the T-cell and APC, respectively, leading to an immune response. At the same time, negative costimulatory signals, downregulate the T-cell immune response. The costimulatory signaling events are not limited to T-cell / APC interactions and also involve T-cell / T-cell, T-cell / B-cell, and T-cell-nonlymphoid cell, including T-cell / cancer cell interactions. The absence of effective co-stimulation can cause T-cell anergy and/or apoptosis. Signaling description: Tumor cells downregulate the expression of CD80 (B7-1) and CD86 (B7-2) molecules and stimulate the expression of CD274 (B7-H1), CD276 (B7-H3), VTCN1(B7-H4), PDCD1LG2 (B7-DC) molecules in order to inactivate the T- lymphocyte clone. CTLA4 and PDCD1 are expressed on the T-cell surface, they negatively regulate T-cell receptor signaling and may be overexpressed in tumors. One major mechanism of cancer immune escape involves clonal deletion of antigen-reactive T-cells through apoptotic cell death. An important mediator of T-cell deletion is the FASLG/FAS system. Neoplasms may actively destroy T-cells, including cytotoxic T-cells by expressing FASLG. Another tumor-expressed ligand, RCAS1 (EBAG9), was also found to induce apoptotic cell death of T, B, and NK cells expressing its receptor. The precise mechanism of this action is yet to be determined. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 18836470 PMID: 19796244 PMID: 21086108 PMID: 24325346 PMID: 27207108 PMID: 28352189 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-7b57015b-c20f-42f3-b48f-baf693602e44 Effector T-cell Inactivation in Cancer Immune Escape uuid-7b57015b-c20f-42f3-b48f-baf693602e44 PS:CellType antigen-presenting cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType effector T-cell PS:Description Effector T-cells may be inactivated in cancer due to increased negative co-stimulation and decreased positive co-stimulation. These changes along with FASLG signaling from cancer cells may lead to T-cell apoptosis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b57015b-c20f-42f3-b48f-baf693602e44 PS:NodeType Pathway PS:Notes Headnote: According to the "two signal" paradigm, full activation of T-cells in response to antigens requires two separate but complementary signals. Specifically, upon antigen encounter, naive T-cells receive one signal through the interaction of their T-cell receptor with the MHC/antigenic peptide complex on an antigen presenting cell (APC) and another signal through the interaction of a pair of positive costimulatory molecules expressed on the T-cell and APC, respectively, leading to an immune response. At the same time, negative costimulatory signals, downregulate the T-cell immune response. The costimulatory signaling events are not limited to T-cell / APC interactions and also involve T-cell / T-cell, T-cell / B-cell, and T-cell-nonlymphoid cell, including T-cell / cancer cell interactions. The absence of effective co-stimulation can cause T-cell anergy and/or apoptosis. Signaling description: Tumor cells downregulate the expression of CD80 (B7-1) and CD86 (B7-2) molecules and stimulate the expression of CD274 (B7-H1), CD276 (B7-H3), VTCN1(B7-H4), PDCD1LG2 (B7-DC) molecules in order to inactivate the T- lymphocyte clone. CTLA4 and PDCD1 are expressed on the T-cell surface, they negatively regulate T-cell receptor signaling and may be overexpressed in tumors. One major mechanism of cancer immune escape involves clonal deletion of antigen-reactive T-cells through apoptotic cell death. An important mediator of T-cell deletion is the FASLG/FAS system. Neoplasms may actively destroy T-cells, including cytotoxic T-cells by expressing FASLG. Another tumor-expressed ligand, RCAS1 (EBAG9), was also found to induce apoptotic cell death of T, B, and NK cells expressing its receptor. The precise mechanism of this action is yet to be determined. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 18836470 PS:PMID 19796244 PS:PMID 21086108 PS:PMID 24325346 PS:PMID 27207108 PS:PMID 28352189 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron CellType: thyroid cell CellType: thyrotroph Description: Hypothyroidism is a pathological state caused by a deficiency of thyroid hormones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b6233bf-bc2e-4c2c-a42f-ada5285c10cb NodeType: Pathway Notes: Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. Many factors influence synthesis of thyroid hormones, particularly levels of hormones of hypothalamus and pituitary, TRH and TSH. Because of that, symptoms of hypothyroidism may significantly vary depending on combination of altered functions of upstream regulators of these hormones. Deficiency in TRH synthesis causes tertiary hypothyroidism. Tertiary hypothyroidism accounts for less than 5% of hypothyroidism cases. It may also be termed hypothalamic-pituitary-axis hypothyroidism. Signaling description: Main regulator of TSH synthesis is TRH which is hypothalamic hormone. A control of TRH synthesis is poorly studied. Nevertheless, it is clear that TRH release is affected by many external factors, such as cold, nutrition, circadian clock, and stress (see TRH Release pathway). Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ: thyroid gland Organ_System: endocrine system PMID: 15481810 PMID: 21062194 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-7b6233bf-bc2e-4c2c-a42f-ada5285c10cb Tertiary Hypothyroidism uuid-7b6233bf-bc2e-4c2c-a42f-ada5285c10cb PS:CellType neuron PS:CellType thyroid cell PS:CellType thyrotroph PS:Description Hypothyroidism is a pathological state caused by a deficiency of thyroid hormones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b6233bf-bc2e-4c2c-a42f-ada5285c10cb PS:NodeType Pathway PS:Notes Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. Many factors influence synthesis of thyroid hormones, particularly levels of hormones of hypothalamus and pituitary, TRH and TSH. Because of that, symptoms of hypothyroidism may significantly vary depending on combination of altered functions of upstream regulators of these hormones. Deficiency in TRH synthesis causes tertiary hypothyroidism. Tertiary hypothyroidism accounts for less than 5% of hypothyroidism cases. It may also be termed hypothalamic-pituitary-axis hypothyroidism. Signaling description: Main regulator of TSH synthesis is TRH which is hypothalamic hormone. A control of TRH synthesis is poorly studied. Nevertheless, it is clear that TRH release is affected by many external factors, such as cold, nutrition, circadian clock, and stress (see TRH Release pathway). Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15481810 PS:PMID 21062194 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b7f0c0a-f821-4e6f-b1d3-3c4621222432 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7b7f0c0a-f821-4e6f-b1d3-3c4621222432 GDNF -> HSF1 Expression Targets uuid-7b7f0c0a-f821-4e6f-b1d3-3c4621222432 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7b7f0c0a-f821-4e6f-b1d3-3c4621222432 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: corneocyte CellType: mast cell Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bbbbfa5-94a0-40de-807f-4d29a0f39a26 NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to an ongoing swelling and redness. AD is associated with the impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together. Corneodesmosomes are formed by members of the cadherin family of extracellular transmembrane glycoproteins including desmoglein (DSG) and desmocollin (DSC). Within the corneocytes, DSG and DSC are linked to keratin filaments through corneodesmosomal plaque proteins including plakoglobin (JUP), desmoplakin (DSP), and plakophilin (PKP). DSG and DSC migrate from the corneocyte envelope into the lipid lamellae sandwiched between the corneocytes and bind to the corneodesmosomal plaque proteins on adjacent cells. Also, filaggrin (FLG) is an epithelial cell protein, which is extensively deaminated through the actions of the peptidyl deiminase (PADI1) enzyme. It is subsequently degraded into small peptides and then into free amino acids, which are then catabolized into the components of natural moisturizing factor (NMF) including lactic acid, sodium pyrrolidone carboxylic acid, urocanate, and urea. The NMF is essential for the retention of water within the corneocytes and results in their optimal hydration and swelling. The human kallikrein (KLK)-related peptidases such as SC chymotryptic enzyme (KLK7) and SC tryptic enzyme (KLK5) are key proteases involved in desquamation. Their increased expression can lead to impaired epidermal barrier function in AD. KLK7, with chymotrypsin-like activity, has been shown to hydrolyze corneodesmosin (CDSN) and desmocollin 1 (DSC1), whereas KLK5 can cleave desmoglein 1 (DSG1) with its trypsin-like activity. Enzymatically active KLK14, also exhibiting trypsin-like activity is present in the SC, where it cleaves DSG1. In addition, SPINK5 is a potent inhibitor of both KLK5 and KLK7, and thus, is critical for epidermal barrier function. As the pH becomes more acidic, the inhibitory potential of SPINK5 is reduced. The inhibition by SPINK5 in the superficial layers of the SC is sufficiently reduced to support localized desquamation. Outcome effects: Following contact with an antigen e.g. Staphylococcus aureus, during the elicitation phase cutaneous professional antigen presenting cells migrate to regional lymph nodes, where they present the processed peptides to naive T-cells. In the presence of IL4, naive T-lymphocytes differentiate toward the Th2 phenotype and induce class switching of B- lymphocytes to IgE production. Circulating IgE binds to high affinity IgE receptors on tissue resident mast cells. A second exposure to the antigen causes cell reactivation, mast cell degranulation, and release of inflammatory molecules such as histamine, IL8, and IL13 which causes a Th2-lymphocyte influx into the skin. However, with the infiltration of eosinophils and macrophages in chronic AD, there is a rise in IL12 expression and a switch to Th1 cellular responses. Acute skin lesions of patients with AD have increased amounts of cells positive for IL4, IL5, and IL13 mRNA compared to normal or uninvolved skin. In contrast, there are few IFNG or IL12 mRNA expressing cells in acute skin lesions of patients with AD. Lastly, recent evidence suggests a possible role for IL33/IL1RL1 pathway in epithelial integrity, allergic immune responses, inflammation, autoimmunity, and fibrosis. IL33-dependent activation of IL1RL1 signaling leads to the activation of MAPK and NF-kB signaling which ultimately have roles in the pathogenesis of AD. The mature form of IL33 is released into the cytoplasm and thus stimulates T-cells, mast cells, or keratino Organ: skin Organ_System: integumentary system PMID: 19494826 PMID: 20081870 PMID: 21249468 PMID: 22499037 PMID: 22561834 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-7bbbbfa5-94a0-40de-807f-4d29a0f39a26 Atopic Dermatitis uuid-7bbbbfa5-94a0-40de-807f-4d29a0f39a26 PS:CellType T-cell PS:CellType corneocyte PS:CellType mast cell PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bbbbfa5-94a0-40de-807f-4d29a0f39a26 PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to an ongoing swelling and redness. AD is associated with the impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Skin penetration barrier is located in the lower part of the stratum corneum (SC). Structural integrity of the SC is maintained by the presence of modified desmosomes known as corneodesmosomes, which bind the corneocytes together. Corneodesmosomes are formed by members of the cadherin family of extracellular transmembrane glycoproteins including desmoglein (DSG) and desmocollin (DSC). Within the corneocytes, DSG and DSC are linked to keratin filaments through corneodesmosomal plaque proteins including plakoglobin (JUP), desmoplakin (DSP), and plakophilin (PKP). DSG and DSC migrate from the corneocyte envelope into the lipid lamellae sandwiched between the corneocytes and bind to the corneodesmosomal plaque proteins on adjacent cells. Also, filaggrin (FLG) is an epithelial cell protein, which is extensively deaminated through the actions of the peptidyl deiminase (PADI1) enzyme. It is subsequently degraded into small peptides and then into free amino acids, which are then catabolized into the components of natural moisturizing factor (NMF) including lactic acid, sodium pyrrolidone carboxylic acid, urocanate, and urea. The NMF is essential for the retention of water within the corneocytes and results in their optimal hydration and swelling. The human kallikrein (KLK)-related peptidases such as SC chymotryptic enzyme (KLK7) and SC tryptic enzyme (KLK5) are key proteases involved in desquamation. Their increased expression can lead to impaired epidermal barrier function in AD. KLK7, with chymotrypsin-like activity, has been shown to hydrolyze corneodesmosin (CDSN) and desmocollin 1 (DSC1), whereas KLK5 can cleave desmoglein 1 (DSG1) with its trypsin-like activity. Enzymatically active KLK14, also exhibiting trypsin-like activity is present in the SC, where it cleaves DSG1. In addition, SPINK5 is a potent inhibitor of both KLK5 and KLK7, and thus, is critical for epidermal barrier function. As the pH becomes more acidic, the inhibitory potential of SPINK5 is reduced. The inhibition by SPINK5 in the superficial layers of the SC is sufficiently reduced to support localized desquamation. Outcome effects: Following contact with an antigen e.g. Staphylococcus aureus, during the elicitation phase cutaneous professional antigen presenting cells migrate to regional lymph nodes, where they present the processed peptides to naive T-cells. In the presence of IL4, naive T-lymphocytes differentiate toward the Th2 phenotype and induce class switching of B- lymphocytes to IgE production. Circulating IgE binds to high affinity IgE receptors on tissue resident mast cells. A second exposure to the antigen causes cell reactivation, mast cell degranulation, and release of inflammatory molecules such as histamine, IL8, and IL13 which causes a Th2-lymphocyte influx into the skin. However, with the infiltration of eosinophils and macrophages in chronic AD, there is a rise in IL12 expression and a switch to Th1 cellular responses. Acute skin lesions of patients with AD have increased amounts of cells positive for IL4, IL5, and IL13 mRNA compared to normal or uninvolved skin. In contrast, there are few IFNG or IL12 mRNA expressing cells in acute skin lesions of patients with AD. Lastly, recent evidence suggests a possible role for IL33/IL1RL1 pathway in epithelial integrity, allergic immune responses, inflammation, autoimmunity, and fibrosis. IL33-dependent activation of IL1RL1 signaling leads to the activation of MAPK and NF-kB signaling which ultimately have roles in the pathogenesis of AD. The mature form of IL33 is released into the cytoplasm and thus stimulates T-cells, mast cells, or keratino PS:Organ skin PS:Organ_System integumentary system PS:PMID 19494826 PS:PMID 20081870 PS:PMID 21249468 PS:PMID 22499037 PS:PMID 22561834 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using iPTMnet database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bbfe6d0-50fa-453d-9193-217a3af7ca5b NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process urn:agi-pathway:uuid-7bbfe6d0-50fa-453d-9193-217a3af7ca5b Proteins Involved in TP53 Sites Modification uuid-7bbfe6d0-50fa-453d-9193-217a3af7ca5b PS:Description Pathway is build using iPTMnet database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bbfe6d0-50fa-453d-9193-217a3af7ca5b PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bc38336-2447-480e-930c-419b3753e585 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7bc38336-2447-480e-930c-419b3753e585 Genes with Mutations Associated with Aging in Humans uuid-7bc38336-2447-480e-930c-419b3753e585 PS:CellType generic PS:Description From Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info/). PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bc38336-2447-480e-930c-419b3753e585 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: granulosa cell CellType: theca cell Description: Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7be51e51-17c2-4102-8e0e-f5388e272241 NodeType: Pathway Notes: Headnote: Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. The origin of hyperandrogenemia arises from excessive luteinizing hormone (LH) stimulation of follicle theca cells. Signaling description: Gonadotropin-releasing hormone (GNRH1) has elevated amplitude of secretion in the pathology and provokes increased LH release from the pituitary. Insulin (INS), IGF1, and retinol enhance LH action by triggering the expression of steroidogenic enzymes including CYP11A1, CYP17A1, HSD3B2, and HSD17B1. INS also promotes LDLR synthesis in the theca cells. LDLR transports cholesterol, which is the substrate for hormone biosynthesis, into the cell. In the pathology, the hormone reduces the synthesis of IGFB1 and SHBG in the liver, thus providing free IGF1 and testosterone. The next step of steroidogenesis in women occurs in granulosa cells where testosterone and its derivatives are converted into estrogens. Normally, the conversion is promoted by CYP19A1. The lack of the enzyme due to a deficiency of stimulatory signals from FSH leads to androgen excess. In some cases, testosterone may be converted into dihydrotestosterone by elevated SRD5A1. Outcome effects: The excess of androgens, particularly dihydrotestosterone, explain hirsutism and acne in PCOS women. Elevated AMH, FST, inhibin complex, and estrogens prevent FSH signaling in granulosa cells disrupting not only estrogen production, but also blocking cell proliferation and differentiation, which are necessary for follicle maturation. The arrested signaling includes the PI3K, PKC, and PKA routes, which normally lead to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 pathway. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. Impaired FSH signaling prevents AKT1 activation, which normally inhibits FOXO1, a negative regulator of cell proliferation and differentiation. The excess of androgens bind to their intracellular receptor (AR) and trigger IGF1R appearance on granulosa cell surfaces. Elevated IGF1 binds to its receptor and induces PI3K activation. Further, PI3K promotes AKT1 phosphorylation of CDKN1B, BAD, and GSK3B leading to their inhibition. These proteins normally promote granulosa cell proliferation. Lastly, the arrested development of follicles at the small preantral follicle stage causes anovulation in PCOS and register as polycystic ovary at an ultrasound examination. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Organ: ovary Organ_System: reproductive system PMID: 12017544 PMID: 16390494 PMID: 18440223 PMID: 19078868 PMID: 20591140 PMID: 21606667 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-7be51e51-17c2-4102-8e0e-f5388e272241 Polycystic Ovary Syndrome uuid-7be51e51-17c2-4102-8e0e-f5388e272241 PS:CellType granulosa cell PS:CellType theca cell PS:Description Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7be51e51-17c2-4102-8e0e-f5388e272241 PS:NodeType Pathway PS:Notes Headnote: Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. The origin of hyperandrogenemia arises from excessive luteinizing hormone (LH) stimulation of follicle theca cells. Signaling description: Gonadotropin-releasing hormone (GNRH1) has elevated amplitude of secretion in the pathology and provokes increased LH release from the pituitary. Insulin (INS), IGF1, and retinol enhance LH action by triggering the expression of steroidogenic enzymes including CYP11A1, CYP17A1, HSD3B2, and HSD17B1. INS also promotes LDLR synthesis in the theca cells. LDLR transports cholesterol, which is the substrate for hormone biosynthesis, into the cell. In the pathology, the hormone reduces the synthesis of IGFB1 and SHBG in the liver, thus providing free IGF1 and testosterone. The next step of steroidogenesis in women occurs in granulosa cells where testosterone and its derivatives are converted into estrogens. Normally, the conversion is promoted by CYP19A1. The lack of the enzyme due to a deficiency of stimulatory signals from FSH leads to androgen excess. In some cases, testosterone may be converted into dihydrotestosterone by elevated SRD5A1. Outcome effects: The excess of androgens, particularly dihydrotestosterone, explain hirsutism and acne in PCOS women. Elevated AMH, FST, inhibin complex, and estrogens prevent FSH signaling in granulosa cells disrupting not only estrogen production, but also blocking cell proliferation and differentiation, which are necessary for follicle maturation. The arrested signaling includes the PI3K, PKC, and PKA routes, which normally lead to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 pathway. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. Impaired FSH signaling prevents AKT1 activation, which normally inhibits FOXO1, a negative regulator of cell proliferation and differentiation. The excess of androgens bind to their intracellular receptor (AR) and trigger IGF1R appearance on granulosa cell surfaces. Elevated IGF1 binds to its receptor and induces PI3K activation. Further, PI3K promotes AKT1 phosphorylation of CDKN1B, BAD, and GSK3B leading to their inhibition. These proteins normally promote granulosa cell proliferation. Lastly, the arrested development of follicles at the small preantral follicle stage causes anovulation in PCOS and register as polycystic ovary at an ultrasound examination. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 12017544 PS:PMID 16390494 PS:PMID 18440223 PS:PMID 19078868 PS:PMID 20591140 PS:PMID 21606667 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The nuclear lamina is a filamentous meshwork underlying the nuclear membrane that provides mechanical stability for the nucleus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bf09acc-695d-40f4-a5ec-efb765644739 NodeType: Pathway Notes: Headnote: Apoptosis is the genetically regulated programmed cell death which occurs in mulaticellular organisms as part of their normal development and functioning. The nuclear lamina is filamentous meshwork underlying the nuclear membrane that provides mechanical stability for the nucleus. Signaling description: During apoptosis, chromatin, the macromolecular complex in which DNA is condensed into a more compact structure and associated with histones and other proteins, is cleaved to oligonucleosomal fragments and the nuclear lamina undergoes proteolysis. The disassembly of the nuclear lamina is induced by phosphorylation during mitosis. In apoptosis, the nuclear lamina (LMNA) is degraded by caspases via proteolytic cleavage. Specifically, the caspases recognize aspartic acid (Asp) residues in lamins. CASP6, CASP3, and CASP7 act in concert with PRKCD which is needed for lamin hyperphosphorylation, and together they bring about an efficient disassembly of the lamina. Outcome effects: Lamin-binding proteins are an important architectural component involved in cell cycle-dependent nuclear structure dynamics. The degradation of lamin-binding proteins is not a general prerequisite for apoptotic events; however the most important structural proteins involved in chromatin organization must be selectively targeted by the apoptotic caspases. Organ: generic Organ_System: generic PMID: 11165516 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7bf09acc-695d-40f4-a5ec-efb765644739 Nuclear Lamina Cleavage uuid-7bf09acc-695d-40f4-a5ec-efb765644739 PS:CellType generic PS:Description The nuclear lamina is a filamentous meshwork underlying the nuclear membrane that provides mechanical stability for the nucleus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bf09acc-695d-40f4-a5ec-efb765644739 PS:NodeType Pathway PS:Notes Headnote: Apoptosis is the genetically regulated programmed cell death which occurs in mulaticellular organisms as part of their normal development and functioning. The nuclear lamina is filamentous meshwork underlying the nuclear membrane that provides mechanical stability for the nucleus. Signaling description: During apoptosis, chromatin, the macromolecular complex in which DNA is condensed into a more compact structure and associated with histones and other proteins, is cleaved to oligonucleosomal fragments and the nuclear lamina undergoes proteolysis. The disassembly of the nuclear lamina is induced by phosphorylation during mitosis. In apoptosis, the nuclear lamina (LMNA) is degraded by caspases via proteolytic cleavage. Specifically, the caspases recognize aspartic acid (Asp) residues in lamins. CASP6, CASP3, and CASP7 act in concert with PRKCD which is needed for lamin hyperphosphorylation, and together they bring about an efficient disassembly of the lamina. Outcome effects: Lamin-binding proteins are an important architectural component involved in cell cycle-dependent nuclear structure dynamics. The degradation of lamin-binding proteins is not a general prerequisite for apoptotic events; however the most important structural proteins involved in chromatin organization must be selectively targeted by the apoptotic caspases. PS:Organ generic PS:Organ_System generic PS:PMID 11165516 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bf0b73f-04c1-4d3c-a675-24822d74de35 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-7bf0b73f-04c1-4d3c-a675-24822d74de35 Genes with Mutations Associated with Atopic Dermatitis uuid-7bf0b73f-04c1-4d3c-a675-24822d74de35 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bf0b73f-04c1-4d3c-a675-24822d74de35 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bfe358f-42c1-477f-b4b7-f6ef12486abd NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In Asia, HCC is commonly related to hepatitis B or C virus (HBV and HCV) infection, while in Africa it is linked to chronic hepatitis B. The incidence is on the rise in some developed countries including Japan, UK, France, and U.S. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. Less common causes of HCC are exposure to dietary hepatocarcinogen like aflatoxin, insulin resistance syndrome, several genetic disorders, and drug-induced (e.g. anabolic steroids). HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: Genetic changes and their biological consequences in human HCC can be divided into several groups including mutation in tumor suppressor genes (TP53, RB1, PTEN, and RUNX3), mutation in oncogenes (MYC, KRAS, HRAS, and BRAF), activation of developmental pathways (WNT/CTNNB1 and NOTCH), and growth factors and their receptors (EGFRs, VEGFRs, IGF1R, TGFBR1, and MET). Outcome effects: The genetic alterations associated with HCC cause block of apoptosis, disruption of cell cycle and differentiation, redundant proliferation and migration of hepatocytes, block of chromatin remodeling and DNA repair, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 20175032 PMID: 20953207 PMID: 22212931 PMID: 22652888 PMID: 23426905 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-7bfe358f-42c1-477f-b4b7-f6ef12486abd Hepatocellular Carcinoma uuid-7bfe358f-42c1-477f-b4b7-f6ef12486abd PS:CellType cancer cell PS:CellType hepatocyte PS:Description Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7bfe358f-42c1-477f-b4b7-f6ef12486abd PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In Asia, HCC is commonly related to hepatitis B or C virus (HBV and HCV) infection, while in Africa it is linked to chronic hepatitis B. The incidence is on the rise in some developed countries including Japan, UK, France, and U.S. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. Less common causes of HCC are exposure to dietary hepatocarcinogen like aflatoxin, insulin resistance syndrome, several genetic disorders, and drug-induced (e.g. anabolic steroids). HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: Genetic changes and their biological consequences in human HCC can be divided into several groups including mutation in tumor suppressor genes (TP53, RB1, PTEN, and RUNX3), mutation in oncogenes (MYC, KRAS, HRAS, and BRAF), activation of developmental pathways (WNT/CTNNB1 and NOTCH), and growth factors and their receptors (EGFRs, VEGFRs, IGF1R, TGFBR1, and MET). Outcome effects: The genetic alterations associated with HCC cause block of apoptosis, disruption of cell cycle and differentiation, redundant proliferation and migration of hepatocytes, block of chromatin remodeling and DNA repair, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 20175032 PS:PMID 20953207 PS:PMID 22212931 PS:PMID 22652888 PS:PMID 23426905 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Low-grade serous ovarian carcinoma (LGSOC) represents approximately 10 percent of all serous ovarian carcinomas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c44cbc1-f94a-45aa-a4c5-2041dbfde173 NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Low-grade serous ovarian carcinoma (LGSOC) represents approximately 10% of all serous ovarian carcinomas. There are a number of important differences between LGSOC and high-grade serous ovarian carcinomas in their clinical and molecular characteristics. Patients with LGSOC are diagnosed at a younger age, have a longer overall survival, and have lower response rates to conventional chemotherapy. Signaling description: LGSOC is characterized by mutations in KRAS, BRAF, and PTEN genes in addition to the overexpression of EGFRs (EGFR and ERBB2) and NOTCH3. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA via SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling; thus, mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival, which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates into the nucleus, where it interacts with T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs regulate Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. In addition, EGFRs interact with SHC1/GRB2/SOS1 and activate BRAF, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. NOTCH3 receptors interact with surface-bound ligands JAG1, JAG2, DLL1, DLL3, and DLL4. Activated membrane-bound NOTCH3 receptor is cleaved by the gamma-secretase complex. NOTCH intracellular domain (NICD) is transported into the nucleus and participates in the formation of the NICD-Mastermind complex by interacting with mastermind-like 1/3 proteins (MAML1/3). NICD-Mastermind complex promotes transcription factors MYC and HES1 and binds TP53. HES1 inhibits CDKN1B, which participates in the regulation of cell proliferation and differentiation. Organ: ovary Organ_System: reproductive system PMID: 18317228 PMID: 19221485 PMID: 19461510 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-7c44cbc1-f94a-45aa-a4c5-2041dbfde173 Low-Grade Serous Ovarian Carcinoma uuid-7c44cbc1-f94a-45aa-a4c5-2041dbfde173 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Low-grade serous ovarian carcinoma (LGSOC) represents approximately 10 percent of all serous ovarian carcinomas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c44cbc1-f94a-45aa-a4c5-2041dbfde173 PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Low-grade serous ovarian carcinoma (LGSOC) represents approximately 10% of all serous ovarian carcinomas. There are a number of important differences between LGSOC and high-grade serous ovarian carcinomas in their clinical and molecular characteristics. Patients with LGSOC are diagnosed at a younger age, have a longer overall survival, and have lower response rates to conventional chemotherapy. Signaling description: LGSOC is characterized by mutations in KRAS, BRAF, and PTEN genes in addition to the overexpression of EGFRs (EGFR and ERBB2) and NOTCH3. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA via SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling; thus, mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival, which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates into the nucleus, where it interacts with T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs regulate Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. In addition, EGFRs interact with SHC1/GRB2/SOS1 and activate BRAF, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. NOTCH3 receptors interact with surface-bound ligands JAG1, JAG2, DLL1, DLL3, and DLL4. Activated membrane-bound NOTCH3 receptor is cleaved by the gamma-secretase complex. NOTCH intracellular domain (NICD) is transported into the nucleus and participates in the formation of the NICD-Mastermind complex by interacting with mastermind-like 1/3 proteins (MAML1/3). NICD-Mastermind complex promotes transcription factors MYC and HES1 and binds TP53. HES1 inhibits CDKN1B, which participates in the regulation of cell proliferation and differentiation. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18317228 PS:PMID 19221485 PS:PMID 19461510 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c8068bc-016d-4819-9f8c-5e930cfcd478 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7c8068bc-016d-4819-9f8c-5e930cfcd478 CLCF1 Expression Targets uuid-7c8068bc-016d-4819-9f8c-5e930cfcd478 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c8068bc-016d-4819-9f8c-5e930cfcd478 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c93e1ed-fb3f-4707-acfd-eca59943a759 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-7c93e1ed-fb3f-4707-acfd-eca59943a759 Estradiol Effects in Menstrual Migrane uuid-7c93e1ed-fb3f-4707-acfd-eca59943a759 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c93e1ed-fb3f-4707-acfd-eca59943a759 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Ion channels of the stomach regulate gastric motility and eating behavior. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c9f70a5-5876-4e52-bc5b-290569fb16b1 NodeType: Pathway Notes: Headnote: Ion channels on mucosal endings of vagal afferent neurons in the stomach wall are involved in appetite regulation. Signaling description: Piezo type mechanosensitive ion channel (PIEZO1) is activated by mechanical stretch. PIEZO1 receptor in concert with TRPV4 transports calcium into the cell. Calcium stimulates acid sensing ion channel (ASIC3), membrane depolarization and more Ca2+influx. Intracellular calcium interacts with and activates GUCA1B which leads to cGMP synthesis and activation of K+ channels. Efflux of K+ leads to membrane depolarization and transmission of the nerve signal by vagal nerve. This leads to activation of gastric motility and eating behavior. Outcome effects: Ion channels in stomach wall regulate gastrointestinal functions and eating behavior by stimulating of the nerve impulse through vagal nerve. Organ: stomach Organ: stomach wall Organ_System: digestive system PMID: 20693874 PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-7c9f70a5-5876-4e52-bc5b-290569fb16b1 Ion Channels of Stomach in Appetite Regulation uuid-7c9f70a5-5876-4e52-bc5b-290569fb16b1 PS:CellType neuron PS:Description Ion channels of the stomach regulate gastric motility and eating behavior. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7c9f70a5-5876-4e52-bc5b-290569fb16b1 PS:NodeType Pathway PS:Notes Headnote: Ion channels on mucosal endings of vagal afferent neurons in the stomach wall are involved in appetite regulation. Signaling description: Piezo type mechanosensitive ion channel (PIEZO1) is activated by mechanical stretch. PIEZO1 receptor in concert with TRPV4 transports calcium into the cell. Calcium stimulates acid sensing ion channel (ASIC3), membrane depolarization and more Ca2+influx. Intracellular calcium interacts with and activates GUCA1B which leads to cGMP synthesis and activation of K+ channels. Efflux of K+ leads to membrane depolarization and transmission of the nerve signal by vagal nerve. This leads to activation of gastric motility and eating behavior. Outcome effects: Ion channels in stomach wall regulate gastrointestinal functions and eating behavior by stimulating of the nerve impulse through vagal nerve. PS:Organ stomach PS:Organ stomach wall PS:Organ_System digestive system PS:PMID 20693874 PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte CellType: striated muscle cell Description: Dilated cardiomyopathy (DCM) is a heart muscle disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ca7992e-22e0-44f6-8451-f0b6a0e1ddda NodeType: Pathway Notes: Dilated cardiomyopathy (DCM) is a heart muscle disorder defined by the presence of dilatation and systolic impairment of the left or both ventricles in the absence of hypertension, coronary artery disease, or valvular abnormalities. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: heart Organ_System: cardiovascular system PMID: 12649072 PMID: 23900355 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-7ca7992e-22e0-44f6-8451-f0b6a0e1ddda Dilated Cardiomyopathy uuid-7ca7992e-22e0-44f6-8451-f0b6a0e1ddda PS:CellType cardiac myocyte PS:CellType striated muscle cell PS:Description Dilated cardiomyopathy (DCM) is a heart muscle disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ca7992e-22e0-44f6-8451-f0b6a0e1ddda PS:NodeType Pathway PS:Notes Dilated cardiomyopathy (DCM) is a heart muscle disorder defined by the presence of dilatation and systolic impairment of the left or both ventricles in the absence of hypertension, coronary artery disease, or valvular abnormalities. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 12649072 PS:PMID 23900355 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: During mitosis, the nuclear envelope (NE) is completely disassembled and removed from the chromatin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cb2c182-35f2-43e3-a922-9e7e40eef522 NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). During mitosis, the nuclear envelope (NE) is completely disassembled and removed from the chromatin. Signaling description: The major components of the NE are the inner and outer membranes, nuclear pore complex, and nuclear lamina which is a filamentous scaffold formed by lamins. Inner nuclear membrane (INM) proteins link the NE membrane to chromatin and the lamina, whereas outer nuclear membrane (ONM) proteins provide a connection from the nucleus to the cytoskeleton. Nuclear envelope proteins that are bound to the lamina include SYNE1, SYNE2, EMD, LBR, and members of the LEM-domain family. LBR interacts with both B-type lamins and CBX5 in conjunction with core histones. TMPO, TOR1AIP1, EMD, and LEMD3, which are members of the LEM-domain family, bind to lamins and interact with chromatin through BANF1. Transcription factors such as RB1, SREBF1, and ZNF239 also bind to the lamina. The lamina is essential for the organization of nuclear pore complexes in the nuclear membrane. Nuclear pore complexes are large macromolecular assemblies with eight-fold rotational symmetry that allow the transport of RNA and ribosomes from the nucleus to the cytoplasm and proteins, carbohydrates, signal molecules, and lipids into the nucleus. They are built from 30 different proteins known as nucleoporins. During mitosis, dynein/dynactin complexes attach to the NE and migrate towards the minus ends of microtubules assembled from cytoplasmic centrosomes in NE invaginations. This generates a tension that tears the NE open at sites distal to the centrosomes. Outcome effects: Lamins and lamin-binding proteins are then phosphorylated by mitotic kinases and dissociate from the lamina and chromatin. Nuclear reassembly after sister chromatid separation requires a timely coordinated and dephosphorylation-dependent association of lamin-binding proteins and lamins with chromosomal proteins and targeting of membranes to specific sites on chromosomes. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7cb2c182-35f2-43e3-a922-9e7e40eef522 Nuclear Envelope in Cell Division uuid-7cb2c182-35f2-43e3-a922-9e7e40eef522 PS:CellType generic PS:Description During mitosis, the nuclear envelope (NE) is completely disassembled and removed from the chromatin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cb2c182-35f2-43e3-a922-9e7e40eef522 PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). During mitosis, the nuclear envelope (NE) is completely disassembled and removed from the chromatin. Signaling description: The major components of the NE are the inner and outer membranes, nuclear pore complex, and nuclear lamina which is a filamentous scaffold formed by lamins. Inner nuclear membrane (INM) proteins link the NE membrane to chromatin and the lamina, whereas outer nuclear membrane (ONM) proteins provide a connection from the nucleus to the cytoskeleton. Nuclear envelope proteins that are bound to the lamina include SYNE1, SYNE2, EMD, LBR, and members of the LEM-domain family. LBR interacts with both B-type lamins and CBX5 in conjunction with core histones. TMPO, TOR1AIP1, EMD, and LEMD3, which are members of the LEM-domain family, bind to lamins and interact with chromatin through BANF1. Transcription factors such as RB1, SREBF1, and ZNF239 also bind to the lamina. The lamina is essential for the organization of nuclear pore complexes in the nuclear membrane. Nuclear pore complexes are large macromolecular assemblies with eight-fold rotational symmetry that allow the transport of RNA and ribosomes from the nucleus to the cytoplasm and proteins, carbohydrates, signal molecules, and lipids into the nucleus. They are built from 30 different proteins known as nucleoporins. During mitosis, dynein/dynactin complexes attach to the NE and migrate towards the minus ends of microtubules assembled from cytoplasmic centrosomes in NE invaginations. This generates a tension that tears the NE open at sites distal to the centrosomes. Outcome effects: Lamins and lamin-binding proteins are then phosphorylated by mitotic kinases and dissociate from the lamina and chromatin. Nuclear reassembly after sister chromatid separation requires a timely coordinated and dephosphorylation-dependent association of lamin-binding proteins and lamins with chromosomal proteins and targeting of membranes to specific sites on chromosomes. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cca646f-9df4-4538-8056-755d2c9ce86f NodeType: Pathway Notes: The enhanced production of proinflammatory cytokines causes neutrophil activation and the failure of endothelial regulatory functions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: Blood Vessels Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: endothelium urn:agi-pathway:uuid-7cca646f-9df4-4538-8056-755d2c9ce86f 2_The role of endothelial cells in pyelonephritis uuid-7cca646f-9df4-4538-8056-755d2c9ce86f PS:CellType endothelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cca646f-9df4-4538-8056-755d2c9ce86f PS:NodeType Pathway PS:Notes The enhanced production of proinflammatory cytokines causes neutrophil activation and the failure of endothelial regulatory functions. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ Blood Vessels PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue endothelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cf5c023-9902-4c3c-9f76-ea668dac6d44 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-7cf5c023-9902-4c3c-9f76-ea668dac6d44 CD19 -> JUN/ELK Signaling uuid-7cf5c023-9902-4c3c-9f76-ea668dac6d44 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cf5c023-9902-4c3c-9f76-ea668dac6d44 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cfbe09c-bd69-47e0-985c-86054541340c NodeType: Pathway Organ: generic Organ_System: generic PMID: 21816244 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-7cfbe09c-bd69-47e0-985c-86054541340c FOXO1 Signaling uuid-7cfbe09c-bd69-47e0-985c-86054541340c PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7cfbe09c-bd69-47e0-985c-86054541340c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21816244 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d0e84a2-d2b7-4e1a-be46-c5b18765e338 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-7d0e84a2-d2b7-4e1a-be46-c5b18765e338 INS Expression targets uuid-7d0e84a2-d2b7-4e1a-be46-c5b18765e338 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d0e84a2-d2b7-4e1a-be46-c5b18765e338 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d2de9fb-b19d-4a0c-9d80-2a3d55de423e NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-7d2de9fb-b19d-4a0c-9d80-2a3d55de423e Proteins with Altered Expression in Endometriosis uuid-7d2de9fb-b19d-4a0c-9d80-2a3d55de423e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d2de9fb-b19d-4a0c-9d80-2a3d55de423e PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d33f0b8-0085-4d6c-bb95-4407d2f1f8f8 NodeType: Pathway Notes: Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Citrullinemia type II is caused by mutations in SLC25A13 gene. Organ: liver PMID: 12111366 PMID: 14598172 PMID: 20301396 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-7d33f0b8-0085-4d6c-bb95-4407d2f1f8f8 Citrullinemia Type II uuid-7d33f0b8-0085-4d6c-bb95-4407d2f1f8f8 PS:CellType hepatocyte PS:Description Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d33f0b8-0085-4d6c-bb95-4407d2f1f8f8 PS:NodeType Pathway PS:Notes Citrullinemia (ICD10 - E72.2) is an autosomal-recessive disease. Citrullinemia type II is caused by mutations in SLC25A13 gene. PS:Organ liver PS:PMID 12111366 PS:PMID 14598172 PS:PMID 20301396 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d74ddea-4b00-42a7-9cd1-4ed26c94b3ca NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7d74ddea-4b00-42a7-9cd1-4ed26c94b3ca HGF -> STAT Expression Targets uuid-7d74ddea-4b00-42a7-9cd1-4ed26c94b3ca PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d74ddea-4b00-42a7-9cd1-4ed26c94b3ca PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d80b970-b7f8-481b-b9d5-a6b8d5996eff NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7d80b970-b7f8-481b-b9d5-a6b8d5996eff Tannate degradation template uuid-7d80b970-b7f8-481b-b9d5-a6b8d5996eff PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d80b970-b7f8-481b-b9d5-a6b8d5996eff PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Bradykinin is a peptide that causes blood vessels to dilate which lowers blood pressure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d88c580-6ab9-49af-b331-9203f393a45b NodeType: Pathway Notes: Headnote: Bradykinin is a peptide that causes blood vessels to dilate, which lowers blood pressure. It is formed during the proteolytic cleavage of its precursor, kininogen (KNG1) in response to tissue damage. The major effects of peptides in inflammation are pain, redness, and a rise in temperature in the inflammatory foci. Signaling description: The biological actions of bradykinin are mediated by B1 (BDKRB1) and B2 (BDKRB2) receptors, which mediate similar effects. Both are typical G-protein coupled receptors. In contrast to constitutive BDKRB2, the expression of BDKRB1 is up-regulated during inflammation. Angiotensin (AGT) induces BDKRB1 expression through the signaling of PI3K. BDKRB1 is also induced by IL1 via the NF-kB transcription factor. BDKRB2 is triggered by bradykinin, but BDKRB1 is activated by the kinin metabolites such as des-Arg(9)-bradykinin or des-Arg-LBK, both of which are generated by CPN1/CPM-mediated cleavage of the C-terminal arginine residue of bradykinin. BDKRB1 and BDKRB2 mediate arachidonic acid release and prostaglandin (PG) synthesis. The activation of BDKRB1 leads to the elevation of intracellular free calcium (Ca2+) activity by increasing Ca2 entry into the cell. Conversely, BDKRB2 acts primarily to release bound intracellular Ca2+. NOS3, IL6, and PGI2 synthesis cause increased blood vessel permeability and vasodilation. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Organ: generic Organ_System: hematological system PMID: 11842287 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-7d88c580-6ab9-49af-b331-9203f393a45b Bradykinin Effects in Inflammation uuid-7d88c580-6ab9-49af-b331-9203f393a45b PS:CellType generic PS:Description Bradykinin is a peptide that causes blood vessels to dilate which lowers blood pressure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d88c580-6ab9-49af-b331-9203f393a45b PS:NodeType Pathway PS:Notes Headnote: Bradykinin is a peptide that causes blood vessels to dilate, which lowers blood pressure. It is formed during the proteolytic cleavage of its precursor, kininogen (KNG1) in response to tissue damage. The major effects of peptides in inflammation are pain, redness, and a rise in temperature in the inflammatory foci. Signaling description: The biological actions of bradykinin are mediated by B1 (BDKRB1) and B2 (BDKRB2) receptors, which mediate similar effects. Both are typical G-protein coupled receptors. In contrast to constitutive BDKRB2, the expression of BDKRB1 is up-regulated during inflammation. Angiotensin (AGT) induces BDKRB1 expression through the signaling of PI3K. BDKRB1 is also induced by IL1 via the NF-kB transcription factor. BDKRB2 is triggered by bradykinin, but BDKRB1 is activated by the kinin metabolites such as des-Arg(9)-bradykinin or des-Arg-LBK, both of which are generated by CPN1/CPM-mediated cleavage of the C-terminal arginine residue of bradykinin. BDKRB1 and BDKRB2 mediate arachidonic acid release and prostaglandin (PG) synthesis. The activation of BDKRB1 leads to the elevation of intracellular free calcium (Ca2+) activity by increasing Ca2 entry into the cell. Conversely, BDKRB2 acts primarily to release bound intracellular Ca2+. NOS3, IL6, and PGI2 synthesis cause increased blood vessel permeability and vasodilation. Highlighted proteins: Protein with increased expression or activity is highlighted in red. PS:Organ generic PS:Organ_System hematological system PS:PMID 11842287 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d8c3d1e-4652-4236-bd18-44ed3509cef1 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: colon Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7d8c3d1e-4652-4236-bd18-44ed3509cef1 Elevated Receptors -> Expression Targets in Colon uuid-7d8c3d1e-4652-4236-bd18-44ed3509cef1 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7d8c3d1e-4652-4236-bd18-44ed3509cef1 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ colon PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7da3cade-c57f-4b79-b065-1b91800978fa NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-7da3cade-c57f-4b79-b065-1b91800978fa Proteins Involved in Melanoma uuid-7da3cade-c57f-4b79-b065-1b91800978fa PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7da3cade-c57f-4b79-b065-1b91800978fa PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7dd2a16a-8923-4eb3-8dbe-c08fe17fe6d6 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-7dd2a16a-8923-4eb3-8dbe-c08fe17fe6d6 PECAM -> SP1 Signaling uuid-7dd2a16a-8923-4eb3-8dbe-c08fe17fe6d6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7dd2a16a-8923-4eb3-8dbe-c08fe17fe6d6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ddc9672-8eeb-41b7-9c50-ee657be1d6fb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7ddc9672-8eeb-41b7-9c50-ee657be1d6fb Biosynthesis of unsaturated fatty acid (n-6 family) template uuid-7ddc9672-8eeb-41b7-9c50-ee657be1d6fb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ddc9672-8eeb-41b7-9c50-ee657be1d6fb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e021e44-3022-48dc-b05d-b4962883f2bb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7e021e44-3022-48dc-b05d-b4962883f2bb Biosynthesis of unsaturated fatty acid (n-3 family) template uuid-7e021e44-3022-48dc-b05d-b4962883f2bb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e021e44-3022-48dc-b05d-b4962883f2bb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/BTRC complex regulates G2/M transition, apoptosis and autophagy. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e16b98e-c633-4907-902c-db8300063d99 NodeType: Pathway Notes: Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/BTRC complex, BTRC (FBXW1) acts as a substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core SCF/BTRC related signaling regulates the cell cycle progression, apoptosis and autophagy. The precise mechanism of the molecular signaling on this pathway is well known and is associated with ubiquitination and degradation of WEE1, FBXO5, CDC25A, CLSPN, DEPTOR, MDM2, ATF4, NFKBIA, CTNNB1, REST. In addition, SCF/BTRC may regulate circadian rhythm. The precise mechanism of circadian rhythm regulation through degradation of PER1/2 is poorly understood. Outcome effects: SCF/BTRC targets and degrades the WEE1, FBXO5, CDC25A, and CLSPN which regulate cyclins/CDK1 complex and thus, causes G2/M transition. SCF/BTRC promotes the ubiquitination of PDCD4, MDM2, ATF4, NFKBIA and CTNNB1 which leads to block of apoptosis. SCF/BTRC regulates autophagy by controlling the ubiquitination and destruction of DEPTOR, an endogenous inhibitor of the MTOR pathway. Animal data: Role of SCF/BTRC in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 22454292 PMID: 22542766 PMID: 26528041 PMID: 27156687 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7e16b98e-c633-4907-902c-db8300063d99 SCF/BTRC Complex uuid-7e16b98e-c633-4907-902c-db8300063d99 PS:CellType generic PS:Description SCF/BTRC complex regulates G2/M transition, apoptosis and autophagy. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e16b98e-c633-4907-902c-db8300063d99 PS:NodeType Pathway PS:Notes Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/BTRC complex, BTRC (FBXW1) acts as a substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core SCF/BTRC related signaling regulates the cell cycle progression, apoptosis and autophagy. The precise mechanism of the molecular signaling on this pathway is well known and is associated with ubiquitination and degradation of WEE1, FBXO5, CDC25A, CLSPN, DEPTOR, MDM2, ATF4, NFKBIA, CTNNB1, REST. In addition, SCF/BTRC may regulate circadian rhythm. The precise mechanism of circadian rhythm regulation through degradation of PER1/2 is poorly understood. Outcome effects: SCF/BTRC targets and degrades the WEE1, FBXO5, CDC25A, and CLSPN which regulate cyclins/CDK1 complex and thus, causes G2/M transition. SCF/BTRC promotes the ubiquitination of PDCD4, MDM2, ATF4, NFKBIA and CTNNB1 which leads to block of apoptosis. SCF/BTRC regulates autophagy by controlling the ubiquitination and destruction of DEPTOR, an endogenous inhibitor of the MTOR pathway. Animal data: Role of SCF/BTRC in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22454292 PS:PMID 22542766 PS:PMID 26528041 PS:PMID 27156687 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: muscle cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e30c56b-246f-4f8c-a7c7-f2b5389b301a NodeType: Pathway Notes: The released adipose tissue substances including IL6, CXCL5 and LEP provoke the inhibition of insulin signal transduction leading to the disruption of glycogen synthesis and lipid metabolism. Overexpressed proteins are highlighted in red. Organ_System: musculoskeletal system PMID: 11080610 PMID: 18220592 PMID: 20157549 PMID: 21811961 PMID: 27003399 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-7e30c56b-246f-4f8c-a7c7-f2b5389b301a Adipokines and Cytokines in Insulin Resistance in Skeletal Muscles uuid-7e30c56b-246f-4f8c-a7c7-f2b5389b301a PS:CellType muscle cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e30c56b-246f-4f8c-a7c7-f2b5389b301a PS:NodeType Pathway PS:Notes The released adipose tissue substances including IL6, CXCL5 and LEP provoke the inhibition of insulin signal transduction leading to the disruption of glycogen synthesis and lipid metabolism. Overexpressed proteins are highlighted in red. PS:Organ_System musculoskeletal system PS:PMID 11080610 PS:PMID 18220592 PS:PMID 20157549 PS:PMID 21811961 PS:PMID 27003399 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e5d6cd4-2d69-41bc-b931-1aa44c875176 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-7e5d6cd4-2d69-41bc-b931-1aa44c875176 PAF-|Cornea healing uuid-7e5d6cd4-2d69-41bc-b931-1aa44c875176 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e5d6cd4-2d69-41bc-b931-1aa44c875176 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e5fb234-5dcf-45e8-a4db-664e2d51bb99 NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-7e5fb234-5dcf-45e8-a4db-664e2d51bb99 Panic Disorder: Posible Action of CCK-4 in Panic Attack Induction uuid-7e5fb234-5dcf-45e8-a4db-664e2d51bb99 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e5fb234-5dcf-45e8-a4db-664e2d51bb99 PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e8870ff-d37d-4166-9d25-ea190b71c011 NodeType: Pathway Notes: Hemophilia A and B are caused by mutations in coagulation factor VIII (F8) and IX (F9), respectively, which cause impairment of the coagulation cascade and the diminished capacity to form a blood clot, thereby predisposing affected individual to bleeding. Pathway 1. Dysfunction of coagulation cascade in hemophilia: Coagulation cascade (Fig. 1). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: blood urn:agi-pathway:uuid-7e8870ff-d37d-4166-9d25-ea190b71c011 1_1_Dysfunction of coagulation cascade in hemophilia uuid-7e8870ff-d37d-4166-9d25-ea190b71c011 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7e8870ff-d37d-4166-9d25-ea190b71c011 PS:NodeType Pathway PS:Notes Hemophilia A and B are caused by mutations in coagulation factor VIII (F8) and IX (F9), respectively, which cause impairment of the coagulation cascade and the diminished capacity to form a blood clot, thereby predisposing affected individual to bleeding. Pathway 1. Dysfunction of coagulation cascade in hemophilia: Coagulation cascade (Fig. 1). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: endothelial cell Description: PDGFB/PDGFRB, FGF/FGFR, EFNA/EPHA2 and HGF/MET provide escape mechanisms from anti-VEGFA therapy that could facilitate resumption of tumor growth. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7eaf10ed-9fce-4e8c-aa45-3ba181bd8887 NodeType: Pathway Notes: Headnote: Angiogenesis is a biological process wherein new blood vessels are formed from pre-existing vessels. The pathology of angiogenesis in tumors is characterized by the escape from the anti-VEGFA treatment through the induction of multiple parallel signaling cascades. Signaling description: Altered forms of PDGFB/PDGFRB, FGF/FGFR, EFNA/EPHA2 and HGF/MET cause changes in PI3K-AKT, RAS-MAPK, PLC-PKC-RAF-MAPK signaling paths. Outcome effects: JUN-FOS, MYC, STAT change their expression due to signaling activation. Their altered expression leads to activation of endothelial cell proliferation, migration and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 18650835 PMID: 20094046 PMID: 21953501 PMID: 23008289 PMID: 26001391 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-7eaf10ed-9fce-4e8c-aa45-3ba181bd8887 VEGF Independent Angiogenesis in Cancer uuid-7eaf10ed-9fce-4e8c-aa45-3ba181bd8887 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType endothelial cell PS:Description PDGFB/PDGFRB, FGF/FGFR, EFNA/EPHA2 and HGF/MET provide escape mechanisms from anti-VEGFA therapy that could facilitate resumption of tumor growth. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7eaf10ed-9fce-4e8c-aa45-3ba181bd8887 PS:NodeType Pathway PS:Notes Headnote: Angiogenesis is a biological process wherein new blood vessels are formed from pre-existing vessels. The pathology of angiogenesis in tumors is characterized by the escape from the anti-VEGFA treatment through the induction of multiple parallel signaling cascades. Signaling description: Altered forms of PDGFB/PDGFRB, FGF/FGFR, EFNA/EPHA2 and HGF/MET cause changes in PI3K-AKT, RAS-MAPK, PLC-PKC-RAF-MAPK signaling paths. Outcome effects: JUN-FOS, MYC, STAT change their expression due to signaling activation. Their altered expression leads to activation of endothelial cell proliferation, migration and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 18650835 PS:PMID 20094046 PS:PMID 21953501 PS:PMID 23008289 PS:PMID 26001391 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ec527d1-0c9e-490d-ad30-9712ffe71d88 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-7ec527d1-0c9e-490d-ad30-9712ffe71d88 acyl-CoA elongase (2.3.1.119) uuid-7ec527d1-0c9e-490d-ad30-9712ffe71d88 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ec527d1-0c9e-490d-ad30-9712ffe71d88 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: M phase (mitosis) is process of division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7efb42ec-aed2-4865-9287-a510c005c411 NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). During the M phase (mitosis) the mother cell divides into two daughter cells, genetically identical to each other and to their parent cell. Signaling description: The CycB - CDK1 complex activates the anaphase-promoting complex (APC/C) which allows the sister chromatids at the metaphase plate to separate and move to the poles. The separation of sister chromatids depends on the breakdown of cohesin that holds the chromatids together. Cohesin breakdown is caused by ESPL1 which is kept inactive until late metaphase by an inhibitory PTTG1. Anaphase begins when APC/C destroys PTTG1. Once the cell has split into two daughter cells, it enters G1. During the M phase, the PLKs activate certain functions of the APC/C. The spindle assembly checkpoint (SAC) during M phase stops the cell cycle (see Spindle Assembly Pathway). SAC occurs in metaphase when all the chromosomes have/should have aligned at the mitotic plate and are under bipolar tension. The proteins responsible for the SAC include MAD2/MAD3, BUB3, and CDC20. CDC20 and the SAC proteins concentrate at the kinetochores before attachment to the spindle assembly. Another regulator of checkpoint activation is kinetochore tension. Aurora-B functions as the tension sensor for improper kinetochore attachments. Outcome effects: Once activated, SAC blocks anaphase entry by inhibiting the APC/C. Following silencing of the spindle checkpoint in mitosis, CycB is degraded by the APC/C or via ubiquitin/proteasome - dependent degradation. Inactivation of the CycB - CDK1 inhibits SAC activity. APC/C activity maintains low CycB levels through the G1 phase until silencing of APC/C in the S phase via direct inactivation by CycA-CDK2. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7efb42ec-aed2-4865-9287-a510c005c411 Metaphase/Anaphase Phase Transition uuid-7efb42ec-aed2-4865-9287-a510c005c411 PS:CellType generic PS:Description M phase (mitosis) is process of division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7efb42ec-aed2-4865-9287-a510c005c411 PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). During the M phase (mitosis) the mother cell divides into two daughter cells, genetically identical to each other and to their parent cell. Signaling description: The CycB - CDK1 complex activates the anaphase-promoting complex (APC/C) which allows the sister chromatids at the metaphase plate to separate and move to the poles. The separation of sister chromatids depends on the breakdown of cohesin that holds the chromatids together. Cohesin breakdown is caused by ESPL1 which is kept inactive until late metaphase by an inhibitory PTTG1. Anaphase begins when APC/C destroys PTTG1. Once the cell has split into two daughter cells, it enters G1. During the M phase, the PLKs activate certain functions of the APC/C. The spindle assembly checkpoint (SAC) during M phase stops the cell cycle (see Spindle Assembly Pathway). SAC occurs in metaphase when all the chromosomes have/should have aligned at the mitotic plate and are under bipolar tension. The proteins responsible for the SAC include MAD2/MAD3, BUB3, and CDC20. CDC20 and the SAC proteins concentrate at the kinetochores before attachment to the spindle assembly. Another regulator of checkpoint activation is kinetochore tension. Aurora-B functions as the tension sensor for improper kinetochore attachments. Outcome effects: Once activated, SAC blocks anaphase entry by inhibiting the APC/C. Following silencing of the spindle checkpoint in mitosis, CycB is degraded by the APC/C or via ubiquitin/proteasome - dependent degradation. Inactivation of the CycB - CDK1 inhibits SAC activity. APC/C activity maintains low CycB levels through the G1 phase until silencing of APC/C in the S phase via direct inactivation by CycA-CDK2. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neural crest cell Description: Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7efe37dc-fc63-4cd8-a331-2c55ef91e612 NodeType: Pathway Notes: Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: A mutation in KIF1-binding protein (KIAA1279) gene is one of the causes of Hirschsprung disease development. Normally, KIAA1279 is required for the organization of axonal microtubules and axonal outgrowth. It also regulates mitochondrial transport by modulating KIF1B motor activity. Outcome effects: When KIAA1279 is mutated, axonal outgrowth and mitochondrial distribution in axons are impaired leading to aganglionosis development. Mutated genes: Mutated gene is shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15883926 PMID: 18192286 PMID: 22174542 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-7efe37dc-fc63-4cd8-a331-2c55ef91e612 KIAA1279 Gene Mutation in Hirschsprung Disease uuid-7efe37dc-fc63-4cd8-a331-2c55ef91e612 PS:CellType neural crest cell PS:Description Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7efe37dc-fc63-4cd8-a331-2c55ef91e612 PS:NodeType Pathway PS:Notes Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: A mutation in KIF1-binding protein (KIAA1279) gene is one of the causes of Hirschsprung disease development. Normally, KIAA1279 is required for the organization of axonal microtubules and axonal outgrowth. It also regulates mitochondrial transport by modulating KIF1B motor activity. Outcome effects: When KIAA1279 is mutated, axonal outgrowth and mitochondrial distribution in axons are impaired leading to aganglionosis development. Mutated genes: Mutated gene is shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15883926 PS:PMID 18192286 PS:PMID 22174542 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f0c8cc0-06ea-4219-968d-69ed4791a7a9 NodeType: Pathway Notes: Obese men show decreased bioavailable levels of androgens and increased levels of estrogens. The latter is due to an increase in aromatase (CYP19A1) activity that mediates peripheral conversion of androgens to estrogens. Organ_System: endocrine system PMID: 16210377 PMID: 17977473 PMID: 21109497 PMID: 21709300 PMID: 22235202 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process Tissue: adipose tissue urn:agi-pathway:uuid-7f0c8cc0-06ea-4219-968d-69ed4791a7a9 Androgens in Adipocyte Activation uuid-7f0c8cc0-06ea-4219-968d-69ed4791a7a9 PS:CellType adipocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f0c8cc0-06ea-4219-968d-69ed4791a7a9 PS:NodeType Pathway PS:Notes Obese men show decreased bioavailable levels of androgens and increased levels of estrogens. The latter is due to an increase in aromatase (CYP19A1) activity that mediates peripheral conversion of androgens to estrogens. PS:Organ_System endocrine system PS:PMID 16210377 PS:PMID 17977473 PS:PMID 21109497 PS:PMID 21709300 PS:PMID 22235202 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f10c572-8fbe-4a55-82ec-2efe33f72886 NodeType: Pathway Notes: The HTLV-1–encoded tax protein can modify NF-kB signaling by interacting with many mitogen-activated protein kinase kinase kinase (MAP3K proteins) and direct interactions with one of the NF-kB signaling pathway proteins—inhibitor of kappa-light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG). NF-kB signaling in CD4+ T cells is necessary for their survival. Interfering with its regulation blocks apoptosis and promotes cell survival. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-7f10c572-8fbe-4a55-82ec-2efe33f72886 5_Tax-mediated dysregulation of NF-kB signaling in HTLV-1 infection uuid-7f10c572-8fbe-4a55-82ec-2efe33f72886 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f10c572-8fbe-4a55-82ec-2efe33f72886 PS:NodeType Pathway PS:Notes The HTLV-1–encoded tax protein can modify NF-kB signaling by interacting with many mitogen-activated protein kinase kinase kinase (MAP3K proteins) and direct interactions with one of the NF-kB signaling pathway proteins—inhibitor of kappa-light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG). NF-kB signaling in CD4+ T cells is necessary for their survival. Interfering with its regulation blocks apoptosis and promotes cell survival. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Synthesized proteins can be transported to a different organelle depending on the protein by co-translational or post-translational translocation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f18eb1f-cdfb-4e7a-ae99-46f8918e5c0e NodeType: Pathway Notes: Headnote: Synthesized proteins can be transported to a different organelle depending on the protein by co-translational or post-translational translocation. In the case of co-translational endoplasmic reticulum (ER) protein import, the N-terminal signal sequence of the protein is bound by the nascent polypeptide-associated complex (NAC) shortly after protein synthesis but before its complete emergence from the ribosome. NAC appears to be displaced from the growing polypeptide chain by the signal recognition particle (SRP) when the signal emerges from the ribosome. Signaling description: Proteins are translocated into the ER lumen or integrated into the ER membrane through a channel formed by the heterotrimeric SEC61 translocon. Within the ER, the SRP sequence in secretory proteins and type I transmembrane proteins is immediately cleaved from the nascent polypeptide by the signal peptidase. The signal sequence of some polytopic membrane proteins is not cleaved off. Most newly synthesized polypeptides are co-translationally modi?ed with N-glycans in the ER. When nascent polypeptides enter the ER lumen, glucose, mannose, and N-acetylglucosamine oligosaccharides are attached to the asparagine residues of the polypeptides by the dolichyl-diphosphooligosaccharide-protein glycotransferase. The two outer glucoses are removed immediately by glucosidase I and glucan 1,3-alpha-glucosidase. The resulting monoglucosylated N-glycans on the polypeptides are recognized by the ER-resident lectin-like chaperones, CANX, CALR, and HSPA5, which promote folding of the glycoproteins. Outcome effects: After the removal of the third glucose by glucan 1,3-alpha-glucosidase, the substrates dissociate from CANX and are transported to the Golgi apparatus through vesicular transport. However, if the polypeptides are incorrectly or immaturely folded, they are re-glucosylated by glycosyl transferase, and again recognized and folded by CANX. Organ: generic Organ_System: generic PMID: 23481039 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7f18eb1f-cdfb-4e7a-ae99-46f8918e5c0e Co-Translational ER Protein Import uuid-7f18eb1f-cdfb-4e7a-ae99-46f8918e5c0e PS:CellType generic PS:Description Synthesized proteins can be transported to a different organelle depending on the protein by co-translational or post-translational translocation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f18eb1f-cdfb-4e7a-ae99-46f8918e5c0e PS:NodeType Pathway PS:Notes Headnote: Synthesized proteins can be transported to a different organelle depending on the protein by co-translational or post-translational translocation. In the case of co-translational endoplasmic reticulum (ER) protein import, the N-terminal signal sequence of the protein is bound by the nascent polypeptide-associated complex (NAC) shortly after protein synthesis but before its complete emergence from the ribosome. NAC appears to be displaced from the growing polypeptide chain by the signal recognition particle (SRP) when the signal emerges from the ribosome. Signaling description: Proteins are translocated into the ER lumen or integrated into the ER membrane through a channel formed by the heterotrimeric SEC61 translocon. Within the ER, the SRP sequence in secretory proteins and type I transmembrane proteins is immediately cleaved from the nascent polypeptide by the signal peptidase. The signal sequence of some polytopic membrane proteins is not cleaved off. Most newly synthesized polypeptides are co-translationally modi?ed with N-glycans in the ER. When nascent polypeptides enter the ER lumen, glucose, mannose, and N-acetylglucosamine oligosaccharides are attached to the asparagine residues of the polypeptides by the dolichyl-diphosphooligosaccharide-protein glycotransferase. The two outer glucoses are removed immediately by glucosidase I and glucan 1,3-alpha-glucosidase. The resulting monoglucosylated N-glycans on the polypeptides are recognized by the ER-resident lectin-like chaperones, CANX, CALR, and HSPA5, which promote folding of the glycoproteins. Outcome effects: After the removal of the third glucose by glucan 1,3-alpha-glucosidase, the substrates dissociate from CANX and are transported to the Golgi apparatus through vesicular transport. However, if the polypeptides are incorrectly or immaturely folded, they are re-glucosylated by glycosyl transferase, and again recognized and folded by CANX. PS:Organ generic PS:Organ_System generic PS:PMID 23481039 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f2a785f-3089-441d-a8ca-9eaf64ff6bf2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-7f2a785f-3089-441d-a8ca-9eaf64ff6bf2 IGF1+>cornea epithelium proliferation uuid-7f2a785f-3089-441d-a8ca-9eaf64ff6bf2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f2a785f-3089-441d-a8ca-9eaf64ff6bf2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage CellType: neutrophil Description: Periodontitis is a disease of the gum and periodontal tissues. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f57d20c-b08a-4260-a616-e921c0e479c4 NodeType: Pathway Notes: Headnote: Periodontitis is a set of inflammatory diseases affecting the periodontium. Periodontitis involves progressive loss of the alveolar bone around the teeth, and if left untreated, can lead to the loosening and subsequent loss of teeth. Periodontitis is caused by microorganisms that adhere to and grow on the tooth's surfaces, along with an over-aggressive immune response against these microorganisms. Mutated cathepsins cause changes in immune response, degradation of extracellular matrix and osteoclast activation. Signaling description: The cathepsin-dependent mechanism underlying the progression of periodontitis still remains largely unknown. Mutations in the cathepsin C gene (CTSC) have been identified in prepubertal aggressive periodontitis. Cathepsin C activity has been found to be significantly lower in tissue extract supernatants and gingival crevicular fluid of patients with periodontitis compared with those of healthy controls. Cathepsin C plays essential role in the host defense against bacteria and is the activator of elastase (ELANE) and proteinase 3 (PRTN3) in human. Proteinase 3 is a serine proteinase that is involved in inflammatory response. Elastase is a serine protease hydrolyzes collagen, elastin, fibronectin and many other proteins that leads to extracellular matrix polymerization. Elastase cleaves CXCR1 (IL-8 receptor on neutrophils), macrophage cell surface CD14 and phosphatidylserine receptor (JMJD6) and indirectly regulates neutrophil function and phagocytic recognition of apoptotic lymphocytic cells. Cathepsin K, B, G (CTSK, CTSB, CTSG) concentrations in gingival crevicular fluid of control subjects were below the limit of detection, whereas those for the periodontal patients were significantly higher. Cathepsins K, G, B are key proteases in the osteoclast activation and extracellular matrix degradation via regulation of matrix metalloproteinases.CTSC with white centered color has mutations. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: mouth Organ_System: digestive system PMID: 17321485 PMID: 18809751 PMID: 23346239 PMID: 24949444 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-7f57d20c-b08a-4260-a616-e921c0e479c4 Cathepsins Role in Periodontitis uuid-7f57d20c-b08a-4260-a616-e921c0e479c4 PS:CellType macrophage PS:CellType neutrophil PS:Description Periodontitis is a disease of the gum and periodontal tissues. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f57d20c-b08a-4260-a616-e921c0e479c4 PS:NodeType Pathway PS:Notes Headnote: Periodontitis is a set of inflammatory diseases affecting the periodontium. Periodontitis involves progressive loss of the alveolar bone around the teeth, and if left untreated, can lead to the loosening and subsequent loss of teeth. Periodontitis is caused by microorganisms that adhere to and grow on the tooth's surfaces, along with an over-aggressive immune response against these microorganisms. Mutated cathepsins cause changes in immune response, degradation of extracellular matrix and osteoclast activation. Signaling description: The cathepsin-dependent mechanism underlying the progression of periodontitis still remains largely unknown. Mutations in the cathepsin C gene (CTSC) have been identified in prepubertal aggressive periodontitis. Cathepsin C activity has been found to be significantly lower in tissue extract supernatants and gingival crevicular fluid of patients with periodontitis compared with those of healthy controls. Cathepsin C plays essential role in the host defense against bacteria and is the activator of elastase (ELANE) and proteinase 3 (PRTN3) in human. Proteinase 3 is a serine proteinase that is involved in inflammatory response. Elastase is a serine protease hydrolyzes collagen, elastin, fibronectin and many other proteins that leads to extracellular matrix polymerization. Elastase cleaves CXCR1 (IL-8 receptor on neutrophils), macrophage cell surface CD14 and phosphatidylserine receptor (JMJD6) and indirectly regulates neutrophil function and phagocytic recognition of apoptotic lymphocytic cells. Cathepsin K, B, G (CTSK, CTSB, CTSG) concentrations in gingival crevicular fluid of control subjects were below the limit of detection, whereas those for the periodontal patients were significantly higher. Cathepsins K, G, B are key proteases in the osteoclast activation and extracellular matrix degradation via regulation of matrix metalloproteinases.CTSC with white centered color has mutations. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ_System digestive system PS:PMID 17321485 PS:PMID 18809751 PS:PMID 23346239 PS:PMID 24949444 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f6c1863-bb1d-48a2-a510-7273ca62fd7f NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. TRRAP/TIP60 chromatin remodeling complex is a common component of many histone acetyltransferase (HAT) complexes. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. In addition to histone acetylase activity on chromatin, the TRRAP/TIP60 complex possesses ATPase, helicase, and structural DNA binding activities. Outcome effects: TRRAP/TIP60 chromatin remodeling complex performs critical functions in a variety of cellular processes including chromatin remodeling, double-strand DNA break repair, and apoptosis. TRRAP is required for mitotic checkpoint and normal cell cycle progression. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-7f6c1863-bb1d-48a2-a510-7273ca62fd7f TRRAP/TIP60 in Chromatin Remodeling uuid-7f6c1863-bb1d-48a2-a510-7273ca62fd7f PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f6c1863-bb1d-48a2-a510-7273ca62fd7f PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. TRRAP/TIP60 chromatin remodeling complex is a common component of many histone acetyltransferase (HAT) complexes. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. In addition to histone acetylase activity on chromatin, the TRRAP/TIP60 complex possesses ATPase, helicase, and structural DNA binding activities. Outcome effects: TRRAP/TIP60 chromatin remodeling complex performs critical functions in a variety of cellular processes including chromatin remodeling, double-strand DNA break repair, and apoptosis. TRRAP is required for mitotic checkpoint and normal cell cycle progression. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f7f89e7-41a1-4246-9e2b-097737551431 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-7f7f89e7-41a1-4246-9e2b-097737551431 CD19/CR2 Expression Targets uuid-7f7f89e7-41a1-4246-9e2b-097737551431 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7f7f89e7-41a1-4246-9e2b-097737551431 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: CD46, CD55 and CD59 are overexpressed in cancer cells and inhibit complement-mediated lysis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fa1978a-92fd-41b8-870e-0613cc478578 NodeType: Pathway Notes: Headnote: CD46, CD55 and CD59 are membrane complement regulatory proteins. They are overexpressed in cancer cells and inhibit complement-mediated lysis of cancer cells. Signaling description: Both CD46 and CD55 inhibit C3 and C4B activation. CD59 binds to C8A and C9 and impairs the formation of membrane attack complex. In cancer, CD46/55/59 can be upregulated by NFKB, CREB1, STAT3 and other transcription factors. Outcome effects: The membrane attack complex formation is blocked and complement-dependent lysis of cancer cell does not occur. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: blood urn:agi-pathway:uuid-7fa1978a-92fd-41b8-870e-0613cc478578 CD46/CD55/CD59 Inhibit Complement Mediated Lysis of Cancer Cells uuid-7fa1978a-92fd-41b8-870e-0613cc478578 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description CD46, CD55 and CD59 are overexpressed in cancer cells and inhibit complement-mediated lysis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fa1978a-92fd-41b8-870e-0613cc478578 PS:NodeType Pathway PS:Notes Headnote: CD46, CD55 and CD59 are membrane complement regulatory proteins. They are overexpressed in cancer cells and inhibit complement-mediated lysis of cancer cells. Signaling description: Both CD46 and CD55 inhibit C3 and C4B activation. CD59 binds to C8A and C9 and impairs the formation of membrane attack complex. In cancer, CD46/55/59 can be upregulated by NFKB, CREB1, STAT3 and other transcription factors. Outcome effects: The membrane attack complex formation is blocked and complement-dependent lysis of cancer cell does not occur. Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fa7fc60-e7ed-490d-86d2-bd564f163047 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-7fa7fc60-e7ed-490d-86d2-bd564f163047 FGF18 -> STAT Expression Targets uuid-7fa7fc60-e7ed-490d-86d2-bd564f163047 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fa7fc60-e7ed-490d-86d2-bd564f163047 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Lipid-derived mediators such as lipoxins, resolvins, and protectins play an important role in the resolution of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fb62930-8a92-4570-9a52-3adb4691aa07 NodeType: Pathway Notes: Headnote: Lipid-derived mediators such as lipoxins, resolvins, and protectins play an important role in the resolution of inflammation. The process of the resolution of inflammation is now considered an active process, where antagonists of proinflammatory mediators lead to phagocytosis of cellular debris and blockage of leukocyte infiltration. During extended inflammation, polymorphonuclear neutrophils (PMNs) may eventually cause trauma and tissue damage through infiltration into tissues. Signaling description: Lipoxins and resolvins turn off the influx of neutrophils while the influx of monocytes and macrophages is further promoted. Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. The negative regulators of the inflammatory response such as IL4, IL13, and proinflammatory cytokines are crucial to the formation of lipoxins. Lipoxins are rapidly biosynthesized in response to stimuli, act locally, and then are rapidly inactivated enzymatically by HPGD. There are two main pathways of lipoxin signaling that require transcellular interactions. One pathway involves platelet-leukocyte (PMN) interactions. Human platelets do not produce lipoxins on their own, but become a major source of lipoxins when platelet-PMN adhesion occurs. In neutrophils, ALOX5 converts arachidonic acid to LTA4, which is then released and further transformed by adherent platelets to lipoxin A4 via ALOX12. A second pathway is initiated at the epithelial mucosal surfaces by arachidonate 15-lipoxygenase that converts arachidonic acid to 15(S)-HPETE. Neutrophils take up 15(S)-HPETE and convert it to lipoxins by ALOX5. Lipoxin B4 is a positional isomer of lipoxin A4. This event not only leads to lipoxin biosynthesis, but also reduces LTA4 formation due to competition effects. The reduction of leukotriene production is the first and most rapid method by which lipoxins reduce inflammation. A third major pathway for lipoxin generation involves aspirin, PTGS2, and ALOX5. Endothelial and epithelial cells express PTGS2 in response to diverse stimuli such as cytokines, hypoxia, and bacterial infections. The action of aspirin involves the inhibition of PTGS2, biosynthesis of prostaglandin and thromboxane, and the generation of endogenous anti-inflammatory aspirin-triggered lipoxins. When aspirin is administered, PTGS2 is irreversibly acetylated, but remains active and changes their products from intermediates for prostaglandin and thromboxane to precursors for aspirin-triggered lipoxin A, specifically 15(R)-HPETE. This precursor carries a carbon-15 alcohol in the R configuration and is rapidly converted by ALOX5 in activated PMN to 15-epimeric-lipoxin A4 (ATL), which carries the C-15 hydroxyl group in the R configuration rather than native 15S-lipoxin A4. ATL, with the 15-hydroxyl group in the R configuration, has been shown to directly bind and signal with ALX with more potent action than the native 15S-lipoxin A4 in vitro and in vivo. ALX is the first cloned and identified lipoxygenase-derived eicosanoid receptor with cell type-specific signaling pathways. In addition, resolvins are a family of potent lipid mediators derived from omega-3 polyunsaturated fatty acids from both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The other family of bioactive chemical signals from DHA such as docosanoids, which possess a conjugated triene double-bond system in their structure, is denoted protectins. EPA-series resolvin synthesis is dependent on aspirin acetylation of PTGS2 in vascular endothelial cells to produce 18(R)-HPEPE, which is further converted to resolvin E1 via ALOX5 in neutrophils. DHA is converted to 17R resolvins by a similar aspirin-triggered PTGS2 mechanism. In the absence of aspirin, PTGS2 in human microvascular endothelial cells converts DHA to 13S-hydroxy-DHA. In an alternative reaction in the absence of aspirin, arachidonate 15-lipoxygenase Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7fb62930-8a92-4570-9a52-3adb4691aa07 Lipoxins and Resolvins in Inflammation Resolution uuid-7fb62930-8a92-4570-9a52-3adb4691aa07 PS:CellType generic PS:Description Lipid-derived mediators such as lipoxins, resolvins, and protectins play an important role in the resolution of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fb62930-8a92-4570-9a52-3adb4691aa07 PS:NodeType Pathway PS:Notes Headnote: Lipid-derived mediators such as lipoxins, resolvins, and protectins play an important role in the resolution of inflammation. The process of the resolution of inflammation is now considered an active process, where antagonists of proinflammatory mediators lead to phagocytosis of cellular debris and blockage of leukocyte infiltration. During extended inflammation, polymorphonuclear neutrophils (PMNs) may eventually cause trauma and tissue damage through infiltration into tissues. Signaling description: Lipoxins and resolvins turn off the influx of neutrophils while the influx of monocytes and macrophages is further promoted. Lipoxins, such as lipoxin A4 and lipoxin B4, are short-lived bioactive lipid mediators generated from arachidonic acid which has anti-inflammatory effects. The negative regulators of the inflammatory response such as IL4, IL13, and proinflammatory cytokines are crucial to the formation of lipoxins. Lipoxins are rapidly biosynthesized in response to stimuli, act locally, and then are rapidly inactivated enzymatically by HPGD. There are two main pathways of lipoxin signaling that require transcellular interactions. One pathway involves platelet-leukocyte (PMN) interactions. Human platelets do not produce lipoxins on their own, but become a major source of lipoxins when platelet-PMN adhesion occurs. In neutrophils, ALOX5 converts arachidonic acid to LTA4, which is then released and further transformed by adherent platelets to lipoxin A4 via ALOX12. A second pathway is initiated at the epithelial mucosal surfaces by arachidonate 15-lipoxygenase that converts arachidonic acid to 15(S)-HPETE. Neutrophils take up 15(S)-HPETE and convert it to lipoxins by ALOX5. Lipoxin B4 is a positional isomer of lipoxin A4. This event not only leads to lipoxin biosynthesis, but also reduces LTA4 formation due to competition effects. The reduction of leukotriene production is the first and most rapid method by which lipoxins reduce inflammation. A third major pathway for lipoxin generation involves aspirin, PTGS2, and ALOX5. Endothelial and epithelial cells express PTGS2 in response to diverse stimuli such as cytokines, hypoxia, and bacterial infections. The action of aspirin involves the inhibition of PTGS2, biosynthesis of prostaglandin and thromboxane, and the generation of endogenous anti-inflammatory aspirin-triggered lipoxins. When aspirin is administered, PTGS2 is irreversibly acetylated, but remains active and changes their products from intermediates for prostaglandin and thromboxane to precursors for aspirin-triggered lipoxin A, specifically 15(R)-HPETE. This precursor carries a carbon-15 alcohol in the R configuration and is rapidly converted by ALOX5 in activated PMN to 15-epimeric-lipoxin A4 (ATL), which carries the C-15 hydroxyl group in the R configuration rather than native 15S-lipoxin A4. ATL, with the 15-hydroxyl group in the R configuration, has been shown to directly bind and signal with ALX with more potent action than the native 15S-lipoxin A4 in vitro and in vivo. ALX is the first cloned and identified lipoxygenase-derived eicosanoid receptor with cell type-specific signaling pathways. In addition, resolvins are a family of potent lipid mediators derived from omega-3 polyunsaturated fatty acids from both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The other family of bioactive chemical signals from DHA such as docosanoids, which possess a conjugated triene double-bond system in their structure, is denoted protectins. EPA-series resolvin synthesis is dependent on aspirin acetylation of PTGS2 in vascular endothelial cells to produce 18(R)-HPEPE, which is further converted to resolvin E1 via ALOX5 in neutrophils. DHA is converted to 17R resolvins by a similar aspirin-triggered PTGS2 mechanism. In the absence of aspirin, PTGS2 in human microvascular endothelial cells converts DHA to 13S-hydroxy-DHA. In an alternative reaction in the absence of aspirin, arachidonate 15-lipoxygenase PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fdc12eb-b09f-4001-a537-bea7e0583a51 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-7fdc12eb-b09f-4001-a537-bea7e0583a51 Proteins Involved in Age-Related Macular Degeneration uuid-7fdc12eb-b09f-4001-a537-bea7e0583a51 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fdc12eb-b09f-4001-a537-bea7e0583a51 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fe6166e-e5cf-4237-b0f5-a9393fd7383b NodeType: Pathway Notes: High level if homocysteine and changes in folate metabolism is implicated in many different diseases, including late pregnancy complications, neurodegenerative and psychiatric diseases, osteoporosis and cancer. Nutrients play direct role in homocysteine level regulation. Organ: generic Organ_System: generic PMID: 20814827 PMID: 23224755 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7fe6166e-e5cf-4237-b0f5-a9393fd7383b Vitamins Insufficiency Causes Homocysteine High Level Synthesis uuid-7fe6166e-e5cf-4237-b0f5-a9393fd7383b PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fe6166e-e5cf-4237-b0f5-a9393fd7383b PS:NodeType Pathway PS:Notes High level if homocysteine and changes in folate metabolism is implicated in many different diseases, including late pregnancy complications, neurodegenerative and psychiatric diseases, osteoporosis and cancer. Nutrients play direct role in homocysteine level regulation. PS:Organ generic PS:Organ_System generic PS:PMID 20814827 PS:PMID 23224755 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fed4b23-6f0b-4adf-93b9-bebaffa8ef79 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7fed4b23-6f0b-4adf-93b9-bebaffa8ef79 HTR7 -> IL6 Production uuid-7fed4b23-6f0b-4adf-93b9-bebaffa8ef79 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7fed4b23-6f0b-4adf-93b9-bebaffa8ef79 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ff89700-dd8d-4e65-84bb-0c039aa2af49 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. This pathway provides several known mechanisms of activation of selective expression of mediators in mast cells. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-7ff89700-dd8d-4e65-84bb-0c039aa2af49 Mast-Cell Activation without Degranulation uuid-7ff89700-dd8d-4e65-84bb-0c039aa2af49 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-7ff89700-dd8d-4e65-84bb-0c039aa2af49 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. This pathway provides several known mechanisms of activation of selective expression of mediators in mast cells. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8001fd5e-1fe3-49d2-8118-0533e1909ba8 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8001fd5e-1fe3-49d2-8118-0533e1909ba8 TNFRSF1A -> AP-1/ATF/TP53 Signaling uuid-8001fd5e-1fe3-49d2-8118-0533e1909ba8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8001fd5e-1fe3-49d2-8118-0533e1909ba8 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Hyaluronic acid and it's receptors, CD44 and HMMR are upregulated in cancers and involved in cancer cells motility, invasion, proliferation and survival. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8008c83f-8e62-472e-aca9-c8b55df84c22 NodeType: Pathway Notes: Headnote: Hyaluronic acid (HA) and it's receptors, CD44 and HMMR (CD168) are upregulated in cancers and involved in motility, invasion, proliferation and survival of cancer cells. Signaling description: HA is produced by hyaluronic acid synthases 1/2/3 (HAS1/2/3) and is involved at all stages of cancer progression. HA associates with CD44, HMMR and LYVE1 receptors. Activated CD44 can act through different signaling pathways. CD44 stimulates PKCE activity, which, in turn, causes NANOG phosphorylation and NANOG-STAT3 complex association with the MIR21 promoter. Then, the upregulation of MIR21 decreases the expression PDCD4 and increases the expression of XIAP, BIRC2/3 and BCL2 thereby inhibiting apoptosis and promoting cell survival. MIR21 also induce chemoresistance through up-regulation of ABCB1 drug transporter. CD44 also can regulate MIR21 expression through MAPK8/JUN pathway by an unknown mechanism. In SRC/TWIST1 signaling, CD44 induces the expression of MIR10B with subsequent over-expression of RHOA/C and induction of cancer cell migration / invasion. SRC along with GRB2 and GAB1 can also activate PI3K/AKT signaling, thus promoting cell proliferation. CD44 upregulates MIR302A through the NANOG/SOX2A/POU5F1 signaling complex. MIR302A then downregulates histone demethylases KDM1A/B and DNA (cytosine-5)-methyltransferase 1 (DNMT1) and induces DNA demethylation leading to anti-apoptotic BIRC2/3 and XIAP expression. CD44 can also directly interact with EZR-RDX-MSX complex facilitating actin organization. CD44 directly interacts with EGFR and ERBB2 and activates cancer-related signaling through these receptors. The hyaluronan receptor HMMR acts in tight cooperation with CD44 and enhances it's signaling. It also forms complexes with MAPK1/2 that sustain high basal motility of cancer cells through the activation of microtubules. Outcome effects: The hyaluronic acid signaling through CD44 and HMMR receptors leads to a great variety of cancer-promoting effects, including activation of cell motility, invasion and proliferation, inhibition of apoptosis and induction of drug resistance. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17392272 PMID: 18490190 PMID: 22847005 PMID: 23888049 PMID: 25081533 PMID: 25954275 PMID: 27070574 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-8008c83f-8e62-472e-aca9-c8b55df84c22 Hyaluronic Acid, CD44 and HMMR in Cancer Cell Invasion and Survival uuid-8008c83f-8e62-472e-aca9-c8b55df84c22 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Hyaluronic acid and it's receptors, CD44 and HMMR are upregulated in cancers and involved in cancer cells motility, invasion, proliferation and survival. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8008c83f-8e62-472e-aca9-c8b55df84c22 PS:NodeType Pathway PS:Notes Headnote: Hyaluronic acid (HA) and it's receptors, CD44 and HMMR (CD168) are upregulated in cancers and involved in motility, invasion, proliferation and survival of cancer cells. Signaling description: HA is produced by hyaluronic acid synthases 1/2/3 (HAS1/2/3) and is involved at all stages of cancer progression. HA associates with CD44, HMMR and LYVE1 receptors. Activated CD44 can act through different signaling pathways. CD44 stimulates PKCE activity, which, in turn, causes NANOG phosphorylation and NANOG-STAT3 complex association with the MIR21 promoter. Then, the upregulation of MIR21 decreases the expression PDCD4 and increases the expression of XIAP, BIRC2/3 and BCL2 thereby inhibiting apoptosis and promoting cell survival. MIR21 also induce chemoresistance through up-regulation of ABCB1 drug transporter. CD44 also can regulate MIR21 expression through MAPK8/JUN pathway by an unknown mechanism. In SRC/TWIST1 signaling, CD44 induces the expression of MIR10B with subsequent over-expression of RHOA/C and induction of cancer cell migration / invasion. SRC along with GRB2 and GAB1 can also activate PI3K/AKT signaling, thus promoting cell proliferation. CD44 upregulates MIR302A through the NANOG/SOX2A/POU5F1 signaling complex. MIR302A then downregulates histone demethylases KDM1A/B and DNA (cytosine-5)-methyltransferase 1 (DNMT1) and induces DNA demethylation leading to anti-apoptotic BIRC2/3 and XIAP expression. CD44 can also directly interact with EZR-RDX-MSX complex facilitating actin organization. CD44 directly interacts with EGFR and ERBB2 and activates cancer-related signaling through these receptors. The hyaluronan receptor HMMR acts in tight cooperation with CD44 and enhances it's signaling. It also forms complexes with MAPK1/2 that sustain high basal motility of cancer cells through the activation of microtubules. Outcome effects: The hyaluronic acid signaling through CD44 and HMMR receptors leads to a great variety of cancer-promoting effects, including activation of cell motility, invasion and proliferation, inhibition of apoptosis and induction of drug resistance. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17392272 PS:PMID 18490190 PS:PMID 22847005 PS:PMID 23888049 PS:PMID 25081533 PS:PMID 25954275 PS:PMID 27070574 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80211f8f-da70-4939-9f13-7a74a1794aa5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-80211f8f-da70-4939-9f13-7a74a1794aa5 CTGF -> AP-1/CREB/MYC Expression Targets uuid-80211f8f-da70-4939-9f13-7a74a1794aa5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80211f8f-da70-4939-9f13-7a74a1794aa5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8033b3f1-3cad-4d8e-9665-afb0b830cd59 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8033b3f1-3cad-4d8e-9665-afb0b830cd59 PRL/GHR -> STAT Expression Targets uuid-8033b3f1-3cad-4d8e-9665-afb0b830cd59 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8033b3f1-3cad-4d8e-9665-afb0b830cd59 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-804603d5-6579-4f66-bdad-70b823d93b87 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-804603d5-6579-4f66-bdad-70b823d93b87 Dopamine Mediated Glutamate Release and Glutamate Uptake Circle uuid-804603d5-6579-4f66-bdad-70b823d93b87 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-804603d5-6579-4f66-bdad-70b823d93b87 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8062a698-1dee-4ea1-ba78-75f464de7caf NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8062a698-1dee-4ea1-ba78-75f464de7caf NTS Expression Targets uuid-8062a698-1dee-4ea1-ba78-75f464de7caf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8062a698-1dee-4ea1-ba78-75f464de7caf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8065181b-1049-44c8-a690-e27f87f43c88 NodeType: Pathway Organ: generic Organ_System: hematological system Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-8065181b-1049-44c8-a690-e27f87f43c88 SARS induces Complement Activation uuid-8065181b-1049-44c8-a690-e27f87f43c88 PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8065181b-1049-44c8-a690-e27f87f43c88 PS:NodeType Pathway PS:Organ generic PS:Organ_System hematological system PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-807fe387-3c80-4af9-be73-8b1a8b1c4c99 NodeType: Pathway Notes: Adipokines (adipocytokines) are proteins such as Leptin secreted by adipocytes. Organ: generic Organ_System: generic PMID: 15867843 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: adipose tissue urn:agi-pathway:uuid-807fe387-3c80-4af9-be73-8b1a8b1c4c99 Adipokines Production by Adipocyte uuid-807fe387-3c80-4af9-be73-8b1a8b1c4c99 PS:CellType adipocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-807fe387-3c80-4af9-be73-8b1a8b1c4c99 PS:NodeType Pathway PS:Notes Adipokines (adipocytokines) are proteins such as Leptin secreted by adipocytes. PS:Organ generic PS:Organ_System generic PS:PMID 15867843 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80ade741-c426-4f4b-8e4b-d0a54aafe456 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-80ade741-c426-4f4b-8e4b-d0a54aafe456 Proteins with Altered Expression in Systemic Scleroderma uuid-80ade741-c426-4f4b-8e4b-d0a54aafe456 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80ade741-c426-4f4b-8e4b-d0a54aafe456 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author PS:Source CellType: endothelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80ca6c19-0022-4582-8711-abda2dc9dc1d NodeType: Pathway Organ: lung PMID: 16917117 PMID: 18596905 PMID: 19139264 PMID: 19286424 PMID: 19555855 PMID: 20833255 PMID: 21641060 PMID: 22401856 PMID: 23662189 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-80ca6c19-0022-4582-8711-abda2dc9dc1d WNT3a,BMP2+>corneal edema uuid-80ca6c19-0022-4582-8711-abda2dc9dc1d PS:CellType endothelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80ca6c19-0022-4582-8711-abda2dc9dc1d PS:NodeType Pathway PS:Organ lung PS:PMID 16917117 PS:PMID 18596905 PS:PMID 19139264 PS:PMID 19286424 PS:PMID 19555855 PS:PMID 20833255 PS:PMID 21641060 PS:PMID 22401856 PS:PMID 23662189 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Specific wavelengths of blue light (roughly 460-480 nm) are detected by photopigment melanopsin in a small percentage (1-2?) of the retinal ganglion cells (non-rod and cone cells). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80f1291e-ea93-45be-9c1f-64e2fe62a978 NodeType: Pathway Notes: Headnote: Specific wavelengths of blue light (roughly 460-480 nm) are detected by photopigment melanopsin in a small percentage (1-2%) of the retinal ganglion cells (non-rod and cone cells). The axons of the melanopsin-containing ganglion cells project to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract in the optic nerve. These neurons release L-glutamate and pituitary adenylate cyclase activating polypeptide (ADCYAP1), which causes the entrainment of CLOCK gene expression in the SCN. Signaling description: In order to inhibit pineal melatonin production, axons from SCN neurons project to the paraventricular nucleus neuron of the hypothalamus, where they release gamma-aminobutyric acid (GABA). Nerve cell bodies in the paraventricular nucleus have axons that descend through the brain stem and eventually form a synapse with neurons in the intermediolateral cell column which are preganglionic sympathetic neurons. The axons of these neurons eventually terminate on pinealocytes following an additional synapse in the superior cervical ganglion. Outcome effects: At night, melanopsin is not activated by light and inhibitory GABAergic SCN neurons are not activated, which results in noradrenaline release by sympathetic superior cervical ganglion resulting in melatonin production and release by pinealocytes. Organ: brain Organ_System: nervous system PMID: 17416998 PMID: 18054803 PMID: 20478436 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-80f1291e-ea93-45be-9c1f-64e2fe62a978 Retinal Ganglion and Suprachiasmatic Nucleus in Melatonin Synthesis Regulation uuid-80f1291e-ea93-45be-9c1f-64e2fe62a978 PS:CellType neuron PS:Description Specific wavelengths of blue light (roughly 460-480 nm) are detected by photopigment melanopsin in a small percentage (1-2?) of the retinal ganglion cells (non-rod and cone cells). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-80f1291e-ea93-45be-9c1f-64e2fe62a978 PS:NodeType Pathway PS:Notes Headnote: Specific wavelengths of blue light (roughly 460-480 nm) are detected by photopigment melanopsin in a small percentage (1-2%) of the retinal ganglion cells (non-rod and cone cells). The axons of the melanopsin-containing ganglion cells project to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract in the optic nerve. These neurons release L-glutamate and pituitary adenylate cyclase activating polypeptide (ADCYAP1), which causes the entrainment of CLOCK gene expression in the SCN. Signaling description: In order to inhibit pineal melatonin production, axons from SCN neurons project to the paraventricular nucleus neuron of the hypothalamus, where they release gamma-aminobutyric acid (GABA). Nerve cell bodies in the paraventricular nucleus have axons that descend through the brain stem and eventually form a synapse with neurons in the intermediolateral cell column which are preganglionic sympathetic neurons. The axons of these neurons eventually terminate on pinealocytes following an additional synapse in the superior cervical ganglion. Outcome effects: At night, melanopsin is not activated by light and inhibitory GABAergic SCN neurons are not activated, which results in noradrenaline release by sympathetic superior cervical ganglion resulting in melatonin production and release by pinealocytes. PS:Organ brain PS:Organ_System nervous system PS:PMID 17416998 PS:PMID 18054803 PS:PMID 20478436 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8111ab3c-8711-441a-93e2-ffa79e8e5dd8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-8111ab3c-8711-441a-93e2-ffa79e8e5dd8 ECM->EMT uuid-8111ab3c-8711-441a-93e2-ffa79e8e5dd8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8111ab3c-8711-441a-93e2-ffa79e8e5dd8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Irreparable DNA lesions trigger cell cycle arrest, apoptosis or cell senescence. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-813840c4-4320-475a-bf2f-c8f12b5b149e NodeType: Pathway Notes: Headnote: The DNA damage response (DDR) is an evolutionarily conserved mechanism that senses DNA breaks and activates downstream DNA repair and cell cycle checkpoints signalings. Signaling description: DDR begins with the recruitment of ATM to DNA double-strand breaks. ATM phosphorylates substrates in the chromatin (such as H2AFX). Phosphorylated H2AFX recruits additional DDR mediators, including MDC1. Outcome effects: Irreparable DNA lesions trigger cell cycle arrest, apoptosis or cell senescence. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. Organ: generic Organ_System: generic PMID: 19597488 PMID: 25815006 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-813840c4-4320-475a-bf2f-c8f12b5b149e Persisted DNA Repair Triggers Genomic Instability uuid-813840c4-4320-475a-bf2f-c8f12b5b149e PS:CellType generic PS:Description Irreparable DNA lesions trigger cell cycle arrest, apoptosis or cell senescence. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-813840c4-4320-475a-bf2f-c8f12b5b149e PS:NodeType Pathway PS:Notes Headnote: The DNA damage response (DDR) is an evolutionarily conserved mechanism that senses DNA breaks and activates downstream DNA repair and cell cycle checkpoints signalings. Signaling description: DDR begins with the recruitment of ATM to DNA double-strand breaks. ATM phosphorylates substrates in the chromatin (such as H2AFX). Phosphorylated H2AFX recruits additional DDR mediators, including MDC1. Outcome effects: Irreparable DNA lesions trigger cell cycle arrest, apoptosis or cell senescence. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 19597488 PS:PMID 25815006 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-817d2f09-325f-4849-bd56-436669f7a39c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-817d2f09-325f-4849-bd56-436669f7a39c ICAM1 Expression Targets uuid-817d2f09-325f-4849-bd56-436669f7a39c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-817d2f09-325f-4849-bd56-436669f7a39c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8195de64-488c-4bc8-b42d-b41ea189b6a6 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-8195de64-488c-4bc8-b42d-b41ea189b6a6 NTSR1 Expression Targets uuid-8195de64-488c-4bc8-b42d-b41ea189b6a6 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8195de64-488c-4bc8-b42d-b41ea189b6a6 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-819ef3d0-3756-4883-9a4c-938497085318 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-819ef3d0-3756-4883-9a4c-938497085318 IL31R -> STAT Signaling uuid-819ef3d0-3756-4883-9a4c-938497085318 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-819ef3d0-3756-4883-9a4c-938497085318 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81a0fc26-b922-49c4-b04e-930125498e19 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-81a0fc26-b922-49c4-b04e-930125498e19 Integrins->IR uuid-81a0fc26-b922-49c4-b04e-930125498e19 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81a0fc26-b922-49c4-b04e-930125498e19 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Germline-activating mutations in RET are associated with primary hyperparathyroidism and Multiple Endocrine Neoplasia Type2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81b9001b-edf7-4e14-9043-0834f29cabd5 NodeType: Pathway Notes: Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-activating mutations in RET are associated with primary hyperparathyroidism and multiple endocrine neoplasia type2. Outcome effects: Mutations in RET cause the disruption of cell survival and increase parathyrocytes proliferation. Organ: Parathyroid gland Organ_System: endocrine system PMID: 10652352 PMID: 16849421 PMID: 23652676 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-81b9001b-edf7-4e14-9043-0834f29cabd5 RET1 Mutation in Hyperparathyroidism uuid-81b9001b-edf7-4e14-9043-0834f29cabd5 PS:CellType parathyroid cell PS:Description Germline-activating mutations in RET are associated with primary hyperparathyroidism and Multiple Endocrine Neoplasia Type2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81b9001b-edf7-4e14-9043-0834f29cabd5 PS:NodeType Pathway PS:Notes Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-activating mutations in RET are associated with primary hyperparathyroidism and multiple endocrine neoplasia type2. Outcome effects: Mutations in RET cause the disruption of cell survival and increase parathyrocytes proliferation. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 10652352 PS:PMID 16849421 PS:PMID 23652676 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81e6f12a-91cc-4839-bd56-da79484f1005 NodeType: Pathway Notes: Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a resultant lack of sex steroids production. HH may be caused by mutation in a number of genes responsible for development and migration of gonadotropin-releasing hormone (GNRH) neurons. About 50% of HH are associated with Kallmann syndrome which is characterized by combination of hypogonadism and altered sense of smell (anosmia/hyposmia). The reason is that both GNRH neurons and olfactory bulb cells have common progenitors in olfactory placode. Signaling description: Mutations in KAL1, FGF8, FGFR1, CHD7, PROC2, PROCR2, and HS6ST1 may cause either Kallmann syndrome or normosmic HH. Mutation in FLRT3, DUSP6, IL17RD, SPRY4, SEMA3A/7A cause Kallmann syndrome.Mutated genes are shown in white-out style. Organ: brain Organ: olfactory bulb Organ: pituitary gland Organ_System: endocrine system PMID: 18034870 PMID: 18566132 PMID: 25254043 PMID: 25306902 PMID: 5071724 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-81e6f12a-91cc-4839-bd56-da79484f1005 GNRH Neurons Development and Migration Impairment in Hypogonadotropic Hypogonadism uuid-81e6f12a-91cc-4839-bd56-da79484f1005 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-81e6f12a-91cc-4839-bd56-da79484f1005 PS:NodeType Pathway PS:Notes Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a resultant lack of sex steroids production. HH may be caused by mutation in a number of genes responsible for development and migration of gonadotropin-releasing hormone (GNRH) neurons. About 50% of HH are associated with Kallmann syndrome which is characterized by combination of hypogonadism and altered sense of smell (anosmia/hyposmia). The reason is that both GNRH neurons and olfactory bulb cells have common progenitors in olfactory placode. Signaling description: Mutations in KAL1, FGF8, FGFR1, CHD7, PROC2, PROCR2, and HS6ST1 may cause either Kallmann syndrome or normosmic HH. Mutation in FLRT3, DUSP6, IL17RD, SPRY4, SEMA3A/7A cause Kallmann syndrome.Mutated genes are shown in white-out style. PS:Organ brain PS:Organ olfactory bulb PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 18034870 PS:PMID 18566132 PS:PMID 25254043 PS:PMID 25306902 PS:PMID 5071724 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-820b5d9f-e2b1-4d27-bfb5-d743f75e89a9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-820b5d9f-e2b1-4d27-bfb5-d743f75e89a9 oxylipin biosynthesis template uuid-820b5d9f-e2b1-4d27-bfb5-d743f75e89a9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-820b5d9f-e2b1-4d27-bfb5-d743f75e89a9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82136efa-6c46-4369-abdd-088718be471e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-82136efa-6c46-4369-abdd-088718be471e IL16-> ATF/CREB/CREBBP Expression Target uuid-82136efa-6c46-4369-abdd-088718be471e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82136efa-6c46-4369-abdd-088718be471e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-825a556c-4302-40a6-8143-f943ccf61068 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-825a556c-4302-40a6-8143-f943ccf61068 FGF8 -> RUNX Expression Targets uuid-825a556c-4302-40a6-8143-f943ccf61068 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-825a556c-4302-40a6-8143-f943ccf61068 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82799e2d-932c-4b03-b5ed-348f026eb588 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-82799e2d-932c-4b03-b5ed-348f026eb588 Histidine biosynthesis template uuid-82799e2d-932c-4b03-b5ed-348f026eb588 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82799e2d-932c-4b03-b5ed-348f026eb588 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-828b5990-2767-4306-9a42-dc9d0162f5e8 NodeType: Pathway Notes: Hemophilia A and B are caused by mutations in coagulation factor VIII (F8) and IX (F9), respectively, which cause impairment of the coagulation cascade and the diminished capacity to form a blood clot, thereby predisposing affected individual to bleeding. Pathway 1. Dysfunction of coagulation cascade in hemophilia: Feedback relations between coagulation and fibrinolysis (Fig. 2). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: blood urn:agi-pathway:uuid-828b5990-2767-4306-9a42-dc9d0162f5e8 1_2_Feedback relations between coagulation and fibrinolysis uuid-828b5990-2767-4306-9a42-dc9d0162f5e8 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-828b5990-2767-4306-9a42-dc9d0162f5e8 PS:NodeType Pathway PS:Notes Hemophilia A and B are caused by mutations in coagulation factor VIII (F8) and IX (F9), respectively, which cause impairment of the coagulation cascade and the diminished capacity to form a blood clot, thereby predisposing affected individual to bleeding. Pathway 1. Dysfunction of coagulation cascade in hemophilia: Feedback relations between coagulation and fibrinolysis (Fig. 2). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Mutant HTT is cleaved at several points to generate toxic. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82c560a3-50f0-4f69-b702-cbfec4f7ab28 NodeType: Pathway Notes: Headnote: Mutant HTT (mHTT) is cleaved at several points to generate toxic fragments with abnormal compact alpha conformation. Proteolytic cleavage of mHTT may be one of the keys for disease pathogenesis. Signaling description: Proteins involved in mHTT cleavage are caspase 3 and 6 (CASP3/6) and calpains 1 and 2 (CAPN1/2). IKBKB may directly regulate the cleavage and neurotoxicity of mHTT. Substantial evidence exists to indicate that Rhes (RASD2) promotes striatal-specific neurodegeneration in Huntington's Disease by sumoylating mHTT and preventing aggregate formation. Golgi protein acyl-CoA binding domain containing 3 (ACBD3) mediates mHTT cytotoxicity via formation of a RASD2/mHTT/ACBD3 complex.RASD2 physiologically active tes mTOR, exerting a major trophic influence. In Huntington Desease, mHTT sequesters RASD2 away from mTOR, thus promoting striatal atrophy.Neuroprotection by HTT is mediated by its sequestration of histone deacetylase-3 (HDAC3), a protein known to promote neuronal death. In contrast to the normal HTT, mHTT interacts poorly with HDAC3, liberating HDAC3 from HTT, thus de-repressing its neurotoxic activity. SUMO-1 modification of mHTT was associated with increased toxicity and decreased aggregation.SUMO-2 and PIAS1 modulate insoluble mHTT accumulation. Phosphorylation of mHTT by AKT1 may abrogate mHTT toxicity.Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 21044641 PMID: 21163446 PMID: 23583659 PMID: 23864673 PMID: 23871671 PMID: 24012756 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-82c560a3-50f0-4f69-b702-cbfec4f7ab28 Huntingtin Mutant Protein Toxicity Effects uuid-82c560a3-50f0-4f69-b702-cbfec4f7ab28 PS:CellType neuron PS:Description Mutant HTT is cleaved at several points to generate toxic. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82c560a3-50f0-4f69-b702-cbfec4f7ab28 PS:NodeType Pathway PS:Notes Headnote: Mutant HTT (mHTT) is cleaved at several points to generate toxic fragments with abnormal compact alpha conformation. Proteolytic cleavage of mHTT may be one of the keys for disease pathogenesis. Signaling description: Proteins involved in mHTT cleavage are caspase 3 and 6 (CASP3/6) and calpains 1 and 2 (CAPN1/2). IKBKB may directly regulate the cleavage and neurotoxicity of mHTT. Substantial evidence exists to indicate that Rhes (RASD2) promotes striatal-specific neurodegeneration in Huntington's Disease by sumoylating mHTT and preventing aggregate formation. Golgi protein acyl-CoA binding domain containing 3 (ACBD3) mediates mHTT cytotoxicity via formation of a RASD2/mHTT/ACBD3 complex.RASD2 physiologically active tes mTOR, exerting a major trophic influence. In Huntington Desease, mHTT sequesters RASD2 away from mTOR, thus promoting striatal atrophy.Neuroprotection by HTT is mediated by its sequestration of histone deacetylase-3 (HDAC3), a protein known to promote neuronal death. In contrast to the normal HTT, mHTT interacts poorly with HDAC3, liberating HDAC3 from HTT, thus de-repressing its neurotoxic activity. SUMO-1 modification of mHTT was associated with increased toxicity and decreased aggregation.SUMO-2 and PIAS1 modulate insoluble mHTT accumulation. Phosphorylation of mHTT by AKT1 may abrogate mHTT toxicity.Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 21044641 PS:PMID 21163446 PS:PMID 23583659 PS:PMID 23864673 PS:PMID 23871671 PS:PMID 24012756 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82dbd6a0-63ff-413a-b680-71970ab07d98 NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The nucleosome-remodeling and histone deacetylation (NURD) chromatin remodeling complex is a novel regulator of DNA damage responses that orchestrates proper signaling and repair of double-strand breaks (DSBs). Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. NURD has both ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation activities to alter nucleosome structure. NURD cooperates with histone deacetylase complex (SIN3A) and together they are involved in transcriptional repression of methylated DNA. Outcome effects: The methyl CpG binding protein (MECP2) as a subunit of NURD complex provides silencing of some methylated genes. In addition, NURD has been shown to be associated with zinc-finger DNA binding proteins such as IKZF1 and to be involved in centromeric silencing. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-82dbd6a0-63ff-413a-b680-71970ab07d98 NURD in Chromatin Remodeling uuid-82dbd6a0-63ff-413a-b680-71970ab07d98 PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82dbd6a0-63ff-413a-b680-71970ab07d98 PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The nucleosome-remodeling and histone deacetylation (NURD) chromatin remodeling complex is a novel regulator of DNA damage responses that orchestrates proper signaling and repair of double-strand breaks (DSBs). Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. NURD has both ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation activities to alter nucleosome structure. NURD cooperates with histone deacetylase complex (SIN3A) and together they are involved in transcriptional repression of methylated DNA. Outcome effects: The methyl CpG binding protein (MECP2) as a subunit of NURD complex provides silencing of some methylated genes. In addition, NURD has been shown to be associated with zinc-finger DNA binding proteins such as IKZF1 and to be involved in centromeric silencing. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Metabolic reprogramming is one of the hallmarks of cancer and is represented by upregulated aerobic glycolysis, glutaminolysis, impairment of Krebs cycle, hyperproduction of lactate and other features Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82f5c6f9-1d09-4f85-ac38-5fac8b66e176 NodeType: Pathway Notes: Headnote: Metabolic reprogramming is one of the hallmarks of cancer and is represented by up-regulated aerobic glycolysis, glutaminolysis, impairment of Krebs cycle, hyperproduction of lactate, as well as other features. Signaling description: Cancer cells strongly up-regulate glucose uptake and glycolysis compared to normal cells in order to give rise to an increased yield of intermediate glycolytic metabolites and the end product pyruvate (it is called Warburg effect or aerobic glycolysis). Glucose import to the cancer cell is increased due to activation of SLC2A1 and SLC2A3 transporters (they are activated due to HIF1A, MYC, RELA overexpression and TP53 down-regulation). Many glycolytic enzymes are upregulated in cancer including HK1/2, GPI, PFKM, ALDOA, GAPDH, PGK1, PGAM1, ENO1/2, PKM. Conversion of pyruvate to lactate is activated due to upregulation of LDHA. Activation of HIF1A, AKT1, MYC, SNAI1 and inactivation of TP53 and PTEN play a major role in upregulation of glycolytic enzymes in cancer cells. Several enzymes of the Krebs cycle (tricarboxylic acid cycle, TCA) have been found mutated in both sporadic and hereditary forms of cancer. They are IDH1/2, SDHA, SDHB, SDHC, SDHD, SDHAF2 and FH. These impairments may lead to production of oncometabolites. See pathway "Krebs Cycle Enzyme Mutations in Cancer" for details. Cancer cells exhibit increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle, nucleotide and fatty acid biosynthesis, redox balance in cancer cells and promotes protein synthesis. Glutamine enters the cell through transporters such as SLC1A5 and SLC38A5 (upregulated by MYC) and may be converted to glutamate and alpha-ketoglutarate or amino-acids (see PW "Metabolic Reprogramming in Cancer Overview" for details). Lactate shuttle (reverse Warburg effect) is transport of lactate from catabolic/stromal cancer cell to anabolic cancer cell. Lactate can be metabolized back to pyruvate or act as a signalling molecule (see pathway "Lactate as a Signalling Molecule in Cancer Cells" for details). Outcome effects: Glycolytic breakdown of glucose and glutaminolysis produce various intermediate metabolites used for biosynthesis of amino acids and proteins, fatty acids and nucleotides and production of energy. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" and "Proteins with Altered Expression in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" and "Genes with Mutations in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20570523 PMID: 23071355 PMID: 23192270 PMID: 23897900 PMID: 23999442 PMID: 24374503 PMID: 24732809 PMID: 26583064 PMID: 27386546 PMID: 27492215 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-82f5c6f9-1d09-4f85-ac38-5fac8b66e176 Metabolic Reprogramming in Cancer: Overview uuid-82f5c6f9-1d09-4f85-ac38-5fac8b66e176 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Metabolic reprogramming is one of the hallmarks of cancer and is represented by upregulated aerobic glycolysis, glutaminolysis, impairment of Krebs cycle, hyperproduction of lactate and other features PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82f5c6f9-1d09-4f85-ac38-5fac8b66e176 PS:NodeType Pathway PS:Notes Headnote: Metabolic reprogramming is one of the hallmarks of cancer and is represented by up-regulated aerobic glycolysis, glutaminolysis, impairment of Krebs cycle, hyperproduction of lactate, as well as other features. Signaling description: Cancer cells strongly up-regulate glucose uptake and glycolysis compared to normal cells in order to give rise to an increased yield of intermediate glycolytic metabolites and the end product pyruvate (it is called Warburg effect or aerobic glycolysis). Glucose import to the cancer cell is increased due to activation of SLC2A1 and SLC2A3 transporters (they are activated due to HIF1A, MYC, RELA overexpression and TP53 down-regulation). Many glycolytic enzymes are upregulated in cancer including HK1/2, GPI, PFKM, ALDOA, GAPDH, PGK1, PGAM1, ENO1/2, PKM. Conversion of pyruvate to lactate is activated due to upregulation of LDHA. Activation of HIF1A, AKT1, MYC, SNAI1 and inactivation of TP53 and PTEN play a major role in upregulation of glycolytic enzymes in cancer cells. Several enzymes of the Krebs cycle (tricarboxylic acid cycle, TCA) have been found mutated in both sporadic and hereditary forms of cancer. They are IDH1/2, SDHA, SDHB, SDHC, SDHD, SDHAF2 and FH. These impairments may lead to production of oncometabolites. See pathway "Krebs Cycle Enzyme Mutations in Cancer" for details. Cancer cells exhibit increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle, nucleotide and fatty acid biosynthesis, redox balance in cancer cells and promotes protein synthesis. Glutamine enters the cell through transporters such as SLC1A5 and SLC38A5 (upregulated by MYC) and may be converted to glutamate and alpha-ketoglutarate or amino-acids (see PW "Metabolic Reprogramming in Cancer Overview" for details). Lactate shuttle (reverse Warburg effect) is transport of lactate from catabolic/stromal cancer cell to anabolic cancer cell. Lactate can be metabolized back to pyruvate or act as a signalling molecule (see pathway "Lactate as a Signalling Molecule in Cancer Cells" for details). Outcome effects: Glycolytic breakdown of glucose and glutaminolysis produce various intermediate metabolites used for biosynthesis of amino acids and proteins, fatty acids and nucleotides and production of energy. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathways "Proteins with Altered Expression in Cancer Metabolic Reprogramming" and "Proteins with Altered Expression in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Mutated genes: Mutated genes are shown in white-out style. See pathways "Genes with Mutations in Cancer Metabolic Reprogramming" and "Genes with Mutations in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20570523 PS:PMID 23071355 PS:PMID 23192270 PS:PMID 23897900 PS:PMID 23999442 PS:PMID 24374503 PS:PMID 24732809 PS:PMID 26583064 PS:PMID 27386546 PS:PMID 27492215 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82f9db16-3db6-461f-99b1-bdb5ef7777f7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-82f9db16-3db6-461f-99b1-bdb5ef7777f7 Thrombopoietin -> FOXO3A Expression Target uuid-82f9db16-3db6-461f-99b1-bdb5ef7777f7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-82f9db16-3db6-461f-99b1-bdb5ef7777f7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-832fadd2-a172-406a-b99d-35e6bc078c30 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-832fadd2-a172-406a-b99d-35e6bc078c30 Bile acids alternative biosynthesis template uuid-832fadd2-a172-406a-b99d-35e6bc078c30 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-832fadd2-a172-406a-b99d-35e6bc078c30 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83404efa-8cb4-4ec7-ab5b-d021d59234f8 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-83404efa-8cb4-4ec7-ab5b-d021d59234f8 Phytosterols biosynthesis template uuid-83404efa-8cb4-4ec7-ab5b-d021d59234f8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83404efa-8cb4-4ec7-ab5b-d021d59234f8 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: Arthralgia, or pain in the joints, is an important hallmark of osteoarthritis (OA). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-834a4a64-bac3-4acc-bd19-15a32e9ece84 NodeType: Pathway Notes: Headnote: Arthralgia refers to pain in the joints, and is an important hallmark of osteoarthritis (OA). In conjunction with increased pressure of synovial fluid, prostaglandin E2 (PGE2) synthesis induced by interleukin 1, beta (IL1B) signaling triggers arthralgia. Signaling description: IL1B is highly expressed in OA cartilage and upregulates PTGES and PTGS2 expression by NF-kB activation. The signaling originates with the activation of IL1R1 by IL1B. The signal is subsequently transduced to the RAC1/MAP3K1/MAP2K1/2/6/MAPK1 axis and triggers NF-kB. IL1R1 with IL1RAP allow MYD88 to recruit IRAK to this receptor-signaling complex. The complex activates TRAF6, which also activates NF-kB (through MAP3K5 and MAP3K7). Outcome effects: NF-kB binds to the promoter regions of PTGES and PTGS2 genes leading to the synthesis of PGE2. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 12082286 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-834a4a64-bac3-4acc-bd19-15a32e9ece84 IL1B Induced Arthralgia uuid-834a4a64-bac3-4acc-bd19-15a32e9ece84 PS:CellType chondrocyte PS:Description Arthralgia, or pain in the joints, is an important hallmark of osteoarthritis (OA). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-834a4a64-bac3-4acc-bd19-15a32e9ece84 PS:NodeType Pathway PS:Notes Headnote: Arthralgia refers to pain in the joints, and is an important hallmark of osteoarthritis (OA). In conjunction with increased pressure of synovial fluid, prostaglandin E2 (PGE2) synthesis induced by interleukin 1, beta (IL1B) signaling triggers arthralgia. Signaling description: IL1B is highly expressed in OA cartilage and upregulates PTGES and PTGS2 expression by NF-kB activation. The signaling originates with the activation of IL1R1 by IL1B. The signal is subsequently transduced to the RAC1/MAP3K1/MAP2K1/2/6/MAPK1 axis and triggers NF-kB. IL1R1 with IL1RAP allow MYD88 to recruit IRAK to this receptor-signaling complex. The complex activates TRAF6, which also activates NF-kB (through MAP3K5 and MAP3K7). Outcome effects: NF-kB binds to the promoter regions of PTGES and PTGS2 genes leading to the synthesis of PGE2. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 12082286 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8361db11-528e-4f79-ae2e-a026e6d3f9d2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8361db11-528e-4f79-ae2e-a026e6d3f9d2 F2 -> AP-1/CREB/ELK/SRF/SP1 Expression Targets uuid-8361db11-528e-4f79-ae2e-a026e6d3f9d2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8361db11-528e-4f79-ae2e-a026e6d3f9d2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-838b776e-6b79-4f69-b575-95574309dc89 NodeType: Pathway Organ: generic Organ_System: generic PMID: 22981653 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-838b776e-6b79-4f69-b575-95574309dc89 Estrogens/ESR1 Genomic Canonical Signaling uuid-838b776e-6b79-4f69-b575-95574309dc89 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-838b776e-6b79-4f69-b575-95574309dc89 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 22981653 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: BBSome is proposed regulator of intraflagellar transport, cilium biogenesis and microtubule organization. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8390fd99-e8c3-4bf0-bfc4-5ad1e9b4f40b NodeType: Pathway Notes: Headnote: The BBSome is an octameric protein complex. It is a component of the basal body and is involved in cargo trafficking to the primary cilium and flagella, cilium biogenesis and microtubule organization. Signaling description: The BBSome is a complex of seven Bardet-Biedl syndrome (BBS) proteins: BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 (TTC8), BBS9 and BBIP10 protein that is linked to the ciliary membrane by the small GTPase BBS3 (ARL6). BBSome is proposed to serve as an adaptor involved in the export of signaling proteins from the cilium, as an IFT regulator and a core IFT component, or as a cargo adaptor. BBSome interaction with SMO, PTCH1 and LEPR leads to receptor internalization. BBSome interaction with PABIN8 (RAB3IP), CEP290, PCM1, and DCTN1 promotes cilium biogenesis and microtubule organization. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: BBSome is a proposed regulator of intraflagellar transport, cilium biogenesis and microtubule organization. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 17574030 PMID: 23945166 PMID: 28342295 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-8390fd99-e8c3-4bf0-bfc4-5ad1e9b4f40b Intraflagellar Transport: BBSome Interaction uuid-8390fd99-e8c3-4bf0-bfc4-5ad1e9b4f40b PS:CellType generic PS:Description BBSome is proposed regulator of intraflagellar transport, cilium biogenesis and microtubule organization. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8390fd99-e8c3-4bf0-bfc4-5ad1e9b4f40b PS:NodeType Pathway PS:Notes Headnote: The BBSome is an octameric protein complex. It is a component of the basal body and is involved in cargo trafficking to the primary cilium and flagella, cilium biogenesis and microtubule organization. Signaling description: The BBSome is a complex of seven Bardet-Biedl syndrome (BBS) proteins: BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 (TTC8), BBS9 and BBIP10 protein that is linked to the ciliary membrane by the small GTPase BBS3 (ARL6). BBSome is proposed to serve as an adaptor involved in the export of signaling proteins from the cilium, as an IFT regulator and a core IFT component, or as a cargo adaptor. BBSome interaction with SMO, PTCH1 and LEPR leads to receptor internalization. BBSome interaction with PABIN8 (RAB3IP), CEP290, PCM1, and DCTN1 promotes cilium biogenesis and microtubule organization. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: BBSome is a proposed regulator of intraflagellar transport, cilium biogenesis and microtubule organization. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17574030 PS:PMID 23945166 PS:PMID 28342295 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83c6a8a1-da77-4aea-9f9d-1ce66c65dbf7 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-83c6a8a1-da77-4aea-9f9d-1ce66c65dbf7 Metabolism of Glucocorticoids and Mineralcorticoids uuid-83c6a8a1-da77-4aea-9f9d-1ce66c65dbf7 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83c6a8a1-da77-4aea-9f9d-1ce66c65dbf7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83c993e9-7f56-4bc7-a2b2-8199a3a34141 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-83c993e9-7f56-4bc7-a2b2-8199a3a34141 Polyphosphate metabolism template uuid-83c993e9-7f56-4bc7-a2b2-8199a3a34141 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83c993e9-7f56-4bc7-a2b2-8199a3a34141 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83cdb7e4-477b-4f0c-8e86-4df6a5c884e1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-83cdb7e4-477b-4f0c-8e86-4df6a5c884e1 Pectin utilization template uuid-83cdb7e4-477b-4f0c-8e86-4df6a5c884e1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83cdb7e4-477b-4f0c-8e86-4df6a5c884e1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83f1f3a0-488b-4378-928c-76fd4556c0f6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-83f1f3a0-488b-4378-928c-76fd4556c0f6 Ins->Glycogenesis uuid-83f1f3a0-488b-4378-928c-76fd4556c0f6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83f1f3a0-488b-4378-928c-76fd4556c0f6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83fa13e4-8cbd-4612-9dc9-4aaaeb760311 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-83fa13e4-8cbd-4612-9dc9-4aaaeb760311 NRG1/Catenin Expression Targets uuid-83fa13e4-8cbd-4612-9dc9-4aaaeb760311 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-83fa13e4-8cbd-4612-9dc9-4aaaeb760311 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-840fdade-c6b1-41a0-b786-0e399f4841d1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-840fdade-c6b1-41a0-b786-0e399f4841d1 Plasmalogen (plasmenyl, alkenyl) phospholipid biosynthesis template uuid-840fdade-c6b1-41a0-b786-0e399f4841d1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-840fdade-c6b1-41a0-b786-0e399f4841d1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-841c5874-701a-4f18-ae5c-99d48ce433f5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-841c5874-701a-4f18-ae5c-99d48ce433f5 IL22 Expression Targets uuid-841c5874-701a-4f18-ae5c-99d48ce433f5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-841c5874-701a-4f18-ae5c-99d48ce433f5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Macrophages are a heterogeneous cell population. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-842998f8-63bb-4ff2-b5cc-c034153c236a NodeType: Pathway Notes: Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Macrophages are a heterogeneous cell population. Classically-activated M1 phenotype macrophages display a response to injury by releasing cytotoxic and proinflammatory mediators, which contribute to tissue injury. Signaling description: M2 phenotype macrophages are activated by Th2 cytokines and have low cytotoxic function, and at the same time high tissue remodeling activity. The molecular mechanisms that regulate the differentiation of M1 and M2 macrophages remain unknown. CSF1 is a potent factor of macrophage differentiation from monocytes in local injury sites. M2 macrophages accumulate at the site of injury later in the inflammatory process. INPP5D appears to repress the generation of M2 macrophages. M2 macrophages down-regulate M1 cell activation and the production of cytotoxic inflammatory mediators. M2 macrophage populations are described as phenotypically distinct; however, they are a cell population with diverse phenotypes that exist in interdependence and are able to transform from one to another. M2 macrophages are subdivided into M2a generation (activated by IL4 or IL13), M2b (activated by immune complexes in combination with IL1B or LPS), and M2c (activated by IL10, TGFB, or glucocorticoids). In general, alternative activation results in M2 macrophages releasing IL10 and exerting selective immunosuppressive activity and inhibiting T-cell proliferation. At the molecular level, IL4 and IL13 signal mediated induction of the transcriptional coactivator, PPARGC1B, which in cooperation with STAT6, appears to be critical for the promotion of alternative macrophage activation. LPS and IL1B trigger M2b-like macrophage polarization via IRF4 signaling. Outcome effects: M2 macrophages phagocytize apoptotic neutrophils, reduce the production of proinflammatory cytokines such as IL10, and increase the synthesis of mediators that are important in tissue remodeling, angiogenesis, and wound repair including VEGFA and TNF. M2 macrophages also stimulate fibroblasts and macrophages to synthesize extracellular matrix proteins. M2 macrophages express chemokines such as CCL17, CCL22, and CCL24. CCL2 and CXCL10 polarize macrophages to an M2-like phenotype. M2c macrophages that are glucocorticoid-activated up regulate genes with known anti-oxidative, anti-inflammatory, and immunosuppressive functions such as ADORA3 and CD163. M2 macrophages exhibit high levels of pathogen and scavenger receptors, such as MC1R, which provide them with stronger endocytotic and phagocytic activities. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-842998f8-63bb-4ff2-b5cc-c034153c236a anti-Inflammatory Function of Macrophage M2 Lineage uuid-842998f8-63bb-4ff2-b5cc-c034153c236a PS:CellType macrophage PS:Description Macrophages are a heterogeneous cell population. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-842998f8-63bb-4ff2-b5cc-c034153c236a PS:NodeType Pathway PS:Notes Headnote: Macrophages are professional phagocytes with the ability to take up pathogens and cell debris during inflammation. Macrophages are a heterogeneous cell population. Classically-activated M1 phenotype macrophages display a response to injury by releasing cytotoxic and proinflammatory mediators, which contribute to tissue injury. Signaling description: M2 phenotype macrophages are activated by Th2 cytokines and have low cytotoxic function, and at the same time high tissue remodeling activity. The molecular mechanisms that regulate the differentiation of M1 and M2 macrophages remain unknown. CSF1 is a potent factor of macrophage differentiation from monocytes in local injury sites. M2 macrophages accumulate at the site of injury later in the inflammatory process. INPP5D appears to repress the generation of M2 macrophages. M2 macrophages down-regulate M1 cell activation and the production of cytotoxic inflammatory mediators. M2 macrophage populations are described as phenotypically distinct; however, they are a cell population with diverse phenotypes that exist in interdependence and are able to transform from one to another. M2 macrophages are subdivided into M2a generation (activated by IL4 or IL13), M2b (activated by immune complexes in combination with IL1B or LPS), and M2c (activated by IL10, TGFB, or glucocorticoids). In general, alternative activation results in M2 macrophages releasing IL10 and exerting selective immunosuppressive activity and inhibiting T-cell proliferation. At the molecular level, IL4 and IL13 signal mediated induction of the transcriptional coactivator, PPARGC1B, which in cooperation with STAT6, appears to be critical for the promotion of alternative macrophage activation. LPS and IL1B trigger M2b-like macrophage polarization via IRF4 signaling. Outcome effects: M2 macrophages phagocytize apoptotic neutrophils, reduce the production of proinflammatory cytokines such as IL10, and increase the synthesis of mediators that are important in tissue remodeling, angiogenesis, and wound repair including VEGFA and TNF. M2 macrophages also stimulate fibroblasts and macrophages to synthesize extracellular matrix proteins. M2 macrophages express chemokines such as CCL17, CCL22, and CCL24. CCL2 and CXCL10 polarize macrophages to an M2-like phenotype. M2c macrophages that are glucocorticoid-activated up regulate genes with known anti-oxidative, anti-inflammatory, and immunosuppressive functions such as ADORA3 and CD163. M2 macrophages exhibit high levels of pathogen and scavenger receptors, such as MC1R, which provide them with stronger endocytotic and phagocytic activities. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84342620-2905-40fb-86ba-838a2bd62483 NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: The cells at the center of inflammation synthesize a large amount of proinflammatory molecules that activate the chemotaxis of neutrophils to the inflammation site and their degranulation. Upon degranulation (exocytosis), neutrophils release the content of their granules, proteins, and small molecules which possess antibacterial properties and slow down the inflammatory reaction. There are four recognized types of neutrophil granules including primary or azurophilic granules, secondary or specific granules, and tertiary or gelatinase granules that contain few antimicrobials but store metalloproteases such as gelatinase. Finally, secretory granules carry cytokines and important phagocytic receptors that are exposed to the neutrophil surface upon priming and fusion of these granules with the plasma membrane. This pathway illustrates the general mechanism of neutrophil degranulation, featuring the example with FPR1. Like other neutrophil activators of bacterial origin, fMLP is normally associated with the degranulation of azurophilic and specific granules, which both primarily contain antimicrobial components. fMLP is a small molecule that is produced during the degradation of bacterial proteins. fMLP is a strong chemoattractant for neutrophils and can trigger release of the contents of neutrophil granules into the extracellular space. Activated FPR1 receptor induces actin polymerization, which leads to cell migration toward a concentration gradient or granule membrane and cell membrane ruffling (degranulation). FPR1, via G protein related signaling, activates Rho family GTPases such as RAC1, RAC2, RHOA, and CDC42, which cause the actin related protein 2/3 complex to promote actin polymerization. Actin cytoskeleton remodeling is responsible for the first phase of exocytosis, which involves the binding of granules to the membrane. RAC1 and RAC2 differentially regulate actin polymerization in neutrophils through uncapping and actin related protein 2/3 complex/CFL1, respectively. RAC2 selectively mobilizes primary granules. In addition, RAC2 is the preferential activator of NAD(P)H oxidase and promotes the respiratory burst of the target cell mediated by neutrophils. Three Src family members, including HCK, FGR, and LYN, have been implicated in the control of exocytosis of granule products from neutrophils by FPR1 stimulation. HCK is associated with the primary granule, whereas FGR becomes associated with secondary granule exocytosis. The selective recruitment of Src kinases indicates that different signaling pathways exist in neutrophils to induce the release of each granule population. It is likely that the process of granule translocation and exocytosis involves the activation and recruitment of several signaling molecules. The FPR1-dependent cascade leads to an increase in calcium (Ca2+) levels, which is required for degranulation. Outcome effects: Increases in intracellular Ca2+ alone are sufficient to induce the release of many granule types in neutrophils. The specific target molecules for Ca2+ in neutrophil degranulation have yet to be identified. For instance, Ca2+ ions can activate proteins such as ANXA5, which results in remodeling of the actin cytoskeleton. A hierarchy of granule release exists in response to elevating concentrations of Ca2+. The order of release is secretory vesicles > tertiary granules > secondary granules > primary granules. The final step of exocytosis involves the formation structure of a fusion complex of membrane bound proteins (SNAP receptors) essential for vesicular docking and fusion. Neutrophils Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-84342620-2905-40fb-86ba-838a2bd62483 Neutrophil Degranulation via FPR1 Signaling uuid-84342620-2905-40fb-86ba-838a2bd62483 PS:CellType neutrophil PS:Description Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84342620-2905-40fb-86ba-838a2bd62483 PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: The cells at the center of inflammation synthesize a large amount of proinflammatory molecules that activate the chemotaxis of neutrophils to the inflammation site and their degranulation. Upon degranulation (exocytosis), neutrophils release the content of their granules, proteins, and small molecules which possess antibacterial properties and slow down the inflammatory reaction. There are four recognized types of neutrophil granules including primary or azurophilic granules, secondary or specific granules, and tertiary or gelatinase granules that contain few antimicrobials but store metalloproteases such as gelatinase. Finally, secretory granules carry cytokines and important phagocytic receptors that are exposed to the neutrophil surface upon priming and fusion of these granules with the plasma membrane. This pathway illustrates the general mechanism of neutrophil degranulation, featuring the example with FPR1. Like other neutrophil activators of bacterial origin, fMLP is normally associated with the degranulation of azurophilic and specific granules, which both primarily contain antimicrobial components. fMLP is a small molecule that is produced during the degradation of bacterial proteins. fMLP is a strong chemoattractant for neutrophils and can trigger release of the contents of neutrophil granules into the extracellular space. Activated FPR1 receptor induces actin polymerization, which leads to cell migration toward a concentration gradient or granule membrane and cell membrane ruffling (degranulation). FPR1, via G protein related signaling, activates Rho family GTPases such as RAC1, RAC2, RHOA, and CDC42, which cause the actin related protein 2/3 complex to promote actin polymerization. Actin cytoskeleton remodeling is responsible for the first phase of exocytosis, which involves the binding of granules to the membrane. RAC1 and RAC2 differentially regulate actin polymerization in neutrophils through uncapping and actin related protein 2/3 complex/CFL1, respectively. RAC2 selectively mobilizes primary granules. In addition, RAC2 is the preferential activator of NAD(P)H oxidase and promotes the respiratory burst of the target cell mediated by neutrophils. Three Src family members, including HCK, FGR, and LYN, have been implicated in the control of exocytosis of granule products from neutrophils by FPR1 stimulation. HCK is associated with the primary granule, whereas FGR becomes associated with secondary granule exocytosis. The selective recruitment of Src kinases indicates that different signaling pathways exist in neutrophils to induce the release of each granule population. It is likely that the process of granule translocation and exocytosis involves the activation and recruitment of several signaling molecules. The FPR1-dependent cascade leads to an increase in calcium (Ca2+) levels, which is required for degranulation. Outcome effects: Increases in intracellular Ca2+ alone are sufficient to induce the release of many granule types in neutrophils. The specific target molecules for Ca2+ in neutrophil degranulation have yet to be identified. For instance, Ca2+ ions can activate proteins such as ANXA5, which results in remodeling of the actin cytoskeleton. A hierarchy of granule release exists in response to elevating concentrations of Ca2+. The order of release is secretory vesicles > tertiary granules > secondary granules > primary granules. The final step of exocytosis involves the formation structure of a fusion complex of membrane bound proteins (SNAP receptors) essential for vesicular docking and fusion. Neutrophils PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is a group of cancers that affects breast tissue. ESR1 signaling plays a key role in BC. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-843bec3c-af87-4091-8523-3f1d3f1a540a NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: The estrogen receptor alpha (ESR1) signaling pathway plays a key role in BC. ESR1 is involved in cell differentiation, apoptosis, and proliferation through diverse mechanisms. The overexpression of membrane-bound ESR1 causes the constitutive activation of AKT1 signaling preventing apoptosis and differentiation of mammary epithelial cells in BC and leads to hyperplastic glandular growth. Nuclear ESR1 induces genes involved in cell proliferation and differentiation. 17beta-estradiol binds and activates membrane-bound ESR1 which activates PIK3CA via PIK3R1. PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene homologs (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 which regulates the transcription of BCL2 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits mitogen-activated protein kinase kinase kinase 5 (MAP3K5), mediated JNK-cascade (MAPK8, MAPK9, and MAPK10), and BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. ESR1 also activates PRKCA via PIK3CA/PIP3/PDPK1. PRKCA activates v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1), which activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation and migration. ESR1 binds src protein tyrosine kinase (SRC) mediated Janus kinases 1/2 (JAK1/2) which are involved in cell growth. Further, ligand-bound cytoplasmic ESR1 moves to the nucleus. 17beta-estradiol/ESR1 co-activator complex recruits transcription factors, SP1- and SP3, which induce the progesterone receptor (PGR) involved in cell differentiation and chromatin remodeling. Nuclear ESR1 interacts with transcription factors, NCOA1/NCOA3/EP300 and forms a transcription complex that binds with KAT2B and JUN/FOS and induces chromatin remodeling and cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: breast Organ_System: integumentary system PMID: 16645038 PMID: 19320640 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-843bec3c-af87-4091-8523-3f1d3f1a540a ESR1 Signaling in Breast Cancer uuid-843bec3c-af87-4091-8523-3f1d3f1a540a PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is a group of cancers that affects breast tissue. ESR1 signaling plays a key role in BC. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-843bec3c-af87-4091-8523-3f1d3f1a540a PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: The estrogen receptor alpha (ESR1) signaling pathway plays a key role in BC. ESR1 is involved in cell differentiation, apoptosis, and proliferation through diverse mechanisms. The overexpression of membrane-bound ESR1 causes the constitutive activation of AKT1 signaling preventing apoptosis and differentiation of mammary epithelial cells in BC and leads to hyperplastic glandular growth. Nuclear ESR1 induces genes involved in cell proliferation and differentiation. 17beta-estradiol binds and activates membrane-bound ESR1 which activates PIK3CA via PIK3R1. PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene homologs (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 which regulates the transcription of BCL2 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits mitogen-activated protein kinase kinase kinase 5 (MAP3K5), mediated JNK-cascade (MAPK8, MAPK9, and MAPK10), and BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. ESR1 also activates PRKCA via PIK3CA/PIP3/PDPK1. PRKCA activates v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1), which activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation and migration. ESR1 binds src protein tyrosine kinase (SRC) mediated Janus kinases 1/2 (JAK1/2) which are involved in cell growth. Further, ligand-bound cytoplasmic ESR1 moves to the nucleus. 17beta-estradiol/ESR1 co-activator complex recruits transcription factors, SP1- and SP3, which induce the progesterone receptor (PGR) involved in cell differentiation and chromatin remodeling. Nuclear ESR1 interacts with transcription factors, NCOA1/NCOA3/EP300 and forms a transcription complex that binds with KAT2B and JUN/FOS and induces chromatin remodeling and cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ breast PS:Organ_System integumentary system PS:PMID 16645038 PS:PMID 19320640 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-844fcd8b-a1eb-4ee0-ab65-b41d22c563a2 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-844fcd8b-a1eb-4ee0-ab65-b41d22c563a2 Arachidonic Acid Metabolism uuid-844fcd8b-a1eb-4ee0-ab65-b41d22c563a2 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-844fcd8b-a1eb-4ee0-ab65-b41d22c563a2 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Hyperhomocysteinemia (HHcy) cause hypercoagulation conditions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84730e68-e931-4c11-baee-b3b85c4258fd NodeType: Pathway Notes: Headnote: Hyperhomocysteinemia is a condition characterized by abnormally high homocysteine in the blood. Mutations in MTHFR (5-MTHF reductase) may lead to hyperhomocysteinemia (HHcy). HHcy was shown to be associated with hypercoagulable states. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: generic Organ_System: hematological system PMID: 17550314 PMID: 18729731 PMID: 19841539 PMID: 21105837 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood urn:agi-pathway:uuid-84730e68-e931-4c11-baee-b3b85c4258fd MTHFR Mutation, Hyperhomocysteinemia and Folate Deficiency uuid-84730e68-e931-4c11-baee-b3b85c4258fd PS:CellType generic PS:Description Hyperhomocysteinemia (HHcy) cause hypercoagulation conditions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84730e68-e931-4c11-baee-b3b85c4258fd PS:NodeType Pathway PS:Notes Headnote: Hyperhomocysteinemia is a condition characterized by abnormally high homocysteine in the blood. Mutations in MTHFR (5-MTHF reductase) may lead to hyperhomocysteinemia (HHcy). HHcy was shown to be associated with hypercoagulable states. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ generic PS:Organ_System hematological system PS:PMID 17550314 PS:PMID 18729731 PS:PMID 19841539 PS:PMID 21105837 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84a5f523-d161-4fb8-9eea-a7eecb8dac1f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-84a5f523-d161-4fb8-9eea-a7eecb8dac1f FGFR1 -> STAT Signaling uuid-84a5f523-d161-4fb8-9eea-a7eecb8dac1f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84a5f523-d161-4fb8-9eea-a7eecb8dac1f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84aed22b-c8c2-4458-9c0c-7e43c355ab83 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-84aed22b-c8c2-4458-9c0c-7e43c355ab83 CD8+ Naive T-cell -> CD4+ Naive T-cell Surface Expression Markers uuid-84aed22b-c8c2-4458-9c0c-7e43c355ab83 PS:CellType T-cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84aed22b-c8c2-4458-9c0c-7e43c355ab83 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84b5c179-8bcb-483a-930e-4271fab6584f NodeType: Pathway Notes: Ectopic endometrium develops resistance to progesterone, one of the hallmarks of endometriosis. Progesterone resistance likely develops due to the downregulation of progesterone receptor (PGR) expression and related signaling mechanisms in endometrial cell. Resistance to progesterone and the decline in retinoic acid synthesis or uptake inhibits physiological apoptosis and stimulates cell proliferation in ectopic endometrium. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-84b5c179-8bcb-483a-930e-4271fab6584f 2_Progesterone resistance stimulates endometriotic cell survival uuid-84b5c179-8bcb-483a-930e-4271fab6584f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84b5c179-8bcb-483a-930e-4271fab6584f PS:NodeType Pathway PS:Notes Ectopic endometrium develops resistance to progesterone, one of the hallmarks of endometriosis. Progesterone resistance likely develops due to the downregulation of progesterone receptor (PGR) expression and related signaling mechanisms in endometrial cell. Resistance to progesterone and the decline in retinoic acid synthesis or uptake inhibits physiological apoptosis and stimulates cell proliferation in ectopic endometrium. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: tanycyte Description: Thyrotropin-releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) hormone that is primarily produced in the paraventricular nucleus of the hypothalamus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84b87e7c-52c6-475c-b139-acc4141a1532 NodeType: Pathway Notes: Headnote: Thyrotropin-releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) hormone that is primarily produced in the paraventricular nucleus of the hypothalamus. The major recognized function of TRH is the maintenance of thyroid hormone homeostasis via the regulation of thyroid-stimulating hormone (TSH). Signaling description: The TRH peptide is synthesized in the hypothalamus and transported by the portal vascular system to the anterior pituitary where it acts on thyrotropic and lactotropic cells to promote the secretion of TSH and prolactin, respectively. Hypothyroidism may occur when the hypothalamus fails to produce sufficient levels of TRH. Therefore, it may also be termed hypothalamic-pituitary-axis hypothyroidism or tertiary hypothyroidism (accounts for less than 5% of hypothyroidism cases). The most prevalent cause of tertiary subtypes is a defective development of hypothalamus leading to multiple hormone deficiencies. Defects in the structure of hypothalamic peptides and their receptors have rarely been identified in the case of central congenital hypothyroidism. TRH is synthesized as a large pre-pro-TRH protein. The pre-pro-TRH processing is mostly mediated by prohormone convertases PCSK1 and PCSK2, which are strongly inhibited by triiodothyronine (T3). In case of primary hypothyroidism, the reduced level of T3 may enhance TRH protein processing and synthesis. Thyroid hormone receptor beta-2 (THRB) is the key isoform responsible for theT3-mediated feedback regulation by hypophysiotropic TRH neurons. Further, SLC16A2 is a thyroid hormone transporter expressed primarily in neurons and tanycytes may also be involved physiological feedback regulation. In addition, LEP acts directly on TRH neurons through the long isoforms of leptin receptor (LEPR) which activates STAT3 signaling. LEP can stimulate TRH expression indirectly by affecting alpha-melanotrophin (POMC)-neurons expressing LEPR that in turn release POMC. POMC, through melanocortin 4 receptor (MC4R) related p-CREB signaling, enhances TRH synthesis. Other neurons stimulated by the MC4R pathway may be involved in sympathetic activity or food intake regulation. Neuropeptide Y (NPY) may regulate TRH neurons through a mechanism depending upon the status of the melanocortin system. Outcome effects: Single nucleotide polymorphisms (SNPs) or mutations in THRB cause insufficient TRH production. Then, SLC16A2 mutations result in hypothyroid TRH neurons regardless of the high concentration of circulating T3. Finally, partial and complete deficiencies of leptin (LEP) are associated with hypothyroidism. . Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ: hypothalamus Organ: liver Organ_System: endocrine system PMID: 15481810 PMID: 16876577 PMID: 20074584 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-84b87e7c-52c6-475c-b139-acc4141a1532 Thyrotropin Releasing Hormone (TRH) Hypothalamic Release in non-Autoimmune Hypothyroidism uuid-84b87e7c-52c6-475c-b139-acc4141a1532 PS:CellType adipocyte PS:CellType tanycyte PS:Description Thyrotropin-releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) hormone that is primarily produced in the paraventricular nucleus of the hypothalamus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84b87e7c-52c6-475c-b139-acc4141a1532 PS:NodeType Pathway PS:Notes Headnote: Thyrotropin-releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) hormone that is primarily produced in the paraventricular nucleus of the hypothalamus. The major recognized function of TRH is the maintenance of thyroid hormone homeostasis via the regulation of thyroid-stimulating hormone (TSH). Signaling description: The TRH peptide is synthesized in the hypothalamus and transported by the portal vascular system to the anterior pituitary where it acts on thyrotropic and lactotropic cells to promote the secretion of TSH and prolactin, respectively. Hypothyroidism may occur when the hypothalamus fails to produce sufficient levels of TRH. Therefore, it may also be termed hypothalamic-pituitary-axis hypothyroidism or tertiary hypothyroidism (accounts for less than 5% of hypothyroidism cases). The most prevalent cause of tertiary subtypes is a defective development of hypothalamus leading to multiple hormone deficiencies. Defects in the structure of hypothalamic peptides and their receptors have rarely been identified in the case of central congenital hypothyroidism. TRH is synthesized as a large pre-pro-TRH protein. The pre-pro-TRH processing is mostly mediated by prohormone convertases PCSK1 and PCSK2, which are strongly inhibited by triiodothyronine (T3). In case of primary hypothyroidism, the reduced level of T3 may enhance TRH protein processing and synthesis. Thyroid hormone receptor beta-2 (THRB) is the key isoform responsible for theT3-mediated feedback regulation by hypophysiotropic TRH neurons. Further, SLC16A2 is a thyroid hormone transporter expressed primarily in neurons and tanycytes may also be involved physiological feedback regulation. In addition, LEP acts directly on TRH neurons through the long isoforms of leptin receptor (LEPR) which activates STAT3 signaling. LEP can stimulate TRH expression indirectly by affecting alpha-melanotrophin (POMC)-neurons expressing LEPR that in turn release POMC. POMC, through melanocortin 4 receptor (MC4R) related p-CREB signaling, enhances TRH synthesis. Other neurons stimulated by the MC4R pathway may be involved in sympathetic activity or food intake regulation. Neuropeptide Y (NPY) may regulate TRH neurons through a mechanism depending upon the status of the melanocortin system. Outcome effects: Single nucleotide polymorphisms (SNPs) or mutations in THRB cause insufficient TRH production. Then, SLC16A2 mutations result in hypothyroid TRH neurons regardless of the high concentration of circulating T3. Finally, partial and complete deficiencies of leptin (LEP) are associated with hypothyroidism. . Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ hypothalamus PS:Organ liver PS:Organ_System endocrine system PS:PMID 15481810 PS:PMID 16876577 PS:PMID 20074584 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84d0a5cd-38bf-445b-bd9f-e28a486fbe60 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-84d0a5cd-38bf-445b-bd9f-e28a486fbe60 Proteins Involved in Rett Syndrome uuid-84d0a5cd-38bf-445b-bd9f-e28a486fbe60 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-84d0a5cd-38bf-445b-bd9f-e28a486fbe60 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: HIF1A plays a critical role in hypoxia-induced angiogenesis. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-850dcbd9-24ee-46a2-acae-9196f3d83a5e NodeType: Pathway Notes: Headnote: The pathology of sustained angiogenesis in tumors is characterized by hyperexpression of multiple pro-angiogenic factors. Activated HIF1A plays a critical role in the expression of pro-angiogenic factors. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. Signaling description: Hypoxia is typical for tumors due to the imbalance between oxygen consumption and supply and is the major inductor of HIF1A. Also, HIF1A can be induced by inactivating mutations of VHL and CDKN2A, BCR-ABL translocation or down-regulation of enzymes and proteins controlling HIF activity (SDHD, SDHB, SDHC, EGLN1, FH). HIF1A in conjunction with EPAS1 (HIF2A) and ARNT (HIF1B) regulate the expression of a suite of pro-angiogenic genes. Outcome effects: VEGFA, ANGPT1, ANGPT2, TRK, KDR and other pro-angiogenic genes are overexpressed due to the activation of HIFs leading to sustained angiogenesis. CCL2, CXCL12, CXCR4 are also overexpressed due to activation of HIFs facilitating migration of endothelial cells. Animal data: not shown Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. Organ: blood vessel Organ_System: cardiovascular system PMID: 16716598 PMID: 22866203 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-850dcbd9-24ee-46a2-acae-9196f3d83a5e HIF1A as Master Regulator of Angiogenesis in Cancer uuid-850dcbd9-24ee-46a2-acae-9196f3d83a5e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description HIF1A plays a critical role in hypoxia-induced angiogenesis. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-850dcbd9-24ee-46a2-acae-9196f3d83a5e PS:NodeType Pathway PS:Notes Headnote: The pathology of sustained angiogenesis in tumors is characterized by hyperexpression of multiple pro-angiogenic factors. Activated HIF1A plays a critical role in the expression of pro-angiogenic factors. HIF1A was shown to be upregulated in many cancer types and regarded as a potential anti-angiogenic drug target. Signaling description: Hypoxia is typical for tumors due to the imbalance between oxygen consumption and supply and is the major inductor of HIF1A. Also, HIF1A can be induced by inactivating mutations of VHL and CDKN2A, BCR-ABL translocation or down-regulation of enzymes and proteins controlling HIF activity (SDHD, SDHB, SDHC, EGLN1, FH). HIF1A in conjunction with EPAS1 (HIF2A) and ARNT (HIF1B) regulate the expression of a suite of pro-angiogenic genes. Outcome effects: VEGFA, ANGPT1, ANGPT2, TRK, KDR and other pro-angiogenic genes are overexpressed due to the activation of HIFs leading to sustained angiogenesis. CCL2, CXCL12, CXCR4 are also overexpressed due to activation of HIFs facilitating migration of endothelial cells. Animal data: not shown Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Induction of Angiogenesis" for details. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 16716598 PS:PMID 22866203 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85182e29-b40a-4cca-b0aa-e29dd2936519 NodeType: Pathway Notes: An imbalance in the number of factors regulating cardiovascular system activity may cause the observed increase in arterial pressure. For example, higher levels of aldosterone change salt and water homeostasis that in turn leads to hypertension. Aldosterone plays an essential role in salt and water homeostasis and correspondingly in blood pressure regulation. Chronic activation of the aldosterone secretion system (specifically the renin-angiotensin-aldosterone system, RAAS) is a major contributing factor to the pathogenesis and progression of arterial hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-85182e29-b40a-4cca-b0aa-e29dd2936519 1_Rise in aldosterone synthesis in adrenal zona glomerulosa cells uuid-85182e29-b40a-4cca-b0aa-e29dd2936519 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85182e29-b40a-4cca-b0aa-e29dd2936519 PS:NodeType Pathway PS:Notes An imbalance in the number of factors regulating cardiovascular system activity may cause the observed increase in arterial pressure. For example, higher levels of aldosterone change salt and water homeostasis that in turn leads to hypertension. Aldosterone plays an essential role in salt and water homeostasis and correspondingly in blood pressure regulation. Chronic activation of the aldosterone secretion system (specifically the renin-angiotensin-aldosterone system, RAAS) is a major contributing factor to the pathogenesis and progression of arterial hypertension. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: regulatory T-cell CellType: thymocyte Description: In APS1 recessive AIRE mutations lead to autoimmunity targetting endocrine tissues. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-852b1003-c034-4d18-a072-f3794f00968d NodeType: Pathway Notes: Headnote: Autoimmune polyglandular syndromes (or autoimmune polyendocrine syndromes) are a group of rare diseases which affect several endocrine organs. Autoimmune polyendocrine syndrome type 1 (APS-1) is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), Whitaker syndrome, and candidiasis-hypoparathyroidism-Addison's disease-syndrome. APS-1 is an autosomal recessive genetic disorder and is caused by a mutation in AIRE gene. The main components of the syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). APS-1 often includes type 1 diabetes as part of the disease phenotype. Signaling description: AIRE gene controls the expression of a set of self-Ag, including insulin in the thymus, leading to the negative selection of self-reactive thymocytes and immune tolerance. Insulin as the target antigen of the autoimmune islet destruction may lead to type 1 diabetes. Thus, metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. MAFA has also been shown to induce insulin expression in the thymus. It has been speculated that thymic insulin expression may be regulated by AIRE/MAFA. Mutation in FOXP3 in Treg cells causes immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. IPEX syndrome is a rare disease which is characterized by hyperactive T cells. Organ: thymus gland Organ_System: lymphatic system PMID: 19328420 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-852b1003-c034-4d18-a072-f3794f00968d Autoimmune Polyglandular Syndromes Progression (Hypothesis) uuid-852b1003-c034-4d18-a072-f3794f00968d PS:CellType T-cell PS:CellType regulatory T-cell PS:CellType thymocyte PS:Description In APS1 recessive AIRE mutations lead to autoimmunity targetting endocrine tissues. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-852b1003-c034-4d18-a072-f3794f00968d PS:NodeType Pathway PS:Notes Headnote: Autoimmune polyglandular syndromes (or autoimmune polyendocrine syndromes) are a group of rare diseases which affect several endocrine organs. Autoimmune polyendocrine syndrome type 1 (APS-1) is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), Whitaker syndrome, and candidiasis-hypoparathyroidism-Addison's disease-syndrome. APS-1 is an autosomal recessive genetic disorder and is caused by a mutation in AIRE gene. The main components of the syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). APS-1 often includes type 1 diabetes as part of the disease phenotype. Signaling description: AIRE gene controls the expression of a set of self-Ag, including insulin in the thymus, leading to the negative selection of self-reactive thymocytes and immune tolerance. Insulin as the target antigen of the autoimmune islet destruction may lead to type 1 diabetes. Thus, metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. MAFA has also been shown to induce insulin expression in the thymus. It has been speculated that thymic insulin expression may be regulated by AIRE/MAFA. Mutation in FOXP3 in Treg cells causes immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. IPEX syndrome is a rare disease which is characterized by hyperactive T cells. PS:Organ thymus gland PS:Organ_System lymphatic system PS:PMID 19328420 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell Description: DCIR1 (CLEC4A) is a membrane receptor with an extracellular C-type lectin-like domain. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85393175-c477-466d-8fe2-339eab66ec14 NodeType: Pathway Notes: Headnote: DCIR1 (CLEC4A) is a membrane receptor with an extracellular C-type lectin-like domain. Signaling description: CLEC4A functions as a pattern recognition receptor that recognizes a variety of beta-1,3-linked and beta-1,6-linked glucans from fungi and plants, and thus, has a role in the innate immune response. CLEC4A is found to be expressed at high levels in blood monocytes, myeloid and plasmacytoid DCs, and macrophages, while occasionally in B-cells. Outcome effects: The activation of CLEC4A leads to its internalization into endosomal compartments, which induces the activation of an unidentified signaling pathway that leads to the downregulation of TLR8-dependent IL12 and TNF expression or TLR9-dependent IFNG and TNF production by either myeloid or plasmacytoid cells. Organ: generic Organ_System: generic PMID: 15481152 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-85393175-c477-466d-8fe2-339eab66ec14 DCIR1 (CLEC4A) Signaling uuid-85393175-c477-466d-8fe2-339eab66ec14 PS:CellType dendritic cell PS:Description DCIR1 (CLEC4A) is a membrane receptor with an extracellular C-type lectin-like domain. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85393175-c477-466d-8fe2-339eab66ec14 PS:NodeType Pathway PS:Notes Headnote: DCIR1 (CLEC4A) is a membrane receptor with an extracellular C-type lectin-like domain. Signaling description: CLEC4A functions as a pattern recognition receptor that recognizes a variety of beta-1,3-linked and beta-1,6-linked glucans from fungi and plants, and thus, has a role in the innate immune response. CLEC4A is found to be expressed at high levels in blood monocytes, myeloid and plasmacytoid DCs, and macrophages, while occasionally in B-cells. Outcome effects: The activation of CLEC4A leads to its internalization into endosomal compartments, which induces the activation of an unidentified signaling pathway that leads to the downregulation of TLR8-dependent IL12 and TNF expression or TLR9-dependent IFNG and TNF production by either myeloid or plasmacytoid cells. PS:Organ generic PS:Organ_System generic PS:PMID 15481152 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85458c18-7b50-4466-8a66-aca95693fa30 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-85458c18-7b50-4466-8a66-aca95693fa30 FCGR3A Expression Targets uuid-85458c18-7b50-4466-8a66-aca95693fa30 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85458c18-7b50-4466-8a66-aca95693fa30 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-856026aa-4da7-4836-b6bf-0cb9dc75f824 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-856026aa-4da7-4836-b6bf-0cb9dc75f824 BMP4/BMPR2 Expression Targets uuid-856026aa-4da7-4836-b6bf-0cb9dc75f824 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-856026aa-4da7-4836-b6bf-0cb9dc75f824 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8565ad64-ae16-428c-90d6-35effe6b4a02 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8565ad64-ae16-428c-90d6-35effe6b4a02 PDCD1 -> ATF/CREB/CREBBP Expression Targets uuid-8565ad64-ae16-428c-90d6-35effe6b4a02 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8565ad64-ae16-428c-90d6-35effe6b4a02 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-856fe378-eedf-41df-9283-df25f770ce15 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-856fe378-eedf-41df-9283-df25f770ce15 CD2 Expression Targets uuid-856fe378-eedf-41df-9283-df25f770ce15 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-856fe378-eedf-41df-9283-df25f770ce15 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-857107da-13e3-4105-a6c0-cb659914e455 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-857107da-13e3-4105-a6c0-cb659914e455 SARS Mpro (NSP5) inhibitors (Predicted) uuid-857107da-13e3-4105-a6c0-cb659914e455 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-857107da-13e3-4105-a6c0-cb659914e455 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-858064c8-b813-4787-bf78-dc004d9cf619 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-858064c8-b813-4787-bf78-dc004d9cf619 Ubiquinoine Biosynthesis in Humans uuid-858064c8-b813-4787-bf78-dc004d9cf619 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-858064c8-b813-4787-bf78-dc004d9cf619 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85acdceb-3de6-4f22-926a-096690fe543d NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: lymph node Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-85acdceb-3de6-4f22-926a-096690fe543d Elevated Receptors -> Expression Targets in Lymph Node uuid-85acdceb-3de6-4f22-926a-096690fe543d PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85acdceb-3de6-4f22-926a-096690fe543d PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Donohue syndrome (Leprechaunism) is a rare severe genetic disorder, characterized by slow physical and mental development, insulin resistance, lipodystrophy and precocious puberty. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85d8b6cd-622f-4a68-82d3-f0c8d6bd402e NodeType: Pathway Notes: Headnote: Donohue syndrome (also known as Leprechaunism) is an extremely rare and severe genetic disorder. Leprechaunism is an autosomal recessive condition with mutations in the insulin receptor gene (INSR). It is characterized by slow physical and mental development and endocrine abnormalities such as insulin resistance, hyperinsulinemia, lipodystrophy, and precocious puberty. Death usually occurs in utero or in the first years of life. Affected infants may have distinctive abnormalities of the head and face (Leprechaun's face), low birth weight, skin abnormalities, hirsutism, low-set prominent ears, broad nose, acanthosis nigricans, flared nostrils, and thick lips. The cause of the disease is the lack of a fully functional insulin receptor, which has major effects during fetal development and thereafter. Signaling description: Normally, insulin (INS) binds to its receptors, INSR and IGF1R. The activation of INSR and IGF1R leads to activation of PI3K pathway, which via PDPK1, results in promotion of downstream targets such as AKT1, MAPK-cascade, and JAK-cascade. AKT1 phosphorylates FOXO1/3 and MTOR which are involved in the control of protein degradation. AKT1 phosphorylates and inhibits GSK3B which leads to increased activity of FASN, ACACB and ACACA which are involved in lipid metabolism. AKT1 phosphorylates and activates TBC1D4 and promotes SLC2A4 in adipose and muscle tissues, thus increasing glucose uptake. MAPK-cascade and JAK-cascade regulate cell proliferation. Many of the issues associated with Donohue syndrome may be due to IGF1R, which regulates growth of the embryo in addition to its well-known role in regulating blood sugar. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: endocrine system Organ_System: integumentary system PMID: 21536711 PMID: 23272513 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-85d8b6cd-622f-4a68-82d3-f0c8d6bd402e Donohue Syndrome Progression (Hypothesis) uuid-85d8b6cd-622f-4a68-82d3-f0c8d6bd402e PS:CellType adipocyte PS:Description Donohue syndrome (Leprechaunism) is a rare severe genetic disorder, characterized by slow physical and mental development, insulin resistance, lipodystrophy and precocious puberty. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85d8b6cd-622f-4a68-82d3-f0c8d6bd402e PS:NodeType Pathway PS:Notes Headnote: Donohue syndrome (also known as Leprechaunism) is an extremely rare and severe genetic disorder. Leprechaunism is an autosomal recessive condition with mutations in the insulin receptor gene (INSR). It is characterized by slow physical and mental development and endocrine abnormalities such as insulin resistance, hyperinsulinemia, lipodystrophy, and precocious puberty. Death usually occurs in utero or in the first years of life. Affected infants may have distinctive abnormalities of the head and face (Leprechaun's face), low birth weight, skin abnormalities, hirsutism, low-set prominent ears, broad nose, acanthosis nigricans, flared nostrils, and thick lips. The cause of the disease is the lack of a fully functional insulin receptor, which has major effects during fetal development and thereafter. Signaling description: Normally, insulin (INS) binds to its receptors, INSR and IGF1R. The activation of INSR and IGF1R leads to activation of PI3K pathway, which via PDPK1, results in promotion of downstream targets such as AKT1, MAPK-cascade, and JAK-cascade. AKT1 phosphorylates FOXO1/3 and MTOR which are involved in the control of protein degradation. AKT1 phosphorylates and inhibits GSK3B which leads to increased activity of FASN, ACACB and ACACA which are involved in lipid metabolism. AKT1 phosphorylates and activates TBC1D4 and promotes SLC2A4 in adipose and muscle tissues, thus increasing glucose uptake. MAPK-cascade and JAK-cascade regulate cell proliferation. Many of the issues associated with Donohue syndrome may be due to IGF1R, which regulates growth of the embryo in addition to its well-known role in regulating blood sugar. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System endocrine system PS:Organ_System integumentary system PS:PMID 21536711 PS:PMID 23272513 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Arterial Hypertension (AH) is a condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85e5a73a-d738-4e89-8c7d-655e32b38db2 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Glucocorticoid-induced hypertension is a poorly understood clinical state and is often associated with the Cushing's disease. This form of hypertension is believed to be mediated by excess sodium (Na+) and water reabsorption by the kidney. Signaling description: The disruption of Na+/K+ homeostasis plays a key role in the development of arterial hypertension. The activity of channels that control electrolyte transport across epithelia in nephrons is regulated by the mineralocorticoid aldosterone and glucocorticoid cortisol. Excessive secretion of cortisol causes arterial hypertension. Cortisol can bind to the mineralocorticoid receptor, NR3C2 and regulate the transcription of a number of genes. Activated NR3C2 translocates into the nucleus, where it interacts with the transcription complex, NCOA1/2/3/EP300/CREB1/CREBP/SP1, to induce the expression of downstream target genes. Outcome effects: The NCOA1/2/3/EP300/CREB1/CREBP/SP1 complex activates the transcription of SGK1, ENaC subunits, ATP1B1, and AQP2. The non-catalytic ATP1B1 subunit binds the catalytic ATP1A1 and forms Na+/K+-transporting ATPase, which catalyzes the hydrolysis of ATP coupled with the Na+ and K+ exchange across the plasma membrane. SGK1 activates the alpha subunit (SCNN1A) of ENaC. Non-voltage-gated Na+ channels including amiloride-sensitive Na+ channels, epithelial Na+ channel (ENaC), and Na+ channel non-neuronal 1 (SCNN1), control Na+ transport across epithelia in nephron collecting ducts. This channel is a heterotrimeric complex consisting of alpha (SCNN1A), beta (SCNN1B) and gamma (SCNN1G) subunits. It has a major role in Na+ homeostasis throuth the Na+ reabsorption. FLNA, FURIN, and CTTN interact with ENaC subunits and are involved in cytoskeletal ENaC regulation. Mutations in SCNN1B and SCNN1G cause Liddle syndrome characterized by increased blood pressure. AQP2 forms a water-specific channel on plasma membranes of nephron collecting ducts that provides water to move down the osmotic gradient. Highlighted proteins: Entities with decreased levels are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 20610969 PMID: 21744056 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-85e5a73a-d738-4e89-8c7d-655e32b38db2 Cortisol Signaling in Arterial Hypertension uuid-85e5a73a-d738-4e89-8c7d-655e32b38db2 PS:CellType epithelial cell PS:Description Arterial Hypertension (AH) is a condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85e5a73a-d738-4e89-8c7d-655e32b38db2 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Glucocorticoid-induced hypertension is a poorly understood clinical state and is often associated with the Cushing's disease. This form of hypertension is believed to be mediated by excess sodium (Na+) and water reabsorption by the kidney. Signaling description: The disruption of Na+/K+ homeostasis plays a key role in the development of arterial hypertension. The activity of channels that control electrolyte transport across epithelia in nephrons is regulated by the mineralocorticoid aldosterone and glucocorticoid cortisol. Excessive secretion of cortisol causes arterial hypertension. Cortisol can bind to the mineralocorticoid receptor, NR3C2 and regulate the transcription of a number of genes. Activated NR3C2 translocates into the nucleus, where it interacts with the transcription complex, NCOA1/2/3/EP300/CREB1/CREBP/SP1, to induce the expression of downstream target genes. Outcome effects: The NCOA1/2/3/EP300/CREB1/CREBP/SP1 complex activates the transcription of SGK1, ENaC subunits, ATP1B1, and AQP2. The non-catalytic ATP1B1 subunit binds the catalytic ATP1A1 and forms Na+/K+-transporting ATPase, which catalyzes the hydrolysis of ATP coupled with the Na+ and K+ exchange across the plasma membrane. SGK1 activates the alpha subunit (SCNN1A) of ENaC. Non-voltage-gated Na+ channels including amiloride-sensitive Na+ channels, epithelial Na+ channel (ENaC), and Na+ channel non-neuronal 1 (SCNN1), control Na+ transport across epithelia in nephron collecting ducts. This channel is a heterotrimeric complex consisting of alpha (SCNN1A), beta (SCNN1B) and gamma (SCNN1G) subunits. It has a major role in Na+ homeostasis throuth the Na+ reabsorption. FLNA, FURIN, and CTTN interact with ENaC subunits and are involved in cytoskeletal ENaC regulation. Mutations in SCNN1B and SCNN1G cause Liddle syndrome characterized by increased blood pressure. AQP2 forms a water-specific channel on plasma membranes of nephron collecting ducts that provides water to move down the osmotic gradient. Highlighted proteins: Entities with decreased levels are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 20610969 PS:PMID 21744056 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85ebecee-464d-4f82-aa15-7d833c979229 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-85ebecee-464d-4f82-aa15-7d833c979229 S100B Expression Targets uuid-85ebecee-464d-4f82-aa15-7d833c979229 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85ebecee-464d-4f82-aa15-7d833c979229 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85f0f88a-17bc-4b7f-b994-092d99b3d8ac NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-85f0f88a-17bc-4b7f-b994-092d99b3d8ac PDGFR -> AP-1/MYC Signaling uuid-85f0f88a-17bc-4b7f-b994-092d99b3d8ac PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-85f0f88a-17bc-4b7f-b994-092d99b3d8ac PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-861cb5a7-2c9b-4163-8315-342a86f7cbda NodeType: Pathway Organ: colon Organ: small intestine Organ_System: digestive system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-861cb5a7-2c9b-4163-8315-342a86f7cbda Proteins with Altered Expression in Celiac Disease uuid-861cb5a7-2c9b-4163-8315-342a86f7cbda PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-861cb5a7-2c9b-4163-8315-342a86f7cbda PS:NodeType Pathway PS:Organ colon PS:Organ small intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Pyelonephritis is a nonspecific inflammation of kidney tubular system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-861ea19d-1c91-4f31-b1d3-673b79fb3021 NodeType: Pathway Notes: Pyelonephritis is a nonspecific inflammation of kidney tubular system. Overexpression of TNF due to inflammation leads to apoptosis and protein degradation. ER stress-associated apoptosis modulates renal fibrosis and remodeling after injury. Organ: kidney Organ_System: urinary tract PMID: 20045381 PMID: 21863214 PMID: 24198613 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-861ea19d-1c91-4f31-b1d3-673b79fb3021 Apoptosis of Renal Tubule Epithelial Cell in Pyelonephritis uuid-861ea19d-1c91-4f31-b1d3-673b79fb3021 PS:CellType epithelial cell PS:Description Pyelonephritis is a nonspecific inflammation of kidney tubular system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-861ea19d-1c91-4f31-b1d3-673b79fb3021 PS:NodeType Pathway PS:Notes Pyelonephritis is a nonspecific inflammation of kidney tubular system. Overexpression of TNF due to inflammation leads to apoptosis and protein degradation. ER stress-associated apoptosis modulates renal fibrosis and remodeling after injury. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 20045381 PS:PMID 21863214 PS:PMID 24198613 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: fibroblast Description: Middle ear cholesteatoma is caused by the hyperproliferation of keratinocytes due to chronic inflammation and it is one of the hyperproliferative epithelial diseases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-862f278c-d461-4886-8140-c5ab56a1dbff NodeType: Pathway Notes: Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Middle ear cholesteatoma is caused by the hyperproliferation of keratinocytes due to chronic inflammation and it is one of the hyperproliferative epithelial diseases. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 12218613 PMID: 23826119 PMID: 9655214 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-862f278c-d461-4886-8140-c5ab56a1dbff Subepithelial Fibroblasts in Middle Ear Cholesteatoma uuid-862f278c-d461-4886-8140-c5ab56a1dbff PS:CellType cancer cell PS:CellType fibroblast PS:Description Middle ear cholesteatoma is caused by the hyperproliferation of keratinocytes due to chronic inflammation and it is one of the hyperproliferative epithelial diseases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-862f278c-d461-4886-8140-c5ab56a1dbff PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Middle ear cholesteatoma is caused by the hyperproliferation of keratinocytes due to chronic inflammation and it is one of the hyperproliferative epithelial diseases. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 12218613 PS:PMID 23826119 PS:PMID 9655214 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-863e6e3e-6f47-4be6-94eb-9fdb6da5f4cd NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-863e6e3e-6f47-4be6-94eb-9fdb6da5f4cd Antibiotic degradation template uuid-863e6e3e-6f47-4be6-94eb-9fdb6da5f4cd PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-863e6e3e-6f47-4be6-94eb-9fdb6da5f4cd PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: The inhibition of apoptosis is one of the key processes in acute myeloid leukemia development and is a collection of several mechanisms. Numerous fusion proteins interact with mediators of apoptosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8653633a-a3a6-4d8c-a5a7-f28bbd6538d7 NodeType: Pathway Notes: Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. A block of differentiation may happen at any stage of myeloblast development in different subtypes of AML. The inhibition of apoptosis is one of the key processes in acute AML development and is a collection of several mechanisms. Signaling description: PML-RAR blocks apoptosis through p53 signaling, while AML1-ETO blocks this process through BCL2. MLL modifies PPP1R15A function and thus inhibits apoptosis. In addition, nucleophosmin (NPM1) mutations are frequent in karyotypically normal AML, occurring in 50-60% of such cases. NPM1 acts as a cellular p53 negative regulator to protect hematopoietic cells from apoptosis. FLT3, a receptor tyrosine kinase is overexpressed in the majority of AML cases and mutated in about 35% of them. FLT3 activates RAS, PI3K, AKT1 and STAT which leads to PIM1/2 activation and BCL2L1 hyperexpression. Furthermore, proto-oncogene, c-kit (KIT) mutations occur in about 20-30% of AML patients. It activates JAK/STAT and PI3K leading to the inhibition of apoptosis. Lastly, KRAS and NRAS mutations are present in approximately 15-25% of AML patients and also have an impact on antiapoptotic signaling. Outcome effects: In AML, numerous fusion proteins interact with mediators of apoptosis. The inhibition of apoptosis leads to the immortalization of leukemia cells and development of the disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: hematological system PMID: 17229639 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-8653633a-a3a6-4d8c-a5a7-f28bbd6538d7 Apoptosis Block in Acute Myeloid Leukemia Cell uuid-8653633a-a3a6-4d8c-a5a7-f28bbd6538d7 PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description The inhibition of apoptosis is one of the key processes in acute myeloid leukemia development and is a collection of several mechanisms. Numerous fusion proteins interact with mediators of apoptosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8653633a-a3a6-4d8c-a5a7-f28bbd6538d7 PS:NodeType Pathway PS:Notes Headnote: Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the uncontrolled increase in the amount of myeloid progenitors. A block of differentiation may happen at any stage of myeloblast development in different subtypes of AML. The inhibition of apoptosis is one of the key processes in acute AML development and is a collection of several mechanisms. Signaling description: PML-RAR blocks apoptosis through p53 signaling, while AML1-ETO blocks this process through BCL2. MLL modifies PPP1R15A function and thus inhibits apoptosis. In addition, nucleophosmin (NPM1) mutations are frequent in karyotypically normal AML, occurring in 50-60% of such cases. NPM1 acts as a cellular p53 negative regulator to protect hematopoietic cells from apoptosis. FLT3, a receptor tyrosine kinase is overexpressed in the majority of AML cases and mutated in about 35% of them. FLT3 activates RAS, PI3K, AKT1 and STAT which leads to PIM1/2 activation and BCL2L1 hyperexpression. Furthermore, proto-oncogene, c-kit (KIT) mutations occur in about 20-30% of AML patients. It activates JAK/STAT and PI3K leading to the inhibition of apoptosis. Lastly, KRAS and NRAS mutations are present in approximately 15-25% of AML patients and also have an impact on antiapoptotic signaling. Outcome effects: In AML, numerous fusion proteins interact with mediators of apoptosis. The inhibition of apoptosis leads to the immortalization of leukemia cells and development of the disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System hematological system PS:PMID 17229639 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Histological examinations of lungs in chronic bronchitis show increased bronchial vascularity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-865da8fe-3176-4c8b-b387-b2998e9f753c NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The two major types of COPD are chronic bronchitis and emphysema. Signaling description: Histological examinations of lungs in chronic bronchitis show increased bronchial vascularity. Outcome effects: These changes are associated with increased VEGFA production in chronic bronchitis and CCND1-dependent endothelial alveolar septal cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 17968307 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-865da8fe-3176-4c8b-b387-b2998e9f753c VEGFA Low Expression Level in Chronic Bronchitis uuid-865da8fe-3176-4c8b-b387-b2998e9f753c PS:CellType endothelial cell PS:Description Histological examinations of lungs in chronic bronchitis show increased bronchial vascularity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-865da8fe-3176-4c8b-b387-b2998e9f753c PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The two major types of COPD are chronic bronchitis and emphysema. Signaling description: Histological examinations of lungs in chronic bronchitis show increased bronchial vascularity. Outcome effects: These changes are associated with increased VEGFA production in chronic bronchitis and CCND1-dependent endothelial alveolar septal cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17968307 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8667f2f9-a427-4d4b-a472-5be87603d65e NodeType: Pathway Notes: Headnote: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Signaling description: Platelet activation and coagulation normally do not occur within an intact blood vessel. After vessel wall injury, platelet-plug formation is initiated by the adherence of platelets to subendothelial collagen. Platelet activation is a dynamic process involving several different pathways. Soluble platelet agonists that are released from damaged cells (e.g. ADP) and produced during coagulation (e.g. thrombin) and inflammation (e.g. platelet-activating factor), which activate platelets via G-protein-coupled receptors (GPCR). Platelets express GNAQ, Ga12/13, Gi/o, and GNAS. GNAQ, Ga12/13, and Gi/o in platelets are coupled to agonist receptors that stimulate platelet activation. GNAS is coupled to receptors for physiological platelet inhibitors such as PGI2 and adenosine that mediate inhibitory signals by stimulating adenylate cyclase-dependent cAMP signaling. Thrombin-induced platelet activation is mediated via a dual system of G-protein coupled protease-activated receptors (PAR) including F2R and F2RL3 in humans. TXA2 activates platelets via the TXA2 receptor, TBXA2R which couples to GNAQ and GNA13. Serotonin recognizes the GNAQ-coupled receptor, HTR2A. ADP induces platelet activation via P2RY1 (GNAQ-coupled) and P2RY12 (Gi/o-coupled). GNAQ has been shown to transmit cellular signals mainly through its interaction and stimulation of phospholipase C-beta (PLCB1). PLCB1 catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to release inositol 1,4,5 -trisphospate (IP3) and diacylglycerol, which activate calcium (Ca2 ) mobilization and protein kinase C (PKC), respectively. The elevation of Ca2+ levels activates multiple signaling events and molecules including actin-myosin interaction, PKC, calmodulin, nitric oxide synthases (NOS), and Ca2+-dependent proteases. Classical PKCs, particularly PRKCA, play a critical and general role in platelet granule secretion and secretion-dependent aggregation. Outcome effects: A common platelet response to agonists is the secretion of granule contents. Platelets contain three major types of granules including alpha-granules (containing adhesion proteins, coagulation and fibrinolytic factors, cytokines, growth factors, and adhesion receptors), dense granules (containing nucleotides like ADP, ATP and GTP, serotonin, histamine, pyrophosphates, divalent cations, etc.), and lysosomes. There are multiple pathways that are important for stimulating granule secretion including calcium signaling, PKC-dependent phosphorylation and regulation of SNAP receptor complexes, signaling via small GTPases such as RAC1 and RHOA, the PI3K/AKT1 signaling pathway, and the signaling pathways of MAPK isoforms p38, integrin activation, the NO/cGMP/PKG pathway (not shown), and others. Finally, GNAQ signaling is important for GPCR-stimulated platelet granule secretion, integrin activation, and consequent platelet aggregation. GNA13 stimulates platelet shape change and granule secretion. Importantly, the GPCR and integrin outside-in signaling pathways coordinate with each other to dynamically regulate RHOA-dependent signaling in platelets. This crosstalk is critical for the processes of shape change, granule secretion, spreading, and clot retraction in platelets. Organ: generic Organ_System: hematological system PMID: 23704217 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-8667f2f9-a427-4d4b-a472-5be87603d65e Platelet Activation via GPCR Signaling uuid-8667f2f9-a427-4d4b-a472-5be87603d65e PS:CellType blood platelet PS:Description The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8667f2f9-a427-4d4b-a472-5be87603d65e PS:NodeType Pathway PS:Notes Headnote: The primary physiological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. Signaling description: Platelet activation and coagulation normally do not occur within an intact blood vessel. After vessel wall injury, platelet-plug formation is initiated by the adherence of platelets to subendothelial collagen. Platelet activation is a dynamic process involving several different pathways. Soluble platelet agonists that are released from damaged cells (e.g. ADP) and produced during coagulation (e.g. thrombin) and inflammation (e.g. platelet-activating factor), which activate platelets via G-protein-coupled receptors (GPCR). Platelets express GNAQ, Ga12/13, Gi/o, and GNAS. GNAQ, Ga12/13, and Gi/o in platelets are coupled to agonist receptors that stimulate platelet activation. GNAS is coupled to receptors for physiological platelet inhibitors such as PGI2 and adenosine that mediate inhibitory signals by stimulating adenylate cyclase-dependent cAMP signaling. Thrombin-induced platelet activation is mediated via a dual system of G-protein coupled protease-activated receptors (PAR) including F2R and F2RL3 in humans. TXA2 activates platelets via the TXA2 receptor, TBXA2R which couples to GNAQ and GNA13. Serotonin recognizes the GNAQ-coupled receptor, HTR2A. ADP induces platelet activation via P2RY1 (GNAQ-coupled) and P2RY12 (Gi/o-coupled). GNAQ has been shown to transmit cellular signals mainly through its interaction and stimulation of phospholipase C-beta (PLCB1). PLCB1 catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to release inositol 1,4,5 -trisphospate (IP3) and diacylglycerol, which activate calcium (Ca2 ) mobilization and protein kinase C (PKC), respectively. The elevation of Ca2+ levels activates multiple signaling events and molecules including actin-myosin interaction, PKC, calmodulin, nitric oxide synthases (NOS), and Ca2+-dependent proteases. Classical PKCs, particularly PRKCA, play a critical and general role in platelet granule secretion and secretion-dependent aggregation. Outcome effects: A common platelet response to agonists is the secretion of granule contents. Platelets contain three major types of granules including alpha-granules (containing adhesion proteins, coagulation and fibrinolytic factors, cytokines, growth factors, and adhesion receptors), dense granules (containing nucleotides like ADP, ATP and GTP, serotonin, histamine, pyrophosphates, divalent cations, etc.), and lysosomes. There are multiple pathways that are important for stimulating granule secretion including calcium signaling, PKC-dependent phosphorylation and regulation of SNAP receptor complexes, signaling via small GTPases such as RAC1 and RHOA, the PI3K/AKT1 signaling pathway, and the signaling pathways of MAPK isoforms p38, integrin activation, the NO/cGMP/PKG pathway (not shown), and others. Finally, GNAQ signaling is important for GPCR-stimulated platelet granule secretion, integrin activation, and consequent platelet aggregation. GNA13 stimulates platelet shape change and granule secretion. Importantly, the GPCR and integrin outside-in signaling pathways coordinate with each other to dynamically regulate RHOA-dependent signaling in platelets. This crosstalk is critical for the processes of shape change, granule secretion, spreading, and clot retraction in platelets. PS:Organ generic PS:Organ_System hematological system PS:PMID 23704217 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-866c8957-60b0-4177-835a-f20bb8793dea NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-866c8957-60b0-4177-835a-f20bb8793dea NRG1 -> MEF/MYOD Expression Targets uuid-866c8957-60b0-4177-835a-f20bb8793dea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-866c8957-60b0-4177-835a-f20bb8793dea PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86757af0-9023-472a-a7a0-e8987d9936af NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-86757af0-9023-472a-a7a0-e8987d9936af Endometrial Cancer Mutated Genes uuid-86757af0-9023-472a-a7a0-e8987d9936af PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86757af0-9023-472a-a7a0-e8987d9936af PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-867e77c4-0ebf-4248-9814-30faf7dfe17c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-867e77c4-0ebf-4248-9814-30faf7dfe17c Phenylalanine metabolism template uuid-867e77c4-0ebf-4248-9814-30faf7dfe17c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-867e77c4-0ebf-4248-9814-30faf7dfe17c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-869a1ec4-37c5-4ff2-9643-c91151d21c8e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-869a1ec4-37c5-4ff2-9643-c91151d21c8e Ascorbate Biosyntesis uuid-869a1ec4-37c5-4ff2-9643-c91151d21c8e PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-869a1ec4-37c5-4ff2-9643-c91151d21c8e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86acb5f6-738c-4917-a5da-692f313ef1d9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-86acb5f6-738c-4917-a5da-692f313ef1d9 Sample of ARDS genetic predisposition variants uuid-86acb5f6-738c-4917-a5da-692f313ef1d9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86acb5f6-738c-4917-a5da-692f313ef1d9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sebocyte Description: Sebocytes produce and secrete lipid-rich sebum into the hair canal and provoke hair loss. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86c5f6c2-4cc2-403d-aded-6d83a50134ca NodeType: Pathway Notes: Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: The sebaceous gland and hair follicles constitute the pilosebaceous unit of the skin. Differentiated sebocytes produce and secrete lipid-rich sebum into the hair canal which empties out to the skin surface. The sebaceous gland is continuously renewed throughout adult life by a population of progenitor cells. It has been shown that the sebum excretion rate is significantly increased in male pattern alopecia. Recent studies suggest that androgens are the positive signal for sebocyte proliferation and the factor that limits their differentiation. However, the mechanism that provides the influence of androgens and androgen receptors (ARs) on proliferation and differentiation is unclear. The peak of AR expression is observed just before the onset of differentiation and then persists during the first accumulation of lipids, marked by FASN and PPARG. Sebocytes derived from bulge stem cells require PPARG for proper homeostasis of the gland. AR functions to prevent TP53 activation, terminate proliferation, and promote MYC-induced differentiation of sebocytes. However, in response to high MYC activity, TP53 can block AR signaling and thereby inhibit differentiation which leads to the expansion of undifferentiated sebocytes. Androgens stimulate sebaceous lipids, while in vivo and in vitro experiments demonstrate that testosterone affects proliferation in human sebocytes, but does not affect lipid synthesis. Therefore, androgens may influence AR cofactors. PPARG is an important AR cofactor which induces the differentiation of sebocytes. The renewal of sebocytes is tightly associated with the regulation of stem cells in the pilosebaceous unit. SOX9 is the earliest marker of both sebocyte progenitor cells and hair follicle stem cells niche. Some patients with androgenetic alopecia (AGA) demonstrate higher SOX9 expression levels in the balding site of the head, as compared to the occipital area. KRT15-positive bulge stem cells have demonstrated their capacity to replenish the sebocyte lineage. Transcription factors, PRDM1 and MYC regulate proliferation and sebaceous gland formation. SHH signaling may be a positive regulator of proliferation of sebocyte progenitor cells. Outcome effects: Sebocyte cell differentiation requires the suppression of canonical WNT/CTNNB1 signaling-related proliferation of progenitor cells. In mouse model, SMAD7 reduces canonical WNT activity and sebocyte differentiation by directly binding to CTNNB1 and recruiting SMURF2, which leads to the degradation of cytoplasmic CTNNB1. DKK1 is an inhibitor of WNT signaling. DKK1 levels are high in the bald scalp compared to the haired scalp of patients with male pattern baldness. In addition, IGF1 signaling has tremendous implications for the differentiation of pilosebaceous cells. TGFB1 signaling maintains sebocytes in an undifferentiated state by decreasing the expression of FADS2 and PPARG as well as lipid accumulation through the TGFBR2/SMAD2 dependent pathway. Mature sebocytes secrete an oily, waxy substance called sebum. Human sebum consists of squalene, esters of glycerol, wax, cholesterol, free cholesterol, and fatty acids. Squalene accumulation may be considered as a marker of sebocyte differentiation and therefore of sebogenesis. Sapienic acid is a sebum fatty acid that is unique to humans. Circulating fatty acids are selectively utilized by the sebaceous gland. Fatty acid transformation leads to the generation of acetyl-CoA which is incorporated into squalene and wax ester synthesis. DGAT1 and DGAT2 Organ: skin Organ_System: integumentary system PMID: 11851890 PMID: 17377380 PMID: 18287092 PMID: 20224686 PMID: 20871834 PMID: 21519409 PMID: 22358062 PMID: 22440736 PMID: 22960253 PMID: 23343495 PMID: 23403291 PMID: 777055 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-86c5f6c2-4cc2-403d-aded-6d83a50134ca Androgens in Sebocyte Maturation uuid-86c5f6c2-4cc2-403d-aded-6d83a50134ca PS:CellType sebocyte PS:Description Sebocytes produce and secrete lipid-rich sebum into the hair canal and provoke hair loss. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86c5f6c2-4cc2-403d-aded-6d83a50134ca PS:NodeType Pathway PS:Notes Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: The sebaceous gland and hair follicles constitute the pilosebaceous unit of the skin. Differentiated sebocytes produce and secrete lipid-rich sebum into the hair canal which empties out to the skin surface. The sebaceous gland is continuously renewed throughout adult life by a population of progenitor cells. It has been shown that the sebum excretion rate is significantly increased in male pattern alopecia. Recent studies suggest that androgens are the positive signal for sebocyte proliferation and the factor that limits their differentiation. However, the mechanism that provides the influence of androgens and androgen receptors (ARs) on proliferation and differentiation is unclear. The peak of AR expression is observed just before the onset of differentiation and then persists during the first accumulation of lipids, marked by FASN and PPARG. Sebocytes derived from bulge stem cells require PPARG for proper homeostasis of the gland. AR functions to prevent TP53 activation, terminate proliferation, and promote MYC-induced differentiation of sebocytes. However, in response to high MYC activity, TP53 can block AR signaling and thereby inhibit differentiation which leads to the expansion of undifferentiated sebocytes. Androgens stimulate sebaceous lipids, while in vivo and in vitro experiments demonstrate that testosterone affects proliferation in human sebocytes, but does not affect lipid synthesis. Therefore, androgens may influence AR cofactors. PPARG is an important AR cofactor which induces the differentiation of sebocytes. The renewal of sebocytes is tightly associated with the regulation of stem cells in the pilosebaceous unit. SOX9 is the earliest marker of both sebocyte progenitor cells and hair follicle stem cells niche. Some patients with androgenetic alopecia (AGA) demonstrate higher SOX9 expression levels in the balding site of the head, as compared to the occipital area. KRT15-positive bulge stem cells have demonstrated their capacity to replenish the sebocyte lineage. Transcription factors, PRDM1 and MYC regulate proliferation and sebaceous gland formation. SHH signaling may be a positive regulator of proliferation of sebocyte progenitor cells. Outcome effects: Sebocyte cell differentiation requires the suppression of canonical WNT/CTNNB1 signaling-related proliferation of progenitor cells. In mouse model, SMAD7 reduces canonical WNT activity and sebocyte differentiation by directly binding to CTNNB1 and recruiting SMURF2, which leads to the degradation of cytoplasmic CTNNB1. DKK1 is an inhibitor of WNT signaling. DKK1 levels are high in the bald scalp compared to the haired scalp of patients with male pattern baldness. In addition, IGF1 signaling has tremendous implications for the differentiation of pilosebaceous cells. TGFB1 signaling maintains sebocytes in an undifferentiated state by decreasing the expression of FADS2 and PPARG as well as lipid accumulation through the TGFBR2/SMAD2 dependent pathway. Mature sebocytes secrete an oily, waxy substance called sebum. Human sebum consists of squalene, esters of glycerol, wax, cholesterol, free cholesterol, and fatty acids. Squalene accumulation may be considered as a marker of sebocyte differentiation and therefore of sebogenesis. Sapienic acid is a sebum fatty acid that is unique to humans. Circulating fatty acids are selectively utilized by the sebaceous gland. Fatty acid transformation leads to the generation of acetyl-CoA which is incorporated into squalene and wax ester synthesis. DGAT1 and DGAT2 PS:Organ skin PS:Organ_System integumentary system PS:PMID 11851890 PS:PMID 17377380 PS:PMID 18287092 PS:PMID 20224686 PS:PMID 20871834 PS:PMID 21519409 PS:PMID 22358062 PS:PMID 22440736 PS:PMID 22960253 PS:PMID 23343495 PS:PMID 23403291 PS:PMID 777055 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86d26359-4613-4991-907c-c77a14ea3682 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-86d26359-4613-4991-907c-c77a14ea3682 FcIgER -> ELK-SRF Signaling uuid-86d26359-4613-4991-907c-c77a14ea3682 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86d26359-4613-4991-907c-c77a14ea3682 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86dc4e7c-b85f-44ab-ac2e-0ef3d9b57a6d NodeType: Pathway Organ: generic Organ_System: generic PMID: 25942647 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-86dc4e7c-b85f-44ab-ac2e-0ef3d9b57a6d PI3K/RAC1 Signaling uuid-86dc4e7c-b85f-44ab-ac2e-0ef3d9b57a6d PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86dc4e7c-b85f-44ab-ac2e-0ef3d9b57a6d PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 25942647 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86e5842a-32a8-4fc2-914b-85e7676552bc NodeType: Pathway Notes: Derivatives of lipids and fatty acids (palmitic acid, stearic acid, and oleic acid) in triglycerides (TGs) are stored in cytoplasmic lipid droplets and used as a source of energy. A common clinical feature of patients with NAFLD is impaired lipid metabolism associated with obesity, insulin resistance (IR), and hyperinsulinemia. TGs accumulate in cytoplasmic lipid droplets forming steatosis. Mitochondria in hepatocytes try to adapt to increased FFAs by enhancing their beta-oxidation rate (the metabolic process of fatty acids degradation). However, increased transport of beta oxidation–derived products leads to increased reactive oxygen species (ROS) release. Excessive ROS release causes oxidative stress (not shown) leading to mitochondrial impairment and further hepatocyte dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-86e5842a-32a8-4fc2-914b-85e7676552bc 1_Triglyceride storage in NAFLD uuid-86e5842a-32a8-4fc2-914b-85e7676552bc PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-86e5842a-32a8-4fc2-914b-85e7676552bc PS:NodeType Pathway PS:Notes Derivatives of lipids and fatty acids (palmitic acid, stearic acid, and oleic acid) in triglycerides (TGs) are stored in cytoplasmic lipid droplets and used as a source of energy. A common clinical feature of patients with NAFLD is impaired lipid metabolism associated with obesity, insulin resistance (IR), and hyperinsulinemia. TGs accumulate in cytoplasmic lipid droplets forming steatosis. Mitochondria in hepatocytes try to adapt to increased FFAs by enhancing their beta-oxidation rate (the metabolic process of fatty acids degradation). However, increased transport of beta oxidation–derived products leads to increased reactive oxygen species (ROS) release. Excessive ROS release causes oxidative stress (not shown) leading to mitochondrial impairment and further hepatocyte dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-871a6f6c-1f3e-405d-974c-630fe452481e NodeType: Pathway Notes: Airway neutrophilia is one of the hallmarks of severe asthma. Neutrophils, the largest class of white blood cells, are major cellular antibacterial agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophilia in asthma is associated with severe asthma and persistent steroid resistance. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-871a6f6c-1f3e-405d-974c-630fe452481e 2_3_Eosinophilia and neutrophilia in asthma: Neutrophil chemotaxis and activation uuid-871a6f6c-1f3e-405d-974c-630fe452481e PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-871a6f6c-1f3e-405d-974c-630fe452481e PS:NodeType Pathway PS:Notes Airway neutrophilia is one of the hallmarks of severe asthma. Neutrophils, the largest class of white blood cells, are major cellular antibacterial agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophilia in asthma is associated with severe asthma and persistent steroid resistance. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Arterial Hypertension is a chronic increase in blood pressure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-871d859d-49cd-4737-8bb3-dad3d21e1950 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone is a key mineralocorticoid hormone that has a fundamental role in salt and water homeostasis and blood pressure regulation. Signaling description: Aldosterone production is regulated through the continuing action of the local and systemic angiotensin II, circulating adrenocorticotropic hormone (ACTH), and serum potassium levels. The continuous stimuli increase aldosterone secretion by increasing the gene expression of CYP11B2. AngII binds AGTR1 to activate PLC, which causes the hydrolysis of PIP2 to diacylglycerol and IP3, which then binds ITPR1 in the endoplasmic reticulum (ER), releasing calcium (Ca2+) and, thus raising the cytosolic Ca2+ concentrations. Diacylglycerol activates PKC, which phosphorylates PRKD1, which then directly phosphorylates and activates CREB1. Further, CREB1 binds NR4A2, FOS, and STAR transcription factors. Further, FOS inhibits the transcription of CYP17A1 and blocks 17-hydroxypregnenolone synthesis. STAR is a crucial protein for the transport of cholesterol to mitochondria, where biosynthesis of steroids is initiated. NR4A2 plays a major role in the stimulation of CYP11B2 gene expression. Aldosterone is synthesized by CYP11B2. K+ can induce CYP11B2 expression in the adrenal as well as the synthesis of aldosterone. Outcome effects: Modest increases in extracellular K+ depolarize the glomerulosa cell, which activates voltage-dependent, L-type calcium channels such as CACNA1C, CACNA2D1, and CACNB2, and increases Ca2+ influx. The membrane depolarization induced by elevated intracellular K+ concentration (via KCNJ5/ KCNK3) causes the activation of FOS and CREB1 genes. The increased intracellular Ca2+ concentration activates CAMK via calmodulin. CAMK phosphorylates and activates CREB1. Possible activating mutations in KCNJ5 and CYP11B2 enhance their functioning. AngII and increased Ca2+ and K+ influx promote constant aldosterone secretion, which activates the expression of CYP11B2. The overproduction of aldosterone causes aldosteronism and leads to arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: adrenal gland Organ: zona glomerulosa Organ_System: endocrine system PMID: 21311022 PMID: 21839803 PMID: 23378101 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-871d859d-49cd-4737-8bb3-dad3d21e1950 Aldosterone Synthesis Chronic Regulation uuid-871d859d-49cd-4737-8bb3-dad3d21e1950 PS:Description Arterial Hypertension is a chronic increase in blood pressure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-871d859d-49cd-4737-8bb3-dad3d21e1950 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone is a key mineralocorticoid hormone that has a fundamental role in salt and water homeostasis and blood pressure regulation. Signaling description: Aldosterone production is regulated through the continuing action of the local and systemic angiotensin II, circulating adrenocorticotropic hormone (ACTH), and serum potassium levels. The continuous stimuli increase aldosterone secretion by increasing the gene expression of CYP11B2. AngII binds AGTR1 to activate PLC, which causes the hydrolysis of PIP2 to diacylglycerol and IP3, which then binds ITPR1 in the endoplasmic reticulum (ER), releasing calcium (Ca2+) and, thus raising the cytosolic Ca2+ concentrations. Diacylglycerol activates PKC, which phosphorylates PRKD1, which then directly phosphorylates and activates CREB1. Further, CREB1 binds NR4A2, FOS, and STAR transcription factors. Further, FOS inhibits the transcription of CYP17A1 and blocks 17-hydroxypregnenolone synthesis. STAR is a crucial protein for the transport of cholesterol to mitochondria, where biosynthesis of steroids is initiated. NR4A2 plays a major role in the stimulation of CYP11B2 gene expression. Aldosterone is synthesized by CYP11B2. K+ can induce CYP11B2 expression in the adrenal as well as the synthesis of aldosterone. Outcome effects: Modest increases in extracellular K+ depolarize the glomerulosa cell, which activates voltage-dependent, L-type calcium channels such as CACNA1C, CACNA2D1, and CACNB2, and increases Ca2+ influx. The membrane depolarization induced by elevated intracellular K+ concentration (via KCNJ5/ KCNK3) causes the activation of FOS and CREB1 genes. The increased intracellular Ca2+ concentration activates CAMK via calmodulin. CAMK phosphorylates and activates CREB1. Possible activating mutations in KCNJ5 and CYP11B2 enhance their functioning. AngII and increased Ca2+ and K+ influx promote constant aldosterone secretion, which activates the expression of CYP11B2. The overproduction of aldosterone causes aldosteronism and leads to arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ adrenal gland PS:Organ zona glomerulosa PS:Organ_System endocrine system PS:PMID 21311022 PS:PMID 21839803 PS:PMID 23378101 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87205fb7-094e-4dea-a588-a01f9d42876e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-87205fb7-094e-4dea-a588-a01f9d42876e cis-Zeatin biosynthesis (cytosol) template uuid-87205fb7-094e-4dea-a588-a01f9d42876e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87205fb7-094e-4dea-a588-a01f9d42876e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide and has an autosomal recessive inheritance. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87736807-c3f0-4428-abcb-300fa1d545f0 NodeType: Pathway Notes: Headnote: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and has an autosomal recessive mode of inheritance. FMF is caused by mutations in the MEFV gene, which encodes pyrin. The disease is more common among people originating from the eastern Mediterranean area including the Jewish, Turkish, Armenian, and Arab populations from this region. In these ethnic groups, the prevalence of FMF is between 1 in 500 and 1 in 1000 and MEFV mutations are very common, with the carrier rate reaching 1 in 5. The disease has spread over the world with the migrations of these populations over the past century. Signaling description: Pyrin can form part of the NLRP3 inflammasome complex and mutations in MEFV are associated with excess inflammation via increased production of IL1B. Pyrin has been suggested to associate with PYCARD and increase IL1B processing. The function of pyrin has not been completely elucidated, but it appears to be a suppressor of CASP1 activation. Outcome effects: CASP1 is the enzyme which stimulates the production of IL1B, a cytokine central to the process of inflammation. Therefore, an ineffective pyrin fails to inhibit inflammation which results in inflammatory episodes at the cell membrane at differing sites. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ_System: hematological system PMID: 17431422 PMID: 24247370 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-87736807-c3f0-4428-abcb-300fa1d545f0 Familial Mediterranean Fever uuid-87736807-c3f0-4428-abcb-300fa1d545f0 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide and has an autosomal recessive inheritance. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87736807-c3f0-4428-abcb-300fa1d545f0 PS:NodeType Pathway PS:Notes Headnote: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and has an autosomal recessive mode of inheritance. FMF is caused by mutations in the MEFV gene, which encodes pyrin. The disease is more common among people originating from the eastern Mediterranean area including the Jewish, Turkish, Armenian, and Arab populations from this region. In these ethnic groups, the prevalence of FMF is between 1 in 500 and 1 in 1000 and MEFV mutations are very common, with the carrier rate reaching 1 in 5. The disease has spread over the world with the migrations of these populations over the past century. Signaling description: Pyrin can form part of the NLRP3 inflammasome complex and mutations in MEFV are associated with excess inflammation via increased production of IL1B. Pyrin has been suggested to associate with PYCARD and increase IL1B processing. The function of pyrin has not been completely elucidated, but it appears to be a suppressor of CASP1 activation. Outcome effects: CASP1 is the enzyme which stimulates the production of IL1B, a cytokine central to the process of inflammation. Therefore, an ineffective pyrin fails to inhibit inflammation which results in inflammatory episodes at the cell membrane at differing sites. Highlighted proteins: Protein with increased expression or activity is highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System hematological system PS:PMID 17431422 PS:PMID 24247370 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87901010-2b5b-42e9-b780-ce7420fce634 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-87901010-2b5b-42e9-b780-ce7420fce634 WNT7B Expression Targets uuid-87901010-2b5b-42e9-b780-ce7420fce634 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87901010-2b5b-42e9-b780-ce7420fce634 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Recessive X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87929e5c-32e0-4660-9da6-dba7716b10fd NodeType: Pathway Notes: Headnote: Ichthyosis is a family of genetic disorders with dry, scaly and thickened skin. X-linked ichthyosis is the second most common ichthyosis, with a prevalence of 1:2000 to 1:6000. Recessive X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Cutaneous manifestations are present soon after birth and usually tend not to improve with age. X-linked Ichthyosis is caused by mutations in the STS gene coding for steroid sulfatase located on the X-chromosome. Signaling description: Cytosolic sulfotransferase SULT2B1 catalyzes the conversion of cholesterol to cholesterol sulfate. Cholesterol sulfotransferase (SULT2B1) activity generates cholesterol sulfate predominately in the lower nucleated cell layers of the epidermis; in contrast, steroid sulfatase (STS), which catalyzes the hydrolysis of cholesterol sulfate peaks in the outer epidermis. Cholesterol sulfate increases the expression of Fra-1, Fra-2, and Jun D members of the AP-1 family of transcription factors leading to enhanced transcriptional regulation of differentiation-linked proteins, such as TG-1 and involucrin, inducing keratinocyte differentiation. Cholesterol sulfate inhibits serine proteases - kallikrein 7 and kallikrein 5 leading to corneodesmosome degradation. Pathological processes underneath the development of X-linked ichthyosis are depicted on the pathway. Outcome effects: Defective steroid sulfatase is unable to hydrolyze cholesterol sulfate leading to the accumulation of cholesterol sulfate and reducing the available cholesterol needed for the formation of extracellular lamellar bilayers. The accumulating cholesterol sulfate is a potent transcriptional regulator in cutaneous and extracutaneous tissues, where it stimulates epidermal differentiation by several mechanisms. First, it activates the eta isoform of protein kinase C, which in turn stimulates the phosphorylation of epidermal structural proteins, while also increasing cornified envelope formation. In addition, cholesterol sulfate regulates other proteins involved in cornified envelope formation, such as transglutaminase 1 and involucrin, operating through an AP-1 binding site in the promoter region of these proteins. The excess cholesterol sulfate in the stratum corneum in X-linked ichthyosis destabilizes permeability barrier homeostasis. Cholesterol sulfate increases stratum corneum retention through its known function as an inhibitor of serine proteases, kallikrein 7 and kallikrein 5, which mediate the initial stages of corneodesmosome degradation. Also, the stratum corneum in X-linked ichthyosis demonstrates abundant Ca++ in extracellular domains, which preferentially localizes along the external faces of opposing corneodesmosomes. Thus, delayed degradation of corneodesmosomes in X-linked ichthyosis could be due in part to leakage of Ca++ into the lower stratum corneum, with formation of Ca++ bridges between adjacent corneodesmosomes. If Ca++ is present in sufficient quantities, it could stabilize the highly-anionic sulfate groups (from persistent cholesterol sulfate) in the extracellular lipids. The cutaneous clinical phenotype can be explained by the impact of excess cholesterol sulfate on epidermal differentiation and lipid synthesis, as well as on the organization of the lamellar lipids that provide the permeability barrier, and the ability of these lipids to inhibit corneodesmosomes proteolysis. The barrier abnormality in X-linked ichthyosis is also due to the decreased cholesterol content of the stratum corneum. Animal data: not shown Highlighted proteins: KLK5, KLK7 and cholesterol are highlighted in blue in order to illustrate the attenuation of corneodesmosome degradation leading to defects in the stratum corneum protective skin barrier. Mutated proteins: STS gene mutated in X-linked ichthyosis is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 24291327 PMID: 26945532 PMID: 27408699 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-87929e5c-32e0-4660-9da6-dba7716b10fd X-Linked Ichthyosis uuid-87929e5c-32e0-4660-9da6-dba7716b10fd PS:CellType keratinocyte PS:Description Recessive X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87929e5c-32e0-4660-9da6-dba7716b10fd PS:NodeType Pathway PS:Notes Headnote: Ichthyosis is a family of genetic disorders with dry, scaly and thickened skin. X-linked ichthyosis is the second most common ichthyosis, with a prevalence of 1:2000 to 1:6000. Recessive X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Cutaneous manifestations are present soon after birth and usually tend not to improve with age. X-linked Ichthyosis is caused by mutations in the STS gene coding for steroid sulfatase located on the X-chromosome. Signaling description: Cytosolic sulfotransferase SULT2B1 catalyzes the conversion of cholesterol to cholesterol sulfate. Cholesterol sulfotransferase (SULT2B1) activity generates cholesterol sulfate predominately in the lower nucleated cell layers of the epidermis; in contrast, steroid sulfatase (STS), which catalyzes the hydrolysis of cholesterol sulfate peaks in the outer epidermis. Cholesterol sulfate increases the expression of Fra-1, Fra-2, and Jun D members of the AP-1 family of transcription factors leading to enhanced transcriptional regulation of differentiation-linked proteins, such as TG-1 and involucrin, inducing keratinocyte differentiation. Cholesterol sulfate inhibits serine proteases - kallikrein 7 and kallikrein 5 leading to corneodesmosome degradation. Pathological processes underneath the development of X-linked ichthyosis are depicted on the pathway. Outcome effects: Defective steroid sulfatase is unable to hydrolyze cholesterol sulfate leading to the accumulation of cholesterol sulfate and reducing the available cholesterol needed for the formation of extracellular lamellar bilayers. The accumulating cholesterol sulfate is a potent transcriptional regulator in cutaneous and extracutaneous tissues, where it stimulates epidermal differentiation by several mechanisms. First, it activates the eta isoform of protein kinase C, which in turn stimulates the phosphorylation of epidermal structural proteins, while also increasing cornified envelope formation. In addition, cholesterol sulfate regulates other proteins involved in cornified envelope formation, such as transglutaminase 1 and involucrin, operating through an AP-1 binding site in the promoter region of these proteins. The excess cholesterol sulfate in the stratum corneum in X-linked ichthyosis destabilizes permeability barrier homeostasis. Cholesterol sulfate increases stratum corneum retention through its known function as an inhibitor of serine proteases, kallikrein 7 and kallikrein 5, which mediate the initial stages of corneodesmosome degradation. Also, the stratum corneum in X-linked ichthyosis demonstrates abundant Ca++ in extracellular domains, which preferentially localizes along the external faces of opposing corneodesmosomes. Thus, delayed degradation of corneodesmosomes in X-linked ichthyosis could be due in part to leakage of Ca++ into the lower stratum corneum, with formation of Ca++ bridges between adjacent corneodesmosomes. If Ca++ is present in sufficient quantities, it could stabilize the highly-anionic sulfate groups (from persistent cholesterol sulfate) in the extracellular lipids. The cutaneous clinical phenotype can be explained by the impact of excess cholesterol sulfate on epidermal differentiation and lipid synthesis, as well as on the organization of the lamellar lipids that provide the permeability barrier, and the ability of these lipids to inhibit corneodesmosomes proteolysis. The barrier abnormality in X-linked ichthyosis is also due to the decreased cholesterol content of the stratum corneum. Animal data: not shown Highlighted proteins: KLK5, KLK7 and cholesterol are highlighted in blue in order to illustrate the attenuation of corneodesmosome degradation leading to defects in the stratum corneum protective skin barrier. Mutated proteins: STS gene mutated in X-linked ichthyosis is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 24291327 PS:PMID 26945532 PS:PMID 27408699 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Epigenetic changes including histone acetylation / deacetylation are thought to play important roles in the onset of genomic instability and progression of cancer in numerous tumor types. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87b2a0ff-79e1-4790-adde-5484f369f76b NodeType: Pathway Notes: Headnote: Epigenetic changes including histone acetylation/deacetylation are thought participate in the onset of genomic instability and progression of cancer in numerous tumor types. The loss of acetylation of specific residues in core histones H2, H3 and H4 have been identified as a marker of tumor cells. Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs).Histone acetylation conducted by HATs removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active euchromatin). The reverse process of chromatin condensation is conducted by HDACs.Three major families of HATs transfer acetyl groups to lysine residues of the core histones include the MYST family (KAT6A/B, KAT5 and others), GNAT family (KAT2A/2B and others), and the CBP/p300 family (CREBBP, EP300 and others). HATs are recruited by transcription factors as co-activators (usually as part of large chromatin remodeling complexes). Importantly, HATs such as KAT2A/2B, EP300, and CREBBP also acetylate a number of non-histone proteins, many of which are involved in oncogenesis. KAT6A/B, KAT5, KAT2B, CREBBP, EP300, NCOA1/3 can be mutated and deregulated in neoplasms. Outcome effects: Deregulation of HATs creates an impairment of histone acetylation and chromatin remodeling leading to oncogenic progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Acetylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Acetylation" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17613546 PMID: 17694074 PMID: 19509247 PMID: 21074720 PMID: 23927873 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-87b2a0ff-79e1-4790-adde-5484f369f76b Acetylases Inhibition in Histone Deacetylation in Cancer uuid-87b2a0ff-79e1-4790-adde-5484f369f76b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Epigenetic changes including histone acetylation / deacetylation are thought to play important roles in the onset of genomic instability and progression of cancer in numerous tumor types. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87b2a0ff-79e1-4790-adde-5484f369f76b PS:NodeType Pathway PS:Notes Headnote: Epigenetic changes including histone acetylation/deacetylation are thought participate in the onset of genomic instability and progression of cancer in numerous tumor types. The loss of acetylation of specific residues in core histones H2, H3 and H4 have been identified as a marker of tumor cells. Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs).Histone acetylation conducted by HATs removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active euchromatin). The reverse process of chromatin condensation is conducted by HDACs.Three major families of HATs transfer acetyl groups to lysine residues of the core histones include the MYST family (KAT6A/B, KAT5 and others), GNAT family (KAT2A/2B and others), and the CBP/p300 family (CREBBP, EP300 and others). HATs are recruited by transcription factors as co-activators (usually as part of large chromatin remodeling complexes). Importantly, HATs such as KAT2A/2B, EP300, and CREBBP also acetylate a number of non-histone proteins, many of which are involved in oncogenesis. KAT6A/B, KAT5, KAT2B, CREBBP, EP300, NCOA1/3 can be mutated and deregulated in neoplasms. Outcome effects: Deregulation of HATs creates an impairment of histone acetylation and chromatin remodeling leading to oncogenic progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Acetylation" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutations and Altered Expression Implicated in Histone Acetylation" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17613546 PS:PMID 17694074 PS:PMID 19509247 PS:PMID 21074720 PS:PMID 23927873 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87ea0783-29bb-40ac-bfb5-f5bf465c328f NodeType: Pathway Notes: Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: Normally, TNF and FASLG interaction with their receptors, TNFRSF1A/TNFRSF1B and FAS, respectively induce apoptosis. The activation of TNFR1 and FAS leads to the recruitment of TRADD-FADD complex and CASP8. CASP8 activates CASP3 via two signaling routes. In the first pathway, CASP8 cleaves BID and its active part is translocated into the mitochondria where it triggers CYCS release through BAX activation. CYCS affects CASP9 which activates CASP3. In the second pathway, CASP8 directly activates CASP3. There exists a further common pathway for TNF and FASLG which includes MAP3K5 activation and also leads to apoptosis. MAP3K5 inactivates the antiapoptotic factor BCL2 through MAPK8 and MAPK14. Through binding to TNFR1, TNF also activates the recruitment of TRADD, which via TRAF2/ MAP3K14, activates NF-kB which is an antiapoptotic transcription factor. NF-kB suppresses apoptosis by inducing the transcription of antiapoptotic genes including BIRC2, BIRC3, and BIRC5. Outcome effects: The antiapoptotic proteins BIRC2, BIRC3, and BIRC5 prevent cytochrome c-induced activation of CASP9, and when they are repressed by DIABLO apoptosis is initiated. Viral Nef protein interacts with MAP3K5 and inhibits it which frees BCL2, which in turn inhibits BAX. This leads to the block the following signal transduction needed for the induction of apoptosis, thereby preventing infected cell death. Highlighted proteins: Viral protein is highlighted in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival. HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. Organ_System: lymphatic system PMID: 18664624 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-87ea0783-29bb-40ac-bfb5-f5bf465c328f Apoptosis Block in Infected Cells uuid-87ea0783-29bb-40ac-bfb5-f5bf465c328f PS:CellType T-cell PS:Description Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS) in which infections and cancers occur. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87ea0783-29bb-40ac-bfb5-f5bf465c328f PS:NodeType Pathway PS:Notes Headnote: Human immunodeficiency virus (HIV) is a lentivirus which causes acquired immunodeficiency syndrome (AIDS), a condition in which the progressive failure of the immune system allows life-threatening opportunistic infections and cancers to occur. Signaling description: Normally, TNF and FASLG interaction with their receptors, TNFRSF1A/TNFRSF1B and FAS, respectively induce apoptosis. The activation of TNFR1 and FAS leads to the recruitment of TRADD-FADD complex and CASP8. CASP8 activates CASP3 via two signaling routes. In the first pathway, CASP8 cleaves BID and its active part is translocated into the mitochondria where it triggers CYCS release through BAX activation. CYCS affects CASP9 which activates CASP3. In the second pathway, CASP8 directly activates CASP3. There exists a further common pathway for TNF and FASLG which includes MAP3K5 activation and also leads to apoptosis. MAP3K5 inactivates the antiapoptotic factor BCL2 through MAPK8 and MAPK14. Through binding to TNFR1, TNF also activates the recruitment of TRADD, which via TRAF2/ MAP3K14, activates NF-kB which is an antiapoptotic transcription factor. NF-kB suppresses apoptosis by inducing the transcription of antiapoptotic genes including BIRC2, BIRC3, and BIRC5. Outcome effects: The antiapoptotic proteins BIRC2, BIRC3, and BIRC5 prevent cytochrome c-induced activation of CASP9, and when they are repressed by DIABLO apoptosis is initiated. Viral Nef protein interacts with MAP3K5 and inhibits it which frees BCL2, which in turn inhibits BAX. This leads to the block the following signal transduction needed for the induction of apoptosis, thereby preventing infected cell death. Highlighted proteins: Viral protein is highlighted in grey. References: 1). Santos-Costa Q, Gracas-Pereira J, Azevedo-Pereira JM (2007) Death on arrival. HIV and apoptosis - an . VIII Congresso Virtual HIV/AIDS - Current research insights into HIV/AIDS and related diseases. ISBN 978-972-95977-7-0. p. 149-96. PS:Organ_System lymphatic system PS:PMID 18664624 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: neuron Description: Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87f730f6-be57-4b25-8b0c-7b852e3ae915 NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Dopamine is the neurotransmitter that helps control muscle movement. Signaling description: Normally, dopamine is synthesized from L-tyrosine by tyrosine hydroxylase (TH) and then transported from the cytosol into synaptic vesicles by VMAT2 (SLC18A2) to be released when necessary. In the synaptic cleft, dopamine interacts with its receptors on the postsynaptic neuron and triggers the transmission of the nerve impulse. The duration of dopaminergic action is limited by dopamine inactivation, i.e. mainly methylation by catechol-O-methyltransferase (COMT) in the prefrontal cortex and re-uptake via the dopamine transporter, DAT1 (SLC6A3) and autoreceptors, DRD2 in the striatum. SLC18A2 is responsible for sequestering dopamine into storage vesicles within the neurons, however it is estimated that about 10% of dopamine escape into the neuronal cytoplasm and is subsequently metabolized by MAOA or MAOB, ALDH1A1 (in cytoplasm), ALDH2 (in mitochondria), and COMT. In addition, it is suggested that ALDH1A1 maintains reduced intraneuronal levels of 3,4-dihydroxyphenylacetaldehyde by catalyzing its metabolism to 3,4-dihydroxyphenylacetic acid. This homeostatic function is crucial because the accumulation of 3,4-dihydroxyphenylacetaldehyde may be neurotoxic and result in neuronal cell death. Outcome effects: The lack of dopamine due to dopaminergic neuron loss causes motor dysfunction in PD. The use of pharmacological agents that affect the mechanism of dopamine synthesis and degradation is the most common strategy for treatment of PD symptoms. Organ: brain Organ_System: nervous system PMID: 10692500 PMID: 11215754 PMID: 16552415 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-87f730f6-be57-4b25-8b0c-7b852e3ae915 Dopamine Metabolism in Parkinson's Disease uuid-87f730f6-be57-4b25-8b0c-7b852e3ae915 PS:CellType neuron PS:Description Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87f730f6-be57-4b25-8b0c-7b852e3ae915 PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Dopamine is the neurotransmitter that helps control muscle movement. Signaling description: Normally, dopamine is synthesized from L-tyrosine by tyrosine hydroxylase (TH) and then transported from the cytosol into synaptic vesicles by VMAT2 (SLC18A2) to be released when necessary. In the synaptic cleft, dopamine interacts with its receptors on the postsynaptic neuron and triggers the transmission of the nerve impulse. The duration of dopaminergic action is limited by dopamine inactivation, i.e. mainly methylation by catechol-O-methyltransferase (COMT) in the prefrontal cortex and re-uptake via the dopamine transporter, DAT1 (SLC6A3) and autoreceptors, DRD2 in the striatum. SLC18A2 is responsible for sequestering dopamine into storage vesicles within the neurons, however it is estimated that about 10% of dopamine escape into the neuronal cytoplasm and is subsequently metabolized by MAOA or MAOB, ALDH1A1 (in cytoplasm), ALDH2 (in mitochondria), and COMT. In addition, it is suggested that ALDH1A1 maintains reduced intraneuronal levels of 3,4-dihydroxyphenylacetaldehyde by catalyzing its metabolism to 3,4-dihydroxyphenylacetic acid. This homeostatic function is crucial because the accumulation of 3,4-dihydroxyphenylacetaldehyde may be neurotoxic and result in neuronal cell death. Outcome effects: The lack of dopamine due to dopaminergic neuron loss causes motor dysfunction in PD. The use of pharmacological agents that affect the mechanism of dopamine synthesis and degradation is the most common strategy for treatment of PD symptoms. PS:Organ brain PS:Organ_System nervous system PS:PMID 10692500 PS:PMID 11215754 PS:PMID 16552415 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87fdd0a9-3f34-4e6b-a2ac-499d7bd00945 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: Parathyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-87fdd0a9-3f34-4e6b-a2ac-499d7bd00945 Elevated Receptors -> Expression Targets in Parathyroid Gland uuid-87fdd0a9-3f34-4e6b-a2ac-499d7bd00945 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-87fdd0a9-3f34-4e6b-a2ac-499d7bd00945 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Lung disease is the major cause of mortality in cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88075ea4-24bd-4855-a52a-8cdae99095d4 NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. It is unclear how the disruptions of ion transport cause lung disease in CF. There are several theories of how the defects in the protein and cellular function cause the clinical effects. In the oxidative stress theory, the mutant CFTR channel fails to transport antioxidants to counteract neutrophil-associated oxidative stress. In CF, the constitutive activation of NF-kB and IL8 expression results in increased chemotaxis of neutrophils and increased amounts of reactive oxygen species (ROS) being generated by neutrophils accumulated in the airway. The activation of macrophages, neutrophils, and eosinophils generates oxygen (O2), which is rapidly converted to H2O2 by superoxide dismutase (SOD1). H2O2 activates NF-kB and mediates other oxidative stress responses. Several cytokines such as IL1B, TNF, and TLRs can activate NF-kB signaling in epithelial cells. AGT, VEGFA, P2RY2, ADORA2B, and ADRB2 are important for the activation of epithelial cells and synthesis of free radicals. There are many other activators that are involved. Cellular signaling pathways include the activation of phospholipase C (PLC), adenylate cyclase (ADCY), and protein kinase C (PKC) in addition to the release of calcium (Ca2+). Outcome effects: In conditions of oxidative stress, epithelial cells begin to produce antioxidants such as glutathione and thiocyanate. The tripeptide, glutathione is formed by the actions of GCLC, GCLM, and glutathione synthetase (GSS). Glutathione reductase (GSR) uses glutathione as a substrate in the detoxification of peroxides such as H2O2 and lipid peroxides. Mutant CFTR in the epithelial cells is unable to channel glutathione and thiocyanate into the airways and decreases the detoxification. Bacterial killing in the airway is diminished as well since thiocyanate also has antimicrobial properties. Thiosulfate sulfurtransferase (TST) expression is induced via cAMP signaling. In addition, glutathione synthesis is regulated by Jun/Fos and NF-kB in alveolar epithelial cells in response to various environmental oxidants and inflammatory stimuli. Low levels of nitric oxide (NO) in CF leads to the decreased activation of membrane cystine and glutamate transport, leading to the reduction of glutathione synthesis in lung cells. The activity of NFE2L2, a transcription factor that regulates antioxidant and cytoprotective protein expression, is diminished in CF. There are no identified explanations for this, but it may be possible that NFE2L2 dysregulation occurs through binding to cAMP-inducible CREBBP, which is competitive to up-regulating NF-kB- CREBBP binding. One potential mechanism for NFE2L2 deficiency is that a decreased interaction with CREBBP reduces nuclear dwell time and DNA binding. Another possible mechanism that inhibits NFE2L2 is its removal from the nucleus via KEAP1 interaction. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 11028671 PMID: 22467641 PMID: 22481418 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-88075ea4-24bd-4855-a52a-8cdae99095d4 CFTR Facilitates Oxidative Stress in Airway Epithelium in CF uuid-88075ea4-24bd-4855-a52a-8cdae99095d4 PS:CellType epithelial cell PS:Description Lung disease is the major cause of mortality in cystic fibrosis (CF) which is an autosomal recessive disease caused by mutations in CFTR gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88075ea4-24bd-4855-a52a-8cdae99095d4 PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: CFTR regulates the movement of chloride (Cl-) and sodium (Na+) ions across epithelial membranes such as the alveolar epithelia located in the lungs. It is unclear how the disruptions of ion transport cause lung disease in CF. There are several theories of how the defects in the protein and cellular function cause the clinical effects. In the oxidative stress theory, the mutant CFTR channel fails to transport antioxidants to counteract neutrophil-associated oxidative stress. In CF, the constitutive activation of NF-kB and IL8 expression results in increased chemotaxis of neutrophils and increased amounts of reactive oxygen species (ROS) being generated by neutrophils accumulated in the airway. The activation of macrophages, neutrophils, and eosinophils generates oxygen (O2), which is rapidly converted to H2O2 by superoxide dismutase (SOD1). H2O2 activates NF-kB and mediates other oxidative stress responses. Several cytokines such as IL1B, TNF, and TLRs can activate NF-kB signaling in epithelial cells. AGT, VEGFA, P2RY2, ADORA2B, and ADRB2 are important for the activation of epithelial cells and synthesis of free radicals. There are many other activators that are involved. Cellular signaling pathways include the activation of phospholipase C (PLC), adenylate cyclase (ADCY), and protein kinase C (PKC) in addition to the release of calcium (Ca2+). Outcome effects: In conditions of oxidative stress, epithelial cells begin to produce antioxidants such as glutathione and thiocyanate. The tripeptide, glutathione is formed by the actions of GCLC, GCLM, and glutathione synthetase (GSS). Glutathione reductase (GSR) uses glutathione as a substrate in the detoxification of peroxides such as H2O2 and lipid peroxides. Mutant CFTR in the epithelial cells is unable to channel glutathione and thiocyanate into the airways and decreases the detoxification. Bacterial killing in the airway is diminished as well since thiocyanate also has antimicrobial properties. Thiosulfate sulfurtransferase (TST) expression is induced via cAMP signaling. In addition, glutathione synthesis is regulated by Jun/Fos and NF-kB in alveolar epithelial cells in response to various environmental oxidants and inflammatory stimuli. Low levels of nitric oxide (NO) in CF leads to the decreased activation of membrane cystine and glutamate transport, leading to the reduction of glutathione synthesis in lung cells. The activity of NFE2L2, a transcription factor that regulates antioxidant and cytoprotective protein expression, is diminished in CF. There are no identified explanations for this, but it may be possible that NFE2L2 dysregulation occurs through binding to cAMP-inducible CREBBP, which is competitive to up-regulating NF-kB- CREBBP binding. One potential mechanism for NFE2L2 deficiency is that a decreased interaction with CREBBP reduces nuclear dwell time and DNA binding. Another possible mechanism that inhibits NFE2L2 is its removal from the nucleus via KEAP1 interaction. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 11028671 PS:PMID 22467641 PS:PMID 22481418 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SIRT6 is the deacetylase which is important for chromatin structure maintenance and genomic stability. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-880915a7-2463-42e1-8048-bc52ea10dd90 NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT6 is the deacetylase which is important for chromatin structure maintenance and genomic stability. Signaling description: SIRT6 requires NAD+ for its function. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT6 is a NAD+-dependent histone deacetylase which has many highly site-specific targets in the nucleus. SIRT6 has specificity for deacetylating lysine 9 of histone H3 (H3K9Ac) and lysine 56 of histone H3 (H3K56). Outcome effects: NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. SIRT6 required for efficient DNA double-strand break repair. SIRT6 also regulates telomere-independent cell aging by inhibiting NF-kB signaling. Animal data: Deficiency of SIRT6 leads to shortened lifespan and an aging-like phenotype in mice. Organ: generic Organ_System: generic PMID: 18226091 PMID: 19135889 PMID: 26191269 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-880915a7-2463-42e1-8048-bc52ea10dd90 SIRT6 Signaling in Aging uuid-880915a7-2463-42e1-8048-bc52ea10dd90 PS:CellType generic PS:Description SIRT6 is the deacetylase which is important for chromatin structure maintenance and genomic stability. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-880915a7-2463-42e1-8048-bc52ea10dd90 PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT6 is the deacetylase which is important for chromatin structure maintenance and genomic stability. Signaling description: SIRT6 requires NAD+ for its function. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT6 is a NAD+-dependent histone deacetylase which has many highly site-specific targets in the nucleus. SIRT6 has specificity for deacetylating lysine 9 of histone H3 (H3K9Ac) and lysine 56 of histone H3 (H3K56). Outcome effects: NAD+ dependency of sirtuins can provide the link between metabolic activity and genome stability during aging. SIRT6 required for efficient DNA double-strand break repair. SIRT6 also regulates telomere-independent cell aging by inhibiting NF-kB signaling. Animal data: Deficiency of SIRT6 leads to shortened lifespan and an aging-like phenotype in mice. PS:Organ generic PS:Organ_System generic PS:PMID 18226091 PS:PMID 19135889 PS:PMID 26191269 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-880af376-4f21-48a1-a30a-e47d6f4ff3ca NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-880af376-4f21-48a1-a30a-e47d6f4ff3ca EGFR -> ZNF259 Signaling uuid-880af376-4f21-48a1-a30a-e47d6f4ff3ca PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-880af376-4f21-48a1-a30a-e47d6f4ff3ca PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88153ab0-ea8d-4974-b550-6aab2ecb773f NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-88153ab0-ea8d-4974-b550-6aab2ecb773f Polysaccharide Degradation uuid-88153ab0-ea8d-4974-b550-6aab2ecb773f PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88153ab0-ea8d-4974-b550-6aab2ecb773f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Acetaminophen (paracetamol) is metabolized primarily in the liver by different metabolic pathways. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8829fc00-d3d5-40ce-a04f-a4e26d18879b NodeType: Pathway Notes: Headnote: Acetaminophen (paracetamol) is a widely used antipyretic and analgesic drug which is a major ingredient in cold and flu remedies. Signaling description: Acetaminophen is metabolized primarily in the liver via different metabolic pathways and approximately 15% of the drug is metabolized by cytochrome CYP2E1 into toxic NAPQI metabolite. This metabolite is capable of directly modifying cysteine residues within a polypeptide chain by arylation mechanism. In hepatocytes, this modification leads to the inactivation of catalase (CAT) and inhibition of Ca2+-transporting ATPase (ATP2B1). The depletion of these proteins causes ROS accumulation, which in turn promotes apoptotic mitochondrial damage. Outcome effects: The described events along with decreased ATP production induce necrotic transformation. Another target of NAPQI is HMG-CoA synthase (HMGCS2), which is one of the key enzymes in ketone biosynthesis. Therefore, this metabolic pathway also becomes blocked by NAPQI. Organ: liver Organ_System: digestive system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-8829fc00-d3d5-40ce-a04f-a4e26d18879b Acetaminophen Induced Hepatotoxicity uuid-8829fc00-d3d5-40ce-a04f-a4e26d18879b PS:CellType hepatocyte PS:Description Acetaminophen (paracetamol) is metabolized primarily in the liver by different metabolic pathways. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8829fc00-d3d5-40ce-a04f-a4e26d18879b PS:NodeType Pathway PS:Notes Headnote: Acetaminophen (paracetamol) is a widely used antipyretic and analgesic drug which is a major ingredient in cold and flu remedies. Signaling description: Acetaminophen is metabolized primarily in the liver via different metabolic pathways and approximately 15% of the drug is metabolized by cytochrome CYP2E1 into toxic NAPQI metabolite. This metabolite is capable of directly modifying cysteine residues within a polypeptide chain by arylation mechanism. In hepatocytes, this modification leads to the inactivation of catalase (CAT) and inhibition of Ca2+-transporting ATPase (ATP2B1). The depletion of these proteins causes ROS accumulation, which in turn promotes apoptotic mitochondrial damage. Outcome effects: The described events along with decreased ATP production induce necrotic transformation. Another target of NAPQI is HMG-CoA synthase (HMGCS2), which is one of the key enzymes in ketone biosynthesis. Therefore, this metabolic pathway also becomes blocked by NAPQI. PS:Organ liver PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-884aa15b-e7c1-46e5-b8d5-2b03f24ce000 NodeType: Pathway Notes: Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Signaling description: Usher proteins localize to the periciliary region and basal bodies next to the connecting cilia and the synaptic region of the photoreceptors. Many of the Usher protein variants for PCDH15, CDH23 and GPR96 found in the cochlea are also found in the retina. Based on the protein interactions and localization at the periciliary membrane complex, an area close to the connecting cilium, implicated in membrane trafficking to the outer segments, it has been proposed that the Usher protein complexes might have a role in the trafficking of vesicular cargo between the inner and outer segments of the photoreceptors. A direct role for the actin binding molecular motor, myosin VIIA (MYO7A), in opsin (RHO) transport through the cilium, has been suggested. This may be a sign of the general involvement for Usher proteins in the transport of cargo between the inner and outer segments of the photoreceptors. Outcome effects: In the absence of MYO7A, there is a significant decrease in outer disk phagocytosis by pigment epithelial cells. MYRIP, a protein that binds MYO7A and directly interacts with RAB27A might be involved in the process of melanosomes transport to the apical microvilli of the retinal pigment epithelium cells. Mutated proteins: Mutated proteins are shown in white-out style. Organ: Retina Organ: eye Organ_System: sensory system PMID: 16219682 PMID: 16987892 PMID: 19056669 PMID: 24239741 PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-884aa15b-e7c1-46e5-b8d5-2b03f24ce000 Proteins Mutated in Photoreceptor and Retinal Pigment Epithelial Cell uuid-884aa15b-e7c1-46e5-b8d5-2b03f24ce000 PS:CellType epithelial cell PS:Description Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-884aa15b-e7c1-46e5-b8d5-2b03f24ce000 PS:NodeType Pathway PS:Notes Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Signaling description: Usher proteins localize to the periciliary region and basal bodies next to the connecting cilia and the synaptic region of the photoreceptors. Many of the Usher protein variants for PCDH15, CDH23 and GPR96 found in the cochlea are also found in the retina. Based on the protein interactions and localization at the periciliary membrane complex, an area close to the connecting cilium, implicated in membrane trafficking to the outer segments, it has been proposed that the Usher protein complexes might have a role in the trafficking of vesicular cargo between the inner and outer segments of the photoreceptors. A direct role for the actin binding molecular motor, myosin VIIA (MYO7A), in opsin (RHO) transport through the cilium, has been suggested. This may be a sign of the general involvement for Usher proteins in the transport of cargo between the inner and outer segments of the photoreceptors. Outcome effects: In the absence of MYO7A, there is a significant decrease in outer disk phagocytosis by pigment epithelial cells. MYRIP, a protein that binds MYO7A and directly interacts with RAB27A might be involved in the process of melanosomes transport to the apical microvilli of the retinal pigment epithelium cells. Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 16219682 PS:PMID 16987892 PS:PMID 19056669 PS:PMID 24239741 PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88747e97-2e39-4309-b660-66aff56e5c70 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-88747e97-2e39-4309-b660-66aff56e5c70 CNR1/2 -> Membrane Transport uuid-88747e97-2e39-4309-b660-66aff56e5c70 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88747e97-2e39-4309-b660-66aff56e5c70 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Fully-folded proteins transport from ER to the Golgi complex. Proteins travel through the secretory pathway in membrane-bound vesicles. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88946c73-8ce7-44fc-ad6f-e7fa964ad260 NodeType: Pathway Notes: Headnote: The endoplasmic reticulum (ER) and Golgi complex are the main components of the secretory pathway. Fully-folded proteins transport from ER to the Golgi complex. Proteins travel through the secretory pathway in membrane-bound vesicles. The process of vesicle budding requires coat proteins that pinch off the vesicle from the donor membrane. Signaling description: There are three types of coated vesicles including vesicles with a COPII coat, vesicles with a COPI coat, and vesicles with a clathrin coat. The inner shell of the coat, or adaptor complex, sorts cargo into the vesicle and recognizes the tethering. Tethers provide a physical connection between the vesicle and target membrane. After tethering is established, fusion is mediated by SNAP receptors that are located on the vesicle and target membrane. RAB proteins may promote the transition from tethering to fusion by recruiting tethers to fusion sites, where they promote SNAP receptor complex assembly. Vesicles with a COPII coat transport proteins from the rough ER to the Golgi and COPII coat vesicles interact with ERGIC. The first step along the mammalian secretory pathway involves the homotypic fusion of COPII vesicles to form vesicular tubular clusters (VTCs), also called the pre-Golgi compartment. Tether protein TRAPPC3 is important for this homotypic membrane fusion event. Secretory cargo is concentrated at ERGIC and may be delivered to pre-Golgi intermediates or directly into tubular membrane clusters due to the activity of COPII complex. SEC23/24 and SEC13, 23, 24, and 31 heterodimers form a COPII-coated bud on the ER membrane. The pre-Golgi structures are associated with microtubules and move in a minus-end-directed manner. COPI machinery regulates retrograde transport from the Golgi complex to the ER and intra-Golgi transport. COPI is a heptameric cytosolic protein complex that, in conjunction with ARF1, assembles onto Golgi membranes. COPI regulates the composition and concentration of SNAP receptor proteins and lipids in the cisternae. Mammalian multi-subunit TRAPP complex is associated with COPI-coated vesicles within the early Golgi, but not at the late Golgi. RAB1A is the proposed main target of TRAPP activity. RAB2A promotes the formation of retrograde-directed vesicles. GAPDH is also involved in COPI vesicle formation and has a critical role at the fission stage. The Golgi transport complex acts as a tethering factor and the increase of Ca2 during the late phase of intra-Golgi transport stimulates the fusion of membranes containing cargo proteins and Golgi cisternae. Ca2 -transporting ATPases play an essential role at this stage. The cis face, or entry face, of the Golgi is where pre-Golgi intermediates first merge together. Outcome effects: The cargo molecules then move through polarized stacks of flattened cisternae enriched in glycoprotein and glycolipid-processing enzymes to the trans-Golgi network. There protein and lipid are packaged into transport intermediates that move through the cytoplasm to fuse with the cell surface or with other compartments of the endosomal system. References:1). Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Organ: generic Organ_System: generic PMID: 19948493 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-88946c73-8ce7-44fc-ad6f-e7fa964ad260 Golgi Transport uuid-88946c73-8ce7-44fc-ad6f-e7fa964ad260 PS:CellType generic PS:Description Fully-folded proteins transport from ER to the Golgi complex. Proteins travel through the secretory pathway in membrane-bound vesicles. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88946c73-8ce7-44fc-ad6f-e7fa964ad260 PS:NodeType Pathway PS:Notes Headnote: The endoplasmic reticulum (ER) and Golgi complex are the main components of the secretory pathway. Fully-folded proteins transport from ER to the Golgi complex. Proteins travel through the secretory pathway in membrane-bound vesicles. The process of vesicle budding requires coat proteins that pinch off the vesicle from the donor membrane. Signaling description: There are three types of coated vesicles including vesicles with a COPII coat, vesicles with a COPI coat, and vesicles with a clathrin coat. The inner shell of the coat, or adaptor complex, sorts cargo into the vesicle and recognizes the tethering. Tethers provide a physical connection between the vesicle and target membrane. After tethering is established, fusion is mediated by SNAP receptors that are located on the vesicle and target membrane. RAB proteins may promote the transition from tethering to fusion by recruiting tethers to fusion sites, where they promote SNAP receptor complex assembly. Vesicles with a COPII coat transport proteins from the rough ER to the Golgi and COPII coat vesicles interact with ERGIC. The first step along the mammalian secretory pathway involves the homotypic fusion of COPII vesicles to form vesicular tubular clusters (VTCs), also called the pre-Golgi compartment. Tether protein TRAPPC3 is important for this homotypic membrane fusion event. Secretory cargo is concentrated at ERGIC and may be delivered to pre-Golgi intermediates or directly into tubular membrane clusters due to the activity of COPII complex. SEC23/24 and SEC13, 23, 24, and 31 heterodimers form a COPII-coated bud on the ER membrane. The pre-Golgi structures are associated with microtubules and move in a minus-end-directed manner. COPI machinery regulates retrograde transport from the Golgi complex to the ER and intra-Golgi transport. COPI is a heptameric cytosolic protein complex that, in conjunction with ARF1, assembles onto Golgi membranes. COPI regulates the composition and concentration of SNAP receptor proteins and lipids in the cisternae. Mammalian multi-subunit TRAPP complex is associated with COPI-coated vesicles within the early Golgi, but not at the late Golgi. RAB1A is the proposed main target of TRAPP activity. RAB2A promotes the formation of retrograde-directed vesicles. GAPDH is also involved in COPI vesicle formation and has a critical role at the fission stage. The Golgi transport complex acts as a tethering factor and the increase of Ca2 during the late phase of intra-Golgi transport stimulates the fusion of membranes containing cargo proteins and Golgi cisternae. Ca2 -transporting ATPases play an essential role at this stage. The cis face, or entry face, of the Golgi is where pre-Golgi intermediates first merge together. Outcome effects: The cargo molecules then move through polarized stacks of flattened cisternae enriched in glycoprotein and glycolipid-processing enzymes to the trans-Golgi network. There protein and lipid are packaged into transport intermediates that move through the cytoplasm to fuse with the cell surface or with other compartments of the endosomal system. References:1). Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. PS:Organ generic PS:Organ_System generic PS:PMID 19948493 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: cardiac stem cell Description: Loss of DREAM complex and increased activity of MYBL2-MuvB-FOXM1 drive cells out of quiescence to proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88a0d3e3-f044-4af2-a610-30dacae86f21 NodeType: Pathway Notes: Headnote: The DREAM complex consists of RBL1 or RBL2, E2F4, E2F5, TFDP and MuvB proteins. DREAM mediates gene repression during G0 and coordinates periodic gene expression with peaks during G1/S and G2/M. Perturbations in DREAM regulation and disassembly of DREAM shifts the balance from quiescence towards proliferation and contribute to increased mitotic gene expression levels frequently observed in cancers. LIN9, LIN54, LIN37, LIN52 and RBBP4 comprise the MuvB core. MuvB also coordinates gene expression during S phase and G2/M through its interactions with MYBL2 and FOXM1. Signaling description: The assembly and function of DREAM may be impaired via diverse mechanisms. Inactivating mutations in tumor suppressor genes LATS1/2 disrupt the DYRK1A-dependent phosphorylation and activation of MuvB subunit LIN52. RBL2 subunit of DREAM may be inactivated due to either a mutation or impairment of TP53/ CDKN1A/ CCNE1 function. MYBL2 and FOXM1 are overexpressed in a number of tumor types. Outcome effects: The hyper-activation of MYBL2 and FOXM1 induce expression of G2-specific genes (CCNB1, CDK1 and others) and cancer cell proliferation. BIRC5 expression inhibits apoptosis. Animal data: The majority of data concerning DREAM complex functioning were obtained in animal models. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: heart Organ_System: cardiovascular system PMID: 20404087 PMID: 21498570 PMID: 23842645 PMID: 26384566 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-88a0d3e3-f044-4af2-a610-30dacae86f21 DREAM Complex and FOXM1/MYBL2 Promote Cell Cycle Progression in Cancer uuid-88a0d3e3-f044-4af2-a610-30dacae86f21 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType cardiac stem cell PS:Description Loss of DREAM complex and increased activity of MYBL2-MuvB-FOXM1 drive cells out of quiescence to proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88a0d3e3-f044-4af2-a610-30dacae86f21 PS:NodeType Pathway PS:Notes Headnote: The DREAM complex consists of RBL1 or RBL2, E2F4, E2F5, TFDP and MuvB proteins. DREAM mediates gene repression during G0 and coordinates periodic gene expression with peaks during G1/S and G2/M. Perturbations in DREAM regulation and disassembly of DREAM shifts the balance from quiescence towards proliferation and contribute to increased mitotic gene expression levels frequently observed in cancers. LIN9, LIN54, LIN37, LIN52 and RBBP4 comprise the MuvB core. MuvB also coordinates gene expression during S phase and G2/M through its interactions with MYBL2 and FOXM1. Signaling description: The assembly and function of DREAM may be impaired via diverse mechanisms. Inactivating mutations in tumor suppressor genes LATS1/2 disrupt the DYRK1A-dependent phosphorylation and activation of MuvB subunit LIN52. RBL2 subunit of DREAM may be inactivated due to either a mutation or impairment of TP53/ CDKN1A/ CCNE1 function. MYBL2 and FOXM1 are overexpressed in a number of tumor types. Outcome effects: The hyper-activation of MYBL2 and FOXM1 induce expression of G2-specific genes (CCNB1, CDK1 and others) and cancer cell proliferation. BIRC5 expression inhibits apoptosis. Animal data: The majority of data concerning DREAM complex functioning were obtained in animal models. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20404087 PS:PMID 21498570 PS:PMID 23842645 PS:PMID 26384566 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88cb0d7a-a89a-4e44-b643-6c1fea61d0a9 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-88cb0d7a-a89a-4e44-b643-6c1fea61d0a9 IL22R -> STAT3 Signaling uuid-88cb0d7a-a89a-4e44-b643-6c1fea61d0a9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88cb0d7a-a89a-4e44-b643-6c1fea61d0a9 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: kidney mesangial cell Description: Glomerulonephritis is an inflammatory disease of the glomeruli and small blood vessels of the kidneys. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f3e62f-87de-4ea3-8fa4-6c9430badbe1 NodeType: Pathway Notes: Glomerulonephritis is an inflammatory disease of the glomeruli and small blood vessels of the kidneys. Overexpression of TGFB1 in renal cells leads to glomerular mesangial cell hypertrophy and glomerular fibrosis by extracellular matrix degradation. Organ: kidney Organ_System: urinary tract PMID: 12529270 PMID: 16408108 PMID: 22811597 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: interstitium urn:agi-pathway:uuid-88f3e62f-87de-4ea3-8fa4-6c9430badbe1 Mesangial Cell Dysfunction in Glomerulonephritis uuid-88f3e62f-87de-4ea3-8fa4-6c9430badbe1 PS:CellType kidney mesangial cell PS:Description Glomerulonephritis is an inflammatory disease of the glomeruli and small blood vessels of the kidneys. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f3e62f-87de-4ea3-8fa4-6c9430badbe1 PS:NodeType Pathway PS:Notes Glomerulonephritis is an inflammatory disease of the glomeruli and small blood vessels of the kidneys. Overexpression of TGFB1 in renal cells leads to glomerular mesangial cell hypertrophy and glomerular fibrosis by extracellular matrix degradation. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 12529270 PS:PMID 16408108 PS:PMID 22811597 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue interstitium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f73f06-7fc6-463f-907f-504caa4a0736 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: mouth Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-88f73f06-7fc6-463f-907f-504caa4a0736 Elevated Receptors -> Expression Targets in Mouth uuid-88f73f06-7fc6-463f-907f-504caa4a0736 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f73f06-7fc6-463f-907f-504caa4a0736 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ mouth PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f86cd1-d3d8-44bd-af71-f03e3ad644e7 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-88f86cd1-d3d8-44bd-af71-f03e3ad644e7 H3 Arginin Modification Sites uuid-88f86cd1-d3d8-44bd-af71-f03e3ad644e7 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-88f86cd1-d3d8-44bd-af71-f03e3ad644e7 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: M-cell Description: Bile acid activates motilin release by M-cells in small intestine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8928e5a6-f356-407a-8052-f9a7b78d4fd8 NodeType: Pathway Notes: Headnote: M-cells are located in the small intestine and secrete motilin (MLN), a small peptide hormone released in response to the bile acid signals. Signaling description: Bile acid interacts with G protein-coupled bile acid receptor 1 (GPBAR1) on the surface of M-cells in the small intestine. Activation of GPBAR1 leads to cAMP synthesis and PKA activation. The precise mechanism of this signaling is unknown. The secretion of motilin can be blocked by acetylcholine (via CHRM1), histamine, ghrelin and glucose. Secreted motilin interacts with motilin receptor (MLNR) located on the postsynaptic surface of vagal nerves. Activation of MLNR leads to an increase of gastric motility. Also, MLNR can interact with arrestin beta 2 (ARRB2). Outcome effects: Bile acid dependent secretion of motilin leads to gastric motility activation. Organ: colon Organ: intestine Organ: small intestine Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-8928e5a6-f356-407a-8052-f9a7b78d4fd8 M-cell: Motilin Release uuid-8928e5a6-f356-407a-8052-f9a7b78d4fd8 PS:CellType M-cell PS:Description Bile acid activates motilin release by M-cells in small intestine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8928e5a6-f356-407a-8052-f9a7b78d4fd8 PS:NodeType Pathway PS:Notes Headnote: M-cells are located in the small intestine and secrete motilin (MLN), a small peptide hormone released in response to the bile acid signals. Signaling description: Bile acid interacts with G protein-coupled bile acid receptor 1 (GPBAR1) on the surface of M-cells in the small intestine. Activation of GPBAR1 leads to cAMP synthesis and PKA activation. The precise mechanism of this signaling is unknown. The secretion of motilin can be blocked by acetylcholine (via CHRM1), histamine, ghrelin and glucose. Secreted motilin interacts with motilin receptor (MLNR) located on the postsynaptic surface of vagal nerves. Activation of MLNR leads to an increase of gastric motility. Also, MLNR can interact with arrestin beta 2 (ARRB2). Outcome effects: Bile acid dependent secretion of motilin leads to gastric motility activation. PS:Organ colon PS:Organ intestine PS:Organ small intestine PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89304268-b1be-412d-b00b-876522025d2c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-89304268-b1be-412d-b00b-876522025d2c Lactate-methylglyoxal metabolism template uuid-89304268-b1be-412d-b00b-876522025d2c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89304268-b1be-412d-b00b-876522025d2c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8930d5f1-480c-452e-ba16-e96f4796f3ca NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-8930d5f1-480c-452e-ba16-e96f4796f3ca TACR1 -> TNF/IL6/IL8 Production uuid-8930d5f1-480c-452e-ba16-e96f4796f3ca PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8930d5f1-480c-452e-ba16-e96f4796f3ca PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8937d24f-0b79-432b-8fb3-1525393180cb NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-8937d24f-0b79-432b-8fb3-1525393180cb PTGIR -> Vasodilation uuid-8937d24f-0b79-432b-8fb3-1525393180cb PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8937d24f-0b79-432b-8fb3-1525393180cb PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8942b763-b96d-4a07-ba96-b80b3a10e96f NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-8942b763-b96d-4a07-ba96-b80b3a10e96f Hemophilia Studied Drugs uuid-8942b763-b96d-4a07-ba96-b80b3a10e96f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8942b763-b96d-4a07-ba96-b80b3a10e96f PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: dopaminergic neuron CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89442973-927c-4f6e-baa9-ecde7d460525 NodeType: Pathway Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-89442973-927c-4f6e-baa9-ecde7d460525 Dopamine Synthesis and Release in Migraine uuid-89442973-927c-4f6e-baa9-ecde7d460525 PS:CellType dopaminergic neuron PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89442973-927c-4f6e-baa9-ecde7d460525 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Human telomeres are the ends of chromosomes which consist of many kilobases of (TTAGGG)n tandemly-repeated DNA sequences with various associated proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-896052d7-bb61-4531-bab9-44f3def84a2b NodeType: Pathway Notes: Headnote: Human telomeres are the ends of chromosomes which consist of many kilobases of (TTAGGG)n tandemly-repeated DNA sequences with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the telomeres with each cell division during each S phase of DNA replication. Signaling description: A cell stops dividing when the telomere length reaches a critical point and the enzyme telomerase can compensate this loss. Mammalian telomerases are composed of the TTAGGG sequence, an RNA molecule TERC, and a catalytic subunit TERT. TERC has an RNA template sequence which pairs with the terminal TTAGGG repeat to initiate elongation of the 3' DNA end. In a single elongation, only one repeat of the sequence can be added. Circularly-permuted sequence GGTTAG terminates the synthesis. TERT determines the availability of the telomerase function. The phosphorylation status of TERT is involved in the modulation of the catalytic activity of telomerase. In mammals, a variety of proteins like DKC1, TEP1, and HNRNPA1 assist in telomerase assembly and facilitate interactions between telomerase and the telomere. Telomeric structural proteins interact with the telomere and regulate the opening and closing of the free telomere end. Outcome effects: Telomeres that end in a 3' overhang (G-strand overhang) bend back and anneal with the complementary sequences in the 5' end of the opposite strand. This creates a telomere T-loop which is stabilized by a set of specialized proteins such as TERF1, TERF2, TINF2, and TNKS. Complex interactions between these proteins, telomeric DNA, and other cellular factors are necessary for maintenance of the telomere. MRE11A complex, the Ku complex (XRCC6 and XRCC5), and ATM function in the detection of short telomeres and trigger DNA damage response pathways or the repair of telomere sequences. A telomere that becomes too short fails to protect the chromosome from DNA damage and when the damage occurs, proteins like TP53 respond by discontinuing cell replication and forcing it into senescence. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-896052d7-bb61-4531-bab9-44f3def84a2b Telomere Maintenance uuid-896052d7-bb61-4531-bab9-44f3def84a2b PS:CellType generic PS:Description Human telomeres are the ends of chromosomes which consist of many kilobases of (TTAGGG)n tandemly-repeated DNA sequences with various associated proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-896052d7-bb61-4531-bab9-44f3def84a2b PS:NodeType Pathway PS:Notes Headnote: Human telomeres are the ends of chromosomes which consist of many kilobases of (TTAGGG)n tandemly-repeated DNA sequences with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the telomeres with each cell division during each S phase of DNA replication. Signaling description: A cell stops dividing when the telomere length reaches a critical point and the enzyme telomerase can compensate this loss. Mammalian telomerases are composed of the TTAGGG sequence, an RNA molecule TERC, and a catalytic subunit TERT. TERC has an RNA template sequence which pairs with the terminal TTAGGG repeat to initiate elongation of the 3' DNA end. In a single elongation, only one repeat of the sequence can be added. Circularly-permuted sequence GGTTAG terminates the synthesis. TERT determines the availability of the telomerase function. The phosphorylation status of TERT is involved in the modulation of the catalytic activity of telomerase. In mammals, a variety of proteins like DKC1, TEP1, and HNRNPA1 assist in telomerase assembly and facilitate interactions between telomerase and the telomere. Telomeric structural proteins interact with the telomere and regulate the opening and closing of the free telomere end. Outcome effects: Telomeres that end in a 3' overhang (G-strand overhang) bend back and anneal with the complementary sequences in the 5' end of the opposite strand. This creates a telomere T-loop which is stabilized by a set of specialized proteins such as TERF1, TERF2, TINF2, and TNKS. Complex interactions between these proteins, telomeric DNA, and other cellular factors are necessary for maintenance of the telomere. MRE11A complex, the Ku complex (XRCC6 and XRCC5), and ATM function in the detection of short telomeres and trigger DNA damage response pathways or the repair of telomere sequences. A telomere that becomes too short fails to protect the chromosome from DNA damage and when the damage occurs, proteins like TP53 respond by discontinuing cell replication and forcing it into senescence. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89841fdc-a293-4564-add6-59f7ecc8010b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-89841fdc-a293-4564-add6-59f7ecc8010b Isoflavonoid Biosynthesis template uuid-89841fdc-a293-4564-add6-59f7ecc8010b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89841fdc-a293-4564-add6-59f7ecc8010b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8994e804-e6f7-4351-b62a-578d5a790120 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8994e804-e6f7-4351-b62a-578d5a790120 IAA degradation (plants) template uuid-8994e804-e6f7-4351-b62a-578d5a790120 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8994e804-e6f7-4351-b62a-578d5a790120 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89c192c7-8faa-4818-ad8a-fa1b9dbd243e NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-89c192c7-8faa-4818-ad8a-fa1b9dbd243e Proteins Involved in Osteoporosis uuid-89c192c7-8faa-4818-ad8a-fa1b9dbd243e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89c192c7-8faa-4818-ad8a-fa1b9dbd243e PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Single-strand nucleotide excision DNA repair may be impaired in cancer due to mutation or deregulation of multiple proteins involved in this process. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89c9f89f-c933-484d-9359-55e93935d248 NodeType: Pathway Notes: Headnote: Several proteins involved in single-strand nucleotide excision DNA repair may be mutated or deregulated in cancer, including XPC, ERCC1/3/4, LIG1 and POLE Signaling description: Nucleotide excision repair (NER) involves more than 30 proteins and their action includes several steps: damage recognition, local opening of the DNA duplex around the lesion, dual incision of the damaged DNA strand, gap repair synthesis and strand ligation. The two distinct forms of NER include global genomic NER (GG-NER) (repairs damage in transcriptionally silent regions of the genome) and transcription-coupled NER (TC-NER) (repairs lesions on actively transcribed DNA). The two pathways are very similar with the exception of their mechanisms of damage recognition. In GG-NER, the initial detection of damaged DNA is performed by the XPC protein complex; whereas, TC-NER does not require XPC and occurs when the transcription apparatus stops at the damaged site. The further steps are similar in the two forms of NER. XPA and replication factor A bind at the site of injury and further proceed with damage recognition. Next, the ERCC3 and ERCC2 helicases (components of TFIIH transcription factor) unwind the DNA duplex close to the lesion and enable RNA polymerase II to initiate transcription. Further, one DNA strand is cleaved by ERCC5 and ERCC1/ ERCC4 endonucleases at positions 3' and 5' to the damage, respectively, generating an oligonucleotide containing the lesion. This oligonucleotide is displaced and facilitates the action of the gap repair synthesis machinery, including DNA polymerase delta and epsilon (POLE) and a number of replication accessory factors. Finally, DNA ligase LIG1 seals the nick in the repaired strand. Some members of single-strand nucleotide excision DNA repair may be mutated or deregulated in cancer, including XPC, ERCC1/3/4, LIG1 and POLE.XPC, LIG1 and POLE are inactivated by mutations. RAD25B stabilizes XPC and can be inhibited by MIR373. ERCC3/4 can be inhibited by MIR192. Transcription of ERCC1 is negatively regulated by HMGA2. The latter can be mutated and overexpressed or activated by downregulation of MIR15A/161/26A1, MIRLET7A1. Outcome effects: The disruption of single-strand nucleotide excision DNA repair machinery leads to genomic instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20177397 PMID: 20965415 PMID: 24947262 PMID: 25017190 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-89c9f89f-c933-484d-9359-55e93935d248 Single Strand Nucleotide Excision DNA Repair Suppression in Cancer uuid-89c9f89f-c933-484d-9359-55e93935d248 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Single-strand nucleotide excision DNA repair may be impaired in cancer due to mutation or deregulation of multiple proteins involved in this process. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-89c9f89f-c933-484d-9359-55e93935d248 PS:NodeType Pathway PS:Notes Headnote: Several proteins involved in single-strand nucleotide excision DNA repair may be mutated or deregulated in cancer, including XPC, ERCC1/3/4, LIG1 and POLE Signaling description: Nucleotide excision repair (NER) involves more than 30 proteins and their action includes several steps: damage recognition, local opening of the DNA duplex around the lesion, dual incision of the damaged DNA strand, gap repair synthesis and strand ligation. The two distinct forms of NER include global genomic NER (GG-NER) (repairs damage in transcriptionally silent regions of the genome) and transcription-coupled NER (TC-NER) (repairs lesions on actively transcribed DNA). The two pathways are very similar with the exception of their mechanisms of damage recognition. In GG-NER, the initial detection of damaged DNA is performed by the XPC protein complex; whereas, TC-NER does not require XPC and occurs when the transcription apparatus stops at the damaged site. The further steps are similar in the two forms of NER. XPA and replication factor A bind at the site of injury and further proceed with damage recognition. Next, the ERCC3 and ERCC2 helicases (components of TFIIH transcription factor) unwind the DNA duplex close to the lesion and enable RNA polymerase II to initiate transcription. Further, one DNA strand is cleaved by ERCC5 and ERCC1/ ERCC4 endonucleases at positions 3' and 5' to the damage, respectively, generating an oligonucleotide containing the lesion. This oligonucleotide is displaced and facilitates the action of the gap repair synthesis machinery, including DNA polymerase delta and epsilon (POLE) and a number of replication accessory factors. Finally, DNA ligase LIG1 seals the nick in the repaired strand. Some members of single-strand nucleotide excision DNA repair may be mutated or deregulated in cancer, including XPC, ERCC1/3/4, LIG1 and POLE.XPC, LIG1 and POLE are inactivated by mutations. RAD25B stabilizes XPC and can be inhibited by MIR373. ERCC3/4 can be inhibited by MIR192. Transcription of ERCC1 is negatively regulated by HMGA2. The latter can be mutated and overexpressed or activated by downregulation of MIR15A/161/26A1, MIRLET7A1. Outcome effects: The disruption of single-strand nucleotide excision DNA repair machinery leads to genomic instability in cancer cells. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20177397 PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a07011f-c222-4d1d-b6e3-bb86836d1c72 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-8a07011f-c222-4d1d-b6e3-bb86836d1c72 B-Cell Receptor -> NFATC Signaling uuid-8a07011f-c222-4d1d-b6e3-bb86836d1c72 PS:CellType B-cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a07011f-c222-4d1d-b6e3-bb86836d1c72 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a16e934-2847-488f-bf9b-4a88af594ebf NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8a16e934-2847-488f-bf9b-4a88af594ebf IL10R -> STAT Signaling uuid-8a16e934-2847-488f-bf9b-4a88af594ebf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a16e934-2847-488f-bf9b-4a88af594ebf PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a196e1e-88b2-4fa4-961d-aa2d49a2bdf6 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-8a196e1e-88b2-4fa4-961d-aa2d49a2bdf6 PECAM -> CTNNB1 Signaling uuid-8a196e1e-88b2-4fa4-961d-aa2d49a2bdf6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a196e1e-88b2-4fa4-961d-aa2d49a2bdf6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a1e5e9c-066b-4c83-9bdb-1a01cfd8e0f0 NodeType: Pathway Notes: The viral protein p12I accumulates in the host cells’ endoplasmic reticulum and Golgi apparatus where it interacts with its major targets, namely, the MHC class I protein complex and interleukin-2 receptor (IL-2R) complex. As a result, p12I stimulates T-cell proliferation and inhibits MHC-I production. On the other hand, p12I lowers the effectiveness of NK-cell binding to the infected T cell by inhibiting IL-2R. Therefore the infected cells are not destroyed by NK cells and continue to produce mature viruses. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-8a1e5e9c-066b-4c83-9bdb-1a01cfd8e0f0 6_p12I Viral protein promotes T-cell activation in HTLV-1 infection uuid-8a1e5e9c-066b-4c83-9bdb-1a01cfd8e0f0 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a1e5e9c-066b-4c83-9bdb-1a01cfd8e0f0 PS:NodeType Pathway PS:Notes The viral protein p12I accumulates in the host cells’ endoplasmic reticulum and Golgi apparatus where it interacts with its major targets, namely, the MHC class I protein complex and interleukin-2 receptor (IL-2R) complex. As a result, p12I stimulates T-cell proliferation and inhibits MHC-I production. On the other hand, p12I lowers the effectiveness of NK-cell binding to the infected T cell by inhibiting IL-2R. Therefore the infected cells are not destroyed by NK cells and continue to produce mature viruses. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a2b3071-c4d2-4084-a3ab-16af3620f5ad NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8a2b3071-c4d2-4084-a3ab-16af3620f5ad WNT9A Expression Targets uuid-8a2b3071-c4d2-4084-a3ab-16af3620f5ad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a2b3071-c4d2-4084-a3ab-16af3620f5ad PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a37e38c-2071-4852-b206-cea55336c2a2 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8a37e38c-2071-4852-b206-cea55336c2a2 TLR4/5/7/9 -> NF-kB Signaling uuid-8a37e38c-2071-4852-b206-cea55336c2a2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a37e38c-2071-4852-b206-cea55336c2a2 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a5d87f3-c065-4d93-9f37-31ede5111f20 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8a5d87f3-c065-4d93-9f37-31ede5111f20 WNT7A Expression Targets uuid-8a5d87f3-c065-4d93-9f37-31ede5111f20 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a5d87f3-c065-4d93-9f37-31ede5111f20 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer sem cell CellType: pericyte CellType: vascular smooth muscle cell Description: TGFB1 signalling plays a major role in VSMCs/pericytes differentiation, proliferation and migration. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a66ed58-d94a-43a8-a7a4-65832a2d1346 NodeType: Pathway Notes: Headnote: Vascular smooth muscle cells (VSMCs) and pericytes belong to the same cell lineage and both cell types are responsible for the contraction of vessels. VSMCs are found in arteries, whereas pericytes are associated with small vessels (arterioles, capillaries, and venules). Endothelial cells and pericytes constantly communicate through reciprocal exchange of growth factors. VSMCs, pericytes and ECs are required for angiogenesis and vasculogenesis, including tumor neovascularization. Signaling description: TGFB1 signaling has a major role in VSMCs/pericytes differentiation, proliferation and migration. Activation of ACVRL1 (ALK1) leads to the phosphorylation of SMAD1/5 and the induction of target genes (ID1/2 and others) that promote cell proliferation and migration, and it opposes VSMCs/pericytes differentiation. Activation of TGFBR1 (ALK5) in mesenchymal cells leads to the phosphorylation of SMAD2/3, thus regulating the expression of specific genes (ACTA2, MYH11, TAGLN, FN1 and others) promoting mitotic and migratory quiescence and differentiation of VSMCs/pericytes. KLF4, GATA6, SRF, MYCOD also be involved in VSMCs/pericytes differentiation. Outcome effects: ACVRL1 signaling may dominate in the early phase of TGFB stimulation, leading to cell proliferation and migration, whereas TGFBR1 signaling dominates later in this process, leading to cell differentiation and extracellular matrix production. Animal data: Most of the insight into molecular processes in VSMCs and pericytes comes from the analysis of genetic mouse models. Organ: blood vessel Organ_System: cardiovascular system PMID: 19164813 PMID: 20073036 PMID: 21839917 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-8a66ed58-d94a-43a8-a7a4-65832a2d1346 Vascular Smooth Muscle Cell/Pericyte Differentiation and Proliferation uuid-8a66ed58-d94a-43a8-a7a4-65832a2d1346 PS:CellType cancer cell PS:CellType cancer sem cell PS:CellType pericyte PS:CellType vascular smooth muscle cell PS:Description TGFB1 signalling plays a major role in VSMCs/pericytes differentiation, proliferation and migration. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a66ed58-d94a-43a8-a7a4-65832a2d1346 PS:NodeType Pathway PS:Notes Headnote: Vascular smooth muscle cells (VSMCs) and pericytes belong to the same cell lineage and both cell types are responsible for the contraction of vessels. VSMCs are found in arteries, whereas pericytes are associated with small vessels (arterioles, capillaries, and venules). Endothelial cells and pericytes constantly communicate through reciprocal exchange of growth factors. VSMCs, pericytes and ECs are required for angiogenesis and vasculogenesis, including tumor neovascularization. Signaling description: TGFB1 signaling has a major role in VSMCs/pericytes differentiation, proliferation and migration. Activation of ACVRL1 (ALK1) leads to the phosphorylation of SMAD1/5 and the induction of target genes (ID1/2 and others) that promote cell proliferation and migration, and it opposes VSMCs/pericytes differentiation. Activation of TGFBR1 (ALK5) in mesenchymal cells leads to the phosphorylation of SMAD2/3, thus regulating the expression of specific genes (ACTA2, MYH11, TAGLN, FN1 and others) promoting mitotic and migratory quiescence and differentiation of VSMCs/pericytes. KLF4, GATA6, SRF, MYCOD also be involved in VSMCs/pericytes differentiation. Outcome effects: ACVRL1 signaling may dominate in the early phase of TGFB stimulation, leading to cell proliferation and migration, whereas TGFBR1 signaling dominates later in this process, leading to cell differentiation and extracellular matrix production. Animal data: Most of the insight into molecular processes in VSMCs and pericytes comes from the analysis of genetic mouse models. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 19164813 PS:PMID 20073036 PS:PMID 21839917 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a7415c8-64a5-4637-9096-246c3e3ca151 NodeType: Pathway Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-8a7415c8-64a5-4637-9096-246c3e3ca151 Proteins Involved in Hearing Loss uuid-8a7415c8-64a5-4637-9096-246c3e3ca151 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a7415c8-64a5-4637-9096-246c3e3ca151 PS:NodeType Pathway PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a829079-57f8-4693-a5ad-34dcad1ebf15 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-8a829079-57f8-4693-a5ad-34dcad1ebf15 Chemokine Receptor Family -> Expression Targets in Lymphoid System uuid-8a829079-57f8-4693-a5ad-34dcad1ebf15 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a829079-57f8-4693-a5ad-34dcad1ebf15 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a8c9e85-1a48-40cf-a1f8-75c083a970c1 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8a8c9e85-1a48-40cf-a1f8-75c083a970c1 CSF2 -> STAT Signaling uuid-8a8c9e85-1a48-40cf-a1f8-75c083a970c1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a8c9e85-1a48-40cf-a1f8-75c083a970c1 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: The polyol pathway is believed to play a role in diabetic microangiopathy. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a8cbfe4-f777-4584-9a40-ad0a300077f3 NodeType: Pathway Notes: Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. The polyol pathway is believed to play a role in diabetic microangiopathy. Signaling description: The polyol pathway of glucose metabolism becomes active only when intracellular glucose levels are elevated. Aldose reductase (AKR1B1), the first and rate-limiting enzyme of the pathway reduces glucose to sorbitol using NADPH as a cofactor. Sorbitol is then metabolized into fructose by sorbitol dehydrogenase (SORD) with NAD usage and NADP production during the reaction. Sorbitol is a hydrophilic molecule and therefore does not diffuse through the cell membrane; thus, it accumulates in the cell inducing osmotic stress. The fructose produced by the polyol pathway can be phosphorylated to fructose-3-phosphate which is broken down to 3-deoxyglucosone. Both compounds are powerful glycosylating agents that are involved in the formation of advanced glycation end products (AGEs). The usage of NADPH by AKR1B1 may lead to less cofactor available for glutathione reductase (GSR). GSR is critical for the maintenance of the intracellular pool of reduced glutathione (GSH). This would reduce the ability of the cell to respond to oxidative stress. The usage of NAD by SORD leads to an increased ratio of NADH/NAD, which has been termed "pseudohypoxia" and is linked to multiple metabolic and signaling changes known to alter cell functioning. It has been proposed that excess NADH may become a substrate for NADH oxidase and this would be a mechanism for the generation of reactive oxygen species. Outcome effects: Thus, activation of the polyol pathway by altering intracellular tonicity, generating AGE precursors, and exposing cells to oxidative stress possibly through decreased antioxidant defenses and generation of oxidant species can initiate and multiply several mechanisms of cellular damage.: Highlighted proteins: Small molcecules with elevated level are highlighted in red, and small moleculces with reduced level is highlighted in blue. Organ: blood vessel Organ_System: endocrine system PMID: 11742414 PMID: 18230954 PMID: 18793542 PMID: 9549756 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-8a8cbfe4-f777-4584-9a40-ad0a300077f3 Polyol Pathway in Diabetic Microangiopathy uuid-8a8cbfe4-f777-4584-9a40-ad0a300077f3 PS:CellType vascular smooth muscle cell PS:Description The polyol pathway is believed to play a role in diabetic microangiopathy. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8a8cbfe4-f777-4584-9a40-ad0a300077f3 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. The polyol pathway is believed to play a role in diabetic microangiopathy. Signaling description: The polyol pathway of glucose metabolism becomes active only when intracellular glucose levels are elevated. Aldose reductase (AKR1B1), the first and rate-limiting enzyme of the pathway reduces glucose to sorbitol using NADPH as a cofactor. Sorbitol is then metabolized into fructose by sorbitol dehydrogenase (SORD) with NAD usage and NADP production during the reaction. Sorbitol is a hydrophilic molecule and therefore does not diffuse through the cell membrane; thus, it accumulates in the cell inducing osmotic stress. The fructose produced by the polyol pathway can be phosphorylated to fructose-3-phosphate which is broken down to 3-deoxyglucosone. Both compounds are powerful glycosylating agents that are involved in the formation of advanced glycation end products (AGEs). The usage of NADPH by AKR1B1 may lead to less cofactor available for glutathione reductase (GSR). GSR is critical for the maintenance of the intracellular pool of reduced glutathione (GSH). This would reduce the ability of the cell to respond to oxidative stress. The usage of NAD by SORD leads to an increased ratio of NADH/NAD, which has been termed "pseudohypoxia" and is linked to multiple metabolic and signaling changes known to alter cell functioning. It has been proposed that excess NADH may become a substrate for NADH oxidase and this would be a mechanism for the generation of reactive oxygen species. Outcome effects: Thus, activation of the polyol pathway by altering intracellular tonicity, generating AGE precursors, and exposing cells to oxidative stress possibly through decreased antioxidant defenses and generation of oxidant species can initiate and multiply several mechanisms of cellular damage.: Highlighted proteins: Small molcecules with elevated level are highlighted in red, and small moleculces with reduced level is highlighted in blue. PS:Organ blood vessel PS:Organ_System endocrine system PS:PMID 11742414 PS:PMID 18230954 PS:PMID 18793542 PS:PMID 9549756 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8aae36be-f46d-4dbe-a237-78cbbab26621 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8aae36be-f46d-4dbe-a237-78cbbab26621 JAG1 Expression Targets uuid-8aae36be-f46d-4dbe-a237-78cbbab26621 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8aae36be-f46d-4dbe-a237-78cbbab26621 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The role of mutations in the SHANK3 gene in the development of autism symptoms of Phelan-McDermid Syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ac0a4b1-b394-4132-a7c7-e4b7fa6d9385 NodeType: Pathway Notes: SHANK3 gene mutations are associated with the development of autism symptoms in patients with Phelan-McDermid Syndrome. Organ_System: nervous system PMID: 25894671 PMID: 26350728 PMID: 26511836 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-8ac0a4b1-b394-4132-a7c7-e4b7fa6d9385 Phelan-McDermid Syndrome uuid-8ac0a4b1-b394-4132-a7c7-e4b7fa6d9385 PS:Description The role of mutations in the SHANK3 gene in the development of autism symptoms of Phelan-McDermid Syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ac0a4b1-b394-4132-a7c7-e4b7fa6d9385 PS:NodeType Pathway PS:Notes SHANK3 gene mutations are associated with the development of autism symptoms in patients with Phelan-McDermid Syndrome. PS:Organ_System nervous system PS:PMID 25894671 PS:PMID 26350728 PS:PMID 26511836 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Germline-inactivating mutations in CDC73 are associated with Hyperparathyroidism-Jaw tumor syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ac74c7f-011e-4900-9d2f-a0a380db710b NodeType: Pathway Notes: Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-inactivating mutations in CDC73 (HRPT2, parafibromin) are associated with hyperparathyroidism-jaw tumor syndrome. Outcome effects: Mutations in CDC73 cause changes in transcription activation, chromatin remodeling and increase parathyrocytes proliferation. Organ: Parathyroid gland Organ_System: endocrine system PMID: 20052758 PMID: 22021426 PMID: 23652676 PMID: 24595969 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-8ac74c7f-011e-4900-9d2f-a0a380db710b CDC73 Mutations Cause Hyperparathyroidism uuid-8ac74c7f-011e-4900-9d2f-a0a380db710b PS:CellType parathyroid cell PS:Description Germline-inactivating mutations in CDC73 are associated with Hyperparathyroidism-Jaw tumor syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ac74c7f-011e-4900-9d2f-a0a380db710b PS:NodeType Pathway PS:Notes Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-inactivating mutations in CDC73 (HRPT2, parafibromin) are associated with hyperparathyroidism-jaw tumor syndrome. Outcome effects: Mutations in CDC73 cause changes in transcription activation, chromatin remodeling and increase parathyrocytes proliferation. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 20052758 PS:PMID 22021426 PS:PMID 23652676 PS:PMID 24595969 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ad27f1e-6ff4-4a51-9cbd-36f013805d0e NodeType: Pathway Organ: penis Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-8ad27f1e-6ff4-4a51-9cbd-36f013805d0e Proteins Involved in Erectile Dysfunction uuid-8ad27f1e-6ff4-4a51-9cbd-36f013805d0e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ad27f1e-6ff4-4a51-9cbd-36f013805d0e PS:NodeType Pathway PS:Organ penis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ad91e36-1960-4cde-a5d1-77d0dc1fabf3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8ad91e36-1960-4cde-a5d1-77d0dc1fabf3 drosopterin and aurodrosopterin biosynthesis template uuid-8ad91e36-1960-4cde-a5d1-77d0dc1fabf3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ad91e36-1960-4cde-a5d1-77d0dc1fabf3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8aec739a-e787-4d16-a5a0-31aef3e7824f NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-8aec739a-e787-4d16-a5a0-31aef3e7824f Model of PPARG signaling in psoriasis uuid-8aec739a-e787-4d16-a5a0-31aef3e7824f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8aec739a-e787-4d16-a5a0-31aef3e7824f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b089604-2008-436b-b7c5-8cbd2ea349f7 NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-8b089604-2008-436b-b7c5-8cbd2ea349f7 Proteins Involved in Congenital Hypothyroidism uuid-8b089604-2008-436b-b7c5-8cbd2ea349f7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b089604-2008-436b-b7c5-8cbd2ea349f7 PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Dendritic cells express a broad range of microbial pattern-recognition receptors, including Toll-like receptors (TLR) and NOD-like receptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b4edd3b-89ec-4c5c-bd3b-04f72e64d90d NodeType: Pathway Notes: Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Dendritic cells express a broad range of microbial pattern-recognition receptors, including Toll-like receptors (TLR) and NOD-like receptors. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 17948929 PMID: 24197332 PMID: 25133031 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-8b4edd3b-89ec-4c5c-bd3b-04f72e64d90d Dendritic Cell Function in Ulcerative Colitis uuid-8b4edd3b-89ec-4c5c-bd3b-04f72e64d90d PS:CellType dendritic cell PS:Description Dendritic cells express a broad range of microbial pattern-recognition receptors, including Toll-like receptors (TLR) and NOD-like receptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b4edd3b-89ec-4c5c-bd3b-04f72e64d90d PS:NodeType Pathway PS:Notes Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Dendritic cells express a broad range of microbial pattern-recognition receptors, including Toll-like receptors (TLR) and NOD-like receptors. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 17948929 PS:PMID 24197332 PS:PMID 25133031 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b502420-97a1-4dd7-a290-952eedffe996 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-8b502420-97a1-4dd7-a290-952eedffe996 Role of TRPM8 in Cold Sensation and Pruritus Inhibition uuid-8b502420-97a1-4dd7-a290-952eedffe996 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b502420-97a1-4dd7-a290-952eedffe996 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b6186ed-7801-4be2-8ab3-4af8d76298b7 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-8b6186ed-7801-4be2-8ab3-4af8d76298b7 Proteins Involved in Primary Ovarian Insufficiency uuid-8b6186ed-7801-4be2-8ab3-4af8d76298b7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b6186ed-7801-4be2-8ab3-4af8d76298b7 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: The mitochondria of patients with Alzheimer's disease produce less ATP and more reactive oxygen species (ROS) in the presence of amyloid beta (Abeta). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b8f8883-e45a-440c-a6a5-793d7d3a7b1e NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The energetic function of mitochondria is altered in the AD brain. Signaling description: The mitochondria of patients with AD produce less ATP and more reactive oxygen species (ROS) in the presence of Abeta and mutant forms of amyloid precursor protein (APP). Abeta and APP co-localize at the mitochondria, however, it is not known whether they penetrate into the mitochondrion or alter the efficiency of protein transport conducted by the TOM complex from outside. Cytotoxic forms of Abeta and APP stimulate the passage of calcium and other small molecules into the intermembrane space through the mPTP pore complex. Calcium causes membrane depolarization and decreases the respiratory chain activity. In neurons of patients with AD, Abeta in the mitochondrial matrix decreases activity of antioxidant enzymes, such as SOD1, SOD2, and CAT, which leads to the increased synthesis of ROS. Outcome effects: Finally, mitochondria dysfunction and damage causes the release of toxic radicals into the cytoplasm of neurons. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12695498 PMID: 17917162 PMID: 21545753 PMID: 22654724 PMID: 9708860 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-8b8f8883-e45a-440c-a6a5-793d7d3a7b1e Mitochondrial Respiratory Chain Dysfunction uuid-8b8f8883-e45a-440c-a6a5-793d7d3a7b1e PS:CellType neuron PS:Description The mitochondria of patients with Alzheimer's disease produce less ATP and more reactive oxygen species (ROS) in the presence of amyloid beta (Abeta). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b8f8883-e45a-440c-a6a5-793d7d3a7b1e PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The energetic function of mitochondria is altered in the AD brain. Signaling description: The mitochondria of patients with AD produce less ATP and more reactive oxygen species (ROS) in the presence of Abeta and mutant forms of amyloid precursor protein (APP). Abeta and APP co-localize at the mitochondria, however, it is not known whether they penetrate into the mitochondrion or alter the efficiency of protein transport conducted by the TOM complex from outside. Cytotoxic forms of Abeta and APP stimulate the passage of calcium and other small molecules into the intermembrane space through the mPTP pore complex. Calcium causes membrane depolarization and decreases the respiratory chain activity. In neurons of patients with AD, Abeta in the mitochondrial matrix decreases activity of antioxidant enzymes, such as SOD1, SOD2, and CAT, which leads to the increased synthesis of ROS. Outcome effects: Finally, mitochondria dysfunction and damage causes the release of toxic radicals into the cytoplasm of neurons. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12695498 PS:PMID 17917162 PS:PMID 21545753 PS:PMID 22654724 PS:PMID 9708860 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Periodontitis - a collective term for separate nosological forms of destruction of the dentition. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b9007c3-aea0-4474-a45c-60d3306b1372 NodeType: Pathway Notes: Headnote: Periodontitis - a collective term for separate nosological forms of destruction of the dentition. Characterized by chronic or acute inflammatory process of periodontal tissue and bone atrophy of the alveolar process (alveolar portion) of the jaw. Clinical manifestations of periodontitis are similar, despite the variety of causes leading to these diseases. Diabetes mellitus is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period, can cause many complications, such as cardiovascular disease, stroke, chronic kidney failure, foot ulcers, and damage to the eyes. Large number of investigations has provided the evidence that type 1 and type 2 diabetes increase the risk and severity of periodontitis, and vice-versa, periodontitis is recognized as the serious complication of diabetes. Signaling description: Despite being extensive research, mechanism underlying the association of periodontitis and diabetes mellitus is not clear. Elevated levels of TNF and IL6 are on the background of diabetes induce the IL6R and TNFR-1 signaling causing the cell proliferation, osteoclast activation, inflammatory and immune responses in periodontal tissue. Hyperglycemia associated with the disturbances in carbohydrates, fat, and protein metabolism leads to non-enzymatic glycation and oxidation of proteins or lipids and to the subsequent formation of advanced glycation endproducts (AGEs). Elevated levels of AGEs are reported in gingival tissues of diabetic patients. It has been shown that AGE-AGER interaction induces the activation of NF?B and subsequent high expression of pro-inflammatory cytokines (TNF, IL1B, IL2, IL6, CXCL8) and cytotoxic peptides defensins (DEFB4A, DEFB103B). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: mouth Organ: periodontium Organ_System: digestive system PMID: 21731243 PMID: 24944840 PMID: 25000662 PMID: 26185600 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-8b9007c3-aea0-4474-a45c-60d3306b1372 Diabetes Induced Periodontitis uuid-8b9007c3-aea0-4474-a45c-60d3306b1372 PS:Description Periodontitis - a collective term for separate nosological forms of destruction of the dentition. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8b9007c3-aea0-4474-a45c-60d3306b1372 PS:NodeType Pathway PS:Notes Headnote: Periodontitis - a collective term for separate nosological forms of destruction of the dentition. Characterized by chronic or acute inflammatory process of periodontal tissue and bone atrophy of the alveolar process (alveolar portion) of the jaw. Clinical manifestations of periodontitis are similar, despite the variety of causes leading to these diseases. Diabetes mellitus is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period, can cause many complications, such as cardiovascular disease, stroke, chronic kidney failure, foot ulcers, and damage to the eyes. Large number of investigations has provided the evidence that type 1 and type 2 diabetes increase the risk and severity of periodontitis, and vice-versa, periodontitis is recognized as the serious complication of diabetes. Signaling description: Despite being extensive research, mechanism underlying the association of periodontitis and diabetes mellitus is not clear. Elevated levels of TNF and IL6 are on the background of diabetes induce the IL6R and TNFR-1 signaling causing the cell proliferation, osteoclast activation, inflammatory and immune responses in periodontal tissue. Hyperglycemia associated with the disturbances in carbohydrates, fat, and protein metabolism leads to non-enzymatic glycation and oxidation of proteins or lipids and to the subsequent formation of advanced glycation endproducts (AGEs). Elevated levels of AGEs are reported in gingival tissues of diabetic patients. It has been shown that AGE-AGER interaction induces the activation of NF?B and subsequent high expression of pro-inflammatory cytokines (TNF, IL1B, IL2, IL6, CXCL8) and cytotoxic peptides defensins (DEFB4A, DEFB103B). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ periodontium PS:Organ_System digestive system PS:PMID 21731243 PS:PMID 24944840 PS:PMID 25000662 PS:PMID 26185600 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bd81fae-5015-41aa-8ced-f7c62e2c1a29 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-8bd81fae-5015-41aa-8ced-f7c62e2c1a29 NSP12 interactions uuid-8bd81fae-5015-41aa-8ced-f7c62e2c1a29 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bd81fae-5015-41aa-8ced-f7c62e2c1a29 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bebcd6d-59d1-43fc-bf27-f8856fd98104 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-8bebcd6d-59d1-43fc-bf27-f8856fd98104 InsR->GLUT4 uuid-8bebcd6d-59d1-43fc-bf27-f8856fd98104 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bebcd6d-59d1-43fc-bf27-f8856fd98104 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bfd7b6d-cfc2-406d-96c3-882461f2747a NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-8bfd7b6d-cfc2-406d-96c3-882461f2747a Elevated Receptors -> Expression Targets in Brain uuid-8bfd7b6d-cfc2-406d-96c3-882461f2747a PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8bfd7b6d-cfc2-406d-96c3-882461f2747a PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c4c37c6-d361-4653-bf28-27d6a313d74e NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-8c4c37c6-d361-4653-bf28-27d6a313d74e IgE Receptors -> Targets in Lymphoid System and Blood uuid-8c4c37c6-d361-4653-bf28-27d6a313d74e PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c4c37c6-d361-4653-bf28-27d6a313d74e PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c58679a-752d-4a79-b7d1-665daf5be632 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-8c58679a-752d-4a79-b7d1-665daf5be632 SARS+>Autophagosome uuid-8c58679a-752d-4a79-b7d1-665daf5be632 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c58679a-752d-4a79-b7d1-665daf5be632 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Invadopodia are dynamic actin-rich membrane protrusions that degrade the extracellular matrix through the local deposition of proteases and are involved in cell invasion. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c7a1903-c2e3-435c-b1d2-943d6209e6c0 NodeType: Pathway Notes: Headnote: Invadopodia are dynamic actin-rich membrane protrusions that degrade the extracellular matrix through the local deposition of proteases and are involved in cell invasion. Invadopodia are found on cancer cells and are similar to the podosomes of normal cells. Signaling description: The activation of EGFR, PDGFR, TGFBR by their ligands has a crucial role in initiation of invadopodia formation. Integrins may have an additional role in this process. The activation of SRC and ABL kinases, PI3K signaling with the formation of PtdIns(3,4) P2 lead to RHOA, CDC42, SH3PXD2A/2B signaling activation. This causes the formation of CTTN/NCK1/WIPF1/WASL complex, that associates with actin related protein 2/3 complex and induces F-actin polymerization. Ion channels (ORAI1, KCNN3, SLC5A1) and AQP1 are also involved in invadopodia formation and cell migration through increasing cell volume during the formation of protrusions. WNT5A/ROR2/IFT20 signaling may have additional functions in invadopodia formation. Outcome effects: The polymerization of F-actin promotes the formation of invadopodia structure. The molecular transport of MMP2/9/14 to the leading edge of invadopodia and it's exocytosis by RAB8A/40B, the exocyst complex, and some other proteins cause local destruction of extracellular matrix surrounding invadopodia, and, thus, cancer cell invasion. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18406052 PMID: 18615630 PMID: 21258212 PMID: 21307399 PMID: 21697900 PMID: 23843616 PMID: 25113547 PMID: 25699257 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-8c7a1903-c2e3-435c-b1d2-943d6209e6c0 Invadopodia Formation in Cancer Cells uuid-8c7a1903-c2e3-435c-b1d2-943d6209e6c0 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Invadopodia are dynamic actin-rich membrane protrusions that degrade the extracellular matrix through the local deposition of proteases and are involved in cell invasion. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c7a1903-c2e3-435c-b1d2-943d6209e6c0 PS:NodeType Pathway PS:Notes Headnote: Invadopodia are dynamic actin-rich membrane protrusions that degrade the extracellular matrix through the local deposition of proteases and are involved in cell invasion. Invadopodia are found on cancer cells and are similar to the podosomes of normal cells. Signaling description: The activation of EGFR, PDGFR, TGFBR by their ligands has a crucial role in initiation of invadopodia formation. Integrins may have an additional role in this process. The activation of SRC and ABL kinases, PI3K signaling with the formation of PtdIns(3,4) P2 lead to RHOA, CDC42, SH3PXD2A/2B signaling activation. This causes the formation of CTTN/NCK1/WIPF1/WASL complex, that associates with actin related protein 2/3 complex and induces F-actin polymerization. Ion channels (ORAI1, KCNN3, SLC5A1) and AQP1 are also involved in invadopodia formation and cell migration through increasing cell volume during the formation of protrusions. WNT5A/ROR2/IFT20 signaling may have additional functions in invadopodia formation. Outcome effects: The polymerization of F-actin promotes the formation of invadopodia structure. The molecular transport of MMP2/9/14 to the leading edge of invadopodia and it's exocytosis by RAB8A/40B, the exocyst complex, and some other proteins cause local destruction of extracellular matrix surrounding invadopodia, and, thus, cancer cell invasion. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18406052 PS:PMID 18615630 PS:PMID 21258212 PS:PMID 21307399 PS:PMID 21697900 PS:PMID 23843616 PS:PMID 25113547 PS:PMID 25699257 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c87ca84-7d43-451c-a1ff-b8477a45b88f NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-8c87ca84-7d43-451c-a1ff-b8477a45b88f Potassium Flux Regulation uuid-8c87ca84-7d43-451c-a1ff-b8477a45b88f PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c87ca84-7d43-451c-a1ff-b8477a45b88f PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: pinealocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c8a48dd-178c-4018-9865-f71817cbf2a6 NodeType: Pathway Notes: Arylalkylamine N-acetyltransferase (AANAT) is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. Melatonin is essential for the function of the circadian clock that influences activity and sleep. AANAT polymorphism is associated with circadian rhythm sleep disorders - delayed sleep phase syndrome. Organ: brain Organ_System: nervous system PMID: 17164235 PMID: 19660984 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-8c8a48dd-178c-4018-9865-f71817cbf2a6 Aralkylamine-N-Acetyltransferase-Associated Sleep Dysregulation uuid-8c8a48dd-178c-4018-9865-f71817cbf2a6 PS:CellType pinealocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c8a48dd-178c-4018-9865-f71817cbf2a6 PS:NodeType Pathway PS:Notes Arylalkylamine N-acetyltransferase (AANAT) is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. Melatonin is essential for the function of the circadian clock that influences activity and sleep. AANAT polymorphism is associated with circadian rhythm sleep disorders - delayed sleep phase syndrome. PS:Organ brain PS:Organ_System nervous system PS:PMID 17164235 PS:PMID 19660984 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c8f78c7-6892-4b96-a03a-6a84d8bd7c1b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8c8f78c7-6892-4b96-a03a-6a84d8bd7c1b Fatty acid alpha-oxidation (peroxisomes) template uuid-8c8f78c7-6892-4b96-a03a-6a84d8bd7c1b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8c8f78c7-6892-4b96-a03a-6a84d8bd7c1b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ccce312-17b9-4a92-b609-2c60e4b55086 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-8ccce312-17b9-4a92-b609-2c60e4b55086 Sensory neuron activation in Asthma uuid-8ccce312-17b9-4a92-b609-2c60e4b55086 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ccce312-17b9-4a92-b609-2c60e4b55086 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8cd75265-7d4a-4df2-8aa9-fb823e34d9b4 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: endometrium urn:agi-pathway:uuid-8cd75265-7d4a-4df2-8aa9-fb823e34d9b4 Elevated Receptors -> Expression Targets in Endometrium uuid-8cd75265-7d4a-4df2-8aa9-fb823e34d9b4 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8cd75265-7d4a-4df2-8aa9-fb823e34d9b4 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue endometrium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ce4f320-c70e-4089-8508-6f07d60fca90 NodeType: Pathway Notes: Kynurenine pathway (KP) has been implicated in the pathogenesis of a number of neurodegenerative and neuroinflammatory disorders. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 22084583 PMID: 22248144 PMID: 22939820 PMID: 23144293 PMID: 24089628 PMID: 25415278 PMID: 26025142 PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-8ce4f320-c70e-4089-8508-6f07d60fca90 Kynurenine Metabolites in Neurotoxicity and Neuroprotection uuid-8ce4f320-c70e-4089-8508-6f07d60fca90 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ce4f320-c70e-4089-8508-6f07d60fca90 PS:NodeType Pathway PS:Notes Kynurenine pathway (KP) has been implicated in the pathogenesis of a number of neurodegenerative and neuroinflammatory disorders. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 22084583 PS:PMID 22248144 PS:PMID 22939820 PS:PMID 23144293 PS:PMID 24089628 PS:PMID 25415278 PS:PMID 26025142 PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8cf5d0d9-3f06-4bf7-8f95-3e104fdf7b13 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-8cf5d0d9-3f06-4bf7-8f95-3e104fdf7b13 ARRB1/ARRB2 non-CanonicalSignaling and HedgehogFamily uuid-8cf5d0d9-3f06-4bf7-8f95-3e104fdf7b13 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8cf5d0d9-3f06-4bf7-8f95-3e104fdf7b13 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d024ed6-2dbd-4c28-a610-65667960648f NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-8d024ed6-2dbd-4c28-a610-65667960648f Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling uuid-8d024ed6-2dbd-4c28-a610-65667960648f PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d024ed6-2dbd-4c28-a610-65667960648f PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d147497-8c93-4256-93d9-f7bb3115f353 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8d147497-8c93-4256-93d9-f7bb3115f353 Ubiquinone-Q10 biosynthesis (eukaryotic) template uuid-8d147497-8c93-4256-93d9-f7bb3115f353 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d147497-8c93-4256-93d9-f7bb3115f353 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d2624ee-c593-460d-848f-075fb1df7590 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-8d2624ee-c593-460d-848f-075fb1df7590 CD72 -> STAT Expression Target uuid-8d2624ee-c593-460d-848f-075fb1df7590 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d2624ee-c593-460d-848f-075fb1df7590 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d2aafeb-1408-4c8c-ad7e-134bda434a8b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8d2aafeb-1408-4c8c-ad7e-134bda434a8b IL16 -> STAT Expression Targets uuid-8d2aafeb-1408-4c8c-ad7e-134bda434a8b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d2aafeb-1408-4c8c-ad7e-134bda434a8b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d45284f-8af6-47e8-a182-c46aee7bd270 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-8d45284f-8af6-47e8-a182-c46aee7bd270 Proteins Involved in Oligodendroglioma uuid-8d45284f-8af6-47e8-a182-c46aee7bd270 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d45284f-8af6-47e8-a182-c46aee7bd270 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d5a3eb5-36dc-4d7d-a244-1ae44c86b4d4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-8d5a3eb5-36dc-4d7d-a244-1ae44c86b4d4 COVID19 viral entry uuid-8d5a3eb5-36dc-4d7d-a244-1ae44c86b4d4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d5a3eb5-36dc-4d7d-a244-1ae44c86b4d4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Cystic Kidney Disease is a group of diseases that cause abnormal cysts in the kidneys. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d6479fc-47c0-4501-b3c9-4b40a6b57fd0 NodeType: Pathway Notes: Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Nephronophthisis, Medullary Sponge Kidney (MSK) etc. Hereditary factors account for the majority of CKD types. ADPKD and ARPKD are the two most common types of CKD with different modes of inheritance; yet in both cases mutations in polycystin genes (PKD1 and 2) are associated with cyst formation. Signaling description: PKD1 is involved in the regulation of several signaling routes, such as the activation of JUN, EIF4E, and CCND1. PKD2 regulates Ca2+ influx through the interaction with PKD1 and activation of ERK-signaling. The exact mechanisms for PKD1 and PKD2 involvement in renal cyst formation are not well understood. One of the hypotheses is depicted on the pathway. Outcome effects: PKD1 regulates JUN activity through JNK-signaling in a GNA12, GNA13, GNAQ and GNB1-dependent manner leading to cell proliferation. In renal epithelial cells, PKD1 inhibits cell size due to the down-regulation of MTOR, RPS6KB1 and EIF4E. Cell growth is regulated by PKD1 through JAK2/STAT3/CCND1 signaling. The ability of PKD2 to regulate Ca2+ influx may account for its capacity to activate ERK-signaling. PKD1 also is involved in fluid secretion via stimulation of PKA/CREBA/CFTR signaling. The increased production of AVP stimulates the proliferation of ADPKD cells and drives fluid secretion via V2R/PKA/ERK and V2R/PKA/CREBA/CFTR, presumably, leading to cyst formation and renal disease.Highlighted protein description: AVP with red highlights has increased expression in ADPKD. Mutated proteins: Mutated PKD1, PKD2, and PKHD1 are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 11912216 PMID: 19255143 PMID: 20980620 PMID: 21255645 PMID: 25186187 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-8d6479fc-47c0-4501-b3c9-4b40a6b57fd0 Polycystins Mutation Effects in Cystic Kidney Disease uuid-8d6479fc-47c0-4501-b3c9-4b40a6b57fd0 PS:Description Cystic Kidney Disease is a group of diseases that cause abnormal cysts in the kidneys. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d6479fc-47c0-4501-b3c9-4b40a6b57fd0 PS:NodeType Pathway PS:Notes Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Nephronophthisis, Medullary Sponge Kidney (MSK) etc. Hereditary factors account for the majority of CKD types. ADPKD and ARPKD are the two most common types of CKD with different modes of inheritance; yet in both cases mutations in polycystin genes (PKD1 and 2) are associated with cyst formation. Signaling description: PKD1 is involved in the regulation of several signaling routes, such as the activation of JUN, EIF4E, and CCND1. PKD2 regulates Ca2+ influx through the interaction with PKD1 and activation of ERK-signaling. The exact mechanisms for PKD1 and PKD2 involvement in renal cyst formation are not well understood. One of the hypotheses is depicted on the pathway. Outcome effects: PKD1 regulates JUN activity through JNK-signaling in a GNA12, GNA13, GNAQ and GNB1-dependent manner leading to cell proliferation. In renal epithelial cells, PKD1 inhibits cell size due to the down-regulation of MTOR, RPS6KB1 and EIF4E. Cell growth is regulated by PKD1 through JAK2/STAT3/CCND1 signaling. The ability of PKD2 to regulate Ca2+ influx may account for its capacity to activate ERK-signaling. PKD1 also is involved in fluid secretion via stimulation of PKA/CREBA/CFTR signaling. The increased production of AVP stimulates the proliferation of ADPKD cells and drives fluid secretion via V2R/PKA/ERK and V2R/PKA/CREBA/CFTR, presumably, leading to cyst formation and renal disease.Highlighted protein description: AVP with red highlights has increased expression in ADPKD. Mutated proteins: Mutated PKD1, PKD2, and PKHD1 are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 11912216 PS:PMID 19255143 PS:PMID 20980620 PS:PMID 21255645 PS:PMID 25186187 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d790a79-b3e6-4583-a195-f0c8d61d2d0b NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-8d790a79-b3e6-4583-a195-f0c8d61d2d0b Genes with Mutations in Cancer-Associated Histone Methylation uuid-8d790a79-b3e6-4583-a195-f0c8d61d2d0b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d790a79-b3e6-4583-a195-f0c8d61d2d0b PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d93d034-2cca-4bb5-9444-2bf508d4ff1a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8d93d034-2cca-4bb5-9444-2bf508d4ff1a Acetylcholine Expression Targets uuid-8d93d034-2cca-4bb5-9444-2bf508d4ff1a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d93d034-2cca-4bb5-9444-2bf508d4ff1a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d9a8411-ff53-4a83-9869-b8c4e6f1a980 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8d9a8411-ff53-4a83-9869-b8c4e6f1a980 TNFRSF1A -> STAT Signaling uuid-8d9a8411-ff53-4a83-9869-b8c4e6f1a980 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8d9a8411-ff53-4a83-9869-b8c4e6f1a980 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8dd5b0da-6997-4c05-8e69-f24ea63430bd NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-8dd5b0da-6997-4c05-8e69-f24ea63430bd Biomarkers for severe COVID19 complications uuid-8dd5b0da-6997-4c05-8e69-f24ea63430bd PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8dd5b0da-6997-4c05-8e69-f24ea63430bd PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: A central role in immune tolerance to commensal fungi is played by tryptophan (trp), an essential, diet-derived amino acid. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e123f03-634b-43fc-bdd1-deb7f28d0fd5 NodeType: Pathway Notes: Headnote: A central task in immune tolerance to commensal fungi is conducted by tryptophan (trp), an essential, diet-derived amino acid. Signaling description: Fungus-induced activation of trp catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) expressed by tolerogenic dendritic cells and epithelial cells leads to the production of immunologically active kynurenine. Outcome effects: This induces the transcription of FOXP3 and down-regulates RORC transcription, thus promoting immune tolerance via Treg cells. Organ: generic Organ_System: lymphatic system PMID: 25256754 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-8e123f03-634b-43fc-bdd1-deb7f28d0fd5 Kynurenine/AHR Signaling in Treg Cell Activation uuid-8e123f03-634b-43fc-bdd1-deb7f28d0fd5 PS:CellType T-cell PS:Description A central role in immune tolerance to commensal fungi is played by tryptophan (trp), an essential, diet-derived amino acid. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e123f03-634b-43fc-bdd1-deb7f28d0fd5 PS:NodeType Pathway PS:Notes Headnote: A central task in immune tolerance to commensal fungi is conducted by tryptophan (trp), an essential, diet-derived amino acid. Signaling description: Fungus-induced activation of trp catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) expressed by tolerogenic dendritic cells and epithelial cells leads to the production of immunologically active kynurenine. Outcome effects: This induces the transcription of FOXP3 and down-regulates RORC transcription, thus promoting immune tolerance via Treg cells. PS:Organ generic PS:Organ_System lymphatic system PS:PMID 25256754 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e163d06-f87f-4dc8-bc69-21fc0d5a34a5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-8e163d06-f87f-4dc8-bc69-21fc0d5a34a5 WNT Canonical Signaling Expression Targets uuid-8e163d06-f87f-4dc8-bc69-21fc0d5a34a5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e163d06-f87f-4dc8-bc69-21fc0d5a34a5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e506d7e-f9fe-4fe9-95cb-72a386fce368 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: adipose tissue urn:agi-pathway:uuid-8e506d7e-f9fe-4fe9-95cb-72a386fce368 Elevated Receptors -> Expression Targets in Adipose Tissue uuid-8e506d7e-f9fe-4fe9-95cb-72a386fce368 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e506d7e-f9fe-4fe9-95cb-72a386fce368 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e563ee2-a703-424f-9305-958de47bd1a1 NodeType: Pathway Notes: Inflammatory mediators are directly involved in the regulation of erythrocyte differentiation. High levels of proinflammatory cytokines inhibit erythropoiesis by blocking the expression of the erythrocyte-specific proteins (HBA1, HBG1, AHSP, GYPA, and EPOR). The low rate of expression and synthesis of erythrocyte-specific proteins slows down the differentiation of erythrocyte precursors. Lack of functional erythrocytes causes a systemic oxygen deficiency and the clinical manifestations of anemia. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-8e563ee2-a703-424f-9305-958de47bd1a1 4_Inflammatory mediators inhibit GATA signaling in erythropoiesis uuid-8e563ee2-a703-424f-9305-958de47bd1a1 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e563ee2-a703-424f-9305-958de47bd1a1 PS:NodeType Pathway PS:Notes Inflammatory mediators are directly involved in the regulation of erythrocyte differentiation. High levels of proinflammatory cytokines inhibit erythropoiesis by blocking the expression of the erythrocyte-specific proteins (HBA1, HBG1, AHSP, GYPA, and EPOR). The low rate of expression and synthesis of erythrocyte-specific proteins slows down the differentiation of erythrocyte precursors. Lack of functional erythrocytes causes a systemic oxygen deficiency and the clinical manifestations of anemia. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e60dc12-2211-4b7f-a25c-d48d1c598fe3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8e60dc12-2211-4b7f-a25c-d48d1c598fe3 Glu/Gln metabolism template uuid-8e60dc12-2211-4b7f-a25c-d48d1c598fe3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e60dc12-2211-4b7f-a25c-d48d1c598fe3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Mitochondrial replication is controlled by chromosomes in the nucleus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e64a71c-1394-4322-955a-27891f08c9aa NodeType: Pathway Notes: Headnote: Mitochondrial replication is controlled by the chromosomes in the nucleus. POLG is involved in copying mitochondrial DNA (mtDNA) during replication. Signaling description: In order for mtDNA replication to occur, the two-subunit POLG, mitochondrial helicase, and single-stranded DNA (ssDNA)-binding protein SSBP are absolutely required. When POLG and C10orf2 are combined, they form a replisome which can utilize duplex DNA as a template to synthesize ssDNA molecules of about 2kb. The addition of SSBP1 further stimulates the reaction and generates DNA products of about 16kb which is the size of the mammalian mtDNA molecule. Circular mtDNA molecule replicates in a D-loop (displacement) configuration because the heavy and light strands have different origins of replication. One strand replicates first, displacing the other strand, until the origin of replication on the other strand is reached. At this point, the other strand begins replicating in the opposite direction until two new mtDNA molecules are synthesized. D-loop has additional functions including attaching mtDNA to the inner membrane and initiation of transcription since promoters for transcription of both DNA chains are located in this region. Outcome effects: mtDNA encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAS (rRNAs), and 13 polypeptides essential for oxidative phosphorylation and electron transport. It has three promoters including heavy strand 1 (H1), heavy strand 2 (H2), and light strand (L). Transcription on the heavy strand results in the synthesis of a polycistronic transcript while the light strand produces either one long transcript or small transcripts which can be used as primers. Subsequently, the transcripts are cut into functional RNA molecules. Prior to transcription, POLRMT, TFAM, and TFB1M or TFB2M proteins assemble at mitochondrial promoters. These factors are required for basal transcription, although the actual molecular events involved in transcriptional initiation are unknown. Lastly, PolyA sequences associate with 3'-tips of mRNA while 5'-tips of these mRNA molecules do not form caps. Splicing does not occur because mitochondrial genes in mammals lack introns. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-8e64a71c-1394-4322-955a-27891f08c9aa Mitochondrial DNA Replication and Transcription uuid-8e64a71c-1394-4322-955a-27891f08c9aa PS:CellType generic PS:Description Mitochondrial replication is controlled by chromosomes in the nucleus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e64a71c-1394-4322-955a-27891f08c9aa PS:NodeType Pathway PS:Notes Headnote: Mitochondrial replication is controlled by the chromosomes in the nucleus. POLG is involved in copying mitochondrial DNA (mtDNA) during replication. Signaling description: In order for mtDNA replication to occur, the two-subunit POLG, mitochondrial helicase, and single-stranded DNA (ssDNA)-binding protein SSBP are absolutely required. When POLG and C10orf2 are combined, they form a replisome which can utilize duplex DNA as a template to synthesize ssDNA molecules of about 2kb. The addition of SSBP1 further stimulates the reaction and generates DNA products of about 16kb which is the size of the mammalian mtDNA molecule. Circular mtDNA molecule replicates in a D-loop (displacement) configuration because the heavy and light strands have different origins of replication. One strand replicates first, displacing the other strand, until the origin of replication on the other strand is reached. At this point, the other strand begins replicating in the opposite direction until two new mtDNA molecules are synthesized. D-loop has additional functions including attaching mtDNA to the inner membrane and initiation of transcription since promoters for transcription of both DNA chains are located in this region. Outcome effects: mtDNA encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAS (rRNAs), and 13 polypeptides essential for oxidative phosphorylation and electron transport. It has three promoters including heavy strand 1 (H1), heavy strand 2 (H2), and light strand (L). Transcription on the heavy strand results in the synthesis of a polycistronic transcript while the light strand produces either one long transcript or small transcripts which can be used as primers. Subsequently, the transcripts are cut into functional RNA molecules. Prior to transcription, POLRMT, TFAM, and TFB1M or TFB2M proteins assemble at mitochondrial promoters. These factors are required for basal transcription, although the actual molecular events involved in transcriptional initiation are unknown. Lastly, PolyA sequences associate with 3'-tips of mRNA while 5'-tips of these mRNA molecules do not form caps. Splicing does not occur because mitochondrial genes in mammals lack introns. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e909ffd-8b26-4dfd-9655-bf4b1bb4f7d0 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-8e909ffd-8b26-4dfd-9655-bf4b1bb4f7d0 KIT -> STAT Signaling uuid-8e909ffd-8b26-4dfd-9655-bf4b1bb4f7d0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8e909ffd-8b26-4dfd-9655-bf4b1bb4f7d0 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8eac0d89-dd99-411e-9ac8-6bad1b1c7df1 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-8eac0d89-dd99-411e-9ac8-6bad1b1c7df1 Proteins Involved in Pyelonephritis uuid-8eac0d89-dd99-411e-9ac8-6bad1b1c7df1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8eac0d89-dd99-411e-9ac8-6bad1b1c7df1 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ebc0639-47ed-4a7b-94f8-02a124495ddb NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-8ebc0639-47ed-4a7b-94f8-02a124495ddb Proteins Involved in Huntington Disease uuid-8ebc0639-47ed-4a7b-94f8-02a124495ddb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ebc0639-47ed-4a7b-94f8-02a124495ddb PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ebfaccf-c2f8-432d-8a55-c80d3d8776bc NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-8ebfaccf-c2f8-432d-8a55-c80d3d8776bc PKA|-DHH+>PI3K uuid-8ebfaccf-c2f8-432d-8a55-c80d3d8776bc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ebfaccf-c2f8-432d-8a55-c80d3d8776bc PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ec138e5-c5fd-4ea8-ada2-2b5fbfbf7c2d NodeType: Pathway Notes: Gluten-derived peptides transported across the intestinal epithelium and high level of interleukin-15 promote cytotoxic effects of intraepithelial lymphocytes such as natural killer cells, neutrophils, and cytotoxic T lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-8ec138e5-c5fd-4ea8-ada2-2b5fbfbf7c2d 2_CD8+ T-cell response and mucosal damage in celiac disease uuid-8ec138e5-c5fd-4ea8-ada2-2b5fbfbf7c2d PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8ec138e5-c5fd-4ea8-ada2-2b5fbfbf7c2d PS:NodeType Pathway PS:Notes Gluten-derived peptides transported across the intestinal epithelium and high level of interleukin-15 promote cytotoxic effects of intraepithelial lymphocytes such as natural killer cells, neutrophils, and cytotoxic T lymphocytes. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Duchenne muscular dystrophy (DMD) is a muscle disorder caused by various mutations in the gene coding for dystrophin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. In DMD, muscle membranes become more fragile and sensitive to mechanical forces. Stretch occurring during exercise can tear membranes of muscle cells allowing extracellular Ca2+ to enter the cell. Stretch-activated Ca2+ channels (SACs) are another source of extra Ca2+ in DMD. Membrane tears and SACs along with the other candidate channels and factors responsible for Ca2+ storage and buffering inside the cells cause severe Ca2+ overload. Outcome effects: Elevated Ca2+ activates Ca2+-dependent proteases such as calpains and therefore increases proteolysis. Many of the muscular structural proteins contain cleavage site for calpains. Calpain cleavage also changes the activity of nitric oxide synthase (NOS) and Ca2+ leak channels. NOS signaling is decreased in dystrophin-deficient muscles, as NOS requires a functional dystrophin for proper localization. It weakens the nitric oxide (NO) protective effect and contributes to oxidative stress which is another prominent feature of dystrophin deficiency. All of these factors contribute to increased cell death and inflammation, resulting in muscular dystrophy. Currently, there is no cure for DMD; however treatment options include anti-inflammatory drugs. NO donors and Ca2+ blockers have been tested in animal models. The up-regulation of utrophin (UTRN), a protein that can partially replace dystrophin in DGC, could also benefit affected muscle. The induction of calcineurin-NFATC1 signaling enhances the expression of UTRN. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 Muscular Dystrophies uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 PS:CellType muscle cell PS:Description Duchenne muscular dystrophy (DMD) is a muscle disorder caused by various mutations in the gene coding for dystrophin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. In DMD, muscle membranes become more fragile and sensitive to mechanical forces. Stretch occurring during exercise can tear membranes of muscle cells allowing extracellular Ca2+ to enter the cell. Stretch-activated Ca2+ channels (SACs) are another source of extra Ca2+ in DMD. Membrane tears and SACs along with the other candidate channels and factors responsible for Ca2+ storage and buffering inside the cells cause severe Ca2+ overload. Outcome effects: Elevated Ca2+ activates Ca2+-dependent proteases such as calpains and therefore increases proteolysis. Many of the muscular structural proteins contain cleavage site for calpains. Calpain cleavage also changes the activity of nitric oxide synthase (NOS) and Ca2+ leak channels. NOS signaling is decreased in dystrophin-deficient muscles, as NOS requires a functional dystrophin for proper localization. It weakens the nitric oxide (NO) protective effect and contributes to oxidative stress which is another prominent feature of dystrophin deficiency. All of these factors contribute to increased cell death and inflammation, resulting in muscular dystrophy. Currently, there is no cure for DMD; however treatment options include anti-inflammatory drugs. NO donors and Ca2+ blockers have been tested in animal models. The up-regulation of utrophin (UTRN), a protein that can partially replace dystrophin in DGC, could also benefit affected muscle. The induction of calcineurin-NFATC1 signaling enhances the expression of UTRN. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f205f8e-5a2c-4a39-a7f2-cc06a39b0e8e NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-8f205f8e-5a2c-4a39-a7f2-cc06a39b0e8e Mucin biosynthesis template uuid-8f205f8e-5a2c-4a39-a7f2-cc06a39b0e8e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f205f8e-5a2c-4a39-a7f2-cc06a39b0e8e PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Th1 cells are very effective in controlling infection of intracellular pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f252d21-96d4-40e0-bd0c-4095cc58428f NodeType: Pathway Notes: Headnote: Th1-cells are very effective in controlling infection of intracellular pathogens. Th1-cells characteristically produce TNF-beta (LTA) and IFN-gamma (IFNG), which induce macrophage activation. Signaling description: IL12, produced by activated monocytes/macrophages and dendritic cells, is the dominant factor promoting Th1-cell polarization. IFNG itself can further enhance IFNG production and therefore enlarge the pool of Th1-cells. IL1 receptor family member, IL18R through IL18 has been demonstrated to synergize with IL12 in enhancing IFN- production by Th1-cells. Other members of the IL12 cytokine family such as IL27 may also have a role in Th1 development. In general, cytokine signaling requires the heterodimerization of receptor chains. This triggers the phosphorylation of Janus kinases (JAK) and recruitment of signal transducers and activators of transcription (STAT), which translocate to the nucleus and mediate the activation of cytokine-responsive genes. Several STAT molecules have been identified as central players in Th1-cell polarization. STAT4 is activated in response to IL12 via IL12R and mediates the up-regulation of IFNG transcripts, leading to the Th1-cytokine pattern. Outcome effects: STAT1 is activated by IFNG signaling and upregulates TBX21, a transcription factor that induces IFNG production and Th1 differentiation. IFNG-mediated induction of TBX21 results in the up-regulation of IL12R, which in turn increases TBX21 levels via STAT4 activation. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-8f252d21-96d4-40e0-bd0c-4095cc58428f Th1-Cell Differentiation uuid-8f252d21-96d4-40e0-bd0c-4095cc58428f PS:CellType T-cell PS:Description Th1 cells are very effective in controlling infection of intracellular pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f252d21-96d4-40e0-bd0c-4095cc58428f PS:NodeType Pathway PS:Notes Headnote: Th1-cells are very effective in controlling infection of intracellular pathogens. Th1-cells characteristically produce TNF-beta (LTA) and IFN-gamma (IFNG), which induce macrophage activation. Signaling description: IL12, produced by activated monocytes/macrophages and dendritic cells, is the dominant factor promoting Th1-cell polarization. IFNG itself can further enhance IFNG production and therefore enlarge the pool of Th1-cells. IL1 receptor family member, IL18R through IL18 has been demonstrated to synergize with IL12 in enhancing IFN- production by Th1-cells. Other members of the IL12 cytokine family such as IL27 may also have a role in Th1 development. In general, cytokine signaling requires the heterodimerization of receptor chains. This triggers the phosphorylation of Janus kinases (JAK) and recruitment of signal transducers and activators of transcription (STAT), which translocate to the nucleus and mediate the activation of cytokine-responsive genes. Several STAT molecules have been identified as central players in Th1-cell polarization. STAT4 is activated in response to IL12 via IL12R and mediates the up-regulation of IFNG transcripts, leading to the Th1-cytokine pattern. Outcome effects: STAT1 is activated by IFNG signaling and upregulates TBX21, a transcription factor that induces IFNG production and Th1 differentiation. IFNG-mediated induction of TBX21 results in the up-regulation of IL12R, which in turn increases TBX21 levels via STAT4 activation. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Inactivation of TGFB signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f86324c-6e53-4c9c-bf3f-941113c4420d NodeType: Pathway Notes: Headnote: The TGFB signaling pathway is involved in various cellular processes including cell growth, differentiation, apoptosis, cellular homeostasis and other vital cellular functions in adult organism, as well as the developing embryo. TGFB induces tumor-suppressive effects that cancer cells must circumvent in order to transform into malignancies. The role of the TGF-beta pathway as a tumor-promoter or suppressor in cancer cells is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. Signaling description: TGF-beta superfamily ligands bind TGFBR2, which recruits and phosphorylates TGFBR1. Then, TGFBR1 phosphorylates receptor-regulated SMADs. Further, SMADs accumulate in the nucleus where they act as transcription factors and participate in the regulation of expression of target genes. Inactivating mutations of TGFBR1/2 or SMAD2/3/4 impair the tumor suppressor function of TGFB signaling leading to uncontrolled cell proliferation. Outcome effects: SMADs activate transcription factors leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18662538 PMID: 25444759 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-8f86324c-6e53-4c9c-bf3f-941113c4420d TGFB Signaling activation by Blocking of Tumor Suppressors uuid-8f86324c-6e53-4c9c-bf3f-941113c4420d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Inactivation of TGFB signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f86324c-6e53-4c9c-bf3f-941113c4420d PS:NodeType Pathway PS:Notes Headnote: The TGFB signaling pathway is involved in various cellular processes including cell growth, differentiation, apoptosis, cellular homeostasis and other vital cellular functions in adult organism, as well as the developing embryo. TGFB induces tumor-suppressive effects that cancer cells must circumvent in order to transform into malignancies. The role of the TGF-beta pathway as a tumor-promoter or suppressor in cancer cells is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. Signaling description: TGF-beta superfamily ligands bind TGFBR2, which recruits and phosphorylates TGFBR1. Then, TGFBR1 phosphorylates receptor-regulated SMADs. Further, SMADs accumulate in the nucleus where they act as transcription factors and participate in the regulation of expression of target genes. Inactivating mutations of TGFBR1/2 or SMAD2/3/4 impair the tumor suppressor function of TGFB signaling leading to uncontrolled cell proliferation. Outcome effects: SMADs activate transcription factors leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18662538 PS:PMID 25444759 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: BMP4 and TGFB1 play important role in lactotroph physiology and prolactin (PRL) expression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f9b6f9f-174d-47d6-8edb-95f42e35502e NodeType: Pathway Notes: Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: BMP4 and TGFB1 have an important role in lactotroph physiology and prolactin (PRL) expression. While, SMAD 2/4 complex is responsible for TGFB1-induced inhibition, SMAD1/4 participates in the stimulatory action of BMP-4. Outcome effects: A physical interaction between SMAD proteins and ESR1 has been shown. BMP-4 or estrogen treatment induces a direct physical interaction between the ESR1 and SMAD-4/1 complex. In contrast, treatment with TGFB1 induces a physical interaction between ESR1 and SMAD-4/2 complex, but not with SMAD1. References: 1). Allyson K. Booth AK, Gutierrez-Hartmann A. Lactotrope Homeostasis and Tumorigenesis Chapter. 2. Signaling Pathways Regulating Pituitary. Available from: http://www.springer.com/cda/content/document/cda_downloaddocument/9783319121130-c1.pdf?SGWID0-0-45-1488650-p177017112. Organ: pituitary gland Organ_System: nervous system PMID: 19342445 PMID: 22298650 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-8f9b6f9f-174d-47d6-8edb-95f42e35502e PRL Expression Regulation by BMP4 and TGFB1 uuid-8f9b6f9f-174d-47d6-8edb-95f42e35502e PS:CellType neuron PS:Description BMP4 and TGFB1 play important role in lactotroph physiology and prolactin (PRL) expression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f9b6f9f-174d-47d6-8edb-95f42e35502e PS:NodeType Pathway PS:Notes Headnote: Prolactin (PRL) is the protein hormone that enables female mammals to produce milk. Signaling description: BMP4 and TGFB1 have an important role in lactotroph physiology and prolactin (PRL) expression. While, SMAD 2/4 complex is responsible for TGFB1-induced inhibition, SMAD1/4 participates in the stimulatory action of BMP-4. Outcome effects: A physical interaction between SMAD proteins and ESR1 has been shown. BMP-4 or estrogen treatment induces a direct physical interaction between the ESR1 and SMAD-4/1 complex. In contrast, treatment with TGFB1 induces a physical interaction between ESR1 and SMAD-4/2 complex, but not with SMAD1. References: 1). Allyson K. Booth AK, Gutierrez-Hartmann A. Lactotrope Homeostasis and Tumorigenesis Chapter. 2. Signaling Pathways Regulating Pituitary. Available from: http://www.springer.com/cda/content/document/cda_downloaddocument/9783319121130-c1.pdf?SGWID0-0-45-1488650-p177017112. PS:Organ pituitary gland PS:Organ_System nervous system PS:PMID 19342445 PS:PMID 22298650 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoblast Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8fc3042c-24fc-45f7-92b1-05453db67768 NodeType: Pathway Notes: Usually, estrogen acts via the estrogen receptor 1 (ESR1) resulting in osteoblast proliferation and differentiation. In postmenopausal osteoporosis, the lack of osteoblast function is due to a deficiency of estrogens. The deficiency of estrogens and polymorphisms in the genes encoding osteoclast-specific proteins leads to impaired osteoblast function affecting bone matrix formation and bone biomineralization. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-8fc3042c-24fc-45f7-92b1-05453db67768 2_Osteoblast-mediated bone demineralization uuid-8fc3042c-24fc-45f7-92b1-05453db67768 PS:CellType osteoblast PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8fc3042c-24fc-45f7-92b1-05453db67768 PS:NodeType Pathway PS:Notes Usually, estrogen acts via the estrogen receptor 1 (ESR1) resulting in osteoblast proliferation and differentiation. In postmenopausal osteoporosis, the lack of osteoblast function is due to a deficiency of estrogens. The deficiency of estrogens and polymorphisms in the genes encoding osteoclast-specific proteins leads to impaired osteoblast function affecting bone matrix formation and bone biomineralization. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8fe0393c-61be-4058-9417-d4619d83525a NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-8fe0393c-61be-4058-9417-d4619d83525a Proteins Involved in Chronic Myeloid Leukemia uuid-8fe0393c-61be-4058-9417-d4619d83525a PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8fe0393c-61be-4058-9417-d4619d83525a PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8feb3fc8-a82d-48b6-a4fb-492ed718b30b NodeType: Pathway Organ: testis Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-8feb3fc8-a82d-48b6-a4fb-492ed718b30b Proteins Involved in Male Infertility uuid-8feb3fc8-a82d-48b6-a4fb-492ed718b30b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8feb3fc8-a82d-48b6-a4fb-492ed718b30b PS:NodeType Pathway PS:Organ testis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90075ee8-64a7-4848-b272-9cbbce3466e0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-90075ee8-64a7-4848-b272-9cbbce3466e0 MSTN/ACVR2/ACVR1 Expression Targets uuid-90075ee8-64a7-4848-b272-9cbbce3466e0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90075ee8-64a7-4848-b272-9cbbce3466e0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-901722da-f2ba-4b78-9596-d87e1b6dac11 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-901722da-f2ba-4b78-9596-d87e1b6dac11 Col6->Circadian rhythm->Autophagy uuid-901722da-f2ba-4b78-9596-d87e1b6dac11 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-901722da-f2ba-4b78-9596-d87e1b6dac11 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90304ae0-8f03-4855-ab47-04b0874d6565 NodeType: Pathway Notes: Headnote: Phenylalanine and tyrosine are the precursors of several neurotransmitters (dopamine, norepinephrine, epinephrine) and melanin; deficiencies in the enzymes involved in their metabolism lead to a variety of syndromes. Phenylalanine is essential (indispensable) amino acid, and therefore must be supplied in its diet. A series of chemical reactions lead to synthesis of neurotransmitters dopamine, noradrenaline and epinephrine, melanin pigment, thyroid hormones and other important substances from phenylalanine (Phe) and tyrosine (Tyr). A number of inherited metabolic disorders is caused by mutations in genes which encode enzymes taking part in Phe and tyrosine Tyr metabolism. These disorders include phenylketonuria, tyrosinemias, alkaptonuria and oculocutaneous albinism. Signaling description: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), this enzyme is necessary to metabolize Phe to Tyr. A rarer form of PKU occurs when the PAH enzyme is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin caused by mutation of quinoid dihydropteridine reductase (QDPR). Tyrosinemia is an error of metabolism in which the body cannot effectively break down the amino acid Tyr. Untreated, tyrosinemia can be fatal. There are three types of tyrosinemia, caused by the deficiency of a different enzyme. Type I Tyrosinemia, also known as hepatorenal tyrosinemia, is the most severe form of the desease. Symptoms include liver and kidney disturbances and mental retardation. It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Type II Tyrosinemia (oculocutaneous tyrosinemia, Richner-Hanhart syndrome) is an autosomal recessive condition with onset between ages 2 and 4 years. This form of the disorder can affect the eyes, skin, and mental development. Type II Tyrosinemia is caused by a deficiency of the enzyme tyrosine aminotransferase (TAT). Type III tyrosinemia is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), encoded by the gene HPD. Characteristic features of type III tyrosinemia include mild mental retardation, seizures, and periodic loss of balance and coordination (intermittent ataxia). Alkaptonuria (black urine disease) is a rare autosomal recessive disorder of Phe and Tyr metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD), which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide, called alkapton, accumulate in the blood and are excreted in urine in large amounts. Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones. Oculocutaneous albinism (OCA) is a form of albinism involving the eyes, skin, and hair. Four types of OCA have been described, all caused by a disruption of melanin synthesis and all autosomal recessive disorders. OCA1,2,3,4 are caused by mutations in tyrosinase (TYR), OCA2, tyrosinase-related protein 1 (TYRP1) and solute carrier family 45, member 2 (SLC45A2), respectively. All these proteins are involved in melanin synthesis / transportation. Outcome effects: Untreated PKU can lead to intellectual disability, seizures, and other serious medical problems. The mainstream treatment for classic PKU patients is a strict Phe-restricted diet supplemented by a medical formula containing amino acids and other nutrients. The primary treatment for type I tyrosinemia is nitisinone (Orfadin). Nitisinone inhibits the conversion of 4-hydroxyphenylpyruvate to homogentisic acid by 4-hydroxyphenylpyruvate dioxygenase (HPD), the second step in tyrosine degradation.Mutated genes are shown in white-out style. Organ_System: nervous system PMID: 17513423 PMID: 20720592 PMID: 24789876 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-90304ae0-8f03-4855-ab47-04b0874d6565 Disorders of Phenylalanine and Tyrosine Metabolism uuid-90304ae0-8f03-4855-ab47-04b0874d6565 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90304ae0-8f03-4855-ab47-04b0874d6565 PS:NodeType Pathway PS:Notes Headnote: Phenylalanine and tyrosine are the precursors of several neurotransmitters (dopamine, norepinephrine, epinephrine) and melanin; deficiencies in the enzymes involved in their metabolism lead to a variety of syndromes. Phenylalanine is essential (indispensable) amino acid, and therefore must be supplied in its diet. A series of chemical reactions lead to synthesis of neurotransmitters dopamine, noradrenaline and epinephrine, melanin pigment, thyroid hormones and other important substances from phenylalanine (Phe) and tyrosine (Tyr). A number of inherited metabolic disorders is caused by mutations in genes which encode enzymes taking part in Phe and tyrosine Tyr metabolism. These disorders include phenylketonuria, tyrosinemias, alkaptonuria and oculocutaneous albinism. Signaling description: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), this enzyme is necessary to metabolize Phe to Tyr. A rarer form of PKU occurs when the PAH enzyme is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin caused by mutation of quinoid dihydropteridine reductase (QDPR). Tyrosinemia is an error of metabolism in which the body cannot effectively break down the amino acid Tyr. Untreated, tyrosinemia can be fatal. There are three types of tyrosinemia, caused by the deficiency of a different enzyme. Type I Tyrosinemia, also known as hepatorenal tyrosinemia, is the most severe form of the desease. Symptoms include liver and kidney disturbances and mental retardation. It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Type II Tyrosinemia (oculocutaneous tyrosinemia, Richner-Hanhart syndrome) is an autosomal recessive condition with onset between ages 2 and 4 years. This form of the disorder can affect the eyes, skin, and mental development. Type II Tyrosinemia is caused by a deficiency of the enzyme tyrosine aminotransferase (TAT). Type III tyrosinemia is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), encoded by the gene HPD. Characteristic features of type III tyrosinemia include mild mental retardation, seizures, and periodic loss of balance and coordination (intermittent ataxia). Alkaptonuria (black urine disease) is a rare autosomal recessive disorder of Phe and Tyr metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD), which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide, called alkapton, accumulate in the blood and are excreted in urine in large amounts. Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones. Oculocutaneous albinism (OCA) is a form of albinism involving the eyes, skin, and hair. Four types of OCA have been described, all caused by a disruption of melanin synthesis and all autosomal recessive disorders. OCA1,2,3,4 are caused by mutations in tyrosinase (TYR), OCA2, tyrosinase-related protein 1 (TYRP1) and solute carrier family 45, member 2 (SLC45A2), respectively. All these proteins are involved in melanin synthesis / transportation. Outcome effects: Untreated PKU can lead to intellectual disability, seizures, and other serious medical problems. The mainstream treatment for classic PKU patients is a strict Phe-restricted diet supplemented by a medical formula containing amino acids and other nutrients. The primary treatment for type I tyrosinemia is nitisinone (Orfadin). Nitisinone inhibits the conversion of 4-hydroxyphenylpyruvate to homogentisic acid by 4-hydroxyphenylpyruvate dioxygenase (HPD), the second step in tyrosine degradation.Mutated genes are shown in white-out style. PS:Organ_System nervous system PS:PMID 17513423 PS:PMID 20720592 PS:PMID 24789876 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: The transmembrane receptor tyrosine kinase, c-Met (MET) is activated by the hepatocyte growth factor/scatter factor (HGF/SF), a multifunctional growth factor that regulates various cell processes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9034cfb0-6495-48c9-925a-0c2ce5eaccf5 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The transmembrane receptor tyrosine kinase, c-Met (MET) is activated by the hepatocyte growth factor/scatter factor (HGF/SF). It has been shown that the inadequate expression of HGF/SF or MET promotes the growth and invasion of prostate cancer cells. In contrast, androgen receptor (AR) inhibits the expression of MET. This is achieved when AR competes with another transcription factor, SP1, for the binding to the promoter of MET. Outcome effects: HGF/SF is a multifunctional growth factor that regulates various cell processes such as cell motility, invasive growth, and angiogenesis. Organ: prostate Organ_System: urinary tract PMID: 17283128 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9034cfb0-6495-48c9-925a-0c2ce5eaccf5 Androgen Receptor/c-Met Signaling in Prostate Cancer uuid-9034cfb0-6495-48c9-925a-0c2ce5eaccf5 PS:CellType cancer cell PS:Description The transmembrane receptor tyrosine kinase, c-Met (MET) is activated by the hepatocyte growth factor/scatter factor (HGF/SF), a multifunctional growth factor that regulates various cell processes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9034cfb0-6495-48c9-925a-0c2ce5eaccf5 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: The transmembrane receptor tyrosine kinase, c-Met (MET) is activated by the hepatocyte growth factor/scatter factor (HGF/SF). It has been shown that the inadequate expression of HGF/SF or MET promotes the growth and invasion of prostate cancer cells. In contrast, androgen receptor (AR) inhibits the expression of MET. This is achieved when AR competes with another transcription factor, SP1, for the binding to the promoter of MET. Outcome effects: HGF/SF is a multifunctional growth factor that regulates various cell processes such as cell motility, invasive growth, and angiogenesis. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 17283128 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta cells and four other endocrine cell types. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90a35cad-ffd8-428f-b296-4c84ee50fa80 NodeType: Pathway Notes: Headnote: The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta cells and four other endocrine cell types. Adult beta cells are heterogeneous, with differences in glucose-responsiveness, insulin promoter activity, and insulin protein levels. The endocrine function of beta cells is to respond to increases in blood glucose levels by secreting insulin. Additional beta cell products are amyloid polypeptide (IAPP or amylin) and C-peptide. Signaling description: During insulin synthesis, preproinsulin (24-residue signal peptide) is initially synthesized. Proinsulin is formed from preproinsulin in the lumen of the rough endoplasmic reticulum (ER). Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases such as PCSK1 and CPE. Endopeptidases release a fragment called the C-peptide and leave 2 peptide chains, the B- and A-chains which are linked by 2 disulfide bonds. Mature IAPP is excised by processing proprotein convertase, PCSK1 and PCSK2, in parallel to proinsulin processing. Amylin is secreted together with insulin in a 20 to 1 molar ratio of insulin to amylin. PCSK1 and PCSK2 are themselves synthesized as inactive pro-PCSK1 and pro-PCSK2, which are activated by specific chaperone proteins, PCSK1N and SCG5, respectively. In isolated rat pancreatic islets, the biosynthesis of PCSK1 is specifically stimulated by glucose. In contrast, PCSK2 biosynthesis is not glucose-regulated. Insulin and C-peptide are then stored in the secretory granules together with islet IAPP. Glucose metabolism is the most important physiological event that stimulates insulin gene transcription and mRNA translation. The transcription factors including MAFA, PDX1, FOXO1, NFE2L2, PAX6, and NEUROD1, which are implicated in the regulation of insulin transcription, have been demonstrated to play a crucial role in human pancreatic beta cell function. Increases in glucose levels (10-30 mM) in mouse insulinoma cell line MIN6 disrupt the interaction of another insulin transcription factor, PDX1 with HDAC1 and HDAC2 and promote its association with EP300. EP300 leads to hyperacetylation of histone H4 and induction of insulin gene transcription. Glucose and glucagon (GCG) have been shown to increase PDX1 levels, as well as its nuclear localization. Several signaling pathways including MAPK14, PI3K, and PASK have been implicated in PDX1 phosphorylation and nucleocytoplasmic shuttling. Glucose has also been shown to regulate nuclear localization as well as transactivation capacity of NEUROD1 via post-transcriptional modification. In animal models, NEUROD1 is modified by phosphorylation via MAPK3/MAPK1 and through acetylation by EP300. Under high-glucose conditions (10-30 mM), NEUROD1 interacts with OGT and becomes O-GlcNAc-modified and translocates from the cytosol into the nucleus. NEUROD1, by glucose influence, modulates the expression of ion channels NNAT and ABCC8. This finding suggests that NEUROD1 may regulate insulin exocytosis in pancreatic beta cells by directly inducing the expression of SEC24D, SNAP25, syntaxin1, and STXBP1. In addition, glucose and GCG regulate insulin translation via EIF2AK3 and WFS1. WFS1 is upregulated by ER stress via ERN1 and EIF2AK3. At the beginning of glucose exposure, ERN1 stimulates insulin synthesis via WFS1, while after prolonged exposure; it may reduce insulin production via XBP1. Glucose and GCG stimulate WFS1 translocation from the ER to the plasma membrane, where WFS1 may form a complex with ADCY8 and calmodulin, which stimulates cAMP synthesis and insulin secretion. Lastly, glucose enhances the binding of the RNA binding protein, PTBP1 to the 5-UTRs of mRNAs for insulin and other cargoes of beta cell granules to increase their stability. Insulin is stored as a crystal chelated with Zn2 . Organ: pancreas Organ_System: endocrine system PMID: 22618775 PMID: 8440711 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-90a35cad-ffd8-428f-b296-4c84ee50fa80 Insulin Synthesis in beta-Cell uuid-90a35cad-ffd8-428f-b296-4c84ee50fa80 PS:CellType insulin-secreting cell PS:Description The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta cells and four other endocrine cell types. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90a35cad-ffd8-428f-b296-4c84ee50fa80 PS:NodeType Pathway PS:Notes Headnote: The endocrine section of the pancreas (islets of Langerhans) consists of insulin-secreting beta cells and four other endocrine cell types. Adult beta cells are heterogeneous, with differences in glucose-responsiveness, insulin promoter activity, and insulin protein levels. The endocrine function of beta cells is to respond to increases in blood glucose levels by secreting insulin. Additional beta cell products are amyloid polypeptide (IAPP or amylin) and C-peptide. Signaling description: During insulin synthesis, preproinsulin (24-residue signal peptide) is initially synthesized. Proinsulin is formed from preproinsulin in the lumen of the rough endoplasmic reticulum (ER). Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases such as PCSK1 and CPE. Endopeptidases release a fragment called the C-peptide and leave 2 peptide chains, the B- and A-chains which are linked by 2 disulfide bonds. Mature IAPP is excised by processing proprotein convertase, PCSK1 and PCSK2, in parallel to proinsulin processing. Amylin is secreted together with insulin in a 20 to 1 molar ratio of insulin to amylin. PCSK1 and PCSK2 are themselves synthesized as inactive pro-PCSK1 and pro-PCSK2, which are activated by specific chaperone proteins, PCSK1N and SCG5, respectively. In isolated rat pancreatic islets, the biosynthesis of PCSK1 is specifically stimulated by glucose. In contrast, PCSK2 biosynthesis is not glucose-regulated. Insulin and C-peptide are then stored in the secretory granules together with islet IAPP. Glucose metabolism is the most important physiological event that stimulates insulin gene transcription and mRNA translation. The transcription factors including MAFA, PDX1, FOXO1, NFE2L2, PAX6, and NEUROD1, which are implicated in the regulation of insulin transcription, have been demonstrated to play a crucial role in human pancreatic beta cell function. Increases in glucose levels (10-30 mM) in mouse insulinoma cell line MIN6 disrupt the interaction of another insulin transcription factor, PDX1 with HDAC1 and HDAC2 and promote its association with EP300. EP300 leads to hyperacetylation of histone H4 and induction of insulin gene transcription. Glucose and glucagon (GCG) have been shown to increase PDX1 levels, as well as its nuclear localization. Several signaling pathways including MAPK14, PI3K, and PASK have been implicated in PDX1 phosphorylation and nucleocytoplasmic shuttling. Glucose has also been shown to regulate nuclear localization as well as transactivation capacity of NEUROD1 via post-transcriptional modification. In animal models, NEUROD1 is modified by phosphorylation via MAPK3/MAPK1 and through acetylation by EP300. Under high-glucose conditions (10-30 mM), NEUROD1 interacts with OGT and becomes O-GlcNAc-modified and translocates from the cytosol into the nucleus. NEUROD1, by glucose influence, modulates the expression of ion channels NNAT and ABCC8. This finding suggests that NEUROD1 may regulate insulin exocytosis in pancreatic beta cells by directly inducing the expression of SEC24D, SNAP25, syntaxin1, and STXBP1. In addition, glucose and GCG regulate insulin translation via EIF2AK3 and WFS1. WFS1 is upregulated by ER stress via ERN1 and EIF2AK3. At the beginning of glucose exposure, ERN1 stimulates insulin synthesis via WFS1, while after prolonged exposure; it may reduce insulin production via XBP1. Glucose and GCG stimulate WFS1 translocation from the ER to the plasma membrane, where WFS1 may form a complex with ADCY8 and calmodulin, which stimulates cAMP synthesis and insulin secretion. Lastly, glucose enhances the binding of the RNA binding protein, PTBP1 to the 5-UTRs of mRNAs for insulin and other cargoes of beta cell granules to increase their stability. Insulin is stored as a crystal chelated with Zn2 . PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22618775 PS:PMID 8440711 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: RNA gene silencing is a process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90b03ab0-312b-4783-b1ae-1e57b4055a75 NodeType: Pathway Notes: Headnote: RNA gene silencing is a process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. In all organisms, the mechanism for RNA silencing involves the cutting of double-stranded RNA (dsRNA) into smaller pieces. Signaling description: When dsRNA is exogenous, such as being introduced by a virus, RNA is imported directly into the cytoplasm and cleaved into short fragments. The initiating dsRNA may also be endogenous, originating in the cell, and expressed from RNA-coding genes in the genome. The cutting of dsRNA into smaller pieces is passed by DICER1 in an ATP-dependent reaction. DICER1 cleaves dsRNA into two classes of smaller RNAs including microRNAs (miRNAs) and small interfering RNAs (siRNAs) that are 21-25 nucleotides long. The miRNAs are expressed polycistronically and endogenously. Let-7 (miR-let-7) family genes code miRNAs that are highly conserved across species in sequence and function. The miRNA genes are generally transcribed by RNA polymerase II. The dsRNA structure of the hairpins in primary-miRNA (pri-miRNA) is recognized by DGCR8 which cleaves the RNA and releases the hairpins to form precursor-miRNA (pre-miRNA). Pre-miRNA hairpins are exported from the nucleus in a process involving exportin 5 (XPO5). Silencing RNA (siRNA) is a short dsRNA that results from being processed by DICER1 which cleaves exogenous long dsRNAs. The siRNAs have 2 strands with a 5' phosphate group and a 3' hydroxyl group. As a result, two dsRNA pathways converge at the RISC complex. Each siRNA and miRNA is unwound into two single-stranded RNAs (ssRNAs), the passenger strand and guide strand. The passenger strand is degraded and the guide strand is incorporated into the RISC complex. A recent consensus model suggests that EIF2C2 is the core component of the RISC complex that directly receives the double-stranded siRNA and cleaves the siRNA passenger strand. Cellular proteins interacting with DICER1, such as FMR, TARBP2, and PRKRA, are also key regulators of RISC complex and DICER1 activity. Outcome effects: In siRNA-guided RNA silencing, RISC complex cleaves the target mRNA at a single site in the center of the duplex region between the guide siRNA and the target mRNA, resulting in gene silencing. In contrast, miRNAs typically have incomplete base pairing to a target and thus may inhibit translation of many different mRNAs with similar sequences. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-90b03ab0-312b-4783-b1ae-1e57b4055a75 RNA Gene Silencing uuid-90b03ab0-312b-4783-b1ae-1e57b4055a75 PS:CellType generic PS:Description RNA gene silencing is a process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90b03ab0-312b-4783-b1ae-1e57b4055a75 PS:NodeType Pathway PS:Notes Headnote: RNA gene silencing is a process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. In all organisms, the mechanism for RNA silencing involves the cutting of double-stranded RNA (dsRNA) into smaller pieces. Signaling description: When dsRNA is exogenous, such as being introduced by a virus, RNA is imported directly into the cytoplasm and cleaved into short fragments. The initiating dsRNA may also be endogenous, originating in the cell, and expressed from RNA-coding genes in the genome. The cutting of dsRNA into smaller pieces is passed by DICER1 in an ATP-dependent reaction. DICER1 cleaves dsRNA into two classes of smaller RNAs including microRNAs (miRNAs) and small interfering RNAs (siRNAs) that are 21-25 nucleotides long. The miRNAs are expressed polycistronically and endogenously. Let-7 (miR-let-7) family genes code miRNAs that are highly conserved across species in sequence and function. The miRNA genes are generally transcribed by RNA polymerase II. The dsRNA structure of the hairpins in primary-miRNA (pri-miRNA) is recognized by DGCR8 which cleaves the RNA and releases the hairpins to form precursor-miRNA (pre-miRNA). Pre-miRNA hairpins are exported from the nucleus in a process involving exportin 5 (XPO5). Silencing RNA (siRNA) is a short dsRNA that results from being processed by DICER1 which cleaves exogenous long dsRNAs. The siRNAs have 2 strands with a 5' phosphate group and a 3' hydroxyl group. As a result, two dsRNA pathways converge at the RISC complex. Each siRNA and miRNA is unwound into two single-stranded RNAs (ssRNAs), the passenger strand and guide strand. The passenger strand is degraded and the guide strand is incorporated into the RISC complex. A recent consensus model suggests that EIF2C2 is the core component of the RISC complex that directly receives the double-stranded siRNA and cleaves the siRNA passenger strand. Cellular proteins interacting with DICER1, such as FMR, TARBP2, and PRKRA, are also key regulators of RISC complex and DICER1 activity. Outcome effects: In siRNA-guided RNA silencing, RISC complex cleaves the target mRNA at a single site in the center of the duplex region between the guide siRNA and the target mRNA, resulting in gene silencing. In contrast, miRNAs typically have incomplete base pairing to a target and thus may inhibit translation of many different mRNAs with similar sequences. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: APC/C-CDC20 complex stimulates sister chromatid cohesion leads to metaphase/anaphase transition. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90d9dc99-8aca-42e3-a3bd-c2698913a358 NodeType: Pathway Notes: Headnote: The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. Many proteins of the APC/C still have unknown functions. APC/C is basically organized into three structural domains, called the 'platform', the 'catalytic' and the 'TPR-arm, lobe or arc lamp'. The platform subcomplex (ANAPC1, ANAPC4, ANAPC5, and ANAPC15) forms a base to join the other subunits of the APC/C. The catalytic core subcomplex (ANAPC2, ANAPC11, and ANAPC10) with E2 enzyme can provide ubiquitylation activity to the APC/C. The TPR-arm consists of several structurally related proteins with multiple tetratricopeptide (TPR) repeats (ANAPC7, ANAPC13, ANAPC16, CDC16, CDC23, CDC26, CDC27) and is required to coordinate assembly of the APC/C and mediate important interactions with regulator proteins that modulate APC/C activity. Signaling description: The core of APC/C-CDC20 complex related signaling through specific subset of substrate proteins leads to metaphase/anaphase transition. Precise mechanism of the molecular signaling on this pathway is partially known and is associated with activation of CDC20._ Outcome effects: Activating regulator protein CDC20 associates with the phosphorylated APC/C in early mitosis. As metaphase begins, the spindle checkpoint inhibits the APC/C until all sister-kinetochores are attached to opposite poles of the mitotic spindle. CDK1 phosphorylates subunits on APC/C that promotes binding to CDC20. The APC/C-CDC20 complex ubiquitinates PTTG1 (securin) and CCNB1 (cyclin B1) for degradation. Once PTTG1 is degraded, ESPL1 (separin) is released and cleaves RAD21. In turn, RAD21 is bound to a member of the cohesin complex (STAG1, STAG2, SMC1A, SMC3) which regulates separation of sister chromatids. Subsequent to cohesin degradation, the sister chromatids are separated and metaphase proceeds to anaphase. When the spindle assembly checkpoint is activated, CDC20 is inhibited in a MAD2L1-dependent process. Animal data: Role of APC/C-CDH1 in the signaling was revealed partially from animal model experiments Organ: generic Organ_System: generic PMID: 21261459 PMID: 25043029 PMID: 25604195 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-90d9dc99-8aca-42e3-a3bd-c2698913a358 APC/C-CDC20 Complex uuid-90d9dc99-8aca-42e3-a3bd-c2698913a358 PS:CellType generic PS:Description APC/C-CDC20 complex stimulates sister chromatid cohesion leads to metaphase/anaphase transition. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90d9dc99-8aca-42e3-a3bd-c2698913a358 PS:NodeType Pathway PS:Notes Headnote: The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. Many proteins of the APC/C still have unknown functions. APC/C is basically organized into three structural domains, called the 'platform', the 'catalytic' and the 'TPR-arm, lobe or arc lamp'. The platform subcomplex (ANAPC1, ANAPC4, ANAPC5, and ANAPC15) forms a base to join the other subunits of the APC/C. The catalytic core subcomplex (ANAPC2, ANAPC11, and ANAPC10) with E2 enzyme can provide ubiquitylation activity to the APC/C. The TPR-arm consists of several structurally related proteins with multiple tetratricopeptide (TPR) repeats (ANAPC7, ANAPC13, ANAPC16, CDC16, CDC23, CDC26, CDC27) and is required to coordinate assembly of the APC/C and mediate important interactions with regulator proteins that modulate APC/C activity. Signaling description: The core of APC/C-CDC20 complex related signaling through specific subset of substrate proteins leads to metaphase/anaphase transition. Precise mechanism of the molecular signaling on this pathway is partially known and is associated with activation of CDC20._ Outcome effects: Activating regulator protein CDC20 associates with the phosphorylated APC/C in early mitosis. As metaphase begins, the spindle checkpoint inhibits the APC/C until all sister-kinetochores are attached to opposite poles of the mitotic spindle. CDK1 phosphorylates subunits on APC/C that promotes binding to CDC20. The APC/C-CDC20 complex ubiquitinates PTTG1 (securin) and CCNB1 (cyclin B1) for degradation. Once PTTG1 is degraded, ESPL1 (separin) is released and cleaves RAD21. In turn, RAD21 is bound to a member of the cohesin complex (STAG1, STAG2, SMC1A, SMC3) which regulates separation of sister chromatids. Subsequent to cohesin degradation, the sister chromatids are separated and metaphase proceeds to anaphase. When the spindle assembly checkpoint is activated, CDC20 is inhibited in a MAD2L1-dependent process. Animal data: Role of APC/C-CDH1 in the signaling was revealed partially from animal model experiments PS:Organ generic PS:Organ_System generic PS:PMID 21261459 PS:PMID 25043029 PS:PMID 25604195 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90dee00e-2d18-4037-ad77-88c0b976f110 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-90dee00e-2d18-4037-ad77-88c0b976f110 CD157 -> cADPR/Calcium Signaling uuid-90dee00e-2d18-4037-ad77-88c0b976f110 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90dee00e-2d18-4037-ad77-88c0b976f110 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90ea3b85-07b2-4b7d-b612-1d536940931a NodeType: Pathway Organ: generic Organ_System: generic PMID: 25183867 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-90ea3b85-07b2-4b7d-b612-1d536940931a Hedgehog Family Signaling uuid-90ea3b85-07b2-4b7d-b612-1d536940931a PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90ea3b85-07b2-4b7d-b612-1d536940931a PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 25183867 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90f9b500-0bc6-4f55-8fd1-b5d97f3e596f NodeType: Pathway Notes: Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located in the uppermost portion of the lateral plasma membrane apical to adherens junctions, and serve to hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each cell surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Occludin (OCLN) is expressed in the tight junctions of both endothelial and epithelial cells. This hydrophilic phosphoprotein has four transmembrane domains and two extracellular loops exposed to the cytosol. OCLN forms complexes with TJP1, TJP2, VAPA, EPB41, CTNNB1, CTNNA1, MLLT4, CGN, and SYMPK. RAB13 and other RAB GTPases facilitate vesicular trafficking of occludins. RAB13 interacts directly with PKA and inhibits PKA-dependent phosphorylation of VASP which is essential for actin remodeling. Similarly, the phosphorylation of SNAP receptors by PKA is implicated in the regulation of vesicle release. The cytoplasmic plaque protein, SYMPK participates in nuclear as well as cytoplasmic polyadenylation and activates mRNA cleavage stimulating factor and HSF1 to regulate mRNA stability/localization and cell adhesion/apoptosis, respectively. Outcome effects: MAGI2 and MAGI3 bind to CTNNB1 at occludin junctions and prevent PTEN degradation. This significantly decreases the proliferative effect of AKT1 and prevents junction disassembly. The increase in PTEN activity also affects ITG/ILK/GSK3/MAPK8 signaling and thus modulates the level of OCLN near tight junctions. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-90f9b500-0bc6-4f55-8fd1-b5d97f3e596f Tight Junction Assembly (Occludin) uuid-90f9b500-0bc6-4f55-8fd1-b5d97f3e596f PS:CellType generic PS:Description Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-90f9b500-0bc6-4f55-8fd1-b5d97f3e596f PS:NodeType Pathway PS:Notes Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located in the uppermost portion of the lateral plasma membrane apical to adherens junctions, and serve to hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each cell surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Occludin (OCLN) is expressed in the tight junctions of both endothelial and epithelial cells. This hydrophilic phosphoprotein has four transmembrane domains and two extracellular loops exposed to the cytosol. OCLN forms complexes with TJP1, TJP2, VAPA, EPB41, CTNNB1, CTNNA1, MLLT4, CGN, and SYMPK. RAB13 and other RAB GTPases facilitate vesicular trafficking of occludins. RAB13 interacts directly with PKA and inhibits PKA-dependent phosphorylation of VASP which is essential for actin remodeling. Similarly, the phosphorylation of SNAP receptors by PKA is implicated in the regulation of vesicle release. The cytoplasmic plaque protein, SYMPK participates in nuclear as well as cytoplasmic polyadenylation and activates mRNA cleavage stimulating factor and HSF1 to regulate mRNA stability/localization and cell adhesion/apoptosis, respectively. Outcome effects: MAGI2 and MAGI3 bind to CTNNB1 at occludin junctions and prevent PTEN degradation. This significantly decreases the proliferative effect of AKT1 and prevents junction disassembly. The increase in PTEN activity also affects ITG/ILK/GSK3/MAPK8 signaling and thus modulates the level of OCLN near tight junctions. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: granulosa cell Description: Follicle-stimulating hormone (FSH) controls granulosa cell proliferation and differentiation and thus promotes folliculogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-914fb7cc-c676-4334-8e93-5fae99a8ed77 NodeType: Pathway Notes: Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Signaling description: Follicle-stimulating hormone (FSH) controls granulosa cell proliferation and differentiation and thus promotes folliculogenesis. The hormone also participates in steroidogenesis. The FSH hormone signaling promotes AMH expression, and the elevated protein in turn reduces the FSH receptor mRNA expression and inhibits the signaling. In polycystic ovary syndrome (PCOS), FSH signaling in granulosa cells activates cell proliferation and differentiation of many follicles at the earliest stages of their development. The signaling is blocked at the stage of small preantral follicle due to elevated AMH and estrogen, which block the FSH synthesis. Outcome effects: The FSH signaling includes PI3K, PKC, and PKA activation, which normally leads to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 signaling route. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. FSH signaling, through PI3K, leads to AKT1 activation which inhibits FOXO1, a negative regulator of cell proliferation and differentiation. FSH plays an important role in steroidogenesis through the activation of GATA4 and CREB1. Outcome effects: Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: ovary Organ_System: reproductive system PMID: 12017544 PMID: 19078868 PMID: 20591140 PMID: 21606667 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-914fb7cc-c676-4334-8e93-5fae99a8ed77 FSH Action in Polycystic Ovary Syndrome uuid-914fb7cc-c676-4334-8e93-5fae99a8ed77 PS:CellType granulosa cell PS:Description Follicle-stimulating hormone (FSH) controls granulosa cell proliferation and differentiation and thus promotes folliculogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-914fb7cc-c676-4334-8e93-5fae99a8ed77 PS:NodeType Pathway PS:Notes Headnote: Polycystic ovary syndrome (PCOS) is a disease generally characterized by hyperandrogenemia, anovulation/oligoovulation, and polycystic ovary. Impaired steroidogenesis, particularly excessive androgen production, is one of the main features in polycystic ovary syndrome (PCOS). Signaling description: Follicle-stimulating hormone (FSH) controls granulosa cell proliferation and differentiation and thus promotes folliculogenesis. The hormone also participates in steroidogenesis. The FSH hormone signaling promotes AMH expression, and the elevated protein in turn reduces the FSH receptor mRNA expression and inhibits the signaling. In polycystic ovary syndrome (PCOS), FSH signaling in granulosa cells activates cell proliferation and differentiation of many follicles at the earliest stages of their development. The signaling is blocked at the stage of small preantral follicle due to elevated AMH and estrogen, which block the FSH synthesis. Outcome effects: The FSH signaling includes PI3K, PKC, and PKA activation, which normally leads to proliferation and differentiation of granulosa cells. PLCB1 provokes Ca2+-dependent PKC activation and affects BRAF, which promotes the MAPK1/MAPK3 signaling route. The pathway recruits CREB1, FOS, and SRF transcription factors, which initiate cell division. In addition, the MAPK1/MAPK3 pathway, along with PKA, promotes GATA4 activation. GATA4 and SRF are responsible for cell differentiation. FSH signaling, through PI3K, leads to AKT1 activation which inhibits FOXO1, a negative regulator of cell proliferation and differentiation. FSH plays an important role in steroidogenesis through the activation of GATA4 and CREB1. Outcome effects: Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 12017544 PS:PMID 19078868 PS:PMID 20591140 PS:PMID 21606667 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91553c80-df53-4598-b475-7c714e9c3ecb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-91553c80-df53-4598-b475-7c714e9c3ecb Heparan sulfate biosynthesis template uuid-91553c80-df53-4598-b475-7c714e9c3ecb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91553c80-df53-4598-b475-7c714e9c3ecb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-915ebfc7-ce80-47f3-be57-75acae1591fa NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-915ebfc7-ce80-47f3-be57-75acae1591fa fast-slow muscle fiber switch uuid-915ebfc7-ce80-47f3-be57-75acae1591fa PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-915ebfc7-ce80-47f3-be57-75acae1591fa PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9168d954-050b-42b2-b529-6c11182f6e1e NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-9168d954-050b-42b2-b529-6c11182f6e1e Genes with Mutations in Cancer-Associated Evading of Growth Suppressors uuid-9168d954-050b-42b2-b529-6c11182f6e1e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9168d954-050b-42b2-b529-6c11182f6e1e PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:NodeType PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Source: Atlas urn:agi-pathway:uuid-91819b31-950a-4ce8-bb90-5d00a535531f 2_levothyroxine and aspirin effects crossing uuid-91819b31-950a-4ce8-bb90-5d00a535531f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91b9cccb-4e24-4b91-ba06-c60ef48071f6 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-91b9cccb-4e24-4b91-ba06-c60ef48071f6 Glu/Gln/Pro Metabolsm uuid-91b9cccb-4e24-4b91-ba06-c60ef48071f6 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91b9cccb-4e24-4b91-ba06-c60ef48071f6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage Description: The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91c25973-5c4c-4e0b-a6e5-92f50121bb63 NodeType: Pathway Notes: Headnote: The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. GAS6 and PROS1 are well known ligands for TAM receptors. TAM receptors have pivotal roles in innate immunity. Signaling description: Toll-like receptor (TLR4/3/9) signaling is stimulated by pathogens in quiescent macrophages and dendritic cells and initiated burst of pro-inflammatory cytokines expression. These cytokine, such as IFNA1, TNF, IL6, IL12A and IL12B lead to inflammatory response activation. Overexpressed cytokines provide feedback on macrophages and dendritic cells and cause activation of the AXL receptor. TAM receptor signaling through SOCS1/3 leads to inhibition of cytokine expression. Precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. AXL receptor signaling requires coordinate interaction with both FNAR and STAT1. Outcome effects: Finally, AXL receptor related inhibition of cytokines expression ends the inflammatory reaction. TAM-deficient mice were shown to develop broad-spectrum autoimmune diseases. Animal data: Role of TAM receptors in the process of clearance of apoptotic cells was revealed from animal model experiments. Highlighted proteins: IFNA1, TNF, IL6, IL12A and IL12B are highlighted in blue in order to illustrate AXL receptor signaling effects on their reduced expression. AXL receptor and SOCS1/3 are highlighted in red color in order to show their activated expression. Organ: generic Organ_System: hematological system PMID: 18083093 PMID: 18083102 PMID: 18421305 PMID: 24186067 PMID: 24596417 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-91c25973-5c4c-4e0b-a6e5-92f50121bb63 AXL Receptor Inhibits Macrophages and Dendritic Cells Function uuid-91c25973-5c4c-4e0b-a6e5-92f50121bb63 PS:CellType dendritic cell PS:CellType macrophage PS:Description The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91c25973-5c4c-4e0b-a6e5-92f50121bb63 PS:NodeType Pathway PS:Notes Headnote: The subfamily of TAM receptors includes AXL, MERTK and TYRO3 receptor protein tyrosine kinases. GAS6 and PROS1 are well known ligands for TAM receptors. TAM receptors have pivotal roles in innate immunity. Signaling description: Toll-like receptor (TLR4/3/9) signaling is stimulated by pathogens in quiescent macrophages and dendritic cells and initiated burst of pro-inflammatory cytokines expression. These cytokine, such as IFNA1, TNF, IL6, IL12A and IL12B lead to inflammatory response activation. Overexpressed cytokines provide feedback on macrophages and dendritic cells and cause activation of the AXL receptor. TAM receptor signaling through SOCS1/3 leads to inhibition of cytokine expression. Precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. AXL receptor signaling requires coordinate interaction with both FNAR and STAT1. Outcome effects: Finally, AXL receptor related inhibition of cytokines expression ends the inflammatory reaction. TAM-deficient mice were shown to develop broad-spectrum autoimmune diseases. Animal data: Role of TAM receptors in the process of clearance of apoptotic cells was revealed from animal model experiments. Highlighted proteins: IFNA1, TNF, IL6, IL12A and IL12B are highlighted in blue in order to illustrate AXL receptor signaling effects on their reduced expression. AXL receptor and SOCS1/3 are highlighted in red color in order to show their activated expression. PS:Organ generic PS:Organ_System hematological system PS:PMID 18083093 PS:PMID 18083102 PS:PMID 18421305 PS:PMID 24186067 PS:PMID 24596417 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. Chronic overexpression of ADK causes seizures. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91dcc165-2102-42a1-ba51-b9c874c31097 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. Under physiological conditions, a major source of synaptic adenosine is the vesicular release of ATP from astrocytes and neurons followed by its extracellular degradation to adenosine by a cascade of ectonucleotidases (ENTPD1 and NT5C1A). Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. The transient downregulation of ADK after acute brain injury protects the brain from seizures. Conversely, chronic overexpression of ADK causes seizures. Normally, the inhibitory effects of adenosine are primarily mediated by the activation of ADORA1 that is linked to inhibitory G proteins, which activate G-protein-dependent inwardly rectifying K channels and inhibit Ca2+ channels. At the same time, downregulation of ADORA1 receptors has been described as a consequence of chronic seizures. In chronic recurrent seizures, astrogliosis (neuroinflammation) leads to the upregulation of ADK. Outcome effects: Normally, as a consequence of ADORA action, the release of various neurotransmitters, particularly glutamate is blocked; whereas, in chronic recurrent seizures, the upregulation of ADK results in a decrease of adenosine and spontaneous recurrent seizures develop. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 17056128 PMID: 23385089 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-91dcc165-2102-42a1-ba51-b9c874c31097 ADK Expression Upregulation uuid-91dcc165-2102-42a1-ba51-b9c874c31097 PS:CellType astrocyte PS:CellType neuron PS:Description Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. Chronic overexpression of ADK causes seizures. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91dcc165-2102-42a1-ba51-b9c874c31097 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. Under physiological conditions, a major source of synaptic adenosine is the vesicular release of ATP from astrocytes and neurons followed by its extracellular degradation to adenosine by a cascade of ectonucleotidases (ENTPD1 and NT5C1A). Adenosine kinase (ADK) is responsible for the removal of adenosine via phosphorylation to AMP. ADK undergoes rapid coordinated changes following brain injury such as epileptic seizures or stroke. The transient downregulation of ADK after acute brain injury protects the brain from seizures. Conversely, chronic overexpression of ADK causes seizures. Normally, the inhibitory effects of adenosine are primarily mediated by the activation of ADORA1 that is linked to inhibitory G proteins, which activate G-protein-dependent inwardly rectifying K channels and inhibit Ca2+ channels. At the same time, downregulation of ADORA1 receptors has been described as a consequence of chronic seizures. In chronic recurrent seizures, astrogliosis (neuroinflammation) leads to the upregulation of ADK. Outcome effects: Normally, as a consequence of ADORA action, the release of various neurotransmitters, particularly glutamate is blocked; whereas, in chronic recurrent seizures, the upregulation of ADK results in a decrease of adenosine and spontaneous recurrent seizures develop. Highlighted proteins: Entities with increased level or activity is highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 17056128 PS:PMID 23385089 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91dda5d1-e49a-485e-a1a1-459bc0445f2d NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-91dda5d1-e49a-485e-a1a1-459bc0445f2d CCL2 Role in CGRP Expression and Release uuid-91dda5d1-e49a-485e-a1a1-459bc0445f2d PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91dda5d1-e49a-485e-a1a1-459bc0445f2d PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91e4069f-a04f-4f07-8cec-d2e8d7663627 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-91e4069f-a04f-4f07-8cec-d2e8d7663627 H2BK120 Epigenetic Modifications - Overview uuid-91e4069f-a04f-4f07-8cec-d2e8d7663627 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91e4069f-a04f-4f07-8cec-d2e8d7663627 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91ebbeea-27d2-46ce-834a-cc99cbe43dba NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-91ebbeea-27d2-46ce-834a-cc99cbe43dba SARS RdRp (NSP12) inhibitors uuid-91ebbeea-27d2-46ce-834a-cc99cbe43dba PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-91ebbeea-27d2-46ce-834a-cc99cbe43dba PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9239b98e-d788-40ed-88a3-f01796a4e9c5 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9239b98e-d788-40ed-88a3-f01796a4e9c5 GGPP, FPP synthesis template uuid-9239b98e-d788-40ed-88a3-f01796a4e9c5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9239b98e-d788-40ed-88a3-f01796a4e9c5 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: An excess of extracellular glutamate is found in human epileptogenic tissue and can induce recurrent seizures and neuronal cell death. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9239f338-6f2e-43bb-b6ef-50506380eb2a NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: An excess of extracellular glutamate is found in human epileptogenic tissue and can induce recurrent seizures and neuronal cell death. This may occur through the activation of neuronal and glial glutamate receptors. Glutamate activates astrocyte metabotropic receptors GRM1/5 leading to intracellular calcium (Ca2+) elevation and Ca2+-dependent release of glutamate, D-serine, and ATP from astrocytes. Astrocyte swelling is typical for epilepsy and opens volume-regulated anion channels (VRACs) which releases glutamate into the extracellular space. Outcome effects: The increased level of glutamate and D-serine in the synaptic cleft leads to postsynaptic motor neuron hyperexcitation. ATP release may lead to astrocyte activation via P2Y receptors (P2RY1/P2RY2) in an autocrine manner, and at the same time, inhibitory signaling to postsynaptic motor neurons via ATP metabolite adenosine. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1). Clasadonte J, Haydon PG (2012) Astrocytes and Epilepsy. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. Coulter DA (2009). 2). Neurotransmitter function. Consequences of Diminished Function of the Glutamine Cycle on Inhibitory Function in the Epileptic Brain. Encyclopedia of Basic Epilepsy Research. pp 877-882.Avialable from: http://www.sciencedirect.com/science/article/pii/B9780123739612003453 3). Organ: brain Organ_System: nervous system PMID: 23376026 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-9239f338-6f2e-43bb-b6ef-50506380eb2a Glutamate, D-Serine, and ATP Release from Astrocytes uuid-9239f338-6f2e-43bb-b6ef-50506380eb2a PS:CellType astrocyte PS:CellType neuron PS:Description An excess of extracellular glutamate is found in human epileptogenic tissue and can induce recurrent seizures and neuronal cell death. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9239f338-6f2e-43bb-b6ef-50506380eb2a PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: An excess of extracellular glutamate is found in human epileptogenic tissue and can induce recurrent seizures and neuronal cell death. This may occur through the activation of neuronal and glial glutamate receptors. Glutamate activates astrocyte metabotropic receptors GRM1/5 leading to intracellular calcium (Ca2+) elevation and Ca2+-dependent release of glutamate, D-serine, and ATP from astrocytes. Astrocyte swelling is typical for epilepsy and opens volume-regulated anion channels (VRACs) which releases glutamate into the extracellular space. Outcome effects: The increased level of glutamate and D-serine in the synaptic cleft leads to postsynaptic motor neuron hyperexcitation. ATP release may lead to astrocyte activation via P2Y receptors (P2RY1/P2RY2) in an autocrine manner, and at the same time, inhibitory signaling to postsynaptic motor neurons via ATP metabolite adenosine. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1). Clasadonte J, Haydon PG (2012) Astrocytes and Epilepsy. Jasper's Basic Mechanisms of the Epilepsies. 4th edition. Coulter DA (2009). 2). Neurotransmitter function. Consequences of Diminished Function of the Glutamine Cycle on Inhibitory Function in the Epileptic Brain. Encyclopedia of Basic Epilepsy Research. pp 877-882.Avialable from: http://www.sciencedirect.com/science/article/pii/B9780123739612003453 3). PS:Organ brain PS:Organ_System nervous system PS:PMID 23376026 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-923ae6c6-11f2-4143-9c06-26643f346911 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-923ae6c6-11f2-4143-9c06-26643f346911 CTF1 Expression Targets uuid-923ae6c6-11f2-4143-9c06-26643f346911 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-923ae6c6-11f2-4143-9c06-26643f346911 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9250e360-ee7d-4cb1-9b9f-077083a4a0a6 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: thymus gland Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-9250e360-ee7d-4cb1-9b9f-077083a4a0a6 NOTCH -> Expression Targets in Thymus uuid-9250e360-ee7d-4cb1-9b9f-077083a4a0a6 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9250e360-ee7d-4cb1-9b9f-077083a4a0a6 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ thymus gland PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-928ed775-2be7-45be-9799-6753f2809b04 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-928ed775-2be7-45be-9799-6753f2809b04 Carotenoid biosynthesis template uuid-928ed775-2be7-45be-9799-6753f2809b04 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-928ed775-2be7-45be-9799-6753f2809b04 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: CD8+ regulatory T-cell CellType: epithelial cell Description: Intestinal epithelial cells express high levels of interleukin-15 which leads to the activation cytotoxic signalling pathway. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92a535c1-0913-4350-8923-e1b4ad1d5657 NodeType: Pathway Notes: Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine which affects genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Intestinal epithelial cells express high levels of interleukin-15, together with MICs and HLA-E. IL-15 leads to the upregulation of NKG2D expression by intraepithelial cytotoxic T-lymphocytes and the cytotoxic signalling pathway associated with this receptor. Consequently, intraepithelial cytotoxic T-lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cells. Furthermore, intraepithelial cytotoxic T- lymphocytes of patients with coeliac disease express CD94-NKG2C-DAP12 immunoreceptor complexes that recognize HLA-E on intestinal epithelial cells and can promote cytokine secretion, proliferation and cytotoxic activity of T-cells in a T-cell receptor (TCR)-independent manner. Outcome effects: Activation of NKG2D in conjunction with IL-15 expression leads to the release of arachidonic acids (and possibly leukotrienes) by intraepithelial cytotoxic T-lymphocytes, which in turn can promote activation of intestinal granulocytes and inflammation.Description of Highlighted proteins: IL15, IL2, IFN-gamma and FASLG are highlighted in red in order to emphasize their increased expression and role in violation of mucosal integrity, epithelial damage and cell damage, resulting in Celiac disease.Description of Mutated genes: MICA gene in white out style has genetic variants which increase susceptibility to Celiac disease. Organ_System: digestive system Organ_System: lymphatic system PMID: 20348961 PMID: 20947431 PMID: 23917697 PMID: 26972670 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-92a535c1-0913-4350-8923-e1b4ad1d5657 CD8+ T-Cell Response in Celiac Disease uuid-92a535c1-0913-4350-8923-e1b4ad1d5657 PS:CellType CD8+ regulatory T-cell PS:CellType epithelial cell PS:Description Intestinal epithelial cells express high levels of interleukin-15 which leads to the activation cytotoxic signalling pathway. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92a535c1-0913-4350-8923-e1b4ad1d5657 PS:NodeType Pathway PS:Notes Headnote: Celiac disease is a life-long gluten-sensitive autoimmune disease of the small intestine which affects genetically susceptible individuals worldwide. Celiac disease is one of the most common diseases, resulting from both environmental (gluten) and genetic factors (human leukocyte antigen (HLA) and non-HLA genes). Signaling description: Intestinal epithelial cells express high levels of interleukin-15, together with MICs and HLA-E. IL-15 leads to the upregulation of NKG2D expression by intraepithelial cytotoxic T-lymphocytes and the cytotoxic signalling pathway associated with this receptor. Consequently, intraepithelial cytotoxic T-lymphocytes acquire killing activity and can target MIC-bearing intestinal epithelial cells. Furthermore, intraepithelial cytotoxic T- lymphocytes of patients with coeliac disease express CD94-NKG2C-DAP12 immunoreceptor complexes that recognize HLA-E on intestinal epithelial cells and can promote cytokine secretion, proliferation and cytotoxic activity of T-cells in a T-cell receptor (TCR)-independent manner. Outcome effects: Activation of NKG2D in conjunction with IL-15 expression leads to the release of arachidonic acids (and possibly leukotrienes) by intraepithelial cytotoxic T-lymphocytes, which in turn can promote activation of intestinal granulocytes and inflammation.Description of Highlighted proteins: IL15, IL2, IFN-gamma and FASLG are highlighted in red in order to emphasize their increased expression and role in violation of mucosal integrity, epithelial damage and cell damage, resulting in Celiac disease.Description of Mutated genes: MICA gene in white out style has genetic variants which increase susceptibility to Celiac disease. PS:Organ_System digestive system PS:Organ_System lymphatic system PS:PMID 20348961 PS:PMID 20947431 PS:PMID 23917697 PS:PMID 26972670 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92beeed6-836a-4861-844a-0d223bcf763b NodeType: Pathway Notes: Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis. The lack of ABCA12 function leads to the disruption of lamellar granule lipid transport in keratinocytes in the upper epidermis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-92beeed6-836a-4861-844a-0d223bcf763b 3_X-linked ichthyosis overview uuid-92beeed6-836a-4861-844a-0d223bcf763b PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92beeed6-836a-4861-844a-0d223bcf763b PS:NodeType Pathway PS:Notes Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis. The lack of ABCA12 function leads to the disruption of lamellar granule lipid transport in keratinocytes in the upper epidermis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron CellType: sensory hair cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92c0721d-e257-4b76-856c-3477aab43216 NodeType: Pathway Notes: Hearing depends on neurotransmission from the cochlear hair cells to the peripheral axon of the spiral ganglion neuron through the glutamatergic synapse. Some genes, encoding proteins implicated in synaptogenesis, may be mutated and exhibit diminished functions in the congenital hearing loss. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: ear Organ_System: sensory system Organelle: synapse PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-92c0721d-e257-4b76-856c-3477aab43216 2_Dysfunctions of cochlear hair cell synapse proteins in hearing loss uuid-92c0721d-e257-4b76-856c-3477aab43216 PS:CellType neuron PS:CellType sensory hair cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92c0721d-e257-4b76-856c-3477aab43216 PS:NodeType Pathway PS:Notes Hearing depends on neurotransmission from the cochlear hair cells to the peripheral axon of the spiral ganglion neuron through the glutamatergic synapse. Some genes, encoding proteins implicated in synaptogenesis, may be mutated and exhibit diminished functions in the congenital hearing loss. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ ear PS:Organ_System sensory system PS:Organelle synapse PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92ccef4a-63b7-49b9-94e3-b6b5e21334ac NodeType: Pathway Organ: generic Organ_System: generic PMID: 19696797 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-92ccef4a-63b7-49b9-94e3-b6b5e21334ac ACE2 internalization uuid-92ccef4a-63b7-49b9-94e3-b6b5e21334ac PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92ccef4a-63b7-49b9-94e3-b6b5e21334ac PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19696797 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92e47e0e-1877-467a-8caf-2116efcd747b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-92e47e0e-1877-467a-8caf-2116efcd747b Glucocorticoid-+>IR uuid-92e47e0e-1877-467a-8caf-2116efcd747b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92e47e0e-1877-467a-8caf-2116efcd747b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of WNT signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92faa76a-48c6-49e2-82b5-fb36127361ec NodeType: Pathway Notes: Headnote: The canonical WNT signaling pathway promotes the accumulation of CTNNB1 in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. The conserved WNT/CTNNB1 pathway regulates stem cell pluripotency and cell fate decisions during embryonic development and is often deregulated in cancer. Signaling description: First, WNT ligands bind to FZD receptors, leading to the formation of a larger cell surface complex with LRP5/6. The activation of the WNT receptor complex triggers displacement of the multifunctional kinase GSK3B from the regulatory APC/AXIN1/GSK3B-complex. In the absence of WNT-signal (off-state), CTNNB undergoes coordinated phosphorylation by CSNK1A1 and the APC/AXIN1/GSK3B-complex leading to its ubiquitination and proteasomal degradation. In the presence of WNT ligand (on-state), the LRP5/6 co-receptor is complexed with WNT-bound FZD. This leads to activation of DLV by sequential phosphorylation, poly-ubiquitination and polymerization, which displaces GSK3B from APC/AXIN1 through an undetermined mechanism that may involve substrate trapping and/or endosome sequestration. The stabilized CTNNB1 is translocated to the nucleus, where it binds to LEF1/TCF4 transcription factors displacing co-repressors and recruiting additional co-activators to WNT target genes. Mutations in CDK1, APC, AXIN1 and other mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. In addition, down-regulation of natural WNT inhibitors SFRPs was described in many cancers. Outcome effects: WNT pathway is kept in the on-state leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15034581 PMID: 17297461 PMID: 18432252 PMID: 18497987 PMID: 22438566 PMID: 22617421 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-92faa76a-48c6-49e2-82b5-fb36127361ec WNT Signaling Activation by Blocking of Tumor Suppressors uuid-92faa76a-48c6-49e2-82b5-fb36127361ec PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of WNT signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-92faa76a-48c6-49e2-82b5-fb36127361ec PS:NodeType Pathway PS:Notes Headnote: The canonical WNT signaling pathway promotes the accumulation of CTNNB1 in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. The conserved WNT/CTNNB1 pathway regulates stem cell pluripotency and cell fate decisions during embryonic development and is often deregulated in cancer. Signaling description: First, WNT ligands bind to FZD receptors, leading to the formation of a larger cell surface complex with LRP5/6. The activation of the WNT receptor complex triggers displacement of the multifunctional kinase GSK3B from the regulatory APC/AXIN1/GSK3B-complex. In the absence of WNT-signal (off-state), CTNNB undergoes coordinated phosphorylation by CSNK1A1 and the APC/AXIN1/GSK3B-complex leading to its ubiquitination and proteasomal degradation. In the presence of WNT ligand (on-state), the LRP5/6 co-receptor is complexed with WNT-bound FZD. This leads to activation of DLV by sequential phosphorylation, poly-ubiquitination and polymerization, which displaces GSK3B from APC/AXIN1 through an undetermined mechanism that may involve substrate trapping and/or endosome sequestration. The stabilized CTNNB1 is translocated to the nucleus, where it binds to LEF1/TCF4 transcription factors displacing co-repressors and recruiting additional co-activators to WNT target genes. Mutations in CDK1, APC, AXIN1 and other mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. In addition, down-regulation of natural WNT inhibitors SFRPs was described in many cancers. Outcome effects: WNT pathway is kept in the on-state leading to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15034581 PS:PMID 17297461 PS:PMID 18432252 PS:PMID 18497987 PS:PMID 22438566 PS:PMID 22617421 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-933fb490-8f76-4954-9aca-be87c56082ac NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-933fb490-8f76-4954-9aca-be87c56082ac AVP/Gs -> MEF/MYOD/NFATC/MYOG Expression Targets uuid-933fb490-8f76-4954-9aca-be87c56082ac PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-933fb490-8f76-4954-9aca-be87c56082ac PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9348f487-df13-4184-8beb-4e353a1b271c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9348f487-df13-4184-8beb-4e353a1b271c INHBA/ACVR2/BMPR Expression Targets uuid-9348f487-df13-4184-8beb-4e353a1b271c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9348f487-df13-4184-8beb-4e353a1b271c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9356f5bf-a02c-4561-b67b-ced012da6a23 NodeType: Pathway Notes: Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in the DUOX2, SLC5A5, TG, TPO, and TSHB genes prevent or reduce the production of thyroid hormones. In iodine sufficient countries, 85% of congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis called dyshormonogenesis. Most commonly, dyshormonogenesis is due to defects in thyroid peroxidase (TPO) activity. TPO uses hydrogen peroxide to couple iodine to thyroglobulin within the thyroid gland forming T3 and T4; while the passage of thyroid hormone into cells is facilitated by thyroid hormone plasma membrane transporters. Outcome effects: Severe defects in TPO lead to total iodide organification defects (TIOD), while less severe mutations cause partial iodide organification defects (PIOD). Pendred's syndrome is caused by a genetic defect in the transmembrane protein, pendrin (SLC26A4), which acts as a chloride-iodide transporter in both the thyroid gland and the inner ear. Mutations in the enzyme dual oxidase 2 (DUOX2) will lead to dyshormonogenesis due to insufficient hydrogen peroxide generation and can be autosomal dominant. The phenotype is heterogeneous and can be permanent or transient and cause TIOD or PIOD. Mutations in the dual oxidase maturation factor (DUOXA2) gene can also lead to deficient iodide organification through similar mechanisms and can cause PIOD. Further, a mutation in monocarboxylase transporter 8 (MCT8) has been reported in five cases as a cause of X-linked hypothyroidism associated with mental retardation and neurologic abnormalities including quadriplegia and is known as Allan-Herndon-Dudley syndrome. The defective transporter appears to impair the passage of T3 into neurons and is characterized by elevated serum T3 levels, low T4 and normal TSH. Other rare causes of dyshormonogenesis include defects in SLC5A5, thyroglobulin (TG), and IDA. . Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 15665157 PMID: 21511237 PMID: 21543982 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9356f5bf-a02c-4561-b67b-ced012da6a23 Iodine Metabolism Related Thyroid Dyshormonogenesis uuid-9356f5bf-a02c-4561-b67b-ced012da6a23 PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9356f5bf-a02c-4561-b67b-ced012da6a23 PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in the DUOX2, SLC5A5, TG, TPO, and TSHB genes prevent or reduce the production of thyroid hormones. In iodine sufficient countries, 85% of congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis called dyshormonogenesis. Most commonly, dyshormonogenesis is due to defects in thyroid peroxidase (TPO) activity. TPO uses hydrogen peroxide to couple iodine to thyroglobulin within the thyroid gland forming T3 and T4; while the passage of thyroid hormone into cells is facilitated by thyroid hormone plasma membrane transporters. Outcome effects: Severe defects in TPO lead to total iodide organification defects (TIOD), while less severe mutations cause partial iodide organification defects (PIOD). Pendred's syndrome is caused by a genetic defect in the transmembrane protein, pendrin (SLC26A4), which acts as a chloride-iodide transporter in both the thyroid gland and the inner ear. Mutations in the enzyme dual oxidase 2 (DUOX2) will lead to dyshormonogenesis due to insufficient hydrogen peroxide generation and can be autosomal dominant. The phenotype is heterogeneous and can be permanent or transient and cause TIOD or PIOD. Mutations in the dual oxidase maturation factor (DUOXA2) gene can also lead to deficient iodide organification through similar mechanisms and can cause PIOD. Further, a mutation in monocarboxylase transporter 8 (MCT8) has been reported in five cases as a cause of X-linked hypothyroidism associated with mental retardation and neurologic abnormalities including quadriplegia and is known as Allan-Herndon-Dudley syndrome. The defective transporter appears to impair the passage of T3 into neurons and is characterized by elevated serum T3 levels, low T4 and normal TSH. Other rare causes of dyshormonogenesis include defects in SLC5A5, thyroglobulin (TG), and IDA. . Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15665157 PS:PMID 21511237 PS:PMID 21543982 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-935bb707-35d2-41e6-8b42-0480919e275d NodeType: Pathway Organ: skin PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-935bb707-35d2-41e6-8b42-0480919e275d Interleukin-17 and interleukin-22 signaling in psoriasis uuid-935bb707-35d2-41e6-8b42-0480919e275d PS:CellType keratinocyte PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-935bb707-35d2-41e6-8b42-0480919e275d PS:NodeType Pathway PS:Organ skin PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9368f9c4-70c9-463d-be28-eec00070c2fe NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-9368f9c4-70c9-463d-be28-eec00070c2fe EGFR transactivation in cornea uuid-9368f9c4-70c9-463d-be28-eec00070c2fe PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9368f9c4-70c9-463d-be28-eec00070c2fe PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9379c9f1-2bb1-407f-9403-39cf25ca9344 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-9379c9f1-2bb1-407f-9403-39cf25ca9344 Genes with Mutations Associated with Ovarian Cancer uuid-9379c9f1-2bb1-407f-9403-39cf25ca9344 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9379c9f1-2bb1-407f-9403-39cf25ca9344 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-937f9e8d-ce99-4ee1-8e88-d024d70557f0 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-937f9e8d-ce99-4ee1-8e88-d024d70557f0 Ca2-induced Lipid A biosynthesis template uuid-937f9e8d-ce99-4ee1-8e88-d024d70557f0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-937f9e8d-ce99-4ee1-8e88-d024d70557f0 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9383a0d6-ba32-4472-9742-56e986d6bcab NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-9383a0d6-ba32-4472-9742-56e986d6bcab InsulinR -> CTNNB/FOXA/FOXO Signaling uuid-9383a0d6-ba32-4472-9742-56e986d6bcab PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9383a0d6-ba32-4472-9742-56e986d6bcab PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-938f496d-4aaf-4885-80f2-37f96804b28b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-938f496d-4aaf-4885-80f2-37f96804b28b IGF1 -> ELK/SRF/HIF1A/MYC/SREBF Expression Targets uuid-938f496d-4aaf-4885-80f2-37f96804b28b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-938f496d-4aaf-4885-80f2-37f96804b28b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93934c80-7fa4-4cb3-b168-2950e1bbf31a NodeType: Pathway Notes: IL-17 and IL-22 promote the proliferation of keratinocytes, a key sign of psoriasis. Keratinocytes synthesize a wide range of proinflammatory cytokines, which attract neutrophils, activate dendritic cells, and maintain the inflammatory reaction in the skin. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-93934c80-7fa4-4cb3-b168-2950e1bbf31a 2_Interleukin-17 and interleukin-22 signaling in psoriasis uuid-93934c80-7fa4-4cb3-b168-2950e1bbf31a PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93934c80-7fa4-4cb3-b168-2950e1bbf31a PS:NodeType Pathway PS:Notes IL-17 and IL-22 promote the proliferation of keratinocytes, a key sign of psoriasis. Keratinocytes synthesize a wide range of proinflammatory cytokines, which attract neutrophils, activate dendritic cells, and maintain the inflammatory reaction in the skin. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93ce46a6-91df-45fa-809f-1e15477c3021 NodeType: Pathway Organ: pancreas Organ_System: endocrine system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-93ce46a6-91df-45fa-809f-1e15477c3021 Proteins Involved in MELAS Syndrome uuid-93ce46a6-91df-45fa-809f-1e15477c3021 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93ce46a6-91df-45fa-809f-1e15477c3021 PS:NodeType Pathway PS:Organ pancreas PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93d7691a-27d2-4148-afd6-026e3a8417a3 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-93d7691a-27d2-4148-afd6-026e3a8417a3 Proteins with Altered Expression in Muscular Dystrophy, Facioscapulohumeral uuid-93d7691a-27d2-4148-afd6-026e3a8417a3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93d7691a-27d2-4148-afd6-026e3a8417a3 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93e85d88-0e9c-4bb4-968a-7ae8ab445ec5 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-93e85d88-0e9c-4bb4-968a-7ae8ab445ec5 Anthranilate alkaloids biosynthesis template uuid-93e85d88-0e9c-4bb4-968a-7ae8ab445ec5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93e85d88-0e9c-4bb4-968a-7ae8ab445ec5 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93f3347e-e065-4e55-ae06-fadac2609506 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-93f3347e-e065-4e55-ae06-fadac2609506 cyclopropane fatty acid (CFA) biosynthesis template uuid-93f3347e-e065-4e55-ae06-fadac2609506 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93f3347e-e065-4e55-ae06-fadac2609506 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93f79eaa-3128-41dd-979e-950f19e50d54 NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-93f79eaa-3128-41dd-979e-950f19e50d54 SWI/SNF BRM/BAF in Chromatin Remodeling uuid-93f79eaa-3128-41dd-979e-950f19e50d54 PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93f79eaa-3128-41dd-979e-950f19e50d54 PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. SWI/SNF chromatin remodeling complex contains either BRG1 (SMARCA4) or BRM (SMARCA2) as the central catalytic ATPase subunit. SWI/SNF can further be subdivided into the BAF and PBAF (polybromo-associated BAF) complexes. The only difference between these complexes is the presence of specific subunits ARID1A or PBRM1, found in BAF or PBAF, respectively. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. SWI/SNF complex disrupts the rotational phasing of DNA on the surface of the histone octamer in an ATP-dependent manner and then targets promoters through the interactions with sequence-specific transcription factors such as glucocorticoid receptor (NR3C1). Outcome effects: SMARCA4 (or SMARCA2) can recognize acetylated lysine residues within histone H3 and H4 tails. SMARCA4 (or SMARCA2) associates with numerous chromatin-modifying complexes including co-activators and co-repressors of transcription. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: melanocyte Description: The actual mechanism by which melanocytes are destroyed in the skin of patients with vitiligo has not been definitively determined. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93fab784-3d7f-4e48-bc46-065728066198 NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin and occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: The actual mechanism of autoimmune-mediated melanocyte apoptosis in vitiligo has not been definitively determined. Vitiligo develops as result of interplay between internal (genetic) and environmental factors. Multiple susceptibility genes including PTPN22, MITF, FAS, and others are involved in vitiligo pathogenesis. Outcome effects: Some of the genes associated with vitiligo pathogenesis encode proteins involved in immune regulation, melanocyte functioning and cellular apoptosis. Dysregulation of the immune response in vitiligo makes the melanocyte an autoimmune target. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Vitiligo susceptibility genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 18548110 PMID: 23226069 PMID: 23539007 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-93fab784-3d7f-4e48-bc46-065728066198 Apoptosis of Melanocyte in Vitiligo uuid-93fab784-3d7f-4e48-bc46-065728066198 PS:CellType melanocyte PS:Description The actual mechanism by which melanocytes are destroyed in the skin of patients with vitiligo has not been definitively determined. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-93fab784-3d7f-4e48-bc46-065728066198 PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin and occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: The actual mechanism of autoimmune-mediated melanocyte apoptosis in vitiligo has not been definitively determined. Vitiligo develops as result of interplay between internal (genetic) and environmental factors. Multiple susceptibility genes including PTPN22, MITF, FAS, and others are involved in vitiligo pathogenesis. Outcome effects: Some of the genes associated with vitiligo pathogenesis encode proteins involved in immune regulation, melanocyte functioning and cellular apoptosis. Dysregulation of the immune response in vitiligo makes the melanocyte an autoimmune target. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Vitiligo susceptibility genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18548110 PS:PMID 23226069 PS:PMID 23539007 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sperm cell Description: Sperm movement is activated by changes in intracellular ion concentration. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-940060bf-39ee-4263-ba11-26367f06ec89 NodeType: Pathway Notes: Headnote: Sperm movement is activated by changes in intracellular ion concentration. Human spermatozoa mature functionally and obtain the ability to fertilize the egg through the processes of hyperactivation, capacitation and acrosomal reaction. Organ: testis Organ_System: reproductive system PMID: 20679352 PMID: 22013213 PMID: 22017176 PMID: 22441763 PMID: 22709980 PMID: 25457194 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-940060bf-39ee-4263-ba11-26367f06ec89 Sperm Motility Impairement in Testicular Male Infertility uuid-940060bf-39ee-4263-ba11-26367f06ec89 PS:CellType sperm cell PS:Description Sperm movement is activated by changes in intracellular ion concentration. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-940060bf-39ee-4263-ba11-26367f06ec89 PS:NodeType Pathway PS:Notes Headnote: Sperm movement is activated by changes in intracellular ion concentration. Human spermatozoa mature functionally and obtain the ability to fertilize the egg through the processes of hyperactivation, capacitation and acrosomal reaction. PS:Organ testis PS:Organ_System reproductive system PS:PMID 20679352 PS:PMID 22013213 PS:PMID 22017176 PS:PMID 22441763 PS:PMID 22709980 PS:PMID 25457194 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Th1 cell CellType: cancer cell CellType: cancer stem cell Description: Endogenous IL12 is important for host resistance to tumors. The major antitumor activities of IL12 rely on its ability to promote Th1 adaptive immunity and CTL response. IL12 is often downregulated in cancers. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9407c65c-2fc8-4007-b5a4-410895854cc8 NodeType: Pathway Notes: Headnote: Endogenous IL12, produced by antigen-presenting cells, is important for host resistance to tumors and is often downregulated in cancers. Overexpression of IL10 and TGFB1 at the sites of inflammation has a major role in downregulation of IL12. Signaling description: Normally, IL12 acts on IL12R on the surface of Th1-cells and induces JAK/STAT4 activation. STAT4 controls the expression of IFNG that activates antitumor cytotoxic lymphocytes (CD8+T-cells and NK-cells). IL12 may also act directly on CTLs. Outcome effects: Normally, CTLs produce perforins (PRF1), granzymes (GZMA/B) and FASLG. These molecules induce the killing of the effector cell (tumor cell). When IL12 is downregulated, the mechanisms mentioned above cease to work. Therefore, downregulation of IL12 promotes cancer progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlights have decreased expression / activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ_System: lymphatic system PMID: 24514955 PMID: 25190142 PMID: 28716888 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-9407c65c-2fc8-4007-b5a4-410895854cc8 IL12 Antitumor Effect is Blocked in Cancer uuid-9407c65c-2fc8-4007-b5a4-410895854cc8 PS:CellType Th1 cell PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Endogenous IL12 is important for host resistance to tumors. The major antitumor activities of IL12 rely on its ability to promote Th1 adaptive immunity and CTL response. IL12 is often downregulated in cancers. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9407c65c-2fc8-4007-b5a4-410895854cc8 PS:NodeType Pathway PS:Notes Headnote: Endogenous IL12, produced by antigen-presenting cells, is important for host resistance to tumors and is often downregulated in cancers. Overexpression of IL10 and TGFB1 at the sites of inflammation has a major role in downregulation of IL12. Signaling description: Normally, IL12 acts on IL12R on the surface of Th1-cells and induces JAK/STAT4 activation. STAT4 controls the expression of IFNG that activates antitumor cytotoxic lymphocytes (CD8+T-cells and NK-cells). IL12 may also act directly on CTLs. Outcome effects: Normally, CTLs produce perforins (PRF1), granzymes (GZMA/B) and FASLG. These molecules induce the killing of the effector cell (tumor cell). When IL12 is downregulated, the mechanisms mentioned above cease to work. Therefore, downregulation of IL12 promotes cancer progression. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlights have decreased expression / activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ_System lymphatic system PS:PMID 24514955 PS:PMID 25190142 PS:PMID 28716888 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Diabetic neuropathy (DN) is the most common chronic complication of diabetes mellitus and a cause of mortality in diabetes patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-941e9b6a-bef9-41b3-86a9-9d02bed7e986 NodeType: Pathway Notes: Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. DN is characterized by microvascular injury which involves small blood vessels which supply the nerves (vasa nervorum) and results from chronic hyperglycemia, which is considered the major initiating factor in the pathogenesis of DN. Signaling description: Elevated glucose causes hyperosmotic stress and cell damage due to intracellular accumulation of sorbitol and fructose. Excess glucose enters the polyol pathway where AKR1B1 reduces glucose to sorbitol, and SORD oxidizes sorbitol to fructose. Diabetes is characterized by the disruption of inositol synthesis. Outcome effects: Disruption of inositol synthesis results in the reduced activity of Na /K -ATPase and PKC, impaired axonal transport, and structural injury of nerves. Highlighted proteins: Small molecules with elevated level are highlighted in red. Small molecules with decreased level are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 18616962 PMID: 24954624 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-941e9b6a-bef9-41b3-86a9-9d02bed7e986 Hyperosmotic Stress in Diabetic Neuropathy uuid-941e9b6a-bef9-41b3-86a9-9d02bed7e986 PS:CellType neuron PS:Description Diabetic neuropathy (DN) is the most common chronic complication of diabetes mellitus and a cause of mortality in diabetes patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-941e9b6a-bef9-41b3-86a9-9d02bed7e986 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. DN is characterized by microvascular injury which involves small blood vessels which supply the nerves (vasa nervorum) and results from chronic hyperglycemia, which is considered the major initiating factor in the pathogenesis of DN. Signaling description: Elevated glucose causes hyperosmotic stress and cell damage due to intracellular accumulation of sorbitol and fructose. Excess glucose enters the polyol pathway where AKR1B1 reduces glucose to sorbitol, and SORD oxidizes sorbitol to fructose. Diabetes is characterized by the disruption of inositol synthesis. Outcome effects: Disruption of inositol synthesis results in the reduced activity of Na /K -ATPase and PKC, impaired axonal transport, and structural injury of nerves. Highlighted proteins: Small molecules with elevated level are highlighted in red. Small molecules with decreased level are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 18616962 PS:PMID 24954624 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9433239e-3a6a-4199-84bb-7e3638c901c7 NodeType: Pathway Organ: generic Organ_System: generic Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-9433239e-3a6a-4199-84bb-7e3638c901c7 SARS inhibits centrosome duplication, stabilises MTOC uuid-9433239e-3a6a-4199-84bb-7e3638c901c7 PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9433239e-3a6a-4199-84bb-7e3638c901c7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: neuron Description: PARK7 is a ubiquitously expressed protein that is mutated in an autosomal recessive, early-onset form of Parkinson's disease (PD). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-943e41c1-5e80-40f9-841c-5b166b0caa81 NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: PARK7 is a ubiquitously expressed protein that is mutated in an autosomal recessive, early-onset form of Parkinson's disease (PD). Mutations disrupt PARK7 protein folding, resulting in a misfolded protein that is prone to aggregation. Misfolded proteins sequestered into pericentriolar inclusions are called aggresomes. Parkin (PARK2) cooperates with heterodimeric E2 enzyme (UBE2N) to mediate K63-linked polyubiquitination of misfolded PARK7. LRRK2 (also known as dardarin)-linked is another form of young onset autosomal dominant PD. It is the most common form of disease, still there is little information about protein function and its pathology. Recent research data suggest that increased kinase activity of mutated LRRK2 contributes to an autophagy deregulation, possibly through the activation of the Ca2 /CaMKK/AMPK pathway. Outcome effects: The polyubiquitination of misfolded PARK7 serves as a signal for the interaction with HDAC6, an adaptor protein that binds the dynein-dynactin complex. Through this interaction, misfolded PARK7 is transported to aggresomes. PARK7 has strong anti-oxidative properties, while a mutated protein is unable to neutralize reactive oxygen species (ROS) which leads to the opening of mPTP and release of CYCS which results in cell death. Normally, PARK7 is processed by caspase-6 (CASP6) and the caspase-6-derived C-terminal fragment of PARK7 prevents p53 (TP53)-dependent cell death. This pathway is blocked due to mutations in PARK7. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17499497 PMID: 22257884 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-943e41c1-5e80-40f9-841c-5b166b0caa81 PARK7 and LRRK2 in Young Onset Parkinson's Disease uuid-943e41c1-5e80-40f9-841c-5b166b0caa81 PS:CellType neuron PS:Description PARK7 is a ubiquitously expressed protein that is mutated in an autosomal recessive, early-onset form of Parkinson's disease (PD). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-943e41c1-5e80-40f9-841c-5b166b0caa81 PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: PARK7 is a ubiquitously expressed protein that is mutated in an autosomal recessive, early-onset form of Parkinson's disease (PD). Mutations disrupt PARK7 protein folding, resulting in a misfolded protein that is prone to aggregation. Misfolded proteins sequestered into pericentriolar inclusions are called aggresomes. Parkin (PARK2) cooperates with heterodimeric E2 enzyme (UBE2N) to mediate K63-linked polyubiquitination of misfolded PARK7. LRRK2 (also known as dardarin)-linked is another form of young onset autosomal dominant PD. It is the most common form of disease, still there is little information about protein function and its pathology. Recent research data suggest that increased kinase activity of mutated LRRK2 contributes to an autophagy deregulation, possibly through the activation of the Ca2 /CaMKK/AMPK pathway. Outcome effects: The polyubiquitination of misfolded PARK7 serves as a signal for the interaction with HDAC6, an adaptor protein that binds the dynein-dynactin complex. Through this interaction, misfolded PARK7 is transported to aggresomes. PARK7 has strong anti-oxidative properties, while a mutated protein is unable to neutralize reactive oxygen species (ROS) which leads to the opening of mPTP and release of CYCS which results in cell death. Normally, PARK7 is processed by caspase-6 (CASP6) and the caspase-6-derived C-terminal fragment of PARK7 prevents p53 (TP53)-dependent cell death. This pathway is blocked due to mutations in PARK7. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17499497 PS:PMID 22257884 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-944bd91c-9286-4ad8-9dee-6bf09828cfd3 NodeType: Pathway Notes: Headnote: Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Signaling description: Nerve impulse triggers the release of glutamate from presynaptic cells, and receptors on the surface of postsynaptic cells bind glutamate and become activated. The excess of glutamate is normally removed from the synaptic cleft by glial cells, but in the event of injury or disease this mechanism may be compromised, which results in the overstimulation of ionotropic glutamate and NMDA receptors in addition to intracellular calcium (Ca2+) overload. Outcome effects: The described events lead to oxidative stress and the induction of apoptosis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-944bd91c-9286-4ad8-9dee-6bf09828cfd3 Glutamate Mediated Neurotoxicity uuid-944bd91c-9286-4ad8-9dee-6bf09828cfd3 PS:CellType generic PS:Description Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-944bd91c-9286-4ad8-9dee-6bf09828cfd3 PS:NodeType Pathway PS:Notes Headnote: Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Signaling description: Nerve impulse triggers the release of glutamate from presynaptic cells, and receptors on the surface of postsynaptic cells bind glutamate and become activated. The excess of glutamate is normally removed from the synaptic cleft by glial cells, but in the event of injury or disease this mechanism may be compromised, which results in the overstimulation of ionotropic glutamate and NMDA receptors in addition to intracellular calcium (Ca2+) overload. Outcome effects: The described events lead to oxidative stress and the induction of apoptosis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Purkinje cell CellType: astrocyte CellType: neuron Description: The cause of familial hemiplegic migraine type 1 (FHM1) consists in mutations in CACNA1A gene that lead to partial or complete loss of Cav2.1 (P/Q voltage-dependent calcium channel) function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94534ecc-373b-427c-9a4c-d9857013ad57 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM1 is caused by mutations in the CACNA1A gene which encodes a subunit of a P/Q voltage-dependent calcium (Ca2+). Mutations in this gene lead to a partial or complete loss of function. Signaling description: The general function of CACNA1A is modulating the release of excitatory neurotransmitters in the neuromuscular synapse and central synapses (predominantly in the cerebellum, stem, and cerebral cortex). In FHM1, specific mutations in the CACNA1A gene cause diverse forms of ion channel malfunction such as conductivity disturbance, alteration of its structure, or shifted kinetics. The altered Ca2+ channels open at a lower voltage, as compared to wild type, and ion flow into the cell occurs following lower depolarization level. The altered ion channels also remain open longer, which results in increased Ca2+ ion flow into the cell. Increased intracellular Ca2+ leads to the release of neurotransmitters, primarily glutamate, into the synaptic cleft. High amounts of glutamate trigger ionotropic receptors (NMDA and AMPA) on postsynaptic neurons, as well as metabotropic receptors (mGluR) on the astrocyte surface. Outcome effects: NMDA receptor activation leads to the release of potassium (K+) from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic Ca2+-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid, which can block K+ large conductance Ca2+-activated channel (KCNMA1). The main function of KCNMA1 is decreasing membrane depolarization by removing K+ from the extracellular space. The excess of glutamate is removed by astrocytes which convert it to glutamine. Glutamine is then transferred into the neurons where it is then converted back to glutamate. Thus, the effects of Ca2+ channel mutations cause the continuous release of glutamate into the synaptic cleft where it causes the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12235360 PMID: 15294146 PMID: 17691981 PMID: 19185185 PMID: 19499287 PMID: 20816411 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-94534ecc-373b-427c-9a4c-d9857013ad57 Glutamate Overdose and Aura Effect in Migraine Type 1 uuid-94534ecc-373b-427c-9a4c-d9857013ad57 PS:CellType Purkinje cell PS:CellType astrocyte PS:CellType neuron PS:Description The cause of familial hemiplegic migraine type 1 (FHM1) consists in mutations in CACNA1A gene that lead to partial or complete loss of Cav2.1 (P/Q voltage-dependent calcium channel) function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94534ecc-373b-427c-9a4c-d9857013ad57 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. FHM1 is caused by mutations in the CACNA1A gene which encodes a subunit of a P/Q voltage-dependent calcium (Ca2+). Mutations in this gene lead to a partial or complete loss of function. Signaling description: The general function of CACNA1A is modulating the release of excitatory neurotransmitters in the neuromuscular synapse and central synapses (predominantly in the cerebellum, stem, and cerebral cortex). In FHM1, specific mutations in the CACNA1A gene cause diverse forms of ion channel malfunction such as conductivity disturbance, alteration of its structure, or shifted kinetics. The altered Ca2+ channels open at a lower voltage, as compared to wild type, and ion flow into the cell occurs following lower depolarization level. The altered ion channels also remain open longer, which results in increased Ca2+ ion flow into the cell. Increased intracellular Ca2+ leads to the release of neurotransmitters, primarily glutamate, into the synaptic cleft. High amounts of glutamate trigger ionotropic receptors (NMDA and AMPA) on postsynaptic neurons, as well as metabotropic receptors (mGluR) on the astrocyte surface. Outcome effects: NMDA receptor activation leads to the release of potassium (K+) from the cell. Hyperdepolarization is important for the progression of cortical depression. Aura preceding migraine attack is the consequence of cortical spreading depression. In addition, the release of K+ causes constriction of proximal blood vessels. According to the vascular theory of migraine pathogenesis, vasoconstriction precedes vasodilation and occurs simultaneously with cortical spreading depression. The activation of neuronal cytosolic Ca2+-dependent phospholipase A2 (PLA2G4A) leads to the synthesis of arachidonic acid, which can block K+ large conductance Ca2+-activated channel (KCNMA1). The main function of KCNMA1 is decreasing membrane depolarization by removing K+ from the extracellular space. The excess of glutamate is removed by astrocytes which convert it to glutamine. Glutamine is then transferred into the neurons where it is then converted back to glutamate. Thus, the effects of Ca2+ channel mutations cause the continuous release of glutamate into the synaptic cleft where it causes the emergence of cortical spreading depression. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12235360 PS:PMID 15294146 PS:PMID 17691981 PS:PMID 19185185 PS:PMID 19499287 PS:PMID 20816411 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9455ff56-5056-44f3-92aa-cba6a7d1fac4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-9455ff56-5056-44f3-92aa-cba6a7d1fac4 Proteins with Altered Expression in Migraine uuid-9455ff56-5056-44f3-92aa-cba6a7d1fac4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9455ff56-5056-44f3-92aa-cba6a7d1fac4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94680408-c681-4f2f-a813-c6ef98bdf7a9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-94680408-c681-4f2f-a813-c6ef98bdf7a9 Salicilyic acid degradation template uuid-94680408-c681-4f2f-a813-c6ef98bdf7a9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94680408-c681-4f2f-a813-c6ef98bdf7a9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-949a2f25-bd32-4b4d-bc2d-1a19bad80e1b NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-949a2f25-bd32-4b4d-bc2d-1a19bad80e1b ADRA2C/ADRB2 -> Vasoconstriction uuid-949a2f25-bd32-4b4d-bc2d-1a19bad80e1b PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-949a2f25-bd32-4b4d-bc2d-1a19bad80e1b PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a41839-47e7-44a1-970a-3dc63a64fb73 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-94a41839-47e7-44a1-970a-3dc63a64fb73 Ser metabolism template uuid-94a41839-47e7-44a1-970a-3dc63a64fb73 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a41839-47e7-44a1-970a-3dc63a64fb73 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: The neural subtype of glioblastoma does not have typical mutations. This subtype is characterized by the expression of neuron markers such as NEFL, GABRA1, SYT1, and SLC12A5. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a88ea6-9146-4101-ab2d-c99f65f70f39 NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The neural subtype does not have typical mutations but in a small percentage of cases mutations in TP53, NF1, PTEN, EGFR, IDH1, PIK3R1, PIK3CA, ERBB2, and RB1 may be found. This subtype is characterized by the expression of neuron markers such as NEFL, GABRA1, SYT1, and SLC12A5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 20129251 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-94a88ea6-9146-4101-ab2d-c99f65f70f39 Neural Subtype of Glioblastoma uuid-94a88ea6-9146-4101-ab2d-c99f65f70f39 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description The neural subtype of glioblastoma does not have typical mutations. This subtype is characterized by the expression of neuron markers such as NEFL, GABRA1, SYT1, and SLC12A5. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a88ea6-9146-4101-ab2d-c99f65f70f39 PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The neural subtype does not have typical mutations but in a small percentage of cases mutations in TP53, NF1, PTEN, EGFR, IDH1, PIK3R1, PIK3CA, ERBB2, and RB1 may be found. This subtype is characterized by the expression of neuron markers such as NEFL, GABRA1, SYT1, and SLC12A5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 20129251 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a9fc5a-41e5-4485-9d16-32909217fc41 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-94a9fc5a-41e5-4485-9d16-32909217fc41 DRD1/3 -> Potassium Uptake uuid-94a9fc5a-41e5-4485-9d16-32909217fc41 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-94a9fc5a-41e5-4485-9d16-32909217fc41 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-952bad9b-6d34-4474-9ee6-8526eae4fd8e NodeType: Pathway Notes: Headnote: Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50. Experimental and clinical evidences strongly indicate the pathogenic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and drusen formation. Signaling description: All the three compliment pathways (classical, alternative and lectin-mediated) are involved in pathogenesis of AMD. Complement pathways components implicated in AMD pathogenesis include C3 and C5, C5b-9 terminal complement complex, complement regulators or inhibitors, that is, complement factor H (CFH), vitronectin (VTN) and clusterin (CLU), complement receptor 1 (CR1), membrane cofactor protein (CD46), and decay accelerating factor (CD55). These components are systemically elevated in patients suffering from AMD and are found in retinal drusen. Numerous studies revealed significant correlations between AMD and polymorphisms of genes encoding for several molecules involved in compliment pathways (CFH, C3, CFI, CFB, C2, CFHR1/3 and others). HTRA1 is one of the major hereditary predisposing factors for AMD. HTRA1 protein is secreted enzyme that cleaves substrates involved in the complement pathway, such as VTN and CLU, and thus implicated in the pathogenesis of AMD. The following complement activators are also founding drusen: amyloid beta, lipofuscin constituents (e.g. A2E), C-reactive protein (CRP), cholesterol, immunoglobulin G, advanced glycation end products (AGE)). Organ: eye Organ_System: sensory system PMID: 19961953 PMID: 21127893 PMID: 23933169 PMID: 24369445 PMID: 24622760 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-952bad9b-6d34-4474-9ee6-8526eae4fd8e Complement Activation in Macular Degeneration uuid-952bad9b-6d34-4474-9ee6-8526eae4fd8e PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-952bad9b-6d34-4474-9ee6-8526eae4fd8e PS:NodeType Pathway PS:Notes Headnote: Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50. Experimental and clinical evidences strongly indicate the pathogenic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and drusen formation. Signaling description: All the three compliment pathways (classical, alternative and lectin-mediated) are involved in pathogenesis of AMD. Complement pathways components implicated in AMD pathogenesis include C3 and C5, C5b-9 terminal complement complex, complement regulators or inhibitors, that is, complement factor H (CFH), vitronectin (VTN) and clusterin (CLU), complement receptor 1 (CR1), membrane cofactor protein (CD46), and decay accelerating factor (CD55). These components are systemically elevated in patients suffering from AMD and are found in retinal drusen. Numerous studies revealed significant correlations between AMD and polymorphisms of genes encoding for several molecules involved in compliment pathways (CFH, C3, CFI, CFB, C2, CFHR1/3 and others). HTRA1 is one of the major hereditary predisposing factors for AMD. HTRA1 protein is secreted enzyme that cleaves substrates involved in the complement pathway, such as VTN and CLU, and thus implicated in the pathogenesis of AMD. The following complement activators are also founding drusen: amyloid beta, lipofuscin constituents (e.g. A2E), C-reactive protein (CRP), cholesterol, immunoglobulin G, advanced glycation end products (AGE)). PS:Organ eye PS:Organ_System sensory system PS:PMID 19961953 PS:PMID 21127893 PS:PMID 23933169 PS:PMID 24369445 PS:PMID 24622760 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-953c2d8a-5a5d-4413-a65e-7f6ea2b69a5d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-953c2d8a-5a5d-4413-a65e-7f6ea2b69a5d ADCYAP1 Expression Targets uuid-953c2d8a-5a5d-4413-a65e-7f6ea2b69a5d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-953c2d8a-5a5d-4413-a65e-7f6ea2b69a5d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-954f99af-6cc0-4ab8-9b5a-8457af368a45 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-954f99af-6cc0-4ab8-9b5a-8457af368a45 GlyR -> Synaptic Inhibition uuid-954f99af-6cc0-4ab8-9b5a-8457af368a45 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-954f99af-6cc0-4ab8-9b5a-8457af368a45 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Gluten induces activation of the synthesis of IL-10 and TNF and impacts to the development of symptoms of autistic disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-955d30db-4ef3-4c85-85a8-46f6a3532310 NodeType: Pathway Notes: Gluten activates IL-10 and TNF synthesis and impacts the development of autistic symptoms. Organ_System: nervous system PMID: 11942558 PMID: 17531383 PMID: 23688532 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-955d30db-4ef3-4c85-85a8-46f6a3532310 Gluten Impact on Neuronal System (Hypothesis) uuid-955d30db-4ef3-4c85-85a8-46f6a3532310 PS:Description Gluten induces activation of the synthesis of IL-10 and TNF and impacts to the development of symptoms of autistic disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-955d30db-4ef3-4c85-85a8-46f6a3532310 PS:NodeType Pathway PS:Notes Gluten activates IL-10 and TNF synthesis and impacts the development of autistic symptoms. PS:Organ_System nervous system PS:PMID 11942558 PS:PMID 17531383 PS:PMID 23688532 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-955de0b5-ebf1-4c89-9e85-e08b2060fc9b NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: prostate Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-955de0b5-ebf1-4c89-9e85-e08b2060fc9b Elevated Receptors -> Expression Targets in Prostate uuid-955de0b5-ebf1-4c89-9e85-e08b2060fc9b PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-955de0b5-ebf1-4c89-9e85-e08b2060fc9b PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ prostate PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956ae643-95e9-4b96-9c80-a41bd3a89ff6 NodeType: Pathway Organ: generic Organ_System: generic PMID: 17481747 PMID: 20626350 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-956ae643-95e9-4b96-9c80-a41bd3a89ff6 P38 MAPK/MAPK14 Signaling uuid-956ae643-95e9-4b96-9c80-a41bd3a89ff6 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956ae643-95e9-4b96-9c80-a41bd3a89ff6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 17481747 PS:PMID 20626350 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956bb728-5c33-430f-9d5b-d16dcdaaadac NodeType: Pathway urn:agi-pathway:uuid-956bb728-5c33-430f-9d5b-d16dcdaaadac Common Genomic Effects of Thyroid Hormones uuid-956bb728-5c33-430f-9d5b-d16dcdaaadac PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956bb728-5c33-430f-9d5b-d16dcdaaadac PS:NodeType Pathway PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Obstetric complications are the hallmark of antiphospholipid syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956d2057-a510-4cfd-8f32-853e2b3c9255 NodeType: Pathway Notes: Headnote: Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable state provoked by antiphospholipid antibodies. APS manifests as recurrent venous or arterial thrombosis and/or fetal loss. Obstetric complications are the hallmark of APS. Signaling description: Antiphospholipid antibodies (aPL) promote activation of platelets. aPL antibodies bind to APOH that in turn binds to platelet receptor LRP8 and GP1BA and induce a procoagulant state. Organ_System: reproductive system PMID: 17894016 PMID: 20822807 PMID: 21556027 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood urn:agi-pathway:uuid-956d2057-a510-4cfd-8f32-853e2b3c9255 Platelet and Coagulation Cascade Activation by Antiphospholipid Antibodies uuid-956d2057-a510-4cfd-8f32-853e2b3c9255 PS:CellType blood platelet PS:Description Obstetric complications are the hallmark of antiphospholipid syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956d2057-a510-4cfd-8f32-853e2b3c9255 PS:NodeType Pathway PS:Notes Headnote: Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable state provoked by antiphospholipid antibodies. APS manifests as recurrent venous or arterial thrombosis and/or fetal loss. Obstetric complications are the hallmark of APS. Signaling description: Antiphospholipid antibodies (aPL) promote activation of platelets. aPL antibodies bind to APOH that in turn binds to platelet receptor LRP8 and GP1BA and induce a procoagulant state. PS:Organ_System reproductive system PS:PMID 17894016 PS:PMID 20822807 PS:PMID 21556027 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Histamine-mediated responses are facilitated by the stimulus-dependent release of stored histamine or accompanied by the induction of histamine synthesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956f97ca-e811-4c69-af5e-9122ebd75d52 NodeType: Pathway Notes: Headnote: Histamines are nitrogenous neurotransmitters produced during an allergic response. Histamine-mediated responses are facilitated by the stimulus-dependent release of stored histamine or accompanied by the induction of histamine synthesis. In the central nervous system (CNS), histamine is synthesized in histaminergic neurons. Signaling description: It has been shown that histamine increases the permeability of the blood-brain barrier. Histamine synthesis can be induced upon various combinations of stimuli; however it is largely unknown how tissue-specific expression of histidine decarboxylase (HDC) is regulated. Histamine receptor H3 (HRH3) is expressed in neurons of the CNS and in presynaptic histaminergic neurons of the peripheral nervous system. In histaminergic neurons, HRH3 acts as a presynaptic autoreceptor inhibiting the release and synthesis of histamine. In non-histaminergic neurons, HRH3 functions as a heteroreceptor and inhibits the release of several important neurotransmitters including serotonin, noradrenaline, acetylcholine, and dopamine. HRH3 acts via Gi/o protein signaling and causes the inhibition of adenylate cyclase (ADCY) and synthesis of histamine. In addition, AKT1/GSK3B kinases have been shown to be activated by HRH3 in neurons to occur through PI3K activation via Gb/g. Outcome effects: In the CNS, AKT1 and GSK3B play a prominent role in brain function and have been implicated in the protection against neuronal apoptosis. The upregulation of AKT1/GSK3B pathway may be the mechanism by which HRH3 exerts its neuroprotective role; however the exact mechanism of this effect remains unknown. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-956f97ca-e811-4c69-af5e-9122ebd75d52 Histamine Receptor H3 Signaling in Neurons uuid-956f97ca-e811-4c69-af5e-9122ebd75d52 PS:CellType neuron PS:Description Histamine-mediated responses are facilitated by the stimulus-dependent release of stored histamine or accompanied by the induction of histamine synthesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-956f97ca-e811-4c69-af5e-9122ebd75d52 PS:NodeType Pathway PS:Notes Headnote: Histamines are nitrogenous neurotransmitters produced during an allergic response. Histamine-mediated responses are facilitated by the stimulus-dependent release of stored histamine or accompanied by the induction of histamine synthesis. In the central nervous system (CNS), histamine is synthesized in histaminergic neurons. Signaling description: It has been shown that histamine increases the permeability of the blood-brain barrier. Histamine synthesis can be induced upon various combinations of stimuli; however it is largely unknown how tissue-specific expression of histidine decarboxylase (HDC) is regulated. Histamine receptor H3 (HRH3) is expressed in neurons of the CNS and in presynaptic histaminergic neurons of the peripheral nervous system. In histaminergic neurons, HRH3 acts as a presynaptic autoreceptor inhibiting the release and synthesis of histamine. In non-histaminergic neurons, HRH3 functions as a heteroreceptor and inhibits the release of several important neurotransmitters including serotonin, noradrenaline, acetylcholine, and dopamine. HRH3 acts via Gi/o protein signaling and causes the inhibition of adenylate cyclase (ADCY) and synthesis of histamine. In addition, AKT1/GSK3B kinases have been shown to be activated by HRH3 in neurons to occur through PI3K activation via Gb/g. Outcome effects: In the CNS, AKT1 and GSK3B play a prominent role in brain function and have been implicated in the protection against neuronal apoptosis. The upregulation of AKT1/GSK3B pathway may be the mechanism by which HRH3 exerts its neuroprotective role; however the exact mechanism of this effect remains unknown. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95736ee7-8e74-4e25-8890-2bff7c568405 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-95736ee7-8e74-4e25-8890-2bff7c568405 Postsynaptic Neuron Activation uuid-95736ee7-8e74-4e25-8890-2bff7c568405 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95736ee7-8e74-4e25-8890-2bff7c568405 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-958f6c53-0640-4941-9bc5-4cd5270b8edc NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-958f6c53-0640-4941-9bc5-4cd5270b8edc Synaptic transmission defects in Huntington uuid-958f6c53-0640-4941-9bc5-4cd5270b8edc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-958f6c53-0640-4941-9bc5-4cd5270b8edc PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9596e6d6-5d1b-493b-83f4-798586b2f11d NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-9596e6d6-5d1b-493b-83f4-798586b2f11d NGFR -> MEF Signaling uuid-9596e6d6-5d1b-493b-83f4-798586b2f11d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9596e6d6-5d1b-493b-83f4-798586b2f11d PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: fibroblast Description: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9598959d-27c8-42bb-a9bc-e89fe662921d NodeType: Pathway Notes: Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Photoaging results from long-term continuous exposure of the skin to ultraviolet (UV) radiation of approximately 300-400 nm. Signaling description: Upon exposure to UV radiation, reactive oxygen species (ROS) are formed in the skin. These ROS can activate the epidermal growth factor receptor (EGFR) and cytokine receptors on the surface of fibroblasts and keratinocytes. Further, the activated receptors stimulate p38 and JNK, members of the MAPK signaling cascade. As a result, c-Fos and c-Jun form AP-1 which stimulates the matrix metalloproteinase (MMP) transcription. Increased MMP transcription accelerates collagen degradation leading to dermal matrix alterations. The EGFR activation has been shown to be crucial for a wide range of UV irradiation-induced responses. EGFR is maintained in an inactive state by protein tyrosine phosphatase kappa (PTPRK), which is inhibited by UV rays, thereby allowing EGFR to become activated. Tumor necrosis factor-alpha (TNF-a) is a proinflammatory cytokine produced in the skin in response to ultraviolet B radiation (UVB) in both keratinocytes and dermal fibroblasts. In case of an extensive exposure to sunlight, increased amounts of TNF-a are produced leading to a systemic effect which, includes UVB-induced apoptosis and the removal of damaged cells. Outcome effects: UV exposure may lead to the induction of receptors for epidermal growth factor, cytokines, and TNF-a in in the skin cells, which eventually causes collagen degradation via the induction of the MAPK signaling cascade, as well as DNA degradation and the UV-induced apoptosis. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. MMP1, MMP2, MMP3, MMP9, MAP3K1 and ROS are highlighted in red in order to emphasize the increase of the ECM degradation and DNA Damage. Organ_System: integumentary system PMID: 16849327 PMID: 25906193 PMID: 26215577 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-9598959d-27c8-42bb-a9bc-e89fe662921d Skin Aging uuid-9598959d-27c8-42bb-a9bc-e89fe662921d PS:CellType fibroblast PS:Description Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9598959d-27c8-42bb-a9bc-e89fe662921d PS:NodeType Pathway PS:Notes Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Photoaging results from long-term continuous exposure of the skin to ultraviolet (UV) radiation of approximately 300-400 nm. Signaling description: Upon exposure to UV radiation, reactive oxygen species (ROS) are formed in the skin. These ROS can activate the epidermal growth factor receptor (EGFR) and cytokine receptors on the surface of fibroblasts and keratinocytes. Further, the activated receptors stimulate p38 and JNK, members of the MAPK signaling cascade. As a result, c-Fos and c-Jun form AP-1 which stimulates the matrix metalloproteinase (MMP) transcription. Increased MMP transcription accelerates collagen degradation leading to dermal matrix alterations. The EGFR activation has been shown to be crucial for a wide range of UV irradiation-induced responses. EGFR is maintained in an inactive state by protein tyrosine phosphatase kappa (PTPRK), which is inhibited by UV rays, thereby allowing EGFR to become activated. Tumor necrosis factor-alpha (TNF-a) is a proinflammatory cytokine produced in the skin in response to ultraviolet B radiation (UVB) in both keratinocytes and dermal fibroblasts. In case of an extensive exposure to sunlight, increased amounts of TNF-a are produced leading to a systemic effect which, includes UVB-induced apoptosis and the removal of damaged cells. Outcome effects: UV exposure may lead to the induction of receptors for epidermal growth factor, cytokines, and TNF-a in in the skin cells, which eventually causes collagen degradation via the induction of the MAPK signaling cascade, as well as DNA degradation and the UV-induced apoptosis. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. MMP1, MMP2, MMP3, MMP9, MAP3K1 and ROS are highlighted in red in order to emphasize the increase of the ECM degradation and DNA Damage. PS:Organ_System integumentary system PS:PMID 16849327 PS:PMID 25906193 PS:PMID 26215577 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95b6d7ed-86f9-45d3-be41-3a49591742be NodeType: Pathway Notes: Fat synthesis (lipolysis) results in the liberation of glycerol and nonesterified fatty acids that are released for use by other organs as energy substrates. Organ: generic Organ_System: generic PMID: 17313320 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: adipose tissue urn:agi-pathway:uuid-95b6d7ed-86f9-45d3-be41-3a49591742be Lipolysis Regulation in Adipocyte uuid-95b6d7ed-86f9-45d3-be41-3a49591742be PS:CellType adipocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95b6d7ed-86f9-45d3-be41-3a49591742be PS:NodeType Pathway PS:Notes Fat synthesis (lipolysis) results in the liberation of glycerol and nonesterified fatty acids that are released for use by other organs as energy substrates. PS:Organ generic PS:Organ_System generic PS:PMID 17313320 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue adipose tissue PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95b8a617-23ec-47c9-bd50-b1a5cd2078be NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-95b8a617-23ec-47c9-bd50-b1a5cd2078be TGFb+>cell migration uuid-95b8a617-23ec-47c9-bd50-b1a5cd2078be PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95b8a617-23ec-47c9-bd50-b1a5cd2078be PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95e9ec65-8ffd-407e-a2dc-5e184b9bab89 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-95e9ec65-8ffd-407e-a2dc-5e184b9bab89 EGF -> CREB/CREBBP/ELK/SRF/MYC Expression Targets uuid-95e9ec65-8ffd-407e-a2dc-5e184b9bab89 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-95e9ec65-8ffd-407e-a2dc-5e184b9bab89 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9609a9ea-44b5-4167-97a6-391e3eeb47e8 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Crohn's disease is primarily a T-helper 1- (Th1) dominant condition while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. Signaling description: The increased production of IL12A and IL12B and other cytokines from dendritic cells in patients with Crohn's disease induce both Th1-cell and Th17-cell mediated immune responses. It has been demonstrated that anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is an effective treatment for Crohn's disease. Th1-cells from lesions of patients with Crohn's disease express high levels of STAT4 and TBX21, transcription factors required for IFGN expression. Outcome effects: Th1 cells are the primary source of inflammatory cytokines, interferon-gamma (IFNG), interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. Activated Th1-cells constantly express high levels of IFGN which leads to chronic inflammation in the gut of patients with Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: lymphatic system PMID: 16679026 PMID: 21551364 PMID: 21945121 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-9609a9ea-44b5-4167-97a6-391e3eeb47e8 Th1-Cell Activation in Crohn's Disease uuid-9609a9ea-44b5-4167-97a6-391e3eeb47e8 PS:CellType T-cell PS:Description Crohn's disease is a inflammatory condition with T-helper 1- (Th1) exsess. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9609a9ea-44b5-4167-97a6-391e3eeb47e8 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Crohn's disease is primarily a T-helper 1- (Th1) dominant condition while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. Signaling description: The increased production of IL12A and IL12B and other cytokines from dendritic cells in patients with Crohn's disease induce both Th1-cell and Th17-cell mediated immune responses. It has been demonstrated that anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is an effective treatment for Crohn's disease. Th1-cells from lesions of patients with Crohn's disease express high levels of STAT4 and TBX21, transcription factors required for IFGN expression. Outcome effects: Th1 cells are the primary source of inflammatory cytokines, interferon-gamma (IFNG), interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. Activated Th1-cells constantly express high levels of IFGN which leads to chronic inflammation in the gut of patients with Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System lymphatic system PS:PMID 16679026 PS:PMID 21551364 PS:PMID 21945121 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: cancer cell CellType: cancer stem cell Description: Cancer cell may inhibit adipocyte differentiation. The precise mechanism and the role of this phenomena is not quite clear. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9645d27d-e865-4303-8fc0-22b8d8e4bc6e NodeType: Pathway Notes: Headnote: Cancer cell were shown to inhibit adipocyte differentiation. The precise mechanism and the role of this phenomenon in cancer progression is not quite clear yet. Probably, it can facilitate th metastatic spread. Signaling description: Cancer cells produce a number of ligands, including TNF, IL6, IL11, WNT3A, WNT10B. They were shown to inhibit PPARG and CEBPA, the cardinal transcription factors for adipocyte differentiation. The precise mechanism of this signaling is yet to be determined. TNF most probably activates NFKB and thereby inhibits PPARG. ILs are proposed to act through their classical signaling routes and may inhibit PPARG and CEBPA through STAT5B. WNTs activate CTNNB1 and thereby inhibit PPARG and CEBPA. Outcome effects: PPARG and CEBPA, the major transcription factors for adipocyte differentiation are inhibited. PMID: 11280794 PMID: 21459803 PMID: 22037646 PMID: 23353703 PMID: 27391920 PMID: 28330687 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: adipose tissue urn:agi-pathway:uuid-9645d27d-e865-4303-8fc0-22b8d8e4bc6e Cancer Cells Inhibit Adipocyte Differentiation uuid-9645d27d-e865-4303-8fc0-22b8d8e4bc6e PS:CellType adipocyte PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Cancer cell may inhibit adipocyte differentiation. The precise mechanism and the role of this phenomena is not quite clear. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9645d27d-e865-4303-8fc0-22b8d8e4bc6e PS:NodeType Pathway PS:Notes Headnote: Cancer cell were shown to inhibit adipocyte differentiation. The precise mechanism and the role of this phenomenon in cancer progression is not quite clear yet. Probably, it can facilitate th metastatic spread. Signaling description: Cancer cells produce a number of ligands, including TNF, IL6, IL11, WNT3A, WNT10B. They were shown to inhibit PPARG and CEBPA, the cardinal transcription factors for adipocyte differentiation. The precise mechanism of this signaling is yet to be determined. TNF most probably activates NFKB and thereby inhibits PPARG. ILs are proposed to act through their classical signaling routes and may inhibit PPARG and CEBPA through STAT5B. WNTs activate CTNNB1 and thereby inhibit PPARG and CEBPA. Outcome effects: PPARG and CEBPA, the major transcription factors for adipocyte differentiation are inhibited. PS:PMID 11280794 PS:PMID 21459803 PS:PMID 22037646 PS:PMID 23353703 PS:PMID 27391920 PS:PMID 28330687 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue adipose tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: PI3K/AKT1/MTOR pathway plays a critical regulatory role in cell growth, proliferation, and protein synthesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96617826-4ec1-4832-bad6-fc2934052fe7 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. Signaling description: PI3K/AKT1/MTOR pathway plays a critical regulatory role in cell growth, proliferation, and protein synthesis. The reasons for the activation of this pathway are not well known but may include B-cell receptor (BCR) and BAFF receptor (TNFSF13B) signaling. High levels of activated AKT1, MTOR, and their downstream targets have been identified in MCL. The loss of expression or inactivating phosphorylation of PTEN, a negative PI3K regulator, has been found in some cases of MCL. No genetic or epigenetic alterations of PTEN have been identified in MCL; however the MIR17HG (miR17-92 cluster), which is frequently amplified and overexpressed in MCL was shown to target PTEN. The constitutive activation of NF-kB has been detected in MCL resulting in the overexpression of antiapoptotic proteins such as CFLAR, BCL2, BCL2L1, and XIAP. BCR signaling, microenvironmental stimuli and TNF signaling may mediate NF-kB activation. The inactivation of NF-kB pathway inhibitors, TNFAIP3 and FAF1 by mutations and deletions have been reported in MCL. Finally, BCR plays a role in pathogenesis of at least a subset of MCL as it transfers activating signal through LYN/SYK/PI3K. Outcome effects: The resulting signaling leads to activation of proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 18410453 PMID: 20940415 PMID: 23023712 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-96617826-4ec1-4832-bad6-fc2934052fe7 mTOR/NF-kB/BCR Signaling Disregulation in Mantle Cell Lymphoma uuid-96617826-4ec1-4832-bad6-fc2934052fe7 PS:CellType B-cell PS:CellType cancer cell PS:Description PI3K/AKT1/MTOR pathway plays a critical regulatory role in cell growth, proliferation, and protein synthesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96617826-4ec1-4832-bad6-fc2934052fe7 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. Signaling description: PI3K/AKT1/MTOR pathway plays a critical regulatory role in cell growth, proliferation, and protein synthesis. The reasons for the activation of this pathway are not well known but may include B-cell receptor (BCR) and BAFF receptor (TNFSF13B) signaling. High levels of activated AKT1, MTOR, and their downstream targets have been identified in MCL. The loss of expression or inactivating phosphorylation of PTEN, a negative PI3K regulator, has been found in some cases of MCL. No genetic or epigenetic alterations of PTEN have been identified in MCL; however the MIR17HG (miR17-92 cluster), which is frequently amplified and overexpressed in MCL was shown to target PTEN. The constitutive activation of NF-kB has been detected in MCL resulting in the overexpression of antiapoptotic proteins such as CFLAR, BCL2, BCL2L1, and XIAP. BCR signaling, microenvironmental stimuli and TNF signaling may mediate NF-kB activation. The inactivation of NF-kB pathway inhibitors, TNFAIP3 and FAF1 by mutations and deletions have been reported in MCL. Finally, BCR plays a role in pathogenesis of at least a subset of MCL as it transfers activating signal through LYN/SYK/PI3K. Outcome effects: The resulting signaling leads to activation of proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 18410453 PS:PMID 20940415 PS:PMID 23023712 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9662419c-8806-40b7-947d-2c6872258caa NodeType: Pathway Notes: Headnote: MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a form of mitochondrial cytopathy. MELAS is caused by mutations in genes of the mitochondrial electron transport chain and/or mitochondrial transfer RNAs. Signaling description: Normally, mitochondrial electron transport chain helps convert oxygen and simple sugars to energy in the form of ATP. Several of the genes affected in MELAS, including ND1, ND5, ND6, CYTB, and COX3, encode proteins of mitochondrial complexes I, III and IV. Mutations in these genes result in impaired oxidative phosphorylation system in mitochondria and then impaired insulin secretory capacity of pancreatic beta cells. Mutations in mitochondrial specific transfer RNA (TRNL1) cause more than 80% of all cases of MELAS. They impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Mutations of other mitochondrial transfer RNA may be found in rare cases of MELAS (including TRNF, TRNV, TRNH, TRNQ, and others which are not included on the pathway). Organ: pancreas Organ_System: endocrine system PMID: 15657614 PMID: 24917879 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9662419c-8806-40b7-947d-2c6872258caa MELAS Syndrome uuid-9662419c-8806-40b7-947d-2c6872258caa PS:CellType insulin-secreting cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9662419c-8806-40b7-947d-2c6872258caa PS:NodeType Pathway PS:Notes Headnote: MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a form of mitochondrial cytopathy. MELAS is caused by mutations in genes of the mitochondrial electron transport chain and/or mitochondrial transfer RNAs. Signaling description: Normally, mitochondrial electron transport chain helps convert oxygen and simple sugars to energy in the form of ATP. Several of the genes affected in MELAS, including ND1, ND5, ND6, CYTB, and COX3, encode proteins of mitochondrial complexes I, III and IV. Mutations in these genes result in impaired oxidative phosphorylation system in mitochondria and then impaired insulin secretory capacity of pancreatic beta cells. Mutations in mitochondrial specific transfer RNA (TRNL1) cause more than 80% of all cases of MELAS. They impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Mutations of other mitochondrial transfer RNA may be found in rare cases of MELAS (including TRNF, TRNV, TRNH, TRNQ, and others which are not included on the pathway). PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 15657614 PS:PMID 24917879 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: arterial smooth muscle cell CellType: cardiac myocyte CellType: fibroblast Description: The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates system blood pressure and electrolyte homeostasis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96789b62-9a54-4dec-9484-d9d8bae13e5b NodeType: Pathway Notes: Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates system blood pressure and electrolyte homeostasis. RAAS is an important regulatory mechanism involved in heart failure. Signaling description: Chronic activation of RAAS is a major contributing factor to the pathogenesis and progression of cardiovascular disease, cardiac vasoconstriction, hypertrophy, and fibrosis. The classic RAAS is a cascade comprised of several different components. When blood pressure is low, the juxtaglomerular apparatus in the kidney secretes renin (REN), which cleaves the inactive angiotensinogen (AGT), a high molecular weight protein released from the liver, converting it into angiotensin I. Further, angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). The angiotensin II receptors are located in arterioles, the adrenal gland, and the circumventricular regions of the brain. Outcome effects: Angiotensin II regulates the constriction of blood vessels resulting in increased blood pressure, stimulation of aldosterone synthesis and release, and induction of thirst and salt appetite. Angiotensin enhances the release of NPPA and NPPB (natriuretic peptides) implicated in the control of extracellular fluid volume and electrolyte homeostasis. Angiotensin also stimulates the secretion of the hormone aldosterone from the adrenal cortex. CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone, which is then hydrolyzed to desoxycorticosterone by CYP21A2. Then, CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. Aldosterone acts on the tubules of the kidneys causing them to reabsorb more sodium (Na+) and water from urine. Potassium (K+) is secreted into the tubules in exchange for Na+, which is excreted. This increases the volume of fluid in the body, which additionally increases the blood pressure. It has been recently discovered that RAAS components are expressed in many tissues such as the heart, kidney, placenta, testis, eye, and lymphocytes. These local tissue RAAS components are believed to contribute to tissue damage. In the heart, chymase (CMA1) and cathepsin G (CTSG) convert angiotensin I to angiotensin II. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: heart Organ_System: cardiovascular system PMID: 20590619 PMID: 21829898 PMID: 21994809 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-96789b62-9a54-4dec-9484-d9d8bae13e5b Renin-Angiotensin-Aldosterone System in Myocardial ischemia uuid-96789b62-9a54-4dec-9484-d9d8bae13e5b PS:CellType arterial smooth muscle cell PS:CellType cardiac myocyte PS:CellType fibroblast PS:Description The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates system blood pressure and electrolyte homeostasis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96789b62-9a54-4dec-9484-d9d8bae13e5b PS:NodeType Pathway PS:Notes Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates system blood pressure and electrolyte homeostasis. RAAS is an important regulatory mechanism involved in heart failure. Signaling description: Chronic activation of RAAS is a major contributing factor to the pathogenesis and progression of cardiovascular disease, cardiac vasoconstriction, hypertrophy, and fibrosis. The classic RAAS is a cascade comprised of several different components. When blood pressure is low, the juxtaglomerular apparatus in the kidney secretes renin (REN), which cleaves the inactive angiotensinogen (AGT), a high molecular weight protein released from the liver, converting it into angiotensin I. Further, angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). The angiotensin II receptors are located in arterioles, the adrenal gland, and the circumventricular regions of the brain. Outcome effects: Angiotensin II regulates the constriction of blood vessels resulting in increased blood pressure, stimulation of aldosterone synthesis and release, and induction of thirst and salt appetite. Angiotensin enhances the release of NPPA and NPPB (natriuretic peptides) implicated in the control of extracellular fluid volume and electrolyte homeostasis. Angiotensin also stimulates the secretion of the hormone aldosterone from the adrenal cortex. CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone, which is then hydrolyzed to desoxycorticosterone by CYP21A2. Then, CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. Aldosterone acts on the tubules of the kidneys causing them to reabsorb more sodium (Na+) and water from urine. Potassium (K+) is secreted into the tubules in exchange for Na+, which is excreted. This increases the volume of fluid in the body, which additionally increases the blood pressure. It has been recently discovered that RAAS components are expressed in many tissues such as the heart, kidney, placenta, testis, eye, and lymphocytes. These local tissue RAAS components are believed to contribute to tissue damage. In the heart, chymase (CMA1) and cathepsin G (CTSG) convert angiotensin I to angiotensin II. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20590619 PS:PMID 21829898 PS:PMID 21994809 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Invariant natural killer T (iNKT) cells are a specialized subset of innate T cells that are highly conserved in mammals. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96a0ab25-707a-4f15-a51a-27a8b6a2b6c5 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Invariant natural killer T (iNKT) cells were shown to protect against type 1 diabetes in various mouse models. Signaling description: iNKT cells are a specialized subset of innate T- cells that are highly conserved in mammals. Invariant NKT cells recognize lipids presented by CD1D molecules. CD1D is a non-polymorphic MHC class I-like molecule that is expressed on antigen-presenting cells. CD1D is also expressed on non-hematopoietic cells. The iNKT cells recognize their lipid ligands on CD1D through their semi-invariant T-cell receptor (TCR). In humans, iNKT cells express Valpha24-Jalpha18 chain paired almost exclusively with a Vbeta11 chain. Similarly to iNKT cells, CD1D is highly conserved in mammals. The first lipid to be identified as an antigen for iNKT cells is alpha-galactosylceramide (alphaGalCer), which remains the most potent activator of iNKT cells. In addition to recognition of lipids on CD1D through their TCR, iNKT cells can be activated by co-stimulatory signals specifically cytokines such as IL12 and IL18. These cytokines co-stimulate iNKT cells in many important physiological examples of iNKT cell activation. Invariant NKT cells characteristically express high levels of the transcription factor promyelocytic leukemia zinc finger (PLZF) encoded by ZBTB16. Many studies have revealed the protective role of iNKT cells against autoimmune diseases and particularly type 1 diabetes. The activation of iNKT cells, with a specific agonist such as alphaGalCer or its analogues, inhibits the development of type 1 diabetes. Outcome effects: It was initially proposed that iNKT cell-mediated protection was associated with the induction of Th2 cell responses to islet autoantigens. However, studies analyzing the protection against diabetes induced by the transfer of anti-islet CD4 and CD8 - cells have revealed that iNKT cells impair the differentiation of these pathogenic T-cells. The autoreactive T-cells become anergic and do not destroy pancreatic islets in mouse model of diabetes. The abortive priming of anti-islet T-cells in pancreatic lymph nodes can be explained by the ability of iNKT cells to promote the recruitment of tolerogenic DCs. It has been shown that iNKT cells prevent and even cure type 1 diabetes in various mouse models. These observations are encouraging for the further development of new therapeutic strategies based on iNKT cell targeting. Upon infection of beta cells, iNKT cells promote the recruitment of plasmacytoid DCs (pDCs) specifically in the pancreas and their production of type 1 IFN, a major antiviral cytokine. This local iNKT-pDC crosstalk is dependent on the TNFRSF4-TNFSF4 pathway. Invariant NKT cells specifically express TNFRSF4 in pancreatic tissue but not in lymphoid tissues. As a result, in the pancreas (but not in the spleen), iNKT cells enhance IFNA1 production by pDCs and inhibit local viral replication. Thus, the diabetogenic effect can be controlled by efficient innate immune cell crosstalk, limiting the activation of diabetogenic T-cells. Following viral infection, iNKT cell-pDC crosstalk dampens diabetogenic CD8 T-cell responses in the pancreas. In this infectious context, iNKT cells producing IL10 in the pancreatic lymph nodes promote the production of TGFB1 by pDCs. Animal data: iNKT cells were shown to protect against type 1 diabetes in various mouse models. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: hematological system PMID: 20577267 PMID: 21712017 PMID: 24478773 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-96a0ab25-707a-4f15-a51a-27a8b6a2b6c5 Natural Killer T-Cell Roles in Diabetes Mellitus Type 1 uuid-96a0ab25-707a-4f15-a51a-27a8b6a2b6c5 PS:CellType natural killer cell PS:Description Invariant natural killer T (iNKT) cells are a specialized subset of innate T cells that are highly conserved in mammals. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96a0ab25-707a-4f15-a51a-27a8b6a2b6c5 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Invariant natural killer T (iNKT) cells were shown to protect against type 1 diabetes in various mouse models. Signaling description: iNKT cells are a specialized subset of innate T- cells that are highly conserved in mammals. Invariant NKT cells recognize lipids presented by CD1D molecules. CD1D is a non-polymorphic MHC class I-like molecule that is expressed on antigen-presenting cells. CD1D is also expressed on non-hematopoietic cells. The iNKT cells recognize their lipid ligands on CD1D through their semi-invariant T-cell receptor (TCR). In humans, iNKT cells express Valpha24-Jalpha18 chain paired almost exclusively with a Vbeta11 chain. Similarly to iNKT cells, CD1D is highly conserved in mammals. The first lipid to be identified as an antigen for iNKT cells is alpha-galactosylceramide (alphaGalCer), which remains the most potent activator of iNKT cells. In addition to recognition of lipids on CD1D through their TCR, iNKT cells can be activated by co-stimulatory signals specifically cytokines such as IL12 and IL18. These cytokines co-stimulate iNKT cells in many important physiological examples of iNKT cell activation. Invariant NKT cells characteristically express high levels of the transcription factor promyelocytic leukemia zinc finger (PLZF) encoded by ZBTB16. Many studies have revealed the protective role of iNKT cells against autoimmune diseases and particularly type 1 diabetes. The activation of iNKT cells, with a specific agonist such as alphaGalCer or its analogues, inhibits the development of type 1 diabetes. Outcome effects: It was initially proposed that iNKT cell-mediated protection was associated with the induction of Th2 cell responses to islet autoantigens. However, studies analyzing the protection against diabetes induced by the transfer of anti-islet CD4 and CD8 - cells have revealed that iNKT cells impair the differentiation of these pathogenic T-cells. The autoreactive T-cells become anergic and do not destroy pancreatic islets in mouse model of diabetes. The abortive priming of anti-islet T-cells in pancreatic lymph nodes can be explained by the ability of iNKT cells to promote the recruitment of tolerogenic DCs. It has been shown that iNKT cells prevent and even cure type 1 diabetes in various mouse models. These observations are encouraging for the further development of new therapeutic strategies based on iNKT cell targeting. Upon infection of beta cells, iNKT cells promote the recruitment of plasmacytoid DCs (pDCs) specifically in the pancreas and their production of type 1 IFN, a major antiviral cytokine. This local iNKT-pDC crosstalk is dependent on the TNFRSF4-TNFSF4 pathway. Invariant NKT cells specifically express TNFRSF4 in pancreatic tissue but not in lymphoid tissues. As a result, in the pancreas (but not in the spleen), iNKT cells enhance IFNA1 production by pDCs and inhibit local viral replication. Thus, the diabetogenic effect can be controlled by efficient innate immune cell crosstalk, limiting the activation of diabetogenic T-cells. Following viral infection, iNKT cell-pDC crosstalk dampens diabetogenic CD8 T-cell responses in the pancreas. In this infectious context, iNKT cells producing IL10 in the pancreatic lymph nodes promote the production of TGFB1 by pDCs. Animal data: iNKT cells were shown to protect against type 1 diabetes in various mouse models. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System hematological system PS:PMID 20577267 PS:PMID 21712017 PS:PMID 24478773 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Adherens junctions are protein complexes that occur at cell-cell junctions in cardiomyocytes, usually more basal than tight junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96ce5553-fd25-4744-91cf-ab9aa781584f NodeType: Pathway Notes: Headnote: Arhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. Signaling description: Adherens junctions are cell-cell junctions that are in cardiomyocytes located usually more basally than tight junctions. An adherens junction is defined as a cell junction, whose cytoplasmic face is linked to the actin cytoskeleton. Adherens junctions contain cadherins, a family of transmembrane proteins that form homodimers in a calcium-dependent manner with other cadherin molecules on adjacent cells. Outcome effects: JUP or gamma-catenin (plakoglobin) binds the catenin-binding region of the cadherin. Alpha-catenin binds the cadherin indirectly via beta-catenin or plakoglobin and links the actin cytoskeleton to cadherin. Recently identified CTNNA3 is a novel ARVC gene. This gene encodes alpha-T-catenin, which binds plakophilin-2 and gamma-catenin and thereby contributes to the formation of the adherens junctions. Organ: heart Organ_System: cardiovascular system PMID: 20301310 PMID: 23468208 PMID: 25516623 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-96ce5553-fd25-4744-91cf-ab9aa781584f Adherens Junctions Dysfunction in Cardiomyocyte uuid-96ce5553-fd25-4744-91cf-ab9aa781584f PS:CellType cardiac myocyte PS:Description Adherens junctions are protein complexes that occur at cell-cell junctions in cardiomyocytes, usually more basal than tight junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96ce5553-fd25-4744-91cf-ab9aa781584f PS:NodeType Pathway PS:Notes Headnote: Arhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. Signaling description: Adherens junctions are cell-cell junctions that are in cardiomyocytes located usually more basally than tight junctions. An adherens junction is defined as a cell junction, whose cytoplasmic face is linked to the actin cytoskeleton. Adherens junctions contain cadherins, a family of transmembrane proteins that form homodimers in a calcium-dependent manner with other cadherin molecules on adjacent cells. Outcome effects: JUP or gamma-catenin (plakoglobin) binds the catenin-binding region of the cadherin. Alpha-catenin binds the cadherin indirectly via beta-catenin or plakoglobin and links the actin cytoskeleton to cadherin. Recently identified CTNNA3 is a novel ARVC gene. This gene encodes alpha-T-catenin, which binds plakophilin-2 and gamma-catenin and thereby contributes to the formation of the adherens junctions. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20301310 PS:PMID 23468208 PS:PMID 25516623 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96cf7a8c-658f-447a-8478-173eeec3a115 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-96cf7a8c-658f-447a-8478-173eeec3a115 IGF1R -> STAT Signaling uuid-96cf7a8c-658f-447a-8478-173eeec3a115 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96cf7a8c-658f-447a-8478-173eeec3a115 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Hyperammonemia Type I (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the CPS1 gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96ed701d-18e6-4a97-b4e1-00678ef17d56 NodeType: Pathway Notes: Hyperammonemia Type I (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the CPS1 gene. Organ: liver PMID: 20301396 PMID: 20800523 PMID: 24772957 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-96ed701d-18e6-4a97-b4e1-00678ef17d56 Hyperammonemia Type I uuid-96ed701d-18e6-4a97-b4e1-00678ef17d56 PS:CellType hepatocyte PS:Description Hyperammonemia Type I (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the CPS1 gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96ed701d-18e6-4a97-b4e1-00678ef17d56 PS:NodeType Pathway PS:Notes Hyperammonemia Type I (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the CPS1 gene. PS:Organ liver PS:PMID 20301396 PS:PMID 20800523 PS:PMID 24772957 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of the Hippo/YAP1 signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96f4ecee-b0bf-46ed-8f01-b023699f1e82 NodeType: Pathway Notes: Headnote: Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. Dysregulation of the Hippo pathway contributes to cancer development. Signaling description: The essential part of Hippo signaling consists of a kinase cascade in which STK3/4 kinases and SAV1 form a complex and phosphorylate LATS1/2 kinases. Next, activated LATS1/2 phosphorylate and inhibit the transcription of YAP1 and WWTR1 co-activators. When dephosphorylated, YAP1/WWTR1 translocate into the nucleus and interact with TEAD, SMAD, RUNX, TP73 and other transcription factors leading to increased expression of genes that up-regulate cell proliferation and down-regulate apoptosis. GNAQ and GNA11-coupled receptor activate YAP and WWTR1 through the RHO-regulated signaling network. Cancer-related GNAQ and GNA11 mutants stimulate LATS inhibition by RHO via actin cytoskeleton reorganization, dephosphorylation and activation of YAP1 and WWTR1. Tumour suppressor adenomatous polyposis coli (APC) inhibits the transcription of YAP1 and WWTR1 and WNT stimulation or loss of APC/AXIN1 causes nuclear localization and activation of YAP1 and WWTR1. Inactivating mutations of tumor suppressors LATS1/2, MOB1A, NF2 and activating mutations/amplifications of YAP1 and WWTR1 are common in cancer. Outcome effects: The activation of YAP1 / WWTR1 and downstream transcription factors leads to uncontrolled cellular proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 23467301 PMID: 25592648 PMID: 26160682 PMID: 26811664 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-96f4ecee-b0bf-46ed-8f01-b023699f1e82 Hippo/YAP1 Signaling Deregulation in Cancer uuid-96f4ecee-b0bf-46ed-8f01-b023699f1e82 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of the Hippo/YAP1 signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-96f4ecee-b0bf-46ed-8f01-b023699f1e82 PS:NodeType Pathway PS:Notes Headnote: Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. Dysregulation of the Hippo pathway contributes to cancer development. Signaling description: The essential part of Hippo signaling consists of a kinase cascade in which STK3/4 kinases and SAV1 form a complex and phosphorylate LATS1/2 kinases. Next, activated LATS1/2 phosphorylate and inhibit the transcription of YAP1 and WWTR1 co-activators. When dephosphorylated, YAP1/WWTR1 translocate into the nucleus and interact with TEAD, SMAD, RUNX, TP73 and other transcription factors leading to increased expression of genes that up-regulate cell proliferation and down-regulate apoptosis. GNAQ and GNA11-coupled receptor activate YAP and WWTR1 through the RHO-regulated signaling network. Cancer-related GNAQ and GNA11 mutants stimulate LATS inhibition by RHO via actin cytoskeleton reorganization, dephosphorylation and activation of YAP1 and WWTR1. Tumour suppressor adenomatous polyposis coli (APC) inhibits the transcription of YAP1 and WWTR1 and WNT stimulation or loss of APC/AXIN1 causes nuclear localization and activation of YAP1 and WWTR1. Inactivating mutations of tumor suppressors LATS1/2, MOB1A, NF2 and activating mutations/amplifications of YAP1 and WWTR1 are common in cancer. Outcome effects: The activation of YAP1 / WWTR1 and downstream transcription factors leads to uncontrolled cellular proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 23467301 PS:PMID 25592648 PS:PMID 26160682 PS:PMID 26811664 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9715cb00-126c-484f-8ffd-3cf8155fd430 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9715cb00-126c-484f-8ffd-3cf8155fd430 Cys biosynthesis template uuid-9715cb00-126c-484f-8ffd-3cf8155fd430 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9715cb00-126c-484f-8ffd-3cf8155fd430 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9722d75d-868d-47cc-ae2c-e3fb4fe25a3d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9722d75d-868d-47cc-ae2c-e3fb4fe25a3d TCA cycle template uuid-9722d75d-868d-47cc-ae2c-e3fb4fe25a3d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9722d75d-868d-47cc-ae2c-e3fb4fe25a3d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-973a11e7-8b5a-4734-9739-ab2c3c34b47c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-973a11e7-8b5a-4734-9739-ab2c3c34b47c GH1/PRLR Expression Targets uuid-973a11e7-8b5a-4734-9739-ab2c3c34b47c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-973a11e7-8b5a-4734-9739-ab2c3c34b47c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-975a3a78-dd2c-42c2-ac7f-9bda1eaa9110 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-975a3a78-dd2c-42c2-ac7f-9bda1eaa9110 CCL2 Expression Targets uuid-975a3a78-dd2c-42c2-ac7f-9bda1eaa9110 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-975a3a78-dd2c-42c2-ac7f-9bda1eaa9110 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-978ca0c1-b6fd-4172-b448-8c66e0dc82e8 NodeType: Pathway Notes: The acute phase, which is characterized by eczematous skin lesions, is facilitated by allergen/IgE-bound Langerhans cells (LCs) and by IgE activated mast cells. Eczematous skin lesions develop as a result of the complex immune and inflammatory responses driven by the release of proinflammatory cytokines and chemokines from various skin-resident cell types. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-978ca0c1-b6fd-4172-b448-8c66e0dc82e8 2_Acute phase initiation in atopic dermatitis uuid-978ca0c1-b6fd-4172-b448-8c66e0dc82e8 PS:CellType T-cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-978ca0c1-b6fd-4172-b448-8c66e0dc82e8 PS:NodeType Pathway PS:Notes The acute phase, which is characterized by eczematous skin lesions, is facilitated by allergen/IgE-bound Langerhans cells (LCs) and by IgE activated mast cells. Eczematous skin lesions develop as a result of the complex immune and inflammatory responses driven by the release of proinflammatory cytokines and chemokines from various skin-resident cell types. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: The principal functions of activated components of the complement system are recognition and clearance of immune complexes and apoptotic cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9792d384-3117-4e8f-89ce-16db0ae4f60b NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Signaling description: Defects in the complement pathway components are linked to SLE. The principal function of the activated components of the complement system is recognition and clearance of immune complexes and apoptotic cells. Complete deficiencies of complement components including C4, C1q and others predispose for the development of SLE. Outcome effects: The link between SLE and complement deficiencies can be explained by impaired elimination of apoptotic material or dysregulation of B-cell toleration, which trigger autoimmunity. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated proteins are shown in white-out style. Organ_System: cardiovascular system PMID: 17603557 PMID: 22795896 PMID: 23227085 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-9792d384-3117-4e8f-89ce-16db0ae4f60b Complement System Defects in Systemic Lupus Erythematosis uuid-9792d384-3117-4e8f-89ce-16db0ae4f60b PS:Description The principal functions of activated components of the complement system are recognition and clearance of immune complexes and apoptotic cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9792d384-3117-4e8f-89ce-16db0ae4f60b PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Signaling description: Defects in the complement pathway components are linked to SLE. The principal function of the activated components of the complement system is recognition and clearance of immune complexes and apoptotic cells. Complete deficiencies of complement components including C4, C1q and others predispose for the development of SLE. Outcome effects: The link between SLE and complement deficiencies can be explained by impaired elimination of apoptotic material or dysregulation of B-cell toleration, which trigger autoimmunity. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ_System cardiovascular system PS:PMID 17603557 PS:PMID 22795896 PS:PMID 23227085 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97a2dd5e-fe54-436e-8bda-39953ca6a757 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-97a2dd5e-fe54-436e-8bda-39953ca6a757 Neuromodulators+>Cornea uuid-97a2dd5e-fe54-436e-8bda-39953ca6a757 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97a2dd5e-fe54-436e-8bda-39953ca6a757 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97ace52a-cce0-4d8d-8c3f-25deb5a1eb76 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-97ace52a-cce0-4d8d-8c3f-25deb5a1eb76 PDGFD -> AP-1 Expression Targets uuid-97ace52a-cce0-4d8d-8c3f-25deb5a1eb76 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97ace52a-cce0-4d8d-8c3f-25deb5a1eb76 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97bd5b1a-9d7a-4203-9845-2b7d3abd9cc4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Receptor Signaling urn:agi-pathway:uuid-97bd5b1a-9d7a-4203-9845-2b7d3abd9cc4 CD2 -> NFATC1 Signaling uuid-97bd5b1a-9d7a-4203-9845-2b7d3abd9cc4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97bd5b1a-9d7a-4203-9845-2b7d3abd9cc4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Receptor Signaling PS:CellType PS:Link PS:NodeType PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97bfce11-ae8b-446d-a223-225c11a8a3cd NodeType: Pathway Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-97bfce11-ae8b-446d-a223-225c11a8a3cd COVID19+>AGER feed forward loop in innate immunity uuid-97bfce11-ae8b-446d-a223-225c11a8a3cd PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97bfce11-ae8b-446d-a223-225c11a8a3cd PS:NodeType Pathway PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell Description: Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97c5a161-7041-482b-9c21-3032174f3efa NodeType: Pathway Notes: Headnote: Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to the absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: Mutations of RET tyrosine kinase receptor, GDNF, NRTN, NRG1/3, EDN3, EDNRB, ECE1, and L1CAM lead to HSCR development. RET mutations are the most frequent genetic abnormities in HSCR. In about 30% of cases, HSCR is associated with other malformations. The syndromic forms of HSCR with Mendelian inheritance include Shah-Waardenburg syndrome, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, and Goldberg-Shprintzen syndrome. Shah-Waardenburg syndrome is caused by mutations in EDNRB, EDN3, and SOX10 and is characterized by sensorineural hearing loss and balance problems in some patients as well as pigmentary abnormalities of the hair, skin, and eyes. Congenital central hypoventilation syndrome and neuroblastoma are caused by mutations in PHOX2B. Mowat-Wilson syndrome is caused by ZEB2 mutations and is characterized by mental retardation, microcephaly, epilepsy, and corpus callosum agenesis. The protein encoded by KIAA1279 is responsible for Goldberg-Shprintzen megacolon syndrome which is characterized by microcephaly, mental retardation, and polymicrogyria. Lastly, L1CAM mutations may be associated with X-linked hydrocephalus and RET mutations may lead to multiple endocrine neoplasia type 2a/b. Mutated genes: Mutated genes are shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15660316 PMID: 22174542 PMID: 22584708 PMID: 23043324 PMID: 23528997 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-97c5a161-7041-482b-9c21-3032174f3efa Syndromic Forms in Hirschsprung Disease uuid-97c5a161-7041-482b-9c21-3032174f3efa PS:CellType B-cell PS:Description Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-97c5a161-7041-482b-9c21-3032174f3efa PS:NodeType Pathway PS:Notes Headnote: Hirschsprung disease (HSCR) is a congenital disorder characterized by intestinal dysmotility due to the absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells. Signaling description: Mutations of RET tyrosine kinase receptor, GDNF, NRTN, NRG1/3, EDN3, EDNRB, ECE1, and L1CAM lead to HSCR development. RET mutations are the most frequent genetic abnormities in HSCR. In about 30% of cases, HSCR is associated with other malformations. The syndromic forms of HSCR with Mendelian inheritance include Shah-Waardenburg syndrome, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, and Goldberg-Shprintzen syndrome. Shah-Waardenburg syndrome is caused by mutations in EDNRB, EDN3, and SOX10 and is characterized by sensorineural hearing loss and balance problems in some patients as well as pigmentary abnormalities of the hair, skin, and eyes. Congenital central hypoventilation syndrome and neuroblastoma are caused by mutations in PHOX2B. Mowat-Wilson syndrome is caused by ZEB2 mutations and is characterized by mental retardation, microcephaly, epilepsy, and corpus callosum agenesis. The protein encoded by KIAA1279 is responsible for Goldberg-Shprintzen megacolon syndrome which is characterized by microcephaly, mental retardation, and polymicrogyria. Lastly, L1CAM mutations may be associated with X-linked hydrocephalus and RET mutations may lead to multiple endocrine neoplasia type 2a/b. Mutated genes: Mutated genes are shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15660316 PS:PMID 22174542 PS:PMID 22584708 PS:PMID 23043324 PS:PMID 23528997 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell CellType: neutrophil Description: N2 neutrophils (tumor-associated neutrophils, TANs) may contribute to tumor-promoting inflammation and tumor progression Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98176c1d-623d-4011-af60-807304ca9b72 NodeType: Pathway Notes: Headnote: Neutrophils can be subdivided into two groups: N1 neutrophils that have anti-tumor activity and N2 neutrophils (tumor-associated neutrophils, TANs) that may have pro-tumor activity. Hypoxia is always present in tumors due to imbalance of oxygen consumption and supply. Hypoxia induces TGFB1 production and inhibits IFNB1 production. These factors are essential for activation of N2 neutrophils. Signaling description: TGFB1, through TGFBR2/1 receptors, activates SMAD which, in turn, activates STAT3. TGFBR1 also promotes PI3K/AKT1/MTOR signaling with subsequent activation of MYC.IFNB1 normally acts through IFNAR1/2 /JAK1/STAT1 and inhibits MYC. When IFNB1 is downregulated, MYC is activated. Outcome effects: STAT3 and MYC regulate expression of multiple factors which participate in tumor-promoting inflammation and tumor progression. Specifically, IL6 and ILB1 enhance inflammation. CXCR4 inhibits neutrophil migration. CCL2/5 promote monocyte migration. VEGFA potentiates vasculogenesis. MMP9 promotes cell invasion, metastatic progression and VEGFA activation. ARG1 inhibits CD8+ T-cell possessing anti-tumor functions. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ_System: lymphatic system PMID: 19732719 PMID: 21798756 PMID: 26819959 PMID: 28283697 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-98176c1d-623d-4011-af60-807304ca9b72 N2 Neutrophils in Tumor-Promoting Inflammation and Tumor Progression uuid-98176c1d-623d-4011-af60-807304ca9b72 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType neutrophil PS:Description N2 neutrophils (tumor-associated neutrophils, TANs) may contribute to tumor-promoting inflammation and tumor progression PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98176c1d-623d-4011-af60-807304ca9b72 PS:NodeType Pathway PS:Notes Headnote: Neutrophils can be subdivided into two groups: N1 neutrophils that have anti-tumor activity and N2 neutrophils (tumor-associated neutrophils, TANs) that may have pro-tumor activity. Hypoxia is always present in tumors due to imbalance of oxygen consumption and supply. Hypoxia induces TGFB1 production and inhibits IFNB1 production. These factors are essential for activation of N2 neutrophils. Signaling description: TGFB1, through TGFBR2/1 receptors, activates SMAD which, in turn, activates STAT3. TGFBR1 also promotes PI3K/AKT1/MTOR signaling with subsequent activation of MYC.IFNB1 normally acts through IFNAR1/2 /JAK1/STAT1 and inhibits MYC. When IFNB1 is downregulated, MYC is activated. Outcome effects: STAT3 and MYC regulate expression of multiple factors which participate in tumor-promoting inflammation and tumor progression. Specifically, IL6 and ILB1 enhance inflammation. CXCR4 inhibits neutrophil migration. CCL2/5 promote monocyte migration. VEGFA potentiates vasculogenesis. MMP9 promotes cell invasion, metastatic progression and VEGFA activation. ARG1 inhibits CD8+ T-cell possessing anti-tumor functions. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ_System lymphatic system PS:PMID 19732719 PS:PMID 21798756 PS:PMID 26819959 PS:PMID 28283697 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9822e206-9e3e-492a-8751-97079bb3ffd0 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-9822e206-9e3e-492a-8751-97079bb3ffd0 GPCRs Desentization uuid-9822e206-9e3e-492a-8751-97079bb3ffd0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9822e206-9e3e-492a-8751-97079bb3ffd0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9852e008-c942-40cb-85fd-1f2e456744db NodeType: Pathway Notes: High glucose levels, the production of inflammatory cytokines, and probably some genetic predisposition promote beta-cell death in the initial stages of the disease. At the time of T2D diagnosis, patients may have lost ~50% of their pancreatic beta cells. The destruction of pancreatic beta cells in type 2 diabetes mellitus occurs gradually, while excessive levels of intracellular glucose, Ca2, and long-chain saturated fatty acids (FFA) trigger cell apoptosis and increase oxidative stress. The primary source of oxidative stress in pancreatic beta cells most likely comes from reactive oxygen species (ROS) generated by the mitochondrial electron transport chain. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-9852e008-c942-40cb-85fd-1f2e456744db 2_Hyperglycemia and hyperlipidemia trigger beta-cell apoptosis uuid-9852e008-c942-40cb-85fd-1f2e456744db PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9852e008-c942-40cb-85fd-1f2e456744db PS:NodeType Pathway PS:Notes High glucose levels, the production of inflammatory cytokines, and probably some genetic predisposition promote beta-cell death in the initial stages of the disease. At the time of T2D diagnosis, patients may have lost ~50% of their pancreatic beta cells. The destruction of pancreatic beta cells in type 2 diabetes mellitus occurs gradually, while excessive levels of intracellular glucose, Ca2, and long-chain saturated fatty acids (FFA) trigger cell apoptosis and increase oxidative stress. The primary source of oxidative stress in pancreatic beta cells most likely comes from reactive oxygen species (ROS) generated by the mitochondrial electron transport chain. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98572835-a5b6-48c8-96a2-0d39111aa49e NodeType: Pathway Organ: generic Organ_System: generic PMID: 23694989 PMID: 25402640 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-98572835-a5b6-48c8-96a2-0d39111aa49e mTOR Signaling Activation by Fatty Acids and Glucose uuid-98572835-a5b6-48c8-96a2-0d39111aa49e PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98572835-a5b6-48c8-96a2-0d39111aa49e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 23694989 PS:PMID 25402640 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98598888-859c-4823-87ba-a7b234e8c888 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-98598888-859c-4823-87ba-a7b234e8c888 Elevated Receptors -> Expression Targets in Skin uuid-98598888-859c-4823-87ba-a7b234e8c888 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98598888-859c-4823-87ba-a7b234e8c888 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9882dd69-7d91-400d-894c-2d85af3ab154 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9882dd69-7d91-400d-894c-2d85af3ab154 TNFSF10 Expression Targets uuid-9882dd69-7d91-400d-894c-2d85af3ab154 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9882dd69-7d91-400d-894c-2d85af3ab154 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98b8736e-b708-4977-9681-3e7929b8f0fc NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-98b8736e-b708-4977-9681-3e7929b8f0fc NOTCH 1/3 -> Expression Targets in Nerve Tissue uuid-98b8736e-b708-4977-9681-3e7929b8f0fc PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98b8736e-b708-4977-9681-3e7929b8f0fc PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98d05da0-d78d-4af8-a892-b99a8cb38813 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-98d05da0-d78d-4af8-a892-b99a8cb38813 ANGPT1 -> STAT Expression Targets uuid-98d05da0-d78d-4af8-a892-b99a8cb38813 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98d05da0-d78d-4af8-a892-b99a8cb38813 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98d31b95-61cd-4e33-a9ad-2af8f8ff8517 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-98d31b95-61cd-4e33-a9ad-2af8f8ff8517 IL6 Expression Targets uuid-98d31b95-61cd-4e33-a9ad-2af8f8ff8517 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98d31b95-61cd-4e33-a9ad-2af8f8ff8517 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98e15d71-36dc-45d4-a337-d419cdc41d06 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-98e15d71-36dc-45d4-a337-d419cdc41d06 Mast cell activation in COVID19 uuid-98e15d71-36dc-45d4-a337-d419cdc41d06 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-98e15d71-36dc-45d4-a337-d419cdc41d06 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99056847-26a1-42ff-aadd-8d08da22004b NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-99056847-26a1-42ff-aadd-8d08da22004b Proteins with Altered Expression in Cancer-Associated DNA Methylation uuid-99056847-26a1-42ff-aadd-8d08da22004b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99056847-26a1-42ff-aadd-8d08da22004b PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Norepinephrine is released from presynaptic nerve terminals of adrenergic neuron by synaptic vesicle exocytosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99105a97-3698-45a2-b161-71623b7bc5b2 NodeType: Pathway Notes: Headnote: The principal means of communication for all neurons is the release of chemical signals at spatially defined locations: synapses for neurons in the brain, or the vasculature for neurons with neuroendocrine terminals. Neuroendocrine neurons generate action potentials upon appropriate stimulation. These action potentials are responsible for the calcium-dependent release of neurotransmitters at neuroendocrine terminals into the vasculature. Targets of neuroendocrine signals are located at some distance from the release sites, and the transmission path is the vasculature rather than the synapse. Adrenergic neuroendocrine neurons must therefore release larger amounts of signal than those that communicate using synaptically released small molecule transmitters. Signaling description: In neuroendocrine neurons, secretion is dependent upon membrane depolarization and Ca2+ entry. Neurotransmitter norepinephrine (noradrenaline) is secreted as a result of tyrosine hydroxylase/dopa decarboxylase/dopamine beta-hydroxylase (TH/DOC/DBH) cascade. The vesicular monoamine transporter (SLC18A2) activity is necessary for the uptake of norepinephrine into secretory vesicles. The following exocytosis of secretory vesicles consists of vesicle trafficking, tethering, docking, priming and fusion. The secretory vesicles are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by specific RAB GTPases. The tethering of the secretory vesicles is mediated by the exocyst complex and RAB proteins, bringing the vesicles very close to the plasma membrane. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex (VAMPs/STX1A/SNAP25). The influx of calcium ions in the priming step is needed for membrane depolarization and trigger vesicle fusion in neurons. The influx of Ca2+ from voltage-dependent calcium channels into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor SYT1 and the partially assembled SNARE complex. SNARE proteins form an incredibly stable SNARE complex which brings the vesicle membrane into close apposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. CPLX1 and SYT1 regulate the norepinephrine release. SNARE disassembly can be induced by a single round of ATP hydrolysis providing by ATPase NSF and NAPA. Norepinephrine binds with adrenoceptors on the effector cell membrane. The extraneuronal norepinephrine uptake is regulated by monoamine oxidase/aldehyde dehydrogenase/catechol O-methyltransferase cascade. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Neurotransmitter norepinephrine is released from presynaptic nerve terminals of adrenergic neuron by synaptic vesicle exocytosis. Animal data: Some of the data was revealed from animal model experiments. Organ: brain Organ_System: nervous system PMID: 22026965 PMID: 24054156 PMID: 28167663 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-99105a97-3698-45a2-b161-71623b7bc5b2 Norepinephrine Neuronal Release uuid-99105a97-3698-45a2-b161-71623b7bc5b2 PS:CellType neuron PS:Description Norepinephrine is released from presynaptic nerve terminals of adrenergic neuron by synaptic vesicle exocytosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99105a97-3698-45a2-b161-71623b7bc5b2 PS:NodeType Pathway PS:Notes Headnote: The principal means of communication for all neurons is the release of chemical signals at spatially defined locations: synapses for neurons in the brain, or the vasculature for neurons with neuroendocrine terminals. Neuroendocrine neurons generate action potentials upon appropriate stimulation. These action potentials are responsible for the calcium-dependent release of neurotransmitters at neuroendocrine terminals into the vasculature. Targets of neuroendocrine signals are located at some distance from the release sites, and the transmission path is the vasculature rather than the synapse. Adrenergic neuroendocrine neurons must therefore release larger amounts of signal than those that communicate using synaptically released small molecule transmitters. Signaling description: In neuroendocrine neurons, secretion is dependent upon membrane depolarization and Ca2+ entry. Neurotransmitter norepinephrine (noradrenaline) is secreted as a result of tyrosine hydroxylase/dopa decarboxylase/dopamine beta-hydroxylase (TH/DOC/DBH) cascade. The vesicular monoamine transporter (SLC18A2) activity is necessary for the uptake of norepinephrine into secretory vesicles. The following exocytosis of secretory vesicles consists of vesicle trafficking, tethering, docking, priming and fusion. The secretory vesicles are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by specific RAB GTPases. The tethering of the secretory vesicles is mediated by the exocyst complex and RAB proteins, bringing the vesicles very close to the plasma membrane. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex (VAMPs/STX1A/SNAP25). The influx of calcium ions in the priming step is needed for membrane depolarization and trigger vesicle fusion in neurons. The influx of Ca2+ from voltage-dependent calcium channels into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor SYT1 and the partially assembled SNARE complex. SNARE proteins form an incredibly stable SNARE complex which brings the vesicle membrane into close apposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. CPLX1 and SYT1 regulate the norepinephrine release. SNARE disassembly can be induced by a single round of ATP hydrolysis providing by ATPase NSF and NAPA. Norepinephrine binds with adrenoceptors on the effector cell membrane. The extraneuronal norepinephrine uptake is regulated by monoamine oxidase/aldehyde dehydrogenase/catechol O-methyltransferase cascade. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Neurotransmitter norepinephrine is released from presynaptic nerve terminals of adrenergic neuron by synaptic vesicle exocytosis. Animal data: Some of the data was revealed from animal model experiments. PS:Organ brain PS:Organ_System nervous system PS:PMID 22026965 PS:PMID 24054156 PS:PMID 28167663 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using iPTMnet database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-993e2a4b-a91e-426e-9d3a-cee5a4cf7832 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-993e2a4b-a91e-426e-9d3a-cee5a4cf7832 RPS6KA5 Modifies Histone 3 uuid-993e2a4b-a91e-426e-9d3a-cee5a4cf7832 PS:Description Pathway is build using iPTMnet database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-993e2a4b-a91e-426e-9d3a-cee5a4cf7832 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-996f6730-6021-433a-a6ef-329c122743d9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-996f6730-6021-433a-a6ef-329c122743d9 UMP pyrimidine precursor biosynthesis template uuid-996f6730-6021-433a-a6ef-329c122743d9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-996f6730-6021-433a-a6ef-329c122743d9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-997524f6-fe65-4db1-ad78-4043e48e7253 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-997524f6-fe65-4db1-ad78-4043e48e7253 WNT4 Expression Targets uuid-997524f6-fe65-4db1-ad78-4043e48e7253 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-997524f6-fe65-4db1-ad78-4043e48e7253 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Nucleotide excision repair (NER) requires the action of more than 30 proteins in a stepwise manner. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99850faf-f3dc-4084-ab64-c81927122dbd NodeType: Pathway Notes: Headnote: Nucleotide excision repair (NER) requires the action of more than 30 proteins in a stepwise manner that includes damage recognition, local opening of the DNA duplex around the lesion, dual incision of the damaged DNA strand, gap repair synthesis, and strand ligation. The most significant lesions are pyrimidine dimers caused by the UV component of sunlight. There are two distinct forms of NER including global genomic NER (GG-NER), which corrects damage in transcriptionally silent areas of the genome and transcription-coupled NER (TC-NER), which repairs lesions on the actively transcribed strand of the DNA. Signaling description: The two NER pathways are generally identical except in their mechanism of damage recognition. In GG-NER, the XPC protein complex is responsible for the initial detection of damaged DNA. TC-NER occurs when the transcription apparatus stops at the site of injury and does not require XPC. The following steps of both GG-NER and TC-NER proceed identically. XPA and replication factor A bind at the site of injury and further aid in damage recognition. Subsequently, ERCC3 and ERCC2 helicases, which are the components of TFIIH transcription factor, unwind the DNA duplex close to the lesion and allow RNA polymerase II to initiate transcription. One strand of the DNA is consequently cleaved by ERCC5 and ERCC1/ ERCC4 endonucleases at positions 3' and 5' to the damage, respectively, generating an oligonucleotide containing the lesion. This oligonucleotide is displaced and allows gap repair synthesis machinery, including DNA polymerase delta and epsilon (POLE) along with several replication accessory factors, to act. Outcome effects: NER is finalized by DNA ligase (LIG1) which seals the nick in the repaired strand. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-99850faf-f3dc-4084-ab64-c81927122dbd Single-Strand Nucleotide Excision uuid-99850faf-f3dc-4084-ab64-c81927122dbd PS:CellType generic PS:Description Nucleotide excision repair (NER) requires the action of more than 30 proteins in a stepwise manner. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99850faf-f3dc-4084-ab64-c81927122dbd PS:NodeType Pathway PS:Notes Headnote: Nucleotide excision repair (NER) requires the action of more than 30 proteins in a stepwise manner that includes damage recognition, local opening of the DNA duplex around the lesion, dual incision of the damaged DNA strand, gap repair synthesis, and strand ligation. The most significant lesions are pyrimidine dimers caused by the UV component of sunlight. There are two distinct forms of NER including global genomic NER (GG-NER), which corrects damage in transcriptionally silent areas of the genome and transcription-coupled NER (TC-NER), which repairs lesions on the actively transcribed strand of the DNA. Signaling description: The two NER pathways are generally identical except in their mechanism of damage recognition. In GG-NER, the XPC protein complex is responsible for the initial detection of damaged DNA. TC-NER occurs when the transcription apparatus stops at the site of injury and does not require XPC. The following steps of both GG-NER and TC-NER proceed identically. XPA and replication factor A bind at the site of injury and further aid in damage recognition. Subsequently, ERCC3 and ERCC2 helicases, which are the components of TFIIH transcription factor, unwind the DNA duplex close to the lesion and allow RNA polymerase II to initiate transcription. One strand of the DNA is consequently cleaved by ERCC5 and ERCC1/ ERCC4 endonucleases at positions 3' and 5' to the damage, respectively, generating an oligonucleotide containing the lesion. This oligonucleotide is displaced and allows gap repair synthesis machinery, including DNA polymerase delta and epsilon (POLE) along with several replication accessory factors, to act. Outcome effects: NER is finalized by DNA ligase (LIG1) which seals the nick in the repaired strand. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99893cfb-2cb6-4ea5-a64c-89288b675959 NodeType: Pathway Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-99893cfb-2cb6-4ea5-a64c-89288b675959 Proteins Involved in Spontaneous Abortion uuid-99893cfb-2cb6-4ea5-a64c-89288b675959 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99893cfb-2cb6-4ea5-a64c-89288b675959 PS:NodeType Pathway PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99a60a68-8092-402b-b737-7009ac8e0ace NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-99a60a68-8092-402b-b737-7009ac8e0ace Chloroquine-|autophagy uuid-99a60a68-8092-402b-b737-7009ac8e0ace PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99a60a68-8092-402b-b737-7009ac8e0ace PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99d21051-033a-4a5f-b278-d6630afa8501 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-99d21051-033a-4a5f-b278-d6630afa8501 Clearance of mHTT aggregates by autophagy uuid-99d21051-033a-4a5f-b278-d6630afa8501 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99d21051-033a-4a5f-b278-d6630afa8501 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cochlear sensory hair cells Description: Noise exposure induces production of cytokines, chemokines, and cell adhesion molecules in the inner ear cell and recruitment of inflammatory cells into the cochlear. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99dd14f9-7f52-4fe6-8354-619aa002691b NodeType: Pathway Notes: Headnote: Noise-induced hearing loss is the result of prolonged exposure to excessive noise that damages cochlear sensory hair cells. Signaling description: Noise exposure induces production of cytokines (TNF, IL1B, IL-6), chemokines (CCL2, CCL4, CXCL12) and cell adhesion molecules (ICAM1, PECAM1, VCAM1) in the inner ear cell and recruitment of inflammatory cells into the cochlear with subsequent cochlear cell damage. Outcome effects: NFkB and JAK2/STAT3 signaling were shown to be involved in pro-inflammatory molecules production in noise-induced hearing loss. Organ: cochlea Organ: ear Organ_System: sensory system PMID: 16376312 PMID: 19185019 PMID: 19285117 PMID: 25275304 PMID: 25852546 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-99dd14f9-7f52-4fe6-8354-619aa002691b Cochlear Inflammation (Noise-Induced) uuid-99dd14f9-7f52-4fe6-8354-619aa002691b PS:CellType cochlear sensory hair cells PS:Description Noise exposure induces production of cytokines, chemokines, and cell adhesion molecules in the inner ear cell and recruitment of inflammatory cells into the cochlear. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99dd14f9-7f52-4fe6-8354-619aa002691b PS:NodeType Pathway PS:Notes Headnote: Noise-induced hearing loss is the result of prolonged exposure to excessive noise that damages cochlear sensory hair cells. Signaling description: Noise exposure induces production of cytokines (TNF, IL1B, IL-6), chemokines (CCL2, CCL4, CXCL12) and cell adhesion molecules (ICAM1, PECAM1, VCAM1) in the inner ear cell and recruitment of inflammatory cells into the cochlear with subsequent cochlear cell damage. Outcome effects: NFkB and JAK2/STAT3 signaling were shown to be involved in pro-inflammatory molecules production in noise-induced hearing loss. PS:Organ cochlea PS:Organ ear PS:Organ_System sensory system PS:PMID 16376312 PS:PMID 19185019 PS:PMID 19285117 PS:PMID 25275304 PS:PMID 25852546 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99e7fc45-f9c0-4848-89ef-424b0df01cc3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-99e7fc45-f9c0-4848-89ef-424b0df01cc3 Circadian rhythm deregulation in DMD uuid-99e7fc45-f9c0-4848-89ef-424b0df01cc3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99e7fc45-f9c0-4848-89ef-424b0df01cc3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99f807e4-7b1f-4e68-98e4-bdfec46736ff NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-99f807e4-7b1f-4e68-98e4-bdfec46736ff AREG -> NCOR2 Expression Targets uuid-99f807e4-7b1f-4e68-98e4-bdfec46736ff PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99f807e4-7b1f-4e68-98e4-bdfec46736ff PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: eosinophil Description: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99fd065b-c196-405e-a60c-06650b43022f NodeType: Pathway Notes: Headnote: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. In healthy humans, eosinophils comprise 1-6% of all white blood cells. Eosinophils circulate in the blood for several hours, however in lung, skin, and several other organs, eosinophils appear only in the case of disease such as allergy or helminth invasion and survive up to 12 days. The products of eosinophil degranulation are toxic to parasites and decrease the intensity of allergic reactions. Signaling description: The maturation of eosinophils generally occurs in bone marrow, but can also take place in the spleen. The translocation of eosinophils from bone marrow to their site of action results from the participation of specific chemokines including CCL11, CCL24, and CCL5. They bind to CCR3 receptor which activates migration, degranulation, and the synthesis of cytokines in eosinophils via a G-protein-dependent mechanism. Degranulation and chemotaxis involve extensive rearrangement of the actin cytoskeleton. The precise mechanism of signaling that leads to remodeling of the cytoskeleton in eosinophils is unknown. The key players in this process are small Rho family of GTPases including RHOA and their effector kinases, ROCK1 and ROCK2, which cause an increase in calcium (Ca2+) levels under the influence of CCR3 ligands. Ligand-bound CCR3 causes activation of MAPK1/MAPK3. The details of MAPK activation signaling are not well established, but it includes RAC1, CDC42, and PAK1 proteins. The activation of MAPK1/MAPK3 pathway mediates the release of arachidonic acid which contributes to the secretion of lipid mediators and leads to inflammatory responses. The additional chemoattractants and activators of eosinophils in inflammation include LTB4, platelet-activating factor, and PGD2. Other cytokines, chemokines, small molecules, and inflammatory mediators also activate eosinophils but to a much lesser extent. During inflammation, the first interaction of circulating granulocytes occurs with the inflamed vascular endothelium of blood vessels. VCAM1, MADCAM1, and CD48, which are expressed on the endothelium, mediate activation through the interaction with alpha4beta7 integrin and CD244 on eosinophils. Similar to other granulocytes, eosinophils are activated by a signal from IgE. Eosinophils express FCER2, which is a Ca2+-dependent lectin receptor with less affinity to IgE as compared to FCER1. Eosinophil expression of FCER1 is minimal and does not activate eosinophils. FCER2 activation pathways lead to degranulation, release of leukotrienes, and cytokine synthesis. An increase in Ca2+ also leads to the synthesis of arachidonic acid and lysophospholipid, which support the fusion of granules with membranes and the release of their content. Eosinophils also express immunoglobulin receptors for IgG (FCGR2B and FCGR2A) and IgA (FCAR). When activated by IgG, FCGR2B receptor appears to be the natural inhibitor of eosinophil function. SIGLEC8 is another example of eosinophil function control. SIGLEC8 is selectively expressed on human eosinophils at a high level and mediates eosinophil apoptosis. SIGLEC8-induced eosinophil death is enhanced by IL5 and CSF2 cytokines. The crosslinking of SIGLEC8 results in the profound inhibition of IgE receptor-triggered histamine and PGD2 release, but interestingly not the release of other newly formed mediators such as cytokines. The exact biochemical identity of the natural tissue ligands for SIGLEC8 and its signaling in eosinophils remains unknown. The expression of complement receptors (CR1, CR3, and CD88) and toll-like receptors (TLR7/8) on eosinophils exist but are not presented on this pathway. Outcome effects: Upon activation, eosinophils release the content of their granules at the site of inflammation. PRG2, RNASE3, EPX, and RNASE2 proteins, which are specific for eosinophils, are the enzymes directly implicated in cell damage that possess neurotoxic, helminthotoxic, and ribonucleolytic act Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-99fd065b-c196-405e-a60c-06650b43022f Eosinophil Activation uuid-99fd065b-c196-405e-a60c-06650b43022f PS:CellType eosinophil PS:Description Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-99fd065b-c196-405e-a60c-06650b43022f PS:NodeType Pathway PS:Notes Headnote: Eosinophils belong to a subtype of leukocytes that contain granules known as granulocytes. In healthy humans, eosinophils comprise 1-6% of all white blood cells. Eosinophils circulate in the blood for several hours, however in lung, skin, and several other organs, eosinophils appear only in the case of disease such as allergy or helminth invasion and survive up to 12 days. The products of eosinophil degranulation are toxic to parasites and decrease the intensity of allergic reactions. Signaling description: The maturation of eosinophils generally occurs in bone marrow, but can also take place in the spleen. The translocation of eosinophils from bone marrow to their site of action results from the participation of specific chemokines including CCL11, CCL24, and CCL5. They bind to CCR3 receptor which activates migration, degranulation, and the synthesis of cytokines in eosinophils via a G-protein-dependent mechanism. Degranulation and chemotaxis involve extensive rearrangement of the actin cytoskeleton. The precise mechanism of signaling that leads to remodeling of the cytoskeleton in eosinophils is unknown. The key players in this process are small Rho family of GTPases including RHOA and their effector kinases, ROCK1 and ROCK2, which cause an increase in calcium (Ca2+) levels under the influence of CCR3 ligands. Ligand-bound CCR3 causes activation of MAPK1/MAPK3. The details of MAPK activation signaling are not well established, but it includes RAC1, CDC42, and PAK1 proteins. The activation of MAPK1/MAPK3 pathway mediates the release of arachidonic acid which contributes to the secretion of lipid mediators and leads to inflammatory responses. The additional chemoattractants and activators of eosinophils in inflammation include LTB4, platelet-activating factor, and PGD2. Other cytokines, chemokines, small molecules, and inflammatory mediators also activate eosinophils but to a much lesser extent. During inflammation, the first interaction of circulating granulocytes occurs with the inflamed vascular endothelium of blood vessels. VCAM1, MADCAM1, and CD48, which are expressed on the endothelium, mediate activation through the interaction with alpha4beta7 integrin and CD244 on eosinophils. Similar to other granulocytes, eosinophils are activated by a signal from IgE. Eosinophils express FCER2, which is a Ca2+-dependent lectin receptor with less affinity to IgE as compared to FCER1. Eosinophil expression of FCER1 is minimal and does not activate eosinophils. FCER2 activation pathways lead to degranulation, release of leukotrienes, and cytokine synthesis. An increase in Ca2+ also leads to the synthesis of arachidonic acid and lysophospholipid, which support the fusion of granules with membranes and the release of their content. Eosinophils also express immunoglobulin receptors for IgG (FCGR2B and FCGR2A) and IgA (FCAR). When activated by IgG, FCGR2B receptor appears to be the natural inhibitor of eosinophil function. SIGLEC8 is another example of eosinophil function control. SIGLEC8 is selectively expressed on human eosinophils at a high level and mediates eosinophil apoptosis. SIGLEC8-induced eosinophil death is enhanced by IL5 and CSF2 cytokines. The crosslinking of SIGLEC8 results in the profound inhibition of IgE receptor-triggered histamine and PGD2 release, but interestingly not the release of other newly formed mediators such as cytokines. The exact biochemical identity of the natural tissue ligands for SIGLEC8 and its signaling in eosinophils remains unknown. The expression of complement receptors (CR1, CR3, and CD88) and toll-like receptors (TLR7/8) on eosinophils exist but are not presented on this pathway. Outcome effects: Upon activation, eosinophils release the content of their granules at the site of inflammation. PRG2, RNASE3, EPX, and RNASE2 proteins, which are specific for eosinophils, are the enzymes directly implicated in cell damage that possess neurotoxic, helminthotoxic, and ribonucleolytic act PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: Many proteins mutated in retinitis pigmentosa normally take part in visual cycle, including RHO, RDH5/12, LRAT, RPE65, RGR, ABCA4, RBP3, and RLBP1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a23d0b1-7cd8-46db-a5c0-6933b81f1a23 NodeType: Pathway Notes: Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Over 50 genes have been associated with RP to date, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. Many proteins mutated in RP normally take part either in phototransduction or in retinol metabolism (visual cycle). Disease causative proteins implicated in visual cycle include rhodopsin (RHO), retinol dehydrogenases 5 and 12 (RDH5/12), lecithin retinol acyltransferase (LRAT), retinal pigment epithelium-specific protein 65kDa (RPE65), non-photoreceptor opsin (RGR), and transporting proteins (ABCA4, RBP3, and RLBP1). Outcome effects: The apoptosis of photoreceptors is a common event in retinal degeneration independently of implicated mutated genes, although the triggering signals leading to retinal cell apoptosis remain largely unknown. Mutated proteins: Mutated gene is shown in white-out style. Organ: Retina Organ: eye Organ_System: sensory system PMID: 16968212 PMID: 20435355 PMID: 21447403 PMID: 23905688 PMID: 24702842 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9a23d0b1-7cd8-46db-a5c0-6933b81f1a23 Rod Visual Cycle Impairment in Retinitis pigmentosa uuid-9a23d0b1-7cd8-46db-a5c0-6933b81f1a23 PS:CellType retina cell PS:Description Many proteins mutated in retinitis pigmentosa normally take part in visual cycle, including RHO, RDH5/12, LRAT, RPE65, RGR, ABCA4, RBP3, and RLBP1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a23d0b1-7cd8-46db-a5c0-6933b81f1a23 PS:NodeType Pathway PS:Notes Headnote: Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities in the photoreceptors (rods and cones) or retinal pigment epithelium, which lead to progressive visual loss. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. RP may occur as part of a syndrome as in Usher syndrome and Bardet-Biedl syndrome. Signaling description: Over 50 genes have been associated with RP to date, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. Many proteins mutated in RP normally take part either in phototransduction or in retinol metabolism (visual cycle). Disease causative proteins implicated in visual cycle include rhodopsin (RHO), retinol dehydrogenases 5 and 12 (RDH5/12), lecithin retinol acyltransferase (LRAT), retinal pigment epithelium-specific protein 65kDa (RPE65), non-photoreceptor opsin (RGR), and transporting proteins (ABCA4, RBP3, and RLBP1). Outcome effects: The apoptosis of photoreceptors is a common event in retinal degeneration independently of implicated mutated genes, although the triggering signals leading to retinal cell apoptosis remain largely unknown. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 16968212 PS:PMID 20435355 PS:PMID 21447403 PS:PMID 23905688 PS:PMID 24702842 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a35eec7-07a3-4204-8562-121e263fb5a6 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-9a35eec7-07a3-4204-8562-121e263fb5a6 TGF-beta Receptors Family -> Expression Targets in Lymphoid System and Blood uuid-9a35eec7-07a3-4204-8562-121e263fb5a6 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a35eec7-07a3-4204-8562-121e263fb5a6 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a365949-6b26-4b45-8130-d6d4a90e22c5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-9a365949-6b26-4b45-8130-d6d4a90e22c5 GH -+>acute IR uuid-9a365949-6b26-4b45-8130-d6d4a90e22c5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a365949-6b26-4b45-8130-d6d4a90e22c5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a4d615b-e6e7-4f3a-849f-530311be158d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-9a4d615b-e6e7-4f3a-849f-530311be158d MSTN-IGF1 Signaling in Muscles Growth uuid-9a4d615b-e6e7-4f3a-849f-530311be158d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a4d615b-e6e7-4f3a-849f-530311be158d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a4ea129-d1ed-4919-a668-96ac8072271a NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-9a4ea129-d1ed-4919-a668-96ac8072271a P2RY2/12/13/14 -> N-Type Calcium Channel uuid-9a4ea129-d1ed-4919-a668-96ac8072271a PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a4ea129-d1ed-4919-a668-96ac8072271a PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a6f6aff-b9cf-49ca-86bf-95bd76da442d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-9a6f6aff-b9cf-49ca-86bf-95bd76da442d HTT-|C/EBP-alpha in blood cells and macrophages uuid-9a6f6aff-b9cf-49ca-86bf-95bd76da442d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a6f6aff-b9cf-49ca-86bf-95bd76da442d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: The endothelium produces vasoconstrictors and the one which has attracted recent interest in Raynaud Disease (RD) is endothelin-1 (EDN1). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a8f7fc9-bafe-4651-a346-aca7b3b4debd NodeType: Pathway Notes: Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Among the the vasoconstrictors produced by the endothelium the one which has been extensively studied recently with regard to Raynaud Disease (RD) is endothelin-1 (EDN1). EDN1 is an extremely potent vasoconstrictor and acts locally by binding to the surface of smooth muscle cells and acts on the vascular endothelium itself in an autocrine manner. EDN1 signaling is mediated by two transmembrane G-protein-coupled receptors (EDNRA and EDNRB) with different binding affinities and physiologic effects. EDNRA receptors are expressed on vascular smooth muscle cells and mediate primarily vasoconstriction; whereas, EDNRB receptors expressed on endothelial cells mediate vasodilatation, and those expressed on smooth muscle cells, conversly, mediate vasoconstriction. Cold exposure initiates cutaneous vasoconstriction through a reflex increase in sympathetic nerve activity and through a direct action on the blood vessel, which enhances the sympathetic constriction. Norepinephrine is the major sympathetic neurotransmitter, which initiates cutaneous vasoconstriction by activating two distinct families of receptors, namely the alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle (VSM) cells. At the same time, cold exposure amplifies constriction mediated by alpha 2-adrenoceptors, while simultaneously reducing the activity of alpha 1-adrenoceptors. Although alpha 2-adrenoceptors represent a family of three different subtypes (a2A, a2B, and a2C), only one subtype, the a2C-adrenoceptor (ADRA2C), appears to be 'thermosensitive'. In contrast to the a2A-adrenoceptors and a2B-adrenoceptors, which are directed to the plasma membrane, ADRA2C is predominantly localized to the ER/Golgi compartments. Cold causes a remarkable functional and spatial rescue of ADRA2C from the trans-Golgi to the cell surface, where they can respond to stimulation. Immediately upon cooling, there is an increased generation of reactive oxygen species (ROS) from VSM mitochondria in cutaneous arteries. This represents the earliest detectable cold-induced response in cutaneous arteries, suggesting that the mitochondria may be the 'thermosensor' responsible for initiating cold-induced vasoconstriction in cutaneous blood vessels. These mitochondrial ROS do not appear to be pathogenic, but instead activate the novel REDOX signaling through the RhoA/Rho kinase (ROCK) pathway. RHOA is a member of the Ras family of small GTP-binding proteins and plays a central role in regulating actin myosin-dependent processes in VSMs including contractility and motility. Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. NO is synthesized from L-arginine by NO synthase (NOS) and three main isoforms of NOS have been identified. In patients with Raynaud Disease (RD), NO production by NOS3 in endothelial cells is decreased. Outcome effects: Reduced NOS3 expression and microcirculatory dysfunction contribute to the development of RD. NOS3 levels are controlled by NOS inhibitor asymmetric dimethylarginine (ADMA). There is evidence to indicate increased circulatory levels of ADMA in the serum of RD patients, suggesting NOS reduction later on in the disease. Further, S-nitrosylation of the ADMA regulating enzyme dimethylarginine dimethylaminohydrolase (DDAH) diminishes DDAH activity and leads to an accumulation of ADMA. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ: bone Organ_System: musculoskeletal system PMID: 17644575 PMID: 18329534 PMID: 22782008 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage urn:agi-pathway:uuid-9a8f7fc9-bafe-4651-a346-aca7b3b4debd Vascular Reactivity in Raynaud Disease uuid-9a8f7fc9-bafe-4651-a346-aca7b3b4debd PS:CellType vascular smooth muscle cell PS:Description The endothelium produces vasoconstrictors and the one which has attracted recent interest in Raynaud Disease (RD) is endothelin-1 (EDN1). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9a8f7fc9-bafe-4651-a346-aca7b3b4debd PS:NodeType Pathway PS:Notes Headnote: Raynaud's disease is a rare disorder in which cold-induced constriction of cutaneous arteries causes episodes of reduced blood flow in the affected areas of the body, typically the fingers, and less commonly the toes. Women are more commonly affected than men. Signaling description: Among the the vasoconstrictors produced by the endothelium the one which has been extensively studied recently with regard to Raynaud Disease (RD) is endothelin-1 (EDN1). EDN1 is an extremely potent vasoconstrictor and acts locally by binding to the surface of smooth muscle cells and acts on the vascular endothelium itself in an autocrine manner. EDN1 signaling is mediated by two transmembrane G-protein-coupled receptors (EDNRA and EDNRB) with different binding affinities and physiologic effects. EDNRA receptors are expressed on vascular smooth muscle cells and mediate primarily vasoconstriction; whereas, EDNRB receptors expressed on endothelial cells mediate vasodilatation, and those expressed on smooth muscle cells, conversly, mediate vasoconstriction. Cold exposure initiates cutaneous vasoconstriction through a reflex increase in sympathetic nerve activity and through a direct action on the blood vessel, which enhances the sympathetic constriction. Norepinephrine is the major sympathetic neurotransmitter, which initiates cutaneous vasoconstriction by activating two distinct families of receptors, namely the alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle (VSM) cells. At the same time, cold exposure amplifies constriction mediated by alpha 2-adrenoceptors, while simultaneously reducing the activity of alpha 1-adrenoceptors. Although alpha 2-adrenoceptors represent a family of three different subtypes (a2A, a2B, and a2C), only one subtype, the a2C-adrenoceptor (ADRA2C), appears to be 'thermosensitive'. In contrast to the a2A-adrenoceptors and a2B-adrenoceptors, which are directed to the plasma membrane, ADRA2C is predominantly localized to the ER/Golgi compartments. Cold causes a remarkable functional and spatial rescue of ADRA2C from the trans-Golgi to the cell surface, where they can respond to stimulation. Immediately upon cooling, there is an increased generation of reactive oxygen species (ROS) from VSM mitochondria in cutaneous arteries. This represents the earliest detectable cold-induced response in cutaneous arteries, suggesting that the mitochondria may be the 'thermosensor' responsible for initiating cold-induced vasoconstriction in cutaneous blood vessels. These mitochondrial ROS do not appear to be pathogenic, but instead activate the novel REDOX signaling through the RhoA/Rho kinase (ROCK) pathway. RHOA is a member of the Ras family of small GTP-binding proteins and plays a central role in regulating actin myosin-dependent processes in VSMs including contractility and motility. Nitric oxide (NO), a free radical, is an important physiological signaling molecule, potent vasodilator, and mediator of oxidative stress. NO is synthesized from L-arginine by NO synthase (NOS) and three main isoforms of NOS have been identified. In patients with Raynaud Disease (RD), NO production by NOS3 in endothelial cells is decreased. Outcome effects: Reduced NOS3 expression and microcirculatory dysfunction contribute to the development of RD. NOS3 levels are controlled by NOS inhibitor asymmetric dimethylarginine (ADMA). There is evidence to indicate increased circulatory levels of ADMA in the serum of RD patients, suggesting NOS reduction later on in the disease. Further, S-nitrosylation of the ADMA regulating enzyme dimethylarginine dimethylaminohydrolase (DDAH) diminishes DDAH activity and leads to an accumulation of ADMA. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ bone PS:Organ_System musculoskeletal system PS:PMID 17644575 PS:PMID 18329534 PS:PMID 22782008 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: This pathway illustrates the processes that occur in neurons on late stages of vasospasm. The result of chronic vasoconstriction lasting several days after SAH is energy and oxygen starvation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9aacbbc8-f9c7-4b1e-8753-e856824e7481 NodeType: Pathway Notes: Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. The chronic vasoconstriction, which lasts several days following SAH results in energy and oxygen (O2) starvation. Outcome effects: The O2 starvation leads to an ATP deficiency, which in turn inhibits ion pumps, primarily the Na+/K+-exchanging ATPase. The resulting misbalance between K+ and Na+ ions results in uncontrolled neuronal necrosis. In addition, there are other vital processes activated by O2 starvation in cells such as the appearance of H2O2 and a decrease of ATP synthesis. The products of neuronal necrosis lead to vasoconstriction of adjacent blood vessels, which expands the injury. The death of neurons occurs adjacent to SAH lesions in the late stages of vasospasm. The extent of necrosis is directly correlated to the severity of SAH. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 15795160 PMID: 23050638 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-9aacbbc8-f9c7-4b1e-8753-e856824e7481 Neurons Necrosis Caused by Energy Deficiency uuid-9aacbbc8-f9c7-4b1e-8753-e856824e7481 PS:CellType neuron PS:Description This pathway illustrates the processes that occur in neurons on late stages of vasospasm. The result of chronic vasoconstriction lasting several days after SAH is energy and oxygen starvation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9aacbbc8-f9c7-4b1e-8753-e856824e7481 PS:NodeType Pathway PS:Notes Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. The chronic vasoconstriction, which lasts several days following SAH results in energy and oxygen (O2) starvation. Outcome effects: The O2 starvation leads to an ATP deficiency, which in turn inhibits ion pumps, primarily the Na+/K+-exchanging ATPase. The resulting misbalance between K+ and Na+ ions results in uncontrolled neuronal necrosis. In addition, there are other vital processes activated by O2 starvation in cells such as the appearance of H2O2 and a decrease of ATP synthesis. The products of neuronal necrosis lead to vasoconstriction of adjacent blood vessels, which expands the injury. The death of neurons occurs adjacent to SAH lesions in the late stages of vasospasm. The extent of necrosis is directly correlated to the severity of SAH. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 15795160 PS:PMID 23050638 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neutrophil Description: Airway neutrophilia is one of the hallmarks of severe asthma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ad47826-61c2-4c4e-9948-911873a14104 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Airway neutrophilia is one of the hallmarks of severe asthma. Signaling description: In vitro studies and mouse models show that IL17F is able to act upon eosinophils to promote neutrophil activation. The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. IL17F is expressed in activated CD4 T-cells, basophils, and mast cells, the three major cell types involved in allergic airway inflammation. In addition, bronchial epithelial cells are a novel cell source of IL17F, which they produce in response to IL33. Outcome effects: The I17RA and IL17RC heterodimer recruits TRAF6, leading to the activation of MAP3K7. The Raf1-MEK1/2-ERK1/2-p90RSK/MSK1-CREB is the central signaling pathway activated by I17RA and IL17RC. On the other hand, IL17F also activates transcriptional factors such as NF-?B. Synergistic effects on eosinophil release of CXCL1, IL-8, and CCL4 were observed during the combined treatment by IL17F and IL23. These effects were dose-dependently enhanced by IL-23, but not IL-17F. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16600024 PMID: 20565710 PMID: 24647471 PMID: 24829928 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9ad47826-61c2-4c4e-9948-911873a14104 Il17 Signaling Related Neutrophilia in Asthma uuid-9ad47826-61c2-4c4e-9948-911873a14104 PS:CellType neutrophil PS:Description Airway neutrophilia is one of the hallmarks of severe asthma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ad47826-61c2-4c4e-9948-911873a14104 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Airway neutrophilia is one of the hallmarks of severe asthma. Signaling description: In vitro studies and mouse models show that IL17F is able to act upon eosinophils to promote neutrophil activation. The asthmatic patients have a significantly higher level of serum IL17F protein as compared to that of healthy subjects. IL17F is expressed in activated CD4 T-cells, basophils, and mast cells, the three major cell types involved in allergic airway inflammation. In addition, bronchial epithelial cells are a novel cell source of IL17F, which they produce in response to IL33. Outcome effects: The I17RA and IL17RC heterodimer recruits TRAF6, leading to the activation of MAP3K7. The Raf1-MEK1/2-ERK1/2-p90RSK/MSK1-CREB is the central signaling pathway activated by I17RA and IL17RC. On the other hand, IL17F also activates transcriptional factors such as NF-?B. Synergistic effects on eosinophil release of CXCL1, IL-8, and CCL4 were observed during the combined treatment by IL17F and IL23. These effects were dose-dependently enhanced by IL-23, but not IL-17F. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16600024 PS:PMID 20565710 PS:PMID 24647471 PS:PMID 24829928 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: erythrocyte Description: Chronic hereditary or acquired hemolytic anemias such as sickle cell disease, thalassemia intermedia, paroxysmal nocturnal hemoglobinuria, and other hemoglobinopathies. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9aebd94f-188a-456a-b114-dfdc6c798499 NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: Chronic hereditary or acquired hemolytic anemias such as sickle cell disease, thalassemia intermedia, paroxysmal nocturnal hemoglobinuria, and other hemoglobinopathies or red blood cell membranopathies are accompanied by PAH development. A central mechanism underlying this disease is intravascular hemolysis, which releases free hemoglobin into plasma. Outcome effects: Free hemoglobin reacts with and catabolizes nitric oxide (NO) at a very high rate: more than 1000 times faster than hemoglobin within the red blood cell. This reaction oxidizes NO to nitrate and inhibits its ability to vasodilate. In addition to the release of hemoglobin, hemolysis releases red blood cell arginase 1 (ARG1), an enzyme that metabolizes arginine to L-ornithine, reducing its availability for de novo NO synthesis. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. Organ: lung Organ_System: cardiovascular system PMID: 15811985 PMID: 19020327 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9aebd94f-188a-456a-b114-dfdc6c798499 Hemolysis Associated Pulmonary Hypertension uuid-9aebd94f-188a-456a-b114-dfdc6c798499 PS:CellType endothelial cell PS:CellType erythrocyte PS:Description Chronic hereditary or acquired hemolytic anemias such as sickle cell disease, thalassemia intermedia, paroxysmal nocturnal hemoglobinuria, and other hemoglobinopathies. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9aebd94f-188a-456a-b114-dfdc6c798499 PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: Chronic hereditary or acquired hemolytic anemias such as sickle cell disease, thalassemia intermedia, paroxysmal nocturnal hemoglobinuria, and other hemoglobinopathies or red blood cell membranopathies are accompanied by PAH development. A central mechanism underlying this disease is intravascular hemolysis, which releases free hemoglobin into plasma. Outcome effects: Free hemoglobin reacts with and catabolizes nitric oxide (NO) at a very high rate: more than 1000 times faster than hemoglobin within the red blood cell. This reaction oxidizes NO to nitrate and inhibits its ability to vasodilate. In addition to the release of hemoglobin, hemolysis releases red blood cell arginase 1 (ARG1), an enzyme that metabolizes arginine to L-ornithine, reducing its availability for de novo NO synthesis. Highlighted proteins: Entities with increased levels or activity are highlighted in red, and entities with decreased levels or activity are highlighted in blue. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 15811985 PS:PMID 19020327 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b1e4f16-b2e1-4515-a909-5ea0004c1f42 NodeType: Pathway Notes: Headnote: Congenital hearing loss is a hearing loss present at birth or developed later due to genetic causes. Multiple mutations in genes, involved in cation transport in the inner ear, are found in congenital syndromic and non-syndromic deafness. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. Mutations in the PCDH15, LHFPL5, TMIE, TMC1 are associated with different forms of congenital deafness. Mutations in the PCDH15 gene are responsible for non-syndromic hearing loss (DFNB23) and Usher syndrome type I (USH1F). TMIE mutation is associated with autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. TMC1 mutation is associated with progressive postlingual hearing loss and profound prelingual deafness. Outcome effects: K+ exits from the hair cells through the KCNQ4 and KCNMA1 channels. KCNQ4 mutations are found in patients with nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. K+ is then taken up via KCNJ10 by supporting Deiters cells and exported out by SLC12A6 and SLC12A7. Mutations in KCNJ10 cause the autosomal recessive EAST syndrome characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy. The knockout of either SLC12A6 or SLC12A7 genes causes deafness in mice. K+ passes fibrocytes of the lateral wall through gap junctions. At least three connexin genes, GJB2, GJB3 and GJB6, all of which are expressed in this gap junction system, are involved in human genetic deafness. Mutations in GJB2 are responsible for as much as 50% of pre-lingual, recessive deafness. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. Further, K+ exits through apical channels KCNQ1 and KCNE1 back to the endolymph. Mutations in Barttin (BSND) have been associated with Bartter syndrome with sensorineural deafness (Bartter syndrome type IV). Barttin is thought to be an accessory subunit of a chloride channel and if mutated disrupts the activity of CLCNKA and CLCNKB. Finally, mutations in the KCNE1 and KCNQ1 genes cause Jervell and Lange-Nielsen syndrome (long QT syndrome, associated with bilateral sensorineural hearing loss). Mutated proteins: Mutated genes are shown in white-out style. Organ: ear Organ_System: sensory system PMID: 16990454 PMID: 17670895 PMID: 17892302 PMID: 18776122 PMID: 18797286 PMID: 24480364 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9b1e4f16-b2e1-4515-a909-5ea0004c1f42 Potassium Cycling in the Inner Ear (Congenital Deafness) uuid-9b1e4f16-b2e1-4515-a909-5ea0004c1f42 PS:CellType sensory hair cell PS:Description Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b1e4f16-b2e1-4515-a909-5ea0004c1f42 PS:NodeType Pathway PS:Notes Headnote: Congenital hearing loss is a hearing loss present at birth or developed later due to genetic causes. Multiple mutations in genes, involved in cation transport in the inner ear, are found in congenital syndromic and non-syndromic deafness. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. Mutations in the PCDH15, LHFPL5, TMIE, TMC1 are associated with different forms of congenital deafness. Mutations in the PCDH15 gene are responsible for non-syndromic hearing loss (DFNB23) and Usher syndrome type I (USH1F). TMIE mutation is associated with autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. TMC1 mutation is associated with progressive postlingual hearing loss and profound prelingual deafness. Outcome effects: K+ exits from the hair cells through the KCNQ4 and KCNMA1 channels. KCNQ4 mutations are found in patients with nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. K+ is then taken up via KCNJ10 by supporting Deiters cells and exported out by SLC12A6 and SLC12A7. Mutations in KCNJ10 cause the autosomal recessive EAST syndrome characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy. The knockout of either SLC12A6 or SLC12A7 genes causes deafness in mice. K+ passes fibrocytes of the lateral wall through gap junctions. At least three connexin genes, GJB2, GJB3 and GJB6, all of which are expressed in this gap junction system, are involved in human genetic deafness. Mutations in GJB2 are responsible for as much as 50% of pre-lingual, recessive deafness. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. Further, K+ exits through apical channels KCNQ1 and KCNE1 back to the endolymph. Mutations in Barttin (BSND) have been associated with Bartter syndrome with sensorineural deafness (Bartter syndrome type IV). Barttin is thought to be an accessory subunit of a chloride channel and if mutated disrupts the activity of CLCNKA and CLCNKB. Finally, mutations in the KCNE1 and KCNQ1 genes cause Jervell and Lange-Nielsen syndrome (long QT syndrome, associated with bilateral sensorineural hearing loss). Mutated proteins: Mutated genes are shown in white-out style. PS:Organ ear PS:Organ_System sensory system PS:PMID 16990454 PS:PMID 17670895 PS:PMID 17892302 PS:PMID 18776122 PS:PMID 18797286 PS:PMID 24480364 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b43ba9f-77ac-49aa-aa14-ccd6fdc9e2c0 NodeType: Pathway Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-9b43ba9f-77ac-49aa-aa14-ccd6fdc9e2c0 Proteins Involved in Breast Cancer Related to WNT Signaling Pathway uuid-9b43ba9f-77ac-49aa-aa14-ccd6fdc9e2c0 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b43ba9f-77ac-49aa-aa14-ccd6fdc9e2c0 PS:NodeType Pathway PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Dihydrotestosterone (DHT) is a key androgen hormone. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b4ffe2d-7ca1-4bf3-b3a7-ff8e6411e12f NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Dihydrotestosterone (DHT) is a key androgen hormone. Androgens (DHT, DHEA (dehydroepiandrosterone), and testosterone) competitively bind the androgen receptor (AR). The androgen-AR complex stimulates androgen-regulated processes such as cell proliferation, cell differentiation, and transcription of androgen-regulated genes. The first step of steroidogenesis is the conversion of cholesterol to pregnenolone by CYP11A1, which is then converted to progesterone via hydroxy-delta-5-steroid dehydrogenase (HSD3B2). CYP17A1 catalyzes the 17alpha-hydroxylation of pregnenolone to 17hydroxy-pregnenolone and progesterone to 17alpha-hydroxy-progesterone. 17hydroxy-pregnenolone is then catalyzed by CYP17A1 to DHEA and 17alpha-hydroxy-progesterone is catalyzed by CYP17A1 to androstenedione. Hydroxy-delta-5-steroid dehydrogenases (HSD3B1,2) metabolize DHEA to androstenedione. Testosterone is synthesized by hydroxysteroid (17-beta) dehydrogenase 1,2,3 (HSD17B1,2,3) and aldo-keto reductase (AKR1C3,4) from androstenedione. DHT is formed by the conversion of testosterone by the enzyme 5-a-reductase (SRD5A1,2) in the prostate, testis, adrenal glands, and hair follicles. Outcome effects: DHT is presumed to play a causative role in the initiation and progression of prostate cancer. Consequently, the androgenic pathway has become an important target for treatment. Organ: prostate Organ_System: urinary tract PMID: 22503713 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9b4ffe2d-7ca1-4bf3-b3a7-ff8e6411e12f Dihydrotestosterone Biosynthesis in Prostate Cancer uuid-9b4ffe2d-7ca1-4bf3-b3a7-ff8e6411e12f PS:CellType cancer cell PS:Description Dihydrotestosterone (DHT) is a key androgen hormone. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b4ffe2d-7ca1-4bf3-b3a7-ff8e6411e12f PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Dihydrotestosterone (DHT) is a key androgen hormone. Androgens (DHT, DHEA (dehydroepiandrosterone), and testosterone) competitively bind the androgen receptor (AR). The androgen-AR complex stimulates androgen-regulated processes such as cell proliferation, cell differentiation, and transcription of androgen-regulated genes. The first step of steroidogenesis is the conversion of cholesterol to pregnenolone by CYP11A1, which is then converted to progesterone via hydroxy-delta-5-steroid dehydrogenase (HSD3B2). CYP17A1 catalyzes the 17alpha-hydroxylation of pregnenolone to 17hydroxy-pregnenolone and progesterone to 17alpha-hydroxy-progesterone. 17hydroxy-pregnenolone is then catalyzed by CYP17A1 to DHEA and 17alpha-hydroxy-progesterone is catalyzed by CYP17A1 to androstenedione. Hydroxy-delta-5-steroid dehydrogenases (HSD3B1,2) metabolize DHEA to androstenedione. Testosterone is synthesized by hydroxysteroid (17-beta) dehydrogenase 1,2,3 (HSD17B1,2,3) and aldo-keto reductase (AKR1C3,4) from androstenedione. DHT is formed by the conversion of testosterone by the enzyme 5-a-reductase (SRD5A1,2) in the prostate, testis, adrenal glands, and hair follicles. Outcome effects: DHT is presumed to play a causative role in the initiation and progression of prostate cancer. Consequently, the androgenic pathway has become an important target for treatment. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 22503713 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b5199ab-e55d-4c54-ae54-d89ea9914ec7 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9b5199ab-e55d-4c54-ae54-d89ea9914ec7 Endocannabinoid biosynthesis uuid-9b5199ab-e55d-4c54-ae54-d89ea9914ec7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b5199ab-e55d-4c54-ae54-d89ea9914ec7 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Arterial hypertension (AH) is characterized by constant high blood pressure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b547bfb-5734-45e5-ac58-4b07fa647c05 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone is a key mineralocorticoid hormone that has a fundamental role in salt and water homeostasis and blood pressure regulation. Signaling description: Aldosterone production is regulated through the continuing action of the local and systemic angiotensin II, circulating adrenocorticotropic hormone (ACTH), and serum potassium levels. All stimuli can have both immediate and continuous effects on aldosterone synthesis and release. Aldosterone synthesis itself involves an acute phase regulated by a steroidogenic acute regulatory protein (STAR), which is crucial for the transport of cholesterol mitochondria, where the biosynthesis of steroids is initiated. AGT binds AGTR1 to activate PLC, which then mediates the cleavage of PIP2 to diacylglycerol and IP3. IP3 binds ITPR1 on the endoplasmic reticulum (ER), which leads to a release calcium (Ca2+) and, thus raises cytosolic Ca2+ levels. Diacylglycerol activates PKC, which phosphorylates PRKD1, which directly phosphorylates and activates CREB1. IP3 mediates the activation of CREB1 via the MAPK pathway. Outcome effects: CREB1 activates STAR and facilitates a rapid influx of cholesterol into the mitochondria. Cholesterol is the primary precursor for steroidogenesis and aldosterone synthesis. A possible activating mutation in CYP11B2 enhances aldosterone synthesis. Adrenocorticotropic hormone (ACTH), which is synthesized from proopiomelanocortin (POMC), is able to quickly stimulate aldosterone production. ACTH binds MC2R, which activates ADCY10 via the GNAS complex. ADCY10 produces cAMP, thereby stimulating the activity of PKA, which phosphorylates and activates STAR and CREB1. Angiotensin II and ACTH rapidly increase aldosterone secretion by increasing STAR expression. The overproduction of aldosterone causes aldosteronism and leads to arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: adrenal gland Organ: brain Organ: pituitary gland Organ: zona glomerulosa Organ_System: endocrine system PMID: 21839803 PMID: 23378101 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-9b547bfb-5734-45e5-ac58-4b07fa647c05 Aldosterone Synthesis Acute Regulation uuid-9b547bfb-5734-45e5-ac58-4b07fa647c05 PS:Description Arterial hypertension (AH) is characterized by constant high blood pressure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b547bfb-5734-45e5-ac58-4b07fa647c05 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone is a key mineralocorticoid hormone that has a fundamental role in salt and water homeostasis and blood pressure regulation. Signaling description: Aldosterone production is regulated through the continuing action of the local and systemic angiotensin II, circulating adrenocorticotropic hormone (ACTH), and serum potassium levels. All stimuli can have both immediate and continuous effects on aldosterone synthesis and release. Aldosterone synthesis itself involves an acute phase regulated by a steroidogenic acute regulatory protein (STAR), which is crucial for the transport of cholesterol mitochondria, where the biosynthesis of steroids is initiated. AGT binds AGTR1 to activate PLC, which then mediates the cleavage of PIP2 to diacylglycerol and IP3. IP3 binds ITPR1 on the endoplasmic reticulum (ER), which leads to a release calcium (Ca2+) and, thus raises cytosolic Ca2+ levels. Diacylglycerol activates PKC, which phosphorylates PRKD1, which directly phosphorylates and activates CREB1. IP3 mediates the activation of CREB1 via the MAPK pathway. Outcome effects: CREB1 activates STAR and facilitates a rapid influx of cholesterol into the mitochondria. Cholesterol is the primary precursor for steroidogenesis and aldosterone synthesis. A possible activating mutation in CYP11B2 enhances aldosterone synthesis. Adrenocorticotropic hormone (ACTH), which is synthesized from proopiomelanocortin (POMC), is able to quickly stimulate aldosterone production. ACTH binds MC2R, which activates ADCY10 via the GNAS complex. ADCY10 produces cAMP, thereby stimulating the activity of PKA, which phosphorylates and activates STAR and CREB1. Angiotensin II and ACTH rapidly increase aldosterone secretion by increasing STAR expression. The overproduction of aldosterone causes aldosteronism and leads to arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ adrenal gland PS:Organ brain PS:Organ pituitary gland PS:Organ zona glomerulosa PS:Organ_System endocrine system PS:PMID 21839803 PS:PMID 23378101 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7698db-70da-4872-a883-c35edc8b0e4a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9b7698db-70da-4872-a883-c35edc8b0e4a Homogalacturonan biosynthesis template uuid-9b7698db-70da-4872-a883-c35edc8b0e4a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7698db-70da-4872-a883-c35edc8b0e4a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Overexpression of CDH2 contributes to cancer cell migration, proliferation and survival. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7877ff-6739-49f5-b316-294cee32e544 NodeType: Pathway Notes: Headnote: Upon loss of CDH1 function during epithelial to mesenchymal transition, CDH2 is highly expressed; this phenomenon is called "cadherin switch". Signaling description: Several transcription factors such as TWIST1, ZEB1/2, SNAI1/2, FOXC1/2, TCF3 up-regulate CDH2 expression in different types of cancer cells. CDH2 stimulates epithelial to mesenchymal transition through forming a complex with CTNNB1 and PTPN1. CDH2 binds to FGFR1 and activates it, which results in PI3K/AKT1, PLCG/PKC and RAF/MAPK signaling and promotion of cell survival, migration, and invasion. CDH2 also facilitates FGF2 binding to FGFR1, thus, preventing ligand-induced internalization, and, thereby, yields sustained signaling. Cleavage and shedding of the extracellular domain of CDH2 by ADAM10 can neutralize CDH2-mediated cell-cell adhesion and stimulate FGFR1 signaling in neighboring cells. Also, NCAM1 can bind FGFR1 and activate it's signaling in some types of cancer cell. SLC9A3R2 links the CDH2/ CTNNB1 complex to PDGFRB to modulate the actin cytoskeleton and regulate cell motility. CDH2 may also stimulate cell migration through binding to CTNND1 and ARHGAP35. Outcome effects: CDH2 activation is involved in cancer cell migration, proliferation and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 14964308 PMID: 20460404 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-9b7877ff-6739-49f5-b316-294cee32e544 CDH2 Activation Promotes Cancer Cell Migration and Survival uuid-9b7877ff-6739-49f5-b316-294cee32e544 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Overexpression of CDH2 contributes to cancer cell migration, proliferation and survival. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7877ff-6739-49f5-b316-294cee32e544 PS:NodeType Pathway PS:Notes Headnote: Upon loss of CDH1 function during epithelial to mesenchymal transition, CDH2 is highly expressed; this phenomenon is called "cadherin switch". Signaling description: Several transcription factors such as TWIST1, ZEB1/2, SNAI1/2, FOXC1/2, TCF3 up-regulate CDH2 expression in different types of cancer cells. CDH2 stimulates epithelial to mesenchymal transition through forming a complex with CTNNB1 and PTPN1. CDH2 binds to FGFR1 and activates it, which results in PI3K/AKT1, PLCG/PKC and RAF/MAPK signaling and promotion of cell survival, migration, and invasion. CDH2 also facilitates FGF2 binding to FGFR1, thus, preventing ligand-induced internalization, and, thereby, yields sustained signaling. Cleavage and shedding of the extracellular domain of CDH2 by ADAM10 can neutralize CDH2-mediated cell-cell adhesion and stimulate FGFR1 signaling in neighboring cells. Also, NCAM1 can bind FGFR1 and activate it's signaling in some types of cancer cell. SLC9A3R2 links the CDH2/ CTNNB1 complex to PDGFRB to modulate the actin cytoskeleton and regulate cell motility. CDH2 may also stimulate cell migration through binding to CTNND1 and ARHGAP35. Outcome effects: CDH2 activation is involved in cancer cell migration, proliferation and survival. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 14964308 PS:PMID 20460404 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: cancer cell CellType: cancer stem cell CellType: myeloid derived suppressor cell Description: Myeloid-derived suppressor cells make impact to tumor immune escape inactivating CD4+ and CD8+ T cells, NK cells and converting macrophages to M2 phenotype. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7d44a0-4bd4-4dee-9575-d45ff99d263e NodeType: Pathway Notes: Headnote: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells of myeloid origin that consists of myeloid progenitors and immature macrophages, immature granulocytes and immature dendritic cells that expands during cancer, inflammation and infection, and has a remarkable ability to suppress the activation of T-cells and natural killer (NK) cells. Signaling description: MDSCs use multiple mechanisms for T-cells inactivation, involving transport and metabolism of amino acids, production of ROS and NO and others. MDSCs produce high levels of intracellular ARG1 that catabolizes arginine and import large amounts of arginine through their SLC7A2 transporter. Consequently, they deplete their environment of arginine and limit arginine availability to T-cells. As a result, T-cells deprived of arginine are CD3z chain (CD247) deficient and arrested in the G0-G1 phase of the cell cycle (CDK4 and CCND3 are inhibited). ARG1 expression may be up-regulated by STAT3, STAT1 and STAT6. MDSCs sequestrate cysteine, an amino acid that T-cells are unable to synthesize de novo and that they require for activation. MDSCs import cysteine through SLC3A2 and SLC7A11 and they do not have any transporter for cysteine export. NOS2 is upregulated by STAT in MDSCs, leading to hyper-production of NO which suppresses T-cell function through a variety of mechanisms that involve the inhibition of JAK3 and STAT5 in T-cells, inhibition of MHC class II expression and the induction of T-cell apoptosis. STAT3 contributes to up-regulation of ROS. S100A8 and S100A9 directly bind to NCF1/2, which are crucial components of the NADPH complex. This binding potentiates NADPH oxidase activation in MDSCs, which causes increased production of ROS, leading to the observed suppressive effects on T-cells. MDSCs mediate down-regulation of L-selectin (SELL) via inhibitory effect of ADAM17. T-cells must have a SELL-high phenotype to home to lymph nodes and inflammatory sites where they encounter antigen and are activated. By down-regulating SELL on T-cells, MDSCs perturb the T-cell trafficking patterns and thereby inhibit T-cell activation. MDSCs cleave L-selectin because they constitutively express ADAM17 at their cell surface. In addition to inhibiting T-cell activation, MDSCs also affect the antitumor immunity by perturbing the innate immunity through their interactions with macrophages and natural killer (NK) cells. M1 or classically activated macrophages promote tumor regression; however, in the presence of MDSCs, macrophages are converted to an M2 or alternatively activated phenotype which enhance tumor progression. This re-polarization is a result of the cross-talk between MDSCs and macrophages which increases the production of IL10 by MDSCs and decreases macrophage production of IL12 also necessary for NK cell activation. MDSCs have an ability to promote the de novo development of FOXP3+ regulatory T (TReg) cells. The induction of TReg cells by MDSCs was found to require the activation of tumor-specific T-cells and the presence of IFNG and IL10. Outcome effects: MDSCs directly or indirectly inactivate T-cells (CD4+ and CD8+) and NK cells and lead to conversion of macrophages to the M2 phenotype. Thereby MDSCs inhibit the immune cells with antitumor functions and promote activation of pro-tumor cells. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. Organ_System: lymphatic system PMID: 17023580 PMID: 18364002 PMID: 19197294 PMID: 19342621 PMID: 20414655 PMID: 23454751 PMID: 24325346 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-9b7d44a0-4bd4-4dee-9575-d45ff99d263e Myeloid Derived Suppressor Cells in Cancer Immune Escape uuid-9b7d44a0-4bd4-4dee-9575-d45ff99d263e PS:CellType T-cell PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType myeloid derived suppressor cell PS:Description Myeloid-derived suppressor cells make impact to tumor immune escape inactivating CD4+ and CD8+ T cells, NK cells and converting macrophages to M2 phenotype. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b7d44a0-4bd4-4dee-9575-d45ff99d263e PS:NodeType Pathway PS:Notes Headnote: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells of myeloid origin that consists of myeloid progenitors and immature macrophages, immature granulocytes and immature dendritic cells that expands during cancer, inflammation and infection, and has a remarkable ability to suppress the activation of T-cells and natural killer (NK) cells. Signaling description: MDSCs use multiple mechanisms for T-cells inactivation, involving transport and metabolism of amino acids, production of ROS and NO and others. MDSCs produce high levels of intracellular ARG1 that catabolizes arginine and import large amounts of arginine through their SLC7A2 transporter. Consequently, they deplete their environment of arginine and limit arginine availability to T-cells. As a result, T-cells deprived of arginine are CD3z chain (CD247) deficient and arrested in the G0-G1 phase of the cell cycle (CDK4 and CCND3 are inhibited). ARG1 expression may be up-regulated by STAT3, STAT1 and STAT6. MDSCs sequestrate cysteine, an amino acid that T-cells are unable to synthesize de novo and that they require for activation. MDSCs import cysteine through SLC3A2 and SLC7A11 and they do not have any transporter for cysteine export. NOS2 is upregulated by STAT in MDSCs, leading to hyper-production of NO which suppresses T-cell function through a variety of mechanisms that involve the inhibition of JAK3 and STAT5 in T-cells, inhibition of MHC class II expression and the induction of T-cell apoptosis. STAT3 contributes to up-regulation of ROS. S100A8 and S100A9 directly bind to NCF1/2, which are crucial components of the NADPH complex. This binding potentiates NADPH oxidase activation in MDSCs, which causes increased production of ROS, leading to the observed suppressive effects on T-cells. MDSCs mediate down-regulation of L-selectin (SELL) via inhibitory effect of ADAM17. T-cells must have a SELL-high phenotype to home to lymph nodes and inflammatory sites where they encounter antigen and are activated. By down-regulating SELL on T-cells, MDSCs perturb the T-cell trafficking patterns and thereby inhibit T-cell activation. MDSCs cleave L-selectin because they constitutively express ADAM17 at their cell surface. In addition to inhibiting T-cell activation, MDSCs also affect the antitumor immunity by perturbing the innate immunity through their interactions with macrophages and natural killer (NK) cells. M1 or classically activated macrophages promote tumor regression; however, in the presence of MDSCs, macrophages are converted to an M2 or alternatively activated phenotype which enhance tumor progression. This re-polarization is a result of the cross-talk between MDSCs and macrophages which increases the production of IL10 by MDSCs and decreases macrophage production of IL12 also necessary for NK cell activation. MDSCs have an ability to promote the de novo development of FOXP3+ regulatory T (TReg) cells. The induction of TReg cells by MDSCs was found to require the activation of tumor-specific T-cells and the presence of IFNG and IL10. Outcome effects: MDSCs directly or indirectly inactivate T-cells (CD4+ and CD8+) and NK cells and lead to conversion of macrophages to the M2 phenotype. Thereby MDSCs inhibit the immune cells with antitumor functions and promote activation of pro-tumor cells. Highlighted proteins: Proteins with blue highlights have reduced expression/activity. Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Cancer Immune Escape" for details. PS:Organ_System lymphatic system PS:PMID 17023580 PS:PMID 18364002 PS:PMID 19197294 PS:PMID 19342621 PS:PMID 20414655 PS:PMID 23454751 PS:PMID 24325346 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b8f8a2a-2dae-47bc-b8ce-df4ca8732dbe NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9b8f8a2a-2dae-47bc-b8ce-df4ca8732dbe PTPRC -> BCL6 Expression Targets uuid-9b8f8a2a-2dae-47bc-b8ce-df4ca8732dbe PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b8f8a2a-2dae-47bc-b8ce-df4ca8732dbe PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b9f79f2-7d56-4ced-aa04-4dee9b7c2a0b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9b9f79f2-7d56-4ced-aa04-4dee9b7c2a0b IFNA1/Gq Expression Targets uuid-9b9f79f2-7d56-4ced-aa04-4dee9b7c2a0b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9b9f79f2-7d56-4ced-aa04-4dee9b7c2a0b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ba01cec-4216-43bc-bdf7-b825b5496958 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-9ba01cec-4216-43bc-bdf7-b825b5496958 ADORA1/2A -> Exocytosis uuid-9ba01cec-4216-43bc-bdf7-b825b5496958 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ba01cec-4216-43bc-bdf7-b825b5496958 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bb40f8d-fce8-4d0e-a657-07837e3be7a2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9bb40f8d-fce8-4d0e-a657-07837e3be7a2 Methyl-IAA interconversion template uuid-9bb40f8d-fce8-4d0e-a657-07837e3be7a2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bb40f8d-fce8-4d0e-a657-07837e3be7a2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bda1db9-f318-442a-b384-e4b40067cc27 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9bda1db9-f318-442a-b384-e4b40067cc27 Biomarkers in Psoriasis uuid-9bda1db9-f318-442a-b384-e4b40067cc27 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bda1db9-f318-442a-b384-e4b40067cc27 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bdf28f9-6f79-412e-9233-2230d6501df8 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-9bdf28f9-6f79-412e-9233-2230d6501df8 HRH1/3 -> Synaptic Transmission uuid-9bdf28f9-6f79-412e-9233-2230d6501df8 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bdf28f9-6f79-412e-9233-2230d6501df8 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The role of mutations in the FMR1 gene in the development of autism symptoms of Fragile X Syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9be5bc9f-9562-43d4-b4dd-2c7139c1c587 NodeType: Pathway Notes: FMR1 gene mutations are associated with the development of autism symptoms in patients with Fragile X Syndrome. Organ_System: nervous system PMID: 27672537 PMID: 27690107 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-9be5bc9f-9562-43d4-b4dd-2c7139c1c587 Fragile X Syndrome uuid-9be5bc9f-9562-43d4-b4dd-2c7139c1c587 PS:Description The role of mutations in the FMR1 gene in the development of autism symptoms of Fragile X Syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9be5bc9f-9562-43d4-b4dd-2c7139c1c587 PS:NodeType Pathway PS:Notes FMR1 gene mutations are associated with the development of autism symptoms in patients with Fragile X Syndrome. PS:Organ_System nervous system PS:PMID 27672537 PS:PMID 27690107 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Type 1 regulatory (Tr1) cells have emerged as key players in the prevention of autoimmunity. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bf30ea3-07d2-4be9-af04-b05bf735e5f2 NodeType: Pathway Notes: Headnote: Type 1 regulatory (Tr1) cells have emerged as key players in the prevention of autoimmunity. They produce high levels of the immunosuppressive IL10 and confer protection against a wide panel of autoimmune diseases. Signaling description: IL-27 has recently been identified as a differentiation factor for the generation of IL10-producing regulatory type 1 (Tr1) T-cells. Three different pathways are induced by IL27 during Tr1 cell differentiation. IL27 drives the expression of the transcription factors Maf and AHR, which bind together to transactivate the IL21 and IL10 promoters. IL21 maintains Maf and AhR expression, while IL10 is essential for the suppressive function of Tr1 cells. IL27-induced AhR, alone or with an unknown cofactor, promotes Granzyme-B (GZMB) expression that mediates the contact-dependent suppressive activity of Tr1 cells. Finally IL27 promotes TBX21 expression that results in IFNG secretion. Outcome effects: IFNG acts on DCs to enhance IL27 expression and further supports Tr1 cell differentiation. Transcription of ICOS is also induced by IL27 and promoted IL10 production. IL27 activates STAT1 and inhibits RORC expression through TBX21-dependent as well as TBX21-independent pathways. Alternatively, IL-27 can promote TBX-21expression in a STAT1 independent pathway via GADD45G. Inhibition of RORC leads to inhibition of Th17 development program. Organ: generic Organ_System: lymphatic system PMID: 19570826 PMID: 20540648 PMID: 20676092 PMID: 20676095 PMID: 21840222 PMID: 21893418 PMID: 22653785 PMID: 23504674 PMID: 23580432 PMID: 23908379 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-9bf30ea3-07d2-4be9-af04-b05bf735e5f2 AHR Signaling in Tr1 Cells Function uuid-9bf30ea3-07d2-4be9-af04-b05bf735e5f2 PS:CellType T-cell PS:Description Type 1 regulatory (Tr1) cells have emerged as key players in the prevention of autoimmunity. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bf30ea3-07d2-4be9-af04-b05bf735e5f2 PS:NodeType Pathway PS:Notes Headnote: Type 1 regulatory (Tr1) cells have emerged as key players in the prevention of autoimmunity. They produce high levels of the immunosuppressive IL10 and confer protection against a wide panel of autoimmune diseases. Signaling description: IL-27 has recently been identified as a differentiation factor for the generation of IL10-producing regulatory type 1 (Tr1) T-cells. Three different pathways are induced by IL27 during Tr1 cell differentiation. IL27 drives the expression of the transcription factors Maf and AHR, which bind together to transactivate the IL21 and IL10 promoters. IL21 maintains Maf and AhR expression, while IL10 is essential for the suppressive function of Tr1 cells. IL27-induced AhR, alone or with an unknown cofactor, promotes Granzyme-B (GZMB) expression that mediates the contact-dependent suppressive activity of Tr1 cells. Finally IL27 promotes TBX21 expression that results in IFNG secretion. Outcome effects: IFNG acts on DCs to enhance IL27 expression and further supports Tr1 cell differentiation. Transcription of ICOS is also induced by IL27 and promoted IL10 production. IL27 activates STAT1 and inhibits RORC expression through TBX21-dependent as well as TBX21-independent pathways. Alternatively, IL-27 can promote TBX-21expression in a STAT1 independent pathway via GADD45G. Inhibition of RORC leads to inhibition of Th17 development program. PS:Organ generic PS:Organ_System lymphatic system PS:PMID 19570826 PS:PMID 20540648 PS:PMID 20676092 PS:PMID 20676095 PS:PMID 21840222 PS:PMID 21893418 PS:PMID 22653785 PS:PMID 23504674 PS:PMID 23580432 PS:PMID 23908379 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bf4a9c9-d9f1-49c5-afa9-48672903ef8d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-9bf4a9c9-d9f1-49c5-afa9-48672903ef8d Gibberellin inactivation template uuid-9bf4a9c9-d9f1-49c5-afa9-48672903ef8d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9bf4a9c9-d9f1-49c5-afa9-48672903ef8d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Insulin resistance is one consequence of obesity and a hallmark of diabetes mellitus type 2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c06ecca-428f-4488-b9d0-4fb39a00203a NodeType: Pathway Notes: Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Proinflammatory cytokines IL6 and TNF are synthesized by the adipose tissue in response to a high-fat diet. IL6 induces SOCS3 overexpression via the JAK/STAT3 axis, as well as the MTOR/PRKCD/MAPK8 mechanism through PTPN11 activation. SOCS3 stops hormone signaling by direct IRS inhibition. Conversely, TNF causes the expression of PTPN1 which dephosphorylates IRS similarly preventing the spread of the signal. In addition, circulating fatty acids are elevated in obese individuals and similarly provoke the insulin resistance causing another pathological feature called hepatic steatosis or fatty liver. The fatty acids which escape oxidation are converted into triglycerides. The precursor of triglycerides, diacylglycerol can activate protein kinase C, theta (PRKCQ). The latter phosphorylates IRS1 and blocks the insulin signal transduction. Outcome effects: The disruption of hormone signaling in hepatocytes is caused by the inactivation of insulin receptor substrates (IRS1 and IRS2). The decreased levels of adiponectin (ADIPOQ) contribute to the escape of fatty acids from oxidation leading to the accumulation of triglycerides and gluconeogenesis resulting in an additional increase of glucose in the blood. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: liver Organ_System: endocrine system PMID: 10903330 PMID: 15166226 PMID: 16613757 PMID: 17512085 PMID: 18997164 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-9c06ecca-428f-4488-b9d0-4fb39a00203a Insulin Resistance in Hepatocytes uuid-9c06ecca-428f-4488-b9d0-4fb39a00203a PS:CellType hepatocyte PS:Description Insulin resistance is one consequence of obesity and a hallmark of diabetes mellitus type 2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c06ecca-428f-4488-b9d0-4fb39a00203a PS:NodeType Pathway PS:Notes Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Proinflammatory cytokines IL6 and TNF are synthesized by the adipose tissue in response to a high-fat diet. IL6 induces SOCS3 overexpression via the JAK/STAT3 axis, as well as the MTOR/PRKCD/MAPK8 mechanism through PTPN11 activation. SOCS3 stops hormone signaling by direct IRS inhibition. Conversely, TNF causes the expression of PTPN1 which dephosphorylates IRS similarly preventing the spread of the signal. In addition, circulating fatty acids are elevated in obese individuals and similarly provoke the insulin resistance causing another pathological feature called hepatic steatosis or fatty liver. The fatty acids which escape oxidation are converted into triglycerides. The precursor of triglycerides, diacylglycerol can activate protein kinase C, theta (PRKCQ). The latter phosphorylates IRS1 and blocks the insulin signal transduction. Outcome effects: The disruption of hormone signaling in hepatocytes is caused by the inactivation of insulin receptor substrates (IRS1 and IRS2). The decreased levels of adiponectin (ADIPOQ) contribute to the escape of fatty acids from oxidation leading to the accumulation of triglycerides and gluconeogenesis resulting in an additional increase of glucose in the blood. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ liver PS:Organ_System endocrine system PS:PMID 10903330 PS:PMID 15166226 PS:PMID 16613757 PS:PMID 17512085 PS:PMID 18997164 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Paneth cell CellType: dendritic cell CellType: epithelial cell CellType: macrophage Description: Crohn's disease is a condition with chronic autoimmune granulomatous inflammation of the gastrointestinal tract. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c17e91b-ddcf-4035-bac4-8bc88fb5aff2 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The inflammation affects all levels of the digestive tube where ulcers and scarring of the bowel wall often occur. Signaling description: It appears that divergent cytokine patterns are involved in the pathogenesis of Crohn's disease. It is primarily a T-helper 1- (Th1) dominant condition while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. The chronic inflammatory response in the gastrointestinal tract in patients with Crohn's disease is thought to be caused by defects in first defense mechanisms to commensal microflora in the gut. The disrupted epithelial and mucosal barrier contributes to increased bacterial penetration. On the pathway, signal transduction cascades and key proteins are shown in a distinct type of cells for simplicity although they act equivalently in each of the cell types. Alterations in the genes (NOD2, TLR4, and CARD9) involved in pathogen pattern recognition in macrophages, Paneth cells and dendritic cells may initiate NF-kB cascade activation leading to the production of pro-inflammatory cytokines. Outcome effects: The strong expression of tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11) facilitates antigen-presenting cells migrating to Peyer's patches (intestinal mesenteric lymph nodes) to present antigens and stimulate T-cell proliferation and differentiation. In patients with Crohn's disease, the T-cell response is more powerful. Th1-cell and Th17-cell mediated responses are the most characteristic of Crohn's disease. Another major contribution to Crohn's disease pathogenesis comes from autophagy. In autophagosomes, microbes are degraded and their antigens are presented to CD4 cells. The efficiency of autophagy may be diminished due to the possible dysfunction of ATG16L1, IRGM and VAMP3 in Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15307167 PMID: 19437144 PMID: 19637358 PMID: 21436303 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9c17e91b-ddcf-4035-bac4-8bc88fb5aff2 Crohn's Disease uuid-9c17e91b-ddcf-4035-bac4-8bc88fb5aff2 PS:CellType Paneth cell PS:CellType dendritic cell PS:CellType epithelial cell PS:CellType macrophage PS:Description Crohn's disease is a condition with chronic autoimmune granulomatous inflammation of the gastrointestinal tract. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c17e91b-ddcf-4035-bac4-8bc88fb5aff2 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The inflammation affects all levels of the digestive tube where ulcers and scarring of the bowel wall often occur. Signaling description: It appears that divergent cytokine patterns are involved in the pathogenesis of Crohn's disease. It is primarily a T-helper 1- (Th1) dominant condition while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis. The chronic inflammatory response in the gastrointestinal tract in patients with Crohn's disease is thought to be caused by defects in first defense mechanisms to commensal microflora in the gut. The disrupted epithelial and mucosal barrier contributes to increased bacterial penetration. On the pathway, signal transduction cascades and key proteins are shown in a distinct type of cells for simplicity although they act equivalently in each of the cell types. Alterations in the genes (NOD2, TLR4, and CARD9) involved in pathogen pattern recognition in macrophages, Paneth cells and dendritic cells may initiate NF-kB cascade activation leading to the production of pro-inflammatory cytokines. Outcome effects: The strong expression of tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11) facilitates antigen-presenting cells migrating to Peyer's patches (intestinal mesenteric lymph nodes) to present antigens and stimulate T-cell proliferation and differentiation. In patients with Crohn's disease, the T-cell response is more powerful. Th1-cell and Th17-cell mediated responses are the most characteristic of Crohn's disease. Another major contribution to Crohn's disease pathogenesis comes from autophagy. In autophagosomes, microbes are degraded and their antigens are presented to CD4 cells. The efficiency of autophagy may be diminished due to the possible dysfunction of ATG16L1, IRGM and VAMP3 in Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15307167 PS:PMID 19437144 PS:PMID 19637358 PS:PMID 21436303 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c1c078c-ede1-4739-8d7b-865e66580575 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-9c1c078c-ede1-4739-8d7b-865e66580575 NCAM1 -> CREB/ELK/SRF/MYC Signaling uuid-9c1c078c-ede1-4739-8d7b-865e66580575 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c1c078c-ede1-4739-8d7b-865e66580575 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: melanocyte Description: The role of melanin in photoprotection is controversial. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c2747f1-e6d4-47dd-863f-45d43a8b104a NodeType: Pathway Notes: Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: UVA radiation is the major component of solar UV radiation; it deeply penetrates into the skin and induces profound alterations in the dermal connective tissue. UVA radiation appears to play a key role in pigmented changes occurring with age, the major sign of skin photoaging. Skin susceptibility to photoaging alterations also depends on constitutive pigmentation. Melanocytes are melanin-producing cells located in the stratum basale of the epidermis. UV radiation mediates the synthesis and release of alpha-melanocyte-stimulating hormone which then promotes pigmentation by binding to the melanocortin 1 receptor on the surface of melanocytes. The production of cyclic adenosine monophosphate downstream of MC1R activates the receptors of MITF. MITF later participates in the conversion of tyrosine into melanin pigments by stimulating the transcription of melanocyte-specific genes. Recent studies have shown that melanin, especially pheomelanin (a yellow/red form of melanin), acts as a potent UV photosensitizer as it produces ROS, induces DNA damage and cause apoptosis of skin cells upon exposure to UV radiation. Outcome effects: The role of melanin in photoprotection is controversial. Melanin functions as a UV-absorbent and has photoprotective properties, yet recent evidence shows that the yellow/red form of melanin (pheomelanin) can have damaging effect on the skin and contribute to photoaging. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is in white-out style. Organ_System: integumentary system PMID: 19050991 PMID: 19675550 PMID: 25234829 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-9c2747f1-e6d4-47dd-863f-45d43a8b104a Melanocyte Role in Skin Aging uuid-9c2747f1-e6d4-47dd-863f-45d43a8b104a PS:CellType melanocyte PS:Description The role of melanin in photoprotection is controversial. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c2747f1-e6d4-47dd-863f-45d43a8b104a PS:NodeType Pathway PS:Notes Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: UVA radiation is the major component of solar UV radiation; it deeply penetrates into the skin and induces profound alterations in the dermal connective tissue. UVA radiation appears to play a key role in pigmented changes occurring with age, the major sign of skin photoaging. Skin susceptibility to photoaging alterations also depends on constitutive pigmentation. Melanocytes are melanin-producing cells located in the stratum basale of the epidermis. UV radiation mediates the synthesis and release of alpha-melanocyte-stimulating hormone which then promotes pigmentation by binding to the melanocortin 1 receptor on the surface of melanocytes. The production of cyclic adenosine monophosphate downstream of MC1R activates the receptors of MITF. MITF later participates in the conversion of tyrosine into melanin pigments by stimulating the transcription of melanocyte-specific genes. Recent studies have shown that melanin, especially pheomelanin (a yellow/red form of melanin), acts as a potent UV photosensitizer as it produces ROS, induces DNA damage and cause apoptosis of skin cells upon exposure to UV radiation. Outcome effects: The role of melanin in photoprotection is controversial. Melanin functions as a UV-absorbent and has photoprotective properties, yet recent evidence shows that the yellow/red form of melanin (pheomelanin) can have damaging effect on the skin and contribute to photoaging. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is in white-out style. PS:Organ_System integumentary system PS:PMID 19050991 PS:PMID 19675550 PS:PMID 25234829 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c2ba646-3103-4e8c-9a9a-2d7e152b43b7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9c2ba646-3103-4e8c-9a9a-2d7e152b43b7 Collagen -> NF-kB Expression Targets uuid-9c2ba646-3103-4e8c-9a9a-2d7e152b43b7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c2ba646-3103-4e8c-9a9a-2d7e152b43b7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Cancer cells strongly upregulate glucose uptake and glycolysis compared to normal cells in order to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c3840fd-d35a-4985-9a2e-3501675505aa NodeType: Pathway Notes: Headnote: In cancer cells, the glucose uptake and glycolysis are strongly un-regulated compared to normal cells, which gives rise to an increased yield of intermediate glycolytic metabolites and the end product, pyruvate. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This occurs even in the presence of sufficient oxygen. This metabolic phenotype is known as the Warburg effect or aerobic glycolysis. Signaling description: In cancer, glucose import is increased through activation of SLC2A1 and SLC2A3 transporters (they are activated due to HIF1A, MYC, RELA over-expression and TP53 down-regulation). Many glycolytic enzymes are up-regulated in cancer including HK1/2, GPI, PFKM, ALDOA, GAPDH, PGK1, PGAM1, ENO1/2, PKM. The conversion of pyruvate to acetyl-CoA is inhibited due to activation of PDK1/3, the inhibitors of PDHA1. The conversion of pyruvate to lactate is activated due to up-regulation of LDHA. The activation of HIF1A, AKT1, MYC, SNAI1 and inactivation of TP53 and PTEN are essential in the up-regulation of glycolytic enzymes in cancer cells. Outcome effects: Glycolytic breakdown of glucose produces various intermediate metabolites, which, as precursors, can be diverted into anabolic pathways including the pentose phosphate pathway, serine and triacylglycerol synthesis pathways for the de novo synthesis of nucleotides, amino acids, and lipids. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18538731 PMID: 23071355 PMID: 23192270 PMID: 23897900 PMID: 24374503 PMID: 24732809 PMID: 27386546 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-9c3840fd-d35a-4985-9a2e-3501675505aa Glycolysis Activation in Cancer (Warburg Effect) uuid-9c3840fd-d35a-4985-9a2e-3501675505aa PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Cancer cells strongly upregulate glucose uptake and glycolysis compared to normal cells in order to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c3840fd-d35a-4985-9a2e-3501675505aa PS:NodeType Pathway PS:Notes Headnote: In cancer cells, the glucose uptake and glycolysis are strongly un-regulated compared to normal cells, which gives rise to an increased yield of intermediate glycolytic metabolites and the end product, pyruvate. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This occurs even in the presence of sufficient oxygen. This metabolic phenotype is known as the Warburg effect or aerobic glycolysis. Signaling description: In cancer, glucose import is increased through activation of SLC2A1 and SLC2A3 transporters (they are activated due to HIF1A, MYC, RELA over-expression and TP53 down-regulation). Many glycolytic enzymes are up-regulated in cancer including HK1/2, GPI, PFKM, ALDOA, GAPDH, PGK1, PGAM1, ENO1/2, PKM. The conversion of pyruvate to acetyl-CoA is inhibited due to activation of PDK1/3, the inhibitors of PDHA1. The conversion of pyruvate to lactate is activated due to up-regulation of LDHA. The activation of HIF1A, AKT1, MYC, SNAI1 and inactivation of TP53 and PTEN are essential in the up-regulation of glycolytic enzymes in cancer cells. Outcome effects: Glycolytic breakdown of glucose produces various intermediate metabolites, which, as precursors, can be diverted into anabolic pathways including the pentose phosphate pathway, serine and triacylglycerol synthesis pathways for the de novo synthesis of nucleotides, amino acids, and lipids. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18538731 PS:PMID 23071355 PS:PMID 23192270 PS:PMID 23897900 PS:PMID 24374503 PS:PMID 24732809 PS:PMID 27386546 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: antigen-presenting cell Description: The antigen presenting cells (dendritic cells, macrophages, lung epithelial cells) are the first cells that recognize allergen. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c4889e4-615a-411e-b1b9-50c034165346 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The antigen presenting cells (dendritic cells, macrophages, lung epithelial cells) are the primary cells in allergen recognition. Antigens, which induce the immune response are called immunogens, and if they elicit allergies they are referred to as allergens. According to the AllFam database of inhaled allergen families, there are now 137 allergens. Antigen presenting cells take up the allergen, process it, and present it in a complex with the MHC molecule as an antigen on their cell surface. The antigen presenting cells induce naïve T-cells towards Th1- or Th2-cell response. Mucosal dendritic cells loaded with antigen migrate from the lungs to the T-cell area of mediastinal lymph nodes (MLNs). Mature dendritic cells in the MLNs select naive T-cells from the polyclonal repertoire of cells. Within 4 days, this will lead to clonal expansion of antigen-specific Th-cells. The allergens also induce signaling when recognized through antigen presenting cell surface pattern recognition receptors (PPRs), such as TLRs, C-type lectins (such as DC-SIGN, MR, dectin1, DEC205 and langerin) and NOD-like receptors. Glycosylation of allergens is required for recognition and uptake by PPRs in dendritic cells as well in other APCs. Mannosylation is the most common glycosylation pattern among allergens with an exception of Der p 2 (Dermatophagoides pteronyssinus) in asthma.The endotoxin lipopolysaccharide (LPS) (cell wall component of Gram-negative bacteria) exposure is positively associated with an increased risk of asthma and asthma severity in both adults and children. Outcome effects: PPRs signaling leads to the release of PGD2, LTC4 and LTD4, histamine, chemokines (CCL17 and CCL22), cytokines (IL4 and TNF). These mediators induce smooth-muscle contraction, goblet-cell hyperplasia and changes to the vessel wall. The allergen increases the expression of CCR7 required for the migration of allergen-loaded DCs to the draining lymph nodes. In the case of house dust mite allergens, the epithelium releases granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to local activation of DC function. The antigen presenting cells can all bind allergen-specific IgE either through FcgRI or CD23, possibly enhancing recognition of the allergen. Organ: lung Organ_System: respiratory system PMID: 11407210 PMID: 16164437 PMID: 20525132 PMID: 22879901 PMID: 24914235 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9c4889e4-615a-411e-b1b9-50c034165346 Antigen-Presenting Cell Role in Asthma uuid-9c4889e4-615a-411e-b1b9-50c034165346 PS:CellType antigen-presenting cell PS:Description The antigen presenting cells (dendritic cells, macrophages, lung epithelial cells) are the first cells that recognize allergen. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c4889e4-615a-411e-b1b9-50c034165346 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The antigen presenting cells (dendritic cells, macrophages, lung epithelial cells) are the primary cells in allergen recognition. Antigens, which induce the immune response are called immunogens, and if they elicit allergies they are referred to as allergens. According to the AllFam database of inhaled allergen families, there are now 137 allergens. Antigen presenting cells take up the allergen, process it, and present it in a complex with the MHC molecule as an antigen on their cell surface. The antigen presenting cells induce naïve T-cells towards Th1- or Th2-cell response. Mucosal dendritic cells loaded with antigen migrate from the lungs to the T-cell area of mediastinal lymph nodes (MLNs). Mature dendritic cells in the MLNs select naive T-cells from the polyclonal repertoire of cells. Within 4 days, this will lead to clonal expansion of antigen-specific Th-cells. The allergens also induce signaling when recognized through antigen presenting cell surface pattern recognition receptors (PPRs), such as TLRs, C-type lectins (such as DC-SIGN, MR, dectin1, DEC205 and langerin) and NOD-like receptors. Glycosylation of allergens is required for recognition and uptake by PPRs in dendritic cells as well in other APCs. Mannosylation is the most common glycosylation pattern among allergens with an exception of Der p 2 (Dermatophagoides pteronyssinus) in asthma.The endotoxin lipopolysaccharide (LPS) (cell wall component of Gram-negative bacteria) exposure is positively associated with an increased risk of asthma and asthma severity in both adults and children. Outcome effects: PPRs signaling leads to the release of PGD2, LTC4 and LTD4, histamine, chemokines (CCL17 and CCL22), cytokines (IL4 and TNF). These mediators induce smooth-muscle contraction, goblet-cell hyperplasia and changes to the vessel wall. The allergen increases the expression of CCR7 required for the migration of allergen-loaded DCs to the draining lymph nodes. In the case of house dust mite allergens, the epithelium releases granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to local activation of DC function. The antigen presenting cells can all bind allergen-specific IgE either through FcgRI or CD23, possibly enhancing recognition of the allergen. PS:Organ lung PS:Organ_System respiratory system PS:PMID 11407210 PS:PMID 16164437 PS:PMID 20525132 PS:PMID 22879901 PS:PMID 24914235 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chromaffin cell Description: Chromaffin cells release catecholamine transmitters (epinephrine, norepinephrine and dopamine) by Ca2+-regulated exocytosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c6dd037-9d61-416b-a015-e7488fc11b25 NodeType: Pathway Notes: Headnote: Catecholamines (epinephrine, norepinephrine and dopamine) released from adrenal chromaffin cells exert profound effects on cardiovascular, endocrine, immune, and nervous system function. Precise regulation of chromaffin cell exocytosis is key to maintaining normal physiological function. Signaling description: In exocrine adrenal chromaffin cells, secretion is dependent upon membrane depolarization and Ca2+ entry. AGT binds to G-protein coupled AGTR1 which triggers ADCY and PKA activation to mediate the enzyme cascade catalyzing the secretion of catecholamines. The vesicular monoamine transporter activity is necessary for the uptake of catecholamines into vesicles. The following exocytosis of secretory vesicles consists of vesicle trafficking, tethering, docking and fusion. The secretory dense-core vesicles (LDCV) are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by a specific RAB GTPases. The tethering of the secretory vesicles is mediated by the exocyst complex and RAB proteins, bringing the vesicles very close to the plasma membrane. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex (VAMPs/STX1A/SNAP25). Cholinergic receptor CHRM3 triggers the activation of PLCB1/DAG/PKC signaling and mediates membrane depolarization resulting in Ca2+ entry through voltage-gated channels. The influx of Ca2+ into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor SYT1 and the partially assembled SNARE complex. SNARE proteins form an incredibly stable SNARE complex which brings the vesicle membrane into close apposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. CPLX1 and SYT1 regulate the catecholamines release. SNARE disassembly can be induced by a single round of ATP hydrolysis provided by ATPase NSF and NAPA. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Chromaffin cells release catecholamine transmitters by Ca2+-regulated exocytosis. Organ: adrenal gland Organ_System: endocrine system PMID: 19745043 PMID: 21046455 PMID: 21061161 PMID: 22560267 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-9c6dd037-9d61-416b-a015-e7488fc11b25 Catecholamines Secretion from Adrenal Gland uuid-9c6dd037-9d61-416b-a015-e7488fc11b25 PS:CellType chromaffin cell PS:Description Chromaffin cells release catecholamine transmitters (epinephrine, norepinephrine and dopamine) by Ca2+-regulated exocytosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c6dd037-9d61-416b-a015-e7488fc11b25 PS:NodeType Pathway PS:Notes Headnote: Catecholamines (epinephrine, norepinephrine and dopamine) released from adrenal chromaffin cells exert profound effects on cardiovascular, endocrine, immune, and nervous system function. Precise regulation of chromaffin cell exocytosis is key to maintaining normal physiological function. Signaling description: In exocrine adrenal chromaffin cells, secretion is dependent upon membrane depolarization and Ca2+ entry. AGT binds to G-protein coupled AGTR1 which triggers ADCY and PKA activation to mediate the enzyme cascade catalyzing the secretion of catecholamines. The vesicular monoamine transporter activity is necessary for the uptake of catecholamines into vesicles. The following exocytosis of secretory vesicles consists of vesicle trafficking, tethering, docking and fusion. The secretory dense-core vesicles (LDCV) are transported by motor kinesin proteins (KIFs) from trans-Golgi complex to the vicinity of plasma membrane along microtubules and actin filaments. Trafficking is regulated by a specific RAB GTPases. The tethering of the secretory vesicles is mediated by the exocyst complex and RAB proteins, bringing the vesicles very close to the plasma membrane. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex (VAMPs/STX1A/SNAP25). Cholinergic receptor CHRM3 triggers the activation of PLCB1/DAG/PKC signaling and mediates membrane depolarization resulting in Ca2+ entry through voltage-gated channels. The influx of Ca2+ into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the calcium sensor SYT1 and the partially assembled SNARE complex. SNARE proteins form an incredibly stable SNARE complex which brings the vesicle membrane into close apposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. CPLX1 and SYT1 regulate the catecholamines release. SNARE disassembly can be induced by a single round of ATP hydrolysis provided by ATPase NSF and NAPA. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Chromaffin cells release catecholamine transmitters by Ca2+-regulated exocytosis. PS:Organ adrenal gland PS:Organ_System endocrine system PS:PMID 19745043 PS:PMID 21046455 PS:PMID 21061161 PS:PMID 22560267 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c7043c0-c698-4fab-b960-1ec3ac2e744d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9c7043c0-c698-4fab-b960-1ec3ac2e744d NTF4 Expression Targets uuid-9c7043c0-c698-4fab-b960-1ec3ac2e744d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9c7043c0-c698-4fab-b960-1ec3ac2e744d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ca2242e-2752-4eca-8020-31dc4a7e2feb NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9ca2242e-2752-4eca-8020-31dc4a7e2feb Thrombopoietin -> SPI1 Expression Targets uuid-9ca2242e-2752-4eca-8020-31dc4a7e2feb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ca2242e-2752-4eca-8020-31dc4a7e2feb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ca56707-e86f-469d-961c-a72952743849 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-9ca56707-e86f-469d-961c-a72952743849 Alanine Metabolism uuid-9ca56707-e86f-469d-961c-a72952743849 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ca56707-e86f-469d-961c-a72952743849 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cc9f28b-b541-4c7f-96ea-5e2a81ee2fbb NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9cc9f28b-b541-4c7f-96ea-5e2a81ee2fbb AGT -> STAT Expression Targets uuid-9cc9f28b-b541-4c7f-96ea-5e2a81ee2fbb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cc9f28b-b541-4c7f-96ea-5e2a81ee2fbb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cd71468-8526-4862-9d9b-38d6def93d98 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9cd71468-8526-4862-9d9b-38d6def93d98 HBEGF -> TP53 Expression Targets uuid-9cd71468-8526-4862-9d9b-38d6def93d98 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cd71468-8526-4862-9d9b-38d6def93d98 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cdc2eb9-7dd5-4977-a5a6-770b7b87b54d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9cdc2eb9-7dd5-4977-a5a6-770b7b87b54d FGF2 -> STAT Expression Targets uuid-9cdc2eb9-7dd5-4977-a5a6-770b7b87b54d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9cdc2eb9-7dd5-4977-a5a6-770b7b87b54d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatic stellate cell Description: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most frequent cause of liver disease in the Western world and is increasing worldwide, paralleling the obesity and metabolic syndrome pandemic. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d120342-b18d-4944-abab-6a52555e3d94 NodeType: Pathway Notes: Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Signaling description: Hepatic stellate cells, also known as perisinusoidal cells or Ito cells are pericytes found in the perisinusoidal space of Disse. The stellate cell is the major cell type involved in liver fibrosis, which is formed in response to liver damage in liver diseases. Stellate cells are activated by paracrine stimuli (such as PDGFA/PDGFB, TGFA, and EGF) produced by hepatocytes, endothelial cells, and other cells of the liver. Ligand-bound growth factor receptors activate MAPK1/3 signaling pathway via SHC1/GRB2/SOS1, and STAT3 via JAK2. In turn, STAT3 promotes KLF6. Outcome effects: The above-mentioned pathways induce matrix metallopeptidases (MMP2/9/13/14), FN1, TIMP1, CDH1, TGFB1, TGFBR1, PLAU, and COL1A1 which are involved in cell proliferation, macrophage chemotaxis, and fibrosis. In addition, fatty acids can modulate inflammation through TLR4. TLR4 activates NF-kB via adaptor proteins and MAPKs. NF-kB promotes interleukins (IL6, IL8, IL2, and IL1A) and CCL2 which are involved in cell proliferation, macrophage chemotaxis, and liver fibrosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: liver Organ_System: digestive system PMID: 23394097 PMID: 25045276 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-9d120342-b18d-4944-abab-6a52555e3d94 Hepatic Stellate Cells in non-Alcoholic Fatty Liver Disease uuid-9d120342-b18d-4944-abab-6a52555e3d94 PS:CellType hepatic stellate cell PS:Description Non-Alcoholic Fatty Liver Disease (NAFLD) is the most frequent cause of liver disease in the Western world and is increasing worldwide, paralleling the obesity and metabolic syndrome pandemic. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d120342-b18d-4944-abab-6a52555e3d94 PS:NodeType Pathway PS:Notes Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Signaling description: Hepatic stellate cells, also known as perisinusoidal cells or Ito cells are pericytes found in the perisinusoidal space of Disse. The stellate cell is the major cell type involved in liver fibrosis, which is formed in response to liver damage in liver diseases. Stellate cells are activated by paracrine stimuli (such as PDGFA/PDGFB, TGFA, and EGF) produced by hepatocytes, endothelial cells, and other cells of the liver. Ligand-bound growth factor receptors activate MAPK1/3 signaling pathway via SHC1/GRB2/SOS1, and STAT3 via JAK2. In turn, STAT3 promotes KLF6. Outcome effects: The above-mentioned pathways induce matrix metallopeptidases (MMP2/9/13/14), FN1, TIMP1, CDH1, TGFB1, TGFBR1, PLAU, and COL1A1 which are involved in cell proliferation, macrophage chemotaxis, and fibrosis. In addition, fatty acids can modulate inflammation through TLR4. TLR4 activates NF-kB via adaptor proteins and MAPKs. NF-kB promotes interleukins (IL6, IL8, IL2, and IL1A) and CCL2 which are involved in cell proliferation, macrophage chemotaxis, and liver fibrosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ liver PS:Organ_System digestive system PS:PMID 23394097 PS:PMID 25045276 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Androgen receptor (AR) expression and activity level changes along with the cell cycle phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d1252ad-7d3f-4a25-ae86-40b4d675fabd NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Androgen receptor (AR) expression and activity level changes along with the cell cycle phases. Upon stimulation by androgens, AR induces cyclin D1 (CCND1) expression possibly through the enhancement of mTOR-dependent translation. It also increases the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A, p21Cip1) and induces the degradation of cyclin-dependent kinase inhibitor 1B (CDKN1B, p27Kip1) during G1 phase. There is a negative feedback loop to modulate androgen-dependent gene expression performed by cyclin D1 that is bound to AR and abolishes its activity (possibly, with the help of HDAC). Furthermore, increased concentration of E2F1 transcription factor has been found to suppress AR gene expression through binding to the AR promoter during S phase. Androgen receptor can be reactivated later in the G2 phase by direct interaction with the cell division cycle 25 homolog B (CDC25B). Cyclin dependent kinase 1 (CDK1/Cdc2) can also activate AR by phosphorylation. By the end of mitosis, AR is thought to be targeted for elimination by one of the ubiquitin ligases such as MDM2. Outcome effects: CDKN1B expression is important for the control of G1 phase progression. CDKN1A is thought to have a dual role in the cell cycle performing negative or positive regulation of cyclin D1/CDK4 (assistance in assembling active complex). Activated CDK4 and CDK2 inactivate retinoblastoma 1 tumor suppressor (RB). RB binds with RB-associated KRAB zinc finger (RBAK) and enhances AR transcriptional activity. Cyclin E1 (CCNE1) has been shown to increase the transcriptional activity of AR. Cyclin E1/CDK2 mediates cell cycle progress from G1 phase into S phase. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: prostate Organ_System: urinary tract PMID: 18301781 PMID: 21782001 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9d1252ad-7d3f-4a25-ae86-40b4d675fabd Androgen Receptor and Cell Cycle in Prostate Cancer uuid-9d1252ad-7d3f-4a25-ae86-40b4d675fabd PS:CellType cancer cell PS:Description Androgen receptor (AR) expression and activity level changes along with the cell cycle phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d1252ad-7d3f-4a25-ae86-40b4d675fabd PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Androgen receptor (AR) expression and activity level changes along with the cell cycle phases. Upon stimulation by androgens, AR induces cyclin D1 (CCND1) expression possibly through the enhancement of mTOR-dependent translation. It also increases the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A, p21Cip1) and induces the degradation of cyclin-dependent kinase inhibitor 1B (CDKN1B, p27Kip1) during G1 phase. There is a negative feedback loop to modulate androgen-dependent gene expression performed by cyclin D1 that is bound to AR and abolishes its activity (possibly, with the help of HDAC). Furthermore, increased concentration of E2F1 transcription factor has been found to suppress AR gene expression through binding to the AR promoter during S phase. Androgen receptor can be reactivated later in the G2 phase by direct interaction with the cell division cycle 25 homolog B (CDC25B). Cyclin dependent kinase 1 (CDK1/Cdc2) can also activate AR by phosphorylation. By the end of mitosis, AR is thought to be targeted for elimination by one of the ubiquitin ligases such as MDM2. Outcome effects: CDKN1B expression is important for the control of G1 phase progression. CDKN1A is thought to have a dual role in the cell cycle performing negative or positive regulation of cyclin D1/CDK4 (assistance in assembling active complex). Activated CDK4 and CDK2 inactivate retinoblastoma 1 tumor suppressor (RB). RB binds with RB-associated KRAB zinc finger (RBAK) and enhances AR transcriptional activity. Cyclin E1 (CCNE1) has been shown to increase the transcriptional activity of AR. Cyclin E1/CDK2 mediates cell cycle progress from G1 phase into S phase. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 18301781 PS:PMID 21782001 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Leukotriene LTB4 can regulate neutrophil activation via presqualene-PP conversions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d1fd5a3-ae1c-4a2e-9933-6996846dba17 NodeType: Pathway Notes: Headnote: Leukotriene LTB4 can regulate neutrophil activation via presqualene-PP conversions. Presqualene-PP is a constituent of polymorphonuclear neutrophil (PMN) cell membranes, which lack squalene cyclase and are unable to use it for cholesterol biosynthesis. Signaling description: LTB4/LTB4R signaling initiates the rapid degradation of presqualene-PP levels, possibly through PKC and PPAPDC2 activation. Presqualene-PP directly inhibits PIK3CG and PLD2. Presqualene-PP degradation, under LTB4, unlocks these regulatory enzymes and leads to neutrophil function activation. Presqualene-PP also interacts with GRB2 and blocks NAD(P)H oxidase assembly for reactive oxygen species (ROS) generation. Outcome effects: Presqualene-PP levels quickly return to baseline in a time frame that parallels cellular deactivation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-9d1fd5a3-ae1c-4a2e-9933-6996846dba17 Leukotriene LTB4 Effect on Neutrophil Activation uuid-9d1fd5a3-ae1c-4a2e-9933-6996846dba17 PS:CellType neutrophil PS:Description Leukotriene LTB4 can regulate neutrophil activation via presqualene-PP conversions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d1fd5a3-ae1c-4a2e-9933-6996846dba17 PS:NodeType Pathway PS:Notes Headnote: Leukotriene LTB4 can regulate neutrophil activation via presqualene-PP conversions. Presqualene-PP is a constituent of polymorphonuclear neutrophil (PMN) cell membranes, which lack squalene cyclase and are unable to use it for cholesterol biosynthesis. Signaling description: LTB4/LTB4R signaling initiates the rapid degradation of presqualene-PP levels, possibly through PKC and PPAPDC2 activation. Presqualene-PP directly inhibits PIK3CG and PLD2. Presqualene-PP degradation, under LTB4, unlocks these regulatory enzymes and leads to neutrophil function activation. Presqualene-PP also interacts with GRB2 and blocks NAD(P)H oxidase assembly for reactive oxygen species (ROS) generation. Outcome effects: Presqualene-PP levels quickly return to baseline in a time frame that parallels cellular deactivation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PMID PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d2660bc-2ab2-493d-af9b-7e6310d0119b NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-9d2660bc-2ab2-493d-af9b-7e6310d0119b TGFB-+>EMT in myofibroblasts uuid-9d2660bc-2ab2-493d-af9b-7e6310d0119b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d2660bc-2ab2-493d-af9b-7e6310d0119b PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d8e2e2d-d0d0-44b6-b03a-99e712b3528f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-9d8e2e2d-d0d0-44b6-b03a-99e712b3528f limbal epithelial stem cells differentiation uuid-9d8e2e2d-d0d0-44b6-b03a-99e712b3528f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9d8e2e2d-d0d0-44b6-b03a-99e712b3528f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9da4c8a6-c1e2-465b-9fb2-cd2b6cd5e1b4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-9da4c8a6-c1e2-465b-9fb2-cd2b6cd5e1b4 EGFR/ERBB2 -> HIF1A Signaling uuid-9da4c8a6-c1e2-465b-9fb2-cd2b6cd5e1b4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9da4c8a6-c1e2-465b-9fb2-cd2b6cd5e1b4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Transcytosis is the process where membrane-bound carriers selectively transport molecules between different parts of the cell. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9da9fe29-2077-4156-a5f4-ec16c3002449 NodeType: Pathway Notes: Headnote: Transcytosis is the process where membrane-bound carriers selectively transport molecules between different parts of the cell. The transport is rapid and a unique vesicle acts as the shuttle between apical and basal surfaces. There are two types of transcytosis including caveolae-mediated and clathrin-mediated, which differ in mechanisms of vesicle formation. Signaling description: Caveolae are pits in the basal and apical membranes of endothelial cells. These vesicles transport cargo, usually fluid, from one surface to another in the cell. Caveolae appear enriched in sphingolipids, cholesterol, and proteins associated with the membrane via lipid anchors such as glycosylphosphatidylinositol diacylglycerol-lyase and non-receptor tyrosine kinases including CSK. Caveolin (CAV) is the major structural component of caveolae. CAV1, CAV2, and CAV3 are important for the structure of caveolae due to their ability to oligomerize and bind cholesterol. Caveolae are most numerous in the microvascular endothelia of the lung and relatively uncommon in the highly restrictive microvascular endothelia of the brain, retina, and testes. CAV1 can bind and promote the assembly of G-proteins, including Src, GRB7, and GNAQ, at the plasma membrane. CAV1 plays a role as a negative regulator of many proteins through the scaffolding motif. Through the inhibition of NOS3 and TRPC1, TRPC4, and TRPV4 channels, CAV1 is involved in calcium (Ca2 ) and nitric oxide (NO) translocation. In addition to their coat proteins, caveolae also contain adapter proteins called cavins including PTRF, SDPR, PRKCDBP, and MURC which may be important in regulating CAV expression and caveolar morphology. Micronutrients do not generally use vesicle-mediated transport to reach the blood stream with the exception of iron (Fe2 ) and vitamin B12. Cargo in the clathrin-mediated transcytotic pathway avoids degradation in lysosomes. Proteins tagged for the lysosome are marked for this pathway by the addition of ubiquitin that is recognized by ESCRT-I which sorts the protein into forming luminal vesicles. The membranes of lysosomes and late endosomes are enriched in a specific set of LAMPs. Lysosomes contain more than 40 hydrolases in an acidic environment (pH of about 5). During synthesis in the ER, lysosomal enzymes such as LIPA are decorated with mannose-6-phosphate residues which are recognized by M6PR and packaged into clathrin-coated endosomes. Outcome effects: When the endosomes lose RAB5A and acquire RAB7A, they become capable of fusion with lysosomes. Lysosomes are acidified by a V-type H -ATPase (V-ATPase) to promote enzymatic activity and control biogenesis steps such as the maturation of hydrolytic enzymes. A lysosomal chaperone (HSPA8) is required for the complete translocation of the substrate protein into the lysosomal matrix. Organ: generic Organ_System: generic PMID: 17644753 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-9da9fe29-2077-4156-a5f4-ec16c3002449 Transcytosis uuid-9da9fe29-2077-4156-a5f4-ec16c3002449 PS:CellType generic PS:Description Transcytosis is the process where membrane-bound carriers selectively transport molecules between different parts of the cell. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9da9fe29-2077-4156-a5f4-ec16c3002449 PS:NodeType Pathway PS:Notes Headnote: Transcytosis is the process where membrane-bound carriers selectively transport molecules between different parts of the cell. The transport is rapid and a unique vesicle acts as the shuttle between apical and basal surfaces. There are two types of transcytosis including caveolae-mediated and clathrin-mediated, which differ in mechanisms of vesicle formation. Signaling description: Caveolae are pits in the basal and apical membranes of endothelial cells. These vesicles transport cargo, usually fluid, from one surface to another in the cell. Caveolae appear enriched in sphingolipids, cholesterol, and proteins associated with the membrane via lipid anchors such as glycosylphosphatidylinositol diacylglycerol-lyase and non-receptor tyrosine kinases including CSK. Caveolin (CAV) is the major structural component of caveolae. CAV1, CAV2, and CAV3 are important for the structure of caveolae due to their ability to oligomerize and bind cholesterol. Caveolae are most numerous in the microvascular endothelia of the lung and relatively uncommon in the highly restrictive microvascular endothelia of the brain, retina, and testes. CAV1 can bind and promote the assembly of G-proteins, including Src, GRB7, and GNAQ, at the plasma membrane. CAV1 plays a role as a negative regulator of many proteins through the scaffolding motif. Through the inhibition of NOS3 and TRPC1, TRPC4, and TRPV4 channels, CAV1 is involved in calcium (Ca2 ) and nitric oxide (NO) translocation. In addition to their coat proteins, caveolae also contain adapter proteins called cavins including PTRF, SDPR, PRKCDBP, and MURC which may be important in regulating CAV expression and caveolar morphology. Micronutrients do not generally use vesicle-mediated transport to reach the blood stream with the exception of iron (Fe2 ) and vitamin B12. Cargo in the clathrin-mediated transcytotic pathway avoids degradation in lysosomes. Proteins tagged for the lysosome are marked for this pathway by the addition of ubiquitin that is recognized by ESCRT-I which sorts the protein into forming luminal vesicles. The membranes of lysosomes and late endosomes are enriched in a specific set of LAMPs. Lysosomes contain more than 40 hydrolases in an acidic environment (pH of about 5). During synthesis in the ER, lysosomal enzymes such as LIPA are decorated with mannose-6-phosphate residues which are recognized by M6PR and packaged into clathrin-coated endosomes. Outcome effects: When the endosomes lose RAB5A and acquire RAB7A, they become capable of fusion with lysosomes. Lysosomes are acidified by a V-type H -ATPase (V-ATPase) to promote enzymatic activity and control biogenesis steps such as the maturation of hydrolytic enzymes. A lysosomal chaperone (HSPA8) is required for the complete translocation of the substrate protein into the lysosomal matrix. PS:Organ generic PS:Organ_System generic PS:PMID 17644753 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9dabcaa8-ea5d-4373-abb2-b79b328da6d1 NodeType: Pathway Notes: Although the majority of ARVD-causing mutations are in genes encoding desmosomal proteins, a few ARVD mutations have been detected in genes unrelated to intercellular junction complexes. Mutated proteins cause cardiomyocyte dysfunction due to defective force transmission between cells, the disruption of normal excitation-contraction coupling, and impairment of cardiomyocyte adhesion and fibrosis induction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: heart Organ_System: cardiovascular system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: myocardium urn:agi-pathway:uuid-9dabcaa8-ea5d-4373-abb2-b79b328da6d1 3_Cardiomyocyte dysfunction unrelated to cell junctions in ARVD uuid-9dabcaa8-ea5d-4373-abb2-b79b328da6d1 PS:CellType cardiac myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9dabcaa8-ea5d-4373-abb2-b79b328da6d1 PS:NodeType Pathway PS:Notes Although the majority of ARVD-causing mutations are in genes encoding desmosomal proteins, a few ARVD mutations have been detected in genes unrelated to intercellular junction complexes. Mutated proteins cause cardiomyocyte dysfunction due to defective force transmission between cells, the disruption of normal excitation-contraction coupling, and impairment of cardiomyocyte adhesion and fibrosis induction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ heart PS:Organ_System cardiovascular system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue myocardium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9db0a42d-5232-4af9-ae60-9a67c5f041ea NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9db0a42d-5232-4af9-ae60-9a67c5f041ea CCL15 Expression Targets uuid-9db0a42d-5232-4af9-ae60-9a67c5f041ea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9db0a42d-5232-4af9-ae60-9a67c5f041ea PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9dbde7d7-b669-422b-ab40-860f95b6b8d7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9dbde7d7-b669-422b-ab40-860f95b6b8d7 EREG -> HIF1A Expression Target uuid-9dbde7d7-b669-422b-ab40-860f95b6b8d7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9dbde7d7-b669-422b-ab40-860f95b6b8d7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e1977eb-3498-4420-900a-7edd9668a1dc NodeType: Pathway Notes: List of peptide hormones that regulates gastrointestinal functions and eating behavior. Organ_System: digestive system Organ_System: nervous system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-9e1977eb-3498-4420-900a-7edd9668a1dc Hormones Underlie Human Gastrointestinal Functions and Eating Behavior uuid-9e1977eb-3498-4420-900a-7edd9668a1dc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e1977eb-3498-4420-900a-7edd9668a1dc PS:NodeType Pathway PS:Notes List of peptide hormones that regulates gastrointestinal functions and eating behavior. PS:Organ_System digestive system PS:Organ_System nervous system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Precise mechanisms by which cilia participate in normal physiology and CKD pathogenesis were largely undefined. One of hypotheses is described on the pathway. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e1a74a6-22df-4e92-b5a4-c0cc444d60bd NodeType: Pathway Notes: Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Medullary Sponge Kidney (MSK), Nephronophthisis. Hereditary factors account for the majority of CKD types. Pathological processes underneath CKD are associated with cilia disorganization and defects in the planar cell polarity. Signaling description: Mutations in PKD1/2, PKHD1, DCDC2, KIF3A, CEP290, NPHP1/3/4, and INVS are associated with CKD. The localization of these proteins in the primary cilium is proposed to be crucial for its function as a mechanosensory antenna of fluid flow in the kidney. However, precise mechanisms by which cilia participate in renal cyst formation are largely undefined. One of the hypotheses is depicted on the pathway. Outcome effects: The PKD1-PKD2 complex located at the primary cilia surface functions as a fluid shear sensor that regulates the calcium signal. KIF3A-KIF3B-KIFAP3 complex is an essential intraflagellar transport-associated kinesin-2 motor. PKHD1 stimulates PKD2 channel activity in the presence of the kinesin-2 motor. CEP290 and DCDC2 interact with KIF3A in microtubule organization. PKD1 binds to the NPHP1-4 complex localized in microtubule-based structures. INVS and KIF3A modulate cytoskeleton organization and cell polarity via the interaction with CTNNB1. Mutated proteins: Mutated PKD1/2, PKHD1, DCDC2, KIF3A, CEP290, and NPHP1 are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 23904226 PMID: 25575298 PMID: 27512790 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-9e1a74a6-22df-4e92-b5a4-c0cc444d60bd Cilia Disorganization uuid-9e1a74a6-22df-4e92-b5a4-c0cc444d60bd PS:CellType epithelial cell PS:Description Precise mechanisms by which cilia participate in normal physiology and CKD pathogenesis were largely undefined. One of hypotheses is described on the pathway. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e1a74a6-22df-4e92-b5a4-c0cc444d60bd PS:NodeType Pathway PS:Notes Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Medullary Sponge Kidney (MSK), Nephronophthisis. Hereditary factors account for the majority of CKD types. Pathological processes underneath CKD are associated with cilia disorganization and defects in the planar cell polarity. Signaling description: Mutations in PKD1/2, PKHD1, DCDC2, KIF3A, CEP290, NPHP1/3/4, and INVS are associated with CKD. The localization of these proteins in the primary cilium is proposed to be crucial for its function as a mechanosensory antenna of fluid flow in the kidney. However, precise mechanisms by which cilia participate in renal cyst formation are largely undefined. One of the hypotheses is depicted on the pathway. Outcome effects: The PKD1-PKD2 complex located at the primary cilia surface functions as a fluid shear sensor that regulates the calcium signal. KIF3A-KIF3B-KIFAP3 complex is an essential intraflagellar transport-associated kinesin-2 motor. PKHD1 stimulates PKD2 channel activity in the presence of the kinesin-2 motor. CEP290 and DCDC2 interact with KIF3A in microtubule organization. PKD1 binds to the NPHP1-4 complex localized in microtubule-based structures. INVS and KIF3A modulate cytoskeleton organization and cell polarity via the interaction with CTNNB1. Mutated proteins: Mutated PKD1/2, PKHD1, DCDC2, KIF3A, CEP290, and NPHP1 are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 23904226 PS:PMID 25575298 PS:PMID 27512790 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e2ca1d5-2460-4be2-b7dd-3702809596f7 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-9e2ca1d5-2460-4be2-b7dd-3702809596f7 Proteins with Altered Expression in Psoriasis uuid-9e2ca1d5-2460-4be2-b7dd-3702809596f7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e2ca1d5-2460-4be2-b7dd-3702809596f7 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e3f05e6-5d21-4b42-881f-2ba42f06e1ed NodeType: Pathway Organ: generic Organ_System: generic PMID: 23328704 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-9e3f05e6-5d21-4b42-881f-2ba42f06e1ed WNT Canonical Signaling uuid-9e3f05e6-5d21-4b42-881f-2ba42f06e1ed PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e3f05e6-5d21-4b42-881f-2ba42f06e1ed PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 23328704 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source PS:Tissue Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e56bccd-7918-465b-b94e-bbd32ea065df NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process Tissue: endothelium urn:agi-pathway:uuid-9e56bccd-7918-465b-b94e-bbd32ea065df Matricellular proteins in corneal cell spreading uuid-9e56bccd-7918-465b-b94e-bbd32ea065df PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e56bccd-7918-465b-b94e-bbd32ea065df PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Tissue endothelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e6317c6-9bcc-4bb5-a9fa-7672d60d02dc NodeType: Pathway Notes: Friedreich's ataxia is a rare autosomal recessive disorder with one case 1 in 50,000 in general human population. Friedreich's ataxia is characterized by progressive nervous system damage with symptoms including poor coordination, neurological complications, scoliosis, heart disease and diabetes. Cognitive function is not affected. As the disease is progressed to an advanced stage, wheelchair may be required for mobility. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: generic urn:agi-pathway:uuid-9e6317c6-9bcc-4bb5-a9fa-7672d60d02dc FXN Role in Friedreich Ataxia Progression uuid-9e6317c6-9bcc-4bb5-a9fa-7672d60d02dc PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e6317c6-9bcc-4bb5-a9fa-7672d60d02dc PS:NodeType Pathway PS:Notes Friedreich's ataxia is a rare autosomal recessive disorder with one case 1 in 50,000 in general human population. Friedreich's ataxia is characterized by progressive nervous system damage with symptoms including poor coordination, neurological complications, scoliosis, heart disease and diabetes. Cognitive function is not affected. As the disease is progressed to an advanced stage, wheelchair may be required for mobility. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e645b9d-170b-4304-9345-519e5d0279eb NodeType: Pathway Notes: Intestine epithelial cells and antigen-presenting cells of the intestine, such as dendritic cells and macrophages, recognize commensal microbiota through toll-like receptors (TLRs) and Nod-like (NOD) receptors, become activated, and in turn secrete cytokines. Cytokines stimulate T-helper 2 cells (Th2) differentiation and their proinflammatory response. The atypically strong Th2 cell response in patients with ulcerative colitis is cytotoxic and results in necrosis of the inner intestine wall. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-9e645b9d-170b-4304-9345-519e5d0279eb 2_Intestine epithelial cells drive immunological responses in ulcerative colitis uuid-9e645b9d-170b-4304-9345-519e5d0279eb PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e645b9d-170b-4304-9345-519e5d0279eb PS:NodeType Pathway PS:Notes Intestine epithelial cells and antigen-presenting cells of the intestine, such as dendritic cells and macrophages, recognize commensal microbiota through toll-like receptors (TLRs) and Nod-like (NOD) receptors, become activated, and in turn secrete cytokines. Cytokines stimulate T-helper 2 cells (Th2) differentiation and their proinflammatory response. The atypically strong Th2 cell response in patients with ulcerative colitis is cytotoxic and results in necrosis of the inner intestine wall. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e708c93-fe99-4315-be61-1e4c621a1812 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-9e708c93-fe99-4315-be61-1e4c621a1812 mir200-| EMT uuid-9e708c93-fe99-4315-be61-1e4c621a1812 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e708c93-fe99-4315-be61-1e4c621a1812 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e889a6b-d433-47e6-acb3-f2e7dc3393eb NodeType: Pathway Organ_System: lymphatic system PMID: 24325346 PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-9e889a6b-d433-47e6-acb3-f2e7dc3393eb Proteins with Altered Expression in Cancer Immune Escape uuid-9e889a6b-d433-47e6-acb3-f2e7dc3393eb PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e889a6b-d433-47e6-acb3-f2e7dc3393eb PS:NodeType Pathway PS:Organ_System lymphatic system PS:PMID 24325346 PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e9cef56-8ba0-471a-9fbb-b44a444153b4 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-9e9cef56-8ba0-471a-9fbb-b44a444153b4 Macrophage activation by OLR1 uuid-9e9cef56-8ba0-471a-9fbb-b44a444153b4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9e9cef56-8ba0-471a-9fbb-b44a444153b4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: NFKB and STAT3 are activated both in immune and tumor cells in different types of cancer and promote cancer initiation and progression. In this pathway we focus on NFKB and STAT3 activation in tumor cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ea0ec40-e9f0-4a1a-acc5-23a39ecea899 NodeType: Pathway Notes: Headnote: Chronic inflammation is one of the leading factors of cancer initiation and progression. Immune cell (predominantly myeloid cells) produce various cytokines and growth factors such as TNF, IL6, IL1B, IL11,IL22, EGF, HGF and others that interact with receptors on the surface of tumor cells. Obesity is also regarded as a chronic inflammation state and makes a great impact into cancer initiation via inflammatory mechanisms. In obesity, adipocytes produce TNF, IL6 and IL1B. Signaling description: STAT3 and NFkB activation is regarded as the major factors of inflammation-induced tumorigenesis and are activated by cytokines and growth factors in a classical manner. While, IL6/11/22 act through JAK/STAT3 signaling; activation by IL1B involves MYD88/RAC1/IRAC/TRAF6/MAP3K1/STAT3 signaling. Growth factors activate JAK/STAT3 through SRC and ABL1, and TNF activates the classical NFkB pathway. Outcome effects: Activated STAT3 and NFkB induce expression of multiple proteins involved in cancer progression. Specifically, BCL2, BCL2L1, BIRC2/3/5, MCL1, CFLAR inhibit apoptosis of cancer cells. IL6, PTGS2 and some other cytokines (not shown in order to simplify the pathway) enhance inflammation. VEGFA induce angiogenesis. MMP2/9 cleave extracellular matrix proteins, thus, promoting cancer cell invasion and migration. MYC, CCND1/2, CCNB1, FGF2, HGF, HIF1A directly or indirectly regulate cancer cell proliferation. In addition, HIF1A inhibits MSH2/6 proteins involved in DNA repair and makes impact into genomic instability. Inhibition of CDH1 and TWIST1 expression induce epithelial to mesenchymal transition. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. Organ: oncogenic Organ_System: oncogenic PMID: 17186030 PMID: 17476347 PMID: 18650914 PMID: 19851315 PMID: 20018552 PMID: 20303878 PMID: 24154716 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-9ea0ec40-e9f0-4a1a-acc5-23a39ecea899 STAT3 and NFkB Activate Inflammation-Induced Tumorigenesis uuid-9ea0ec40-e9f0-4a1a-acc5-23a39ecea899 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description NFKB and STAT3 are activated both in immune and tumor cells in different types of cancer and promote cancer initiation and progression. In this pathway we focus on NFKB and STAT3 activation in tumor cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ea0ec40-e9f0-4a1a-acc5-23a39ecea899 PS:NodeType Pathway PS:Notes Headnote: Chronic inflammation is one of the leading factors of cancer initiation and progression. Immune cell (predominantly myeloid cells) produce various cytokines and growth factors such as TNF, IL6, IL1B, IL11,IL22, EGF, HGF and others that interact with receptors on the surface of tumor cells. Obesity is also regarded as a chronic inflammation state and makes a great impact into cancer initiation via inflammatory mechanisms. In obesity, adipocytes produce TNF, IL6 and IL1B. Signaling description: STAT3 and NFkB activation is regarded as the major factors of inflammation-induced tumorigenesis and are activated by cytokines and growth factors in a classical manner. While, IL6/11/22 act through JAK/STAT3 signaling; activation by IL1B involves MYD88/RAC1/IRAC/TRAF6/MAP3K1/STAT3 signaling. Growth factors activate JAK/STAT3 through SRC and ABL1, and TNF activates the classical NFkB pathway. Outcome effects: Activated STAT3 and NFkB induce expression of multiple proteins involved in cancer progression. Specifically, BCL2, BCL2L1, BIRC2/3/5, MCL1, CFLAR inhibit apoptosis of cancer cells. IL6, PTGS2 and some other cytokines (not shown in order to simplify the pathway) enhance inflammation. VEGFA induce angiogenesis. MMP2/9 cleave extracellular matrix proteins, thus, promoting cancer cell invasion and migration. MYC, CCND1/2, CCNB1, FGF2, HGF, HIF1A directly or indirectly regulate cancer cell proliferation. In addition, HIF1A inhibits MSH2/6 proteins involved in DNA repair and makes impact into genomic instability. Inhibition of CDH1 and TWIST1 expression induce epithelial to mesenchymal transition. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. See pathway "Proteins with Altered Expression in Tumor-Promoting Inflammation" for details. Mutated proteins: not shown. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17186030 PS:PMID 17476347 PS:PMID 18650914 PS:PMID 19851315 PS:PMID 20018552 PS:PMID 20303878 PS:PMID 24154716 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eaabc27-0d7f-4dfa-9e3a-842c2878e868 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-9eaabc27-0d7f-4dfa-9e3a-842c2878e868 ADRA1 -> Vasoconstriction uuid-9eaabc27-0d7f-4dfa-9e3a-842c2878e868 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eaabc27-0d7f-4dfa-9e3a-842c2878e868 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eb036f0-4196-4741-b7b3-ccd898a45bc4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9eb036f0-4196-4741-b7b3-ccd898a45bc4 CD40LG -> NF-kB/ELK/SRF -> CREB/NFATC Expression Targets uuid-9eb036f0-4196-4741-b7b3-ccd898a45bc4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eb036f0-4196-4741-b7b3-ccd898a45bc4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Endoplasmic-Reticulum (ER) stress is a potent inducer of apoptosis and VEGFA expression in retinal pigment epithelium (RPE) cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ec08c64-4d76-4380-9b32-9af114a525a2 NodeType: Pathway Notes: Headnote: Endoplasmic-Reticulum (ER) stress is a potent inducer of apoptosis and VEGFA expression in retinal pigment epithelium (RPE) cells. Signaling description: Oxidized LDL and homocysteine can activate VEGFA expression via EIF2AK3/ATF4 signaling and in that way trigger neovascularization. 7-Ketocholesterol induces ERN1 signaling and activates caspase-8 (CASP8) and caspase-12 (CASP12). Epidemiological studies have revealed that smoking is a strong risk factor for AMD. Cigarette smoke, which contains benzopyrene, is a potent inducer of ER stress via the EIF2AK3 pathway. Benzopyrene can increase the activity of multiple caspases, including, caspase-3, caspase-9 and caspase-12 in human RPE cells.During ER stress, activated EIF2AK3 phosphorylates EIF2S1, which in turn contributes to the activation of nuclear factor kB (NF-kB), a potent transcriptional factor that regulates angiogenesis and inflammation in proliferative retinal diseases. Increasing levels of inflammatory mediators, such as IL6 and IL8 were been found in the retinas from patients with neovascularisation. Organ: eye Organ_System: sensory system PMID: 20683548 PMID: 23850759 PMID: 25529848 PMID: 26278049 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-9ec08c64-4d76-4380-9b32-9af114a525a2 ER Stress in Macular Degeneration uuid-9ec08c64-4d76-4380-9b32-9af114a525a2 PS:CellType epithelial cell PS:Description Endoplasmic-Reticulum (ER) stress is a potent inducer of apoptosis and VEGFA expression in retinal pigment epithelium (RPE) cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ec08c64-4d76-4380-9b32-9af114a525a2 PS:NodeType Pathway PS:Notes Headnote: Endoplasmic-Reticulum (ER) stress is a potent inducer of apoptosis and VEGFA expression in retinal pigment epithelium (RPE) cells. Signaling description: Oxidized LDL and homocysteine can activate VEGFA expression via EIF2AK3/ATF4 signaling and in that way trigger neovascularization. 7-Ketocholesterol induces ERN1 signaling and activates caspase-8 (CASP8) and caspase-12 (CASP12). Epidemiological studies have revealed that smoking is a strong risk factor for AMD. Cigarette smoke, which contains benzopyrene, is a potent inducer of ER stress via the EIF2AK3 pathway. Benzopyrene can increase the activity of multiple caspases, including, caspase-3, caspase-9 and caspase-12 in human RPE cells.During ER stress, activated EIF2AK3 phosphorylates EIF2S1, which in turn contributes to the activation of nuclear factor kB (NF-kB), a potent transcriptional factor that regulates angiogenesis and inflammation in proliferative retinal diseases. Increasing levels of inflammatory mediators, such as IL6 and IL8 were been found in the retinas from patients with neovascularisation. PS:Organ eye PS:Organ_System sensory system PS:PMID 20683548 PS:PMID 23850759 PS:PMID 25529848 PS:PMID 26278049 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ed89824-7196-465f-823d-faf97de0cd72 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-9ed89824-7196-465f-823d-faf97de0cd72 EDN->EMT uuid-9ed89824-7196-465f-823d-faf97de0cd72 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9ed89824-7196-465f-823d-faf97de0cd72 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eee2c43-6b3f-4220-a181-3c0deb064fc0 NodeType: Pathway Notes: A lack of estrogens causes the activation of osteoclasts, which leads to bone resorption in type I osteoporosis. An estrogen deficiency may induce osteoclast activation. Usually, estrogens prevent bone loss by blocking the production of proinflammatory cytokines such as TNF by bone marrow and bone cells and by preventing excess osteoclast differentiation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-9eee2c43-6b3f-4220-a181-3c0deb064fc0 1_Osteoclast-mediated bone resorption in postmenopausal women uuid-9eee2c43-6b3f-4220-a181-3c0deb064fc0 PS:CellType osteoclast PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9eee2c43-6b3f-4220-a181-3c0deb064fc0 PS:NodeType Pathway PS:Notes A lack of estrogens causes the activation of osteoclasts, which leads to bone resorption in type I osteoporosis. An estrogen deficiency may induce osteoclast activation. Usually, estrogens prevent bone loss by blocking the production of proinflammatory cytokines such as TNF by bone marrow and bone cells and by preventing excess osteoclast differentiation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f2213a9-7b1d-4547-bb7d-d964fdb7cd83 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-9f2213a9-7b1d-4547-bb7d-d964fdb7cd83 Familial Mediterranean Fever Mutated Genes uuid-9f2213a9-7b1d-4547-bb7d-d964fdb7cd83 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f2213a9-7b1d-4547-bb7d-d964fdb7cd83 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f44bc18-8a28-4429-9494-0f767ea397d3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-9f44bc18-8a28-4429-9494-0f767ea397d3 BTC -> CTNN Expression Targets uuid-9f44bc18-8a28-4429-9494-0f767ea397d3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f44bc18-8a28-4429-9494-0f767ea397d3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The INS/IGF1/IRS2/AKT1 pathway leads to the deactivation of FOXO1 and decrease in beta cell proliferation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f8e1efb-c0ca-4db9-91af-9760d061983c NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: In pancreatic beta-cells, FOXO1 inhibition is mediated in part by PDX1 inhibition. In response to oxidative stress, FOXO1 increases the expression of INS and two insulin gene transcription factors, NEUROD1 and MAFA. The acetylation/deacetylation state of FOXO1 is crucial in this process. SIRT1 deacetylases FOXO1 and promotes the expression of INS. EIF2AK2 can be activated by glucolipotoxicity and pro-inflammatory cytokines in pancreatic-beta cells. Activated EIF2AK2 significantly inhibits cell proliferation by arresting the cell cycle at G1 phase. Decreased CCND1 and CCND2 levels as well as the increase of CDKN1B and TP53 levels are associated with anti-proliferative effects of EIF2AK2. Proteasome-dependent degradation takes part in reducing the CCND1 and CCND2 levels. Moreover, EIF2AK2 activation abrogates the pro-proliferative effects of IGFI by activating MAPK8 and disrupting the IRS2/PI3K/AKT1 signaling pathway. Further, SREBF1 suppresses INS/IGF1-related insulin secretion and beta-cell proliferation. SREBF1 target genes are involved in lipid synthesis. SREBF1 suppresses IRS2 activity. The overexpression of SREBF1 has been shown to suppress PDX1 expression both in vivo and in vitro. SYTL4 has been discovered as a direct target of SREBF1 and its knockdown restored insulin secretion in animal models. SYTL4 interacts with insulin-containing vesicles for exocytosis. In rat beta cells, SREBF1 is up-regulated by dietary intake of carbohydrates, sugars, and saturated fatty acids and down-regulated by polyunsaturated fatty acids such as eicosapentaenoate (EPA). In a state of high nutrition, SREBF1 was found to accumulate UCP2 in beta cells. Outcome effects: The INS/IGF1/IRS2/AKT1 pathway deactivates FOXO1 and decreases beta-cell proliferation. However, FOXO1 can still have a role in promoting beta-cell function. The role of FOXO1 in beta-cell function has been studied in mice lacking FOXO1 in their beta-cells. FOXO1 ablation has been shown to cause hyperglycemia with reduced beta-cell mass, physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that the loss of beta-cell mass was due to beta cell dedifferentiation, and not death. Dedifferentiated beta cells reverted to progenitor-like cells expressing NEUROG3, POU5F1, NANOG, and MYCL. A subset of FOXO1-deficient beta-cells adopted the alpha-cell fate, resulting in hyperglucagonemia. Further, SREBF1 accumulates UCP2 in beta-cells. In turn, UCP2 mediates ATP production from mitochondria and thereby regulates insulin secretion in pancreatic beta-cells. Animal data: rodent model. Organ: pancreas Organ_System: endocrine system PMID: 19410555 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9f8e1efb-c0ca-4db9-91af-9760d061983c FOXO1 and SREBP-1C Role in beta-Cell Suppression (Rodent Model) uuid-9f8e1efb-c0ca-4db9-91af-9760d061983c PS:CellType insulin-secreting cell PS:Description The INS/IGF1/IRS2/AKT1 pathway leads to the deactivation of FOXO1 and decrease in beta cell proliferation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f8e1efb-c0ca-4db9-91af-9760d061983c PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: In pancreatic beta-cells, FOXO1 inhibition is mediated in part by PDX1 inhibition. In response to oxidative stress, FOXO1 increases the expression of INS and two insulin gene transcription factors, NEUROD1 and MAFA. The acetylation/deacetylation state of FOXO1 is crucial in this process. SIRT1 deacetylases FOXO1 and promotes the expression of INS. EIF2AK2 can be activated by glucolipotoxicity and pro-inflammatory cytokines in pancreatic-beta cells. Activated EIF2AK2 significantly inhibits cell proliferation by arresting the cell cycle at G1 phase. Decreased CCND1 and CCND2 levels as well as the increase of CDKN1B and TP53 levels are associated with anti-proliferative effects of EIF2AK2. Proteasome-dependent degradation takes part in reducing the CCND1 and CCND2 levels. Moreover, EIF2AK2 activation abrogates the pro-proliferative effects of IGFI by activating MAPK8 and disrupting the IRS2/PI3K/AKT1 signaling pathway. Further, SREBF1 suppresses INS/IGF1-related insulin secretion and beta-cell proliferation. SREBF1 target genes are involved in lipid synthesis. SREBF1 suppresses IRS2 activity. The overexpression of SREBF1 has been shown to suppress PDX1 expression both in vivo and in vitro. SYTL4 has been discovered as a direct target of SREBF1 and its knockdown restored insulin secretion in animal models. SYTL4 interacts with insulin-containing vesicles for exocytosis. In rat beta cells, SREBF1 is up-regulated by dietary intake of carbohydrates, sugars, and saturated fatty acids and down-regulated by polyunsaturated fatty acids such as eicosapentaenoate (EPA). In a state of high nutrition, SREBF1 was found to accumulate UCP2 in beta cells. Outcome effects: The INS/IGF1/IRS2/AKT1 pathway deactivates FOXO1 and decreases beta-cell proliferation. However, FOXO1 can still have a role in promoting beta-cell function. The role of FOXO1 in beta-cell function has been studied in mice lacking FOXO1 in their beta-cells. FOXO1 ablation has been shown to cause hyperglycemia with reduced beta-cell mass, physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that the loss of beta-cell mass was due to beta cell dedifferentiation, and not death. Dedifferentiated beta cells reverted to progenitor-like cells expressing NEUROG3, POU5F1, NANOG, and MYCL. A subset of FOXO1-deficient beta-cells adopted the alpha-cell fate, resulting in hyperglucagonemia. Further, SREBF1 accumulates UCP2 in beta-cells. In turn, UCP2 mediates ATP production from mitochondria and thereby regulates insulin secretion in pancreatic beta-cells. Animal data: rodent model. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19410555 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: Impaired renal uric acid excretion is a prevalent cause of gout. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f961bae-7233-48d2-9d01-2196f685b28e NodeType: Pathway Notes: Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. Impaired renal uric acid excretion is the prevalent cause of gout. Signaling description: In general, the process of renal urate transport consists of four steps including glomerular filtration, near-complete reabsorption of filtered urate, subsequent secretion, and postsecretory reabsorption in the remaining proximal tubule. Normally, following glomerular filtration of 100% of urate, 98% of it is reabsorbed in the first part of the proximal tubule, followed by 50% secretion in the second part of the tubule with further reabsorption of approximately 40-48%, resulting in a net reabsorption of approximately 90% leading to only 8-12% of uric acid being excreted by the kidney. In pathology, impaired function of uric acid transporters cause decreased urate excretion. Outcome effects: Abnormalities in SLC22A12 and SLC2A9 genes cause increased urate reabsorption. SLC2A9 is a high-affinity urate transporter, and it functions in renal urate reabsorption by transporting urate from tubular cells to the peritubular interstitium following the uptake of urate from the luminal space by SLC22A12. Urate secretion from blood into the epithelial cell occurs via several transporters including SLC22A6 and SLC22A8, and from the cell to the tubule space (where urine is located) via another group of transporters including SLC17A1, SLC17A3, ABCG2, ABCC4, and LGALS9. Loss of function mutations in ABCG2 and SLC17A3 genes impair uric acid secretion thereby promoting its accumulation in the serum. Further, downregulation of SLC22 transporter expression by estrogens in premenopausal women diminishes urate reabsorption. As a result, elevated urate levels may cause clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 23089270 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-9f961bae-7233-48d2-9d01-2196f685b28e Uric Acid Excretion Impairement in Kidney in Gout uuid-9f961bae-7233-48d2-9d01-2196f685b28e PS:CellType epithelial cell PS:Description Impaired renal uric acid excretion is a prevalent cause of gout. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9f961bae-7233-48d2-9d01-2196f685b28e PS:NodeType Pathway PS:Notes Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. Impaired renal uric acid excretion is the prevalent cause of gout. Signaling description: In general, the process of renal urate transport consists of four steps including glomerular filtration, near-complete reabsorption of filtered urate, subsequent secretion, and postsecretory reabsorption in the remaining proximal tubule. Normally, following glomerular filtration of 100% of urate, 98% of it is reabsorbed in the first part of the proximal tubule, followed by 50% secretion in the second part of the tubule with further reabsorption of approximately 40-48%, resulting in a net reabsorption of approximately 90% leading to only 8-12% of uric acid being excreted by the kidney. In pathology, impaired function of uric acid transporters cause decreased urate excretion. Outcome effects: Abnormalities in SLC22A12 and SLC2A9 genes cause increased urate reabsorption. SLC2A9 is a high-affinity urate transporter, and it functions in renal urate reabsorption by transporting urate from tubular cells to the peritubular interstitium following the uptake of urate from the luminal space by SLC22A12. Urate secretion from blood into the epithelial cell occurs via several transporters including SLC22A6 and SLC22A8, and from the cell to the tubule space (where urine is located) via another group of transporters including SLC17A1, SLC17A3, ABCG2, ABCC4, and LGALS9. Loss of function mutations in ABCG2 and SLC17A3 genes impair uric acid secretion thereby promoting its accumulation in the serum. Further, downregulation of SLC22 transporter expression by estrogens in premenopausal women diminishes urate reabsorption. As a result, elevated urate levels may cause clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 23089270 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fb078c5-e061-40ce-ac8a-a34824a7cb99 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-9fb078c5-e061-40ce-ac8a-a34824a7cb99 CD19 Expression Targets uuid-9fb078c5-e061-40ce-ac8a-a34824a7cb99 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fb078c5-e061-40ce-ac8a-a34824a7cb99 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fb9ef05-af52-4b6f-a0c9-ceffb3b4db22 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-9fb9ef05-af52-4b6f-a0c9-ceffb3b4db22 COVID19 proteins uuid-9fb9ef05-af52-4b6f-a0c9-ceffb3b4db22 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fb9ef05-af52-4b6f-a0c9-ceffb3b4db22 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fd0a94d-9831-49d7-afe5-5cb277c6cefb NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-9fd0a94d-9831-49d7-afe5-5cb277c6cefb T-lymphoid precursor cell -> CD8+ Naive T-cell Surface Expression Markers uuid-9fd0a94d-9831-49d7-afe5-5cb277c6cefb PS:CellType T-cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fd0a94d-9831-49d7-afe5-5cb277c6cefb PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Insulin growth factor 1 (IGF1) and myostatin (MSTN) are important regulators of muscle size. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fd9f54d-9a7e-41d3-b2eb-350a6c71677a NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Insulin growth factor 1 (IGF1) and myostatin (MSTN) are important regulators of muscle size. IGF1 stimulates muscle hypertrophy, while MSTN represses hypertrophy and induces atrophy. IGF1 and MSTN signaling pathways interact with each other. MSTN decreases the phosphorylation of AKT1, which occurs as a result of IGF1 action. It can also increase the activity of FOXO, a factor that is repressed by IGF1/AKT1 signaling. Outcome effects: The inhibition of AKT1 and activation of FOXO lead to a blockade of IGF1 action, prevention of myogenesis, and activation of atrophy. In turn, IGF1/AKT1 signaling represses FOXO thereby preventing some of the MSTN effects. The balance between IGF1 and MSTN signaling is important for muscle size determination. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-9fd9f54d-9a7e-41d3-b2eb-350a6c71677a Myostatin-IGF1 Crosstalk in Skeletal Muscles in Muscular Dystrophies uuid-9fd9f54d-9a7e-41d3-b2eb-350a6c71677a PS:CellType muscle cell PS:Description Insulin growth factor 1 (IGF1) and myostatin (MSTN) are important regulators of muscle size. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fd9f54d-9a7e-41d3-b2eb-350a6c71677a PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Insulin growth factor 1 (IGF1) and myostatin (MSTN) are important regulators of muscle size. IGF1 stimulates muscle hypertrophy, while MSTN represses hypertrophy and induces atrophy. IGF1 and MSTN signaling pathways interact with each other. MSTN decreases the phosphorylation of AKT1, which occurs as a result of IGF1 action. It can also increase the activity of FOXO, a factor that is repressed by IGF1/AKT1 signaling. Outcome effects: The inhibition of AKT1 and activation of FOXO lead to a blockade of IGF1 action, prevention of myogenesis, and activation of atrophy. In turn, IGF1/AKT1 signaling represses FOXO thereby preventing some of the MSTN effects. The balance between IGF1 and MSTN signaling is important for muscle size determination. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fdbd346-7213-4dcd-a09c-041143c879d7 NodeType: Pathway Notes: HIV targets several cell types including T-cell subsets, monocytes, macrophages, and dendritic cells (DCs) through different recognition mechanisms. However, the primary target of HIV is mucosal CD4+ memory T cells expressing CD4+ and CCR5 and mucosal macrophages expressing CCR5. The formation of viral synapses and the accumulation of HIV in mucosal macrophages are important for HIV progression. Following HIV penetration of the host cell, the virus modulates transcriptional regulation, mRNA processing, intracellular protein transport, and the cytoskeleton to maintain viral reproduction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-9fdbd346-7213-4dcd-a09c-041143c879d7 1_HIV entrance to the host cell and viral reproduction uuid-9fdbd346-7213-4dcd-a09c-041143c879d7 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fdbd346-7213-4dcd-a09c-041143c879d7 PS:NodeType Pathway PS:Notes HIV targets several cell types including T-cell subsets, monocytes, macrophages, and dendritic cells (DCs) through different recognition mechanisms. However, the primary target of HIV is mucosal CD4+ memory T cells expressing CD4+ and CCR5 and mucosal macrophages expressing CCR5. The formation of viral synapses and the accumulation of HIV in mucosal macrophages are important for HIV progression. Following HIV penetration of the host cell, the virus modulates transcriptional regulation, mRNA processing, intracellular protein transport, and the cytoskeleton to maintain viral reproduction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fdde8d9-ba7c-4393-9cb1-ac6d5e26c142 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-9fdde8d9-ba7c-4393-9cb1-ac6d5e26c142 Methionine Metabolism uuid-9fdde8d9-ba7c-4393-9cb1-ac6d5e26c142 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fdde8d9-ba7c-4393-9cb1-ac6d5e26c142 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: leukocyte Description: Endothelial cells are involved in many aspects of vascular biology including inflammation and angiogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fe11ece-b51d-477b-b7e0-6e55527e6a05 NodeType: Pathway Notes: Headnote: Endothelial cells are involved in many aspects of vascular biology including inflammation and angiogenesis. Endothelial-leukocyte cell adhesion plays a major role in cellular communication and regulation and is significant for the development and maintenance of tissues. Signaling description: Leukocytes are key players in the inflammatory response due to their antimicrobial, secretory, and phagocytic activities. Leukocytes leave the circulation after passing through the endothelial layer.The process of leukocyte adhesion to the endothelium involves three stages: rolling, integrin activation, and stable adhesion followed by migration through the endothelium. At each stage, special intracellular molecular bonds are required. On the endothelial cell surface, SELE and SELP are initially involved in the process of leukocyte-endothelial cell interaction. In addition, cell adhesion molecules, such as ICAM and VCAM, on the surface of endothelial cells are key proteins that provide endothelial cell adhesiveness. Outcome effects: The passage of leukocytes through the endothelium requires the activation of leukocyte motility via a family of integrins on the surface of leukocytes. Integrin-related intra-leukocyte signaling occurs through the activation of actin-linked proteins including ACTN1, VCL, PTK2, and TLN1. The activation of actin filaments results in contraction of the cell, which helps the passage of leukocytes through the extracellular space (for more details, see ""Neutrophil Activation via Adherence on Endothelial Cells""). Organ: blood vessel Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-9fe11ece-b51d-477b-b7e0-6e55527e6a05 Leukocyte Adhesion to Endothelial Cell uuid-9fe11ece-b51d-477b-b7e0-6e55527e6a05 PS:CellType endothelial cell PS:CellType leukocyte PS:Description Endothelial cells are involved in many aspects of vascular biology including inflammation and angiogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fe11ece-b51d-477b-b7e0-6e55527e6a05 PS:NodeType Pathway PS:Notes Headnote: Endothelial cells are involved in many aspects of vascular biology including inflammation and angiogenesis. Endothelial-leukocyte cell adhesion plays a major role in cellular communication and regulation and is significant for the development and maintenance of tissues. Signaling description: Leukocytes are key players in the inflammatory response due to their antimicrobial, secretory, and phagocytic activities. Leukocytes leave the circulation after passing through the endothelial layer.The process of leukocyte adhesion to the endothelium involves three stages: rolling, integrin activation, and stable adhesion followed by migration through the endothelium. At each stage, special intracellular molecular bonds are required. On the endothelial cell surface, SELE and SELP are initially involved in the process of leukocyte-endothelial cell interaction. In addition, cell adhesion molecules, such as ICAM and VCAM, on the surface of endothelial cells are key proteins that provide endothelial cell adhesiveness. Outcome effects: The passage of leukocytes through the endothelium requires the activation of leukocyte motility via a family of integrins on the surface of leukocytes. Integrin-related intra-leukocyte signaling occurs through the activation of actin-linked proteins including ACTN1, VCL, PTK2, and TLN1. The activation of actin filaments results in contraction of the cell, which helps the passage of leukocytes through the extracellular space (for more details, see ""Neutrophil Activation via Adherence on Endothelial Cells""). PS:Organ blood vessel PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fe40ec8-426d-4a26-b9e7-62dd503a6dd1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-9fe40ec8-426d-4a26-b9e7-62dd503a6dd1 SARS Viroponins (ORF3a, E) uuid-9fe40ec8-426d-4a26-b9e7-62dd503a6dd1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9fe40ec8-426d-4a26-b9e7-62dd503a6dd1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9feed285-efec-489e-9e70-df8cf63d6299 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-9feed285-efec-489e-9e70-df8cf63d6299 AAT Deficiency_Mutated genes uuid-9feed285-efec-489e-9e70-df8cf63d6299 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-9feed285-efec-489e-9e70-df8cf63d6299 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a02fc684-dc0f-4931-9cbc-1f2e379d4298 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a02fc684-dc0f-4931-9cbc-1f2e379d4298 BMP6/ACVR2A Expression Targets uuid-a02fc684-dc0f-4931-9cbc-1f2e379d4298 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a02fc684-dc0f-4931-9cbc-1f2e379d4298 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of PI3K-AKT-MTOR signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a037bad3-3de4-4db1-9503-27378bec4bc3 NodeType: Pathway Notes: Headnote: The PI3K/AKT/MTOR pathway is an essential player in cell cycle regulation. Therefore, it is directly related to cellular quiescence, proliferation, longevity and is often dysregulated in cancer. Signaling description: Direct activation of PI3K by activated G protein-coupled receptors or receptor tyrosine kinase leads to phosphorylation and activation of AKT which, in turn, activates multiple downstream targets. Activating mutations of PIK3CA, PIK3R1, AKT1/2/3 contribute to cancer progression. Outcome effects: Due to lack of natural inhibitors, PI3K-AKT-MTOR signaling is switched on which leads to uncontrolled cell proliferation, inhibition of apoptosis and cancer progression. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15023437 PMID: 18794884 PMID: 19275762 PMID: 21487159 PMID: 24782981 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a037bad3-3de4-4db1-9503-27378bec4bc3 PI3K/AKT/MTOR Signaling Activation by Blocking of Tumor Suppressors uuid-a037bad3-3de4-4db1-9503-27378bec4bc3 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of PI3K-AKT-MTOR signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a037bad3-3de4-4db1-9503-27378bec4bc3 PS:NodeType Pathway PS:Notes Headnote: The PI3K/AKT/MTOR pathway is an essential player in cell cycle regulation. Therefore, it is directly related to cellular quiescence, proliferation, longevity and is often dysregulated in cancer. Signaling description: Direct activation of PI3K by activated G protein-coupled receptors or receptor tyrosine kinase leads to phosphorylation and activation of AKT which, in turn, activates multiple downstream targets. Activating mutations of PIK3CA, PIK3R1, AKT1/2/3 contribute to cancer progression. Outcome effects: Due to lack of natural inhibitors, PI3K-AKT-MTOR signaling is switched on which leads to uncontrolled cell proliferation, inhibition of apoptosis and cancer progression. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15023437 PS:PMID 18794884 PS:PMID 19275762 PS:PMID 21487159 PS:PMID 24782981 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a06c00a2-1783-4113-b4bf-cf136b2675e3 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-a06c00a2-1783-4113-b4bf-cf136b2675e3 Elevated Receptors -> Expression Targets in Blood uuid-a06c00a2-1783-4113-b4bf-cf136b2675e3 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a06c00a2-1783-4113-b4bf-cf136b2675e3 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a075a6ef-a070-4cc1-98d9-e7acfcf64b4e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a075a6ef-a070-4cc1-98d9-e7acfcf64b4e Morphine Expression Targets uuid-a075a6ef-a070-4cc1-98d9-e7acfcf64b4e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a075a6ef-a070-4cc1-98d9-e7acfcf64b4e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a080d547-f16b-453c-8f30-b7f5d1118a66 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a080d547-f16b-453c-8f30-b7f5d1118a66 COVID19 clinical trials uuid-a080d547-f16b-453c-8f30-b7f5d1118a66 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a080d547-f16b-453c-8f30-b7f5d1118a66 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0999a9f-eabb-49d4-9ef3-5f589462c483 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a0999a9f-eabb-49d4-9ef3-5f589462c483 SARS Spike (S) protein inhibitors uuid-a0999a9f-eabb-49d4-9ef3-5f589462c483 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0999a9f-eabb-49d4-9ef3-5f589462c483 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: Specific role of macrophages was described in age-related macular degeneration. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a09de414-828e-4ebe-8fe2-2532d93d7145 NodeType: Pathway Notes: TLR3 signaling was shown to play controversial role in retinal pigment epithelium cells (RPE). In the one hand, TLR3 activation by double-stranded RNA may activate caspase-3-mediated apoptotic death in RPE via IRF3 and probably IRF7. In the other hand, activation of TLR3 by poly(I:C) protects RPE from oxidative stress and cell death. Organ: Retina Organ: eye Organ_System: sensory system PMID: 20237997 PMID: 21884302 PMID: 22175541 PMID: 23933169 PMID: 26260587 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a09de414-828e-4ebe-8fe2-2532d93d7145 IL10/STAT3 Signaling in M2 Macrophage and Retinal Angiogenesis uuid-a09de414-828e-4ebe-8fe2-2532d93d7145 PS:CellType macrophage PS:Description Specific role of macrophages was described in age-related macular degeneration. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a09de414-828e-4ebe-8fe2-2532d93d7145 PS:NodeType Pathway PS:Notes TLR3 signaling was shown to play controversial role in retinal pigment epithelium cells (RPE). In the one hand, TLR3 activation by double-stranded RNA may activate caspase-3-mediated apoptotic death in RPE via IRF3 and probably IRF7. In the other hand, activation of TLR3 by poly(I:C) protects RPE from oxidative stress and cell death. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 20237997 PS:PMID 21884302 PS:PMID 22175541 PS:PMID 23933169 PS:PMID 26260587 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: Glucocorticoid resistance in COPD is associated with reduced activation and expression of histone deacetylase 2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0bb8aef-9bd9-40db-8085-474a2f2194a1 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Glucocorticoid resistance in COPD is associated with reduced activation and expression of histone deacetylase 2 (HDAC2). Superoxide anions and nitric oxide (NO) generated by cigarette smoke and inflammatory cells combine to form peroxynitrite. Peroxynitrite nitrates HDAC2, which inactivates it and results in its degradation by the proteasome. Oxidative stress also activates PI3K, which inactivates HDAC2. Outcome effects: The loss of HDAC2 function results in an enhanced inflammatory gene expression and blocks the anti-inflammatory action of corticosteroids. SIRT1 and SIRT6 normally inhibit RELA-associated cytokine production; however they are downregulated in lung cells from COPD patients as a result of cigarette smoke exposure. In normal conditions, deacetylation of the glucocorticoid receptor (NR3C1) by HDAC2 enables RELA suppression. When HDAC2 is downregulated, RELA suppression by NR3C1 fails to occur. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue Organ: lung Organ_System: respiratory system PMID: 16865089 PMID: 23977698 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a0bb8aef-9bd9-40db-8085-474a2f2194a1 Glucocorticoid Resistance uuid-a0bb8aef-9bd9-40db-8085-474a2f2194a1 PS:CellType macrophage PS:Description Glucocorticoid resistance in COPD is associated with reduced activation and expression of histone deacetylase 2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0bb8aef-9bd9-40db-8085-474a2f2194a1 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Glucocorticoid resistance in COPD is associated with reduced activation and expression of histone deacetylase 2 (HDAC2). Superoxide anions and nitric oxide (NO) generated by cigarette smoke and inflammatory cells combine to form peroxynitrite. Peroxynitrite nitrates HDAC2, which inactivates it and results in its degradation by the proteasome. Oxidative stress also activates PI3K, which inactivates HDAC2. Outcome effects: The loss of HDAC2 function results in an enhanced inflammatory gene expression and blocks the anti-inflammatory action of corticosteroids. SIRT1 and SIRT6 normally inhibit RELA-associated cytokine production; however they are downregulated in lung cells from COPD patients as a result of cigarette smoke exposure. In normal conditions, deacetylation of the glucocorticoid receptor (NR3C1) by HDAC2 enables RELA suppression. When HDAC2 is downregulated, RELA suppression by NR3C1 fails to occur. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue PS:Organ lung PS:Organ_System respiratory system PS:PMID 16865089 PS:PMID 23977698 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0c63208-ec44-4ff4-a948-61f7ded9331f NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-a0c63208-ec44-4ff4-a948-61f7ded9331f Branched Chain Amino Acids Metabolism uuid-a0c63208-ec44-4ff4-a948-61f7ded9331f PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a0c63208-ec44-4ff4-a948-61f7ded9331f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: There are 17 identified CXC chemokines in mammals. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a10a23f6-67c7-43f1-a5cd-99c29c9ec4f0 NodeType: Pathway Notes: Headnote: There are 17 identified CXC chemokines in mammals. They are subdivided into two categories including those with a specific motif of glutamic acid-leucine-arginine (ELR) immediately before the first cysteine residue of the CXC motif (ELR-positive) and those without an ELR motif (ELR-negative). Signaling description: ELR-positive CXC chemokines specifically induce the migration of neutrophils and interact with chemokine receptors such as CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, which are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, which is a large family of G-protein-linked receptors known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals named CXCR1 through 7. Intracellular signaling by chemokine receptors is dependent on neighboring G-proteins. G-proteins exist as heterotrimers and are composed of three distinct subunits. When the molecule GDP is bound to the G-protein subunit, the G-protein is in an inactive state. Following the binding of the chemokine ligand, chemokine receptors associate with G-proteins, allowing the exchange of GDP for GTP, and the dissociation of the different G-protein subunits. The subunit Gb/g activates PLCB1 that is associated with the cell membrane. PLC cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) to form two second messenger molecules including inositol 1,4,5 -trisphosphate (IP3) and diacylglycerol. Diacylglycerol activates protein kinase C (PKC) and IP3 triggers the release of calcium (Ca2+) from intracellular stores. Outcome effects: The described events promote many signaling cascades, which cause a cellular response. CXCL8 (IL8) binds to its specific receptors, CXCR1 or CXCR2. A rise in intracellular Ca2+ activates phospholipase D (PLD), which in turn, initiates the MAP kinase pathway. Concurrently, the G-protein subunit G alpha i (GNAI1) directly activates protein tyrosine kinase (PTK2) which phosphorylates serine and threonine residues in the tail of the chemokine receptor, causing its desensitization or inactivation. The initiated MAP kinase pathway activates specific cellular mechanisms involved in chemotaxis, degranulation, release of superoxide anions, and changes in the avidity of cell adhesion molecules called integrins. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Biological Process Tissue: generic urn:agi-pathway:uuid-a10a23f6-67c7-43f1-a5cd-99c29c9ec4f0 CXC Chemokine Receptor Signaling uuid-a10a23f6-67c7-43f1-a5cd-99c29c9ec4f0 PS:CellType generic PS:Description There are 17 identified CXC chemokines in mammals. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a10a23f6-67c7-43f1-a5cd-99c29c9ec4f0 PS:NodeType Pathway PS:Notes Headnote: There are 17 identified CXC chemokines in mammals. They are subdivided into two categories including those with a specific motif of glutamic acid-leucine-arginine (ELR) immediately before the first cysteine residue of the CXC motif (ELR-positive) and those without an ELR motif (ELR-negative). Signaling description: ELR-positive CXC chemokines specifically induce the migration of neutrophils and interact with chemokine receptors such as CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, which are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, which is a large family of G-protein-linked receptors known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals named CXCR1 through 7. Intracellular signaling by chemokine receptors is dependent on neighboring G-proteins. G-proteins exist as heterotrimers and are composed of three distinct subunits. When the molecule GDP is bound to the G-protein subunit, the G-protein is in an inactive state. Following the binding of the chemokine ligand, chemokine receptors associate with G-proteins, allowing the exchange of GDP for GTP, and the dissociation of the different G-protein subunits. The subunit Gb/g activates PLCB1 that is associated with the cell membrane. PLC cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) to form two second messenger molecules including inositol 1,4,5 -trisphosphate (IP3) and diacylglycerol. Diacylglycerol activates protein kinase C (PKC) and IP3 triggers the release of calcium (Ca2+) from intracellular stores. Outcome effects: The described events promote many signaling cascades, which cause a cellular response. CXCL8 (IL8) binds to its specific receptors, CXCR1 or CXCR2. A rise in intracellular Ca2+ activates phospholipase D (PLD), which in turn, initiates the MAP kinase pathway. Concurrently, the G-protein subunit G alpha i (GNAI1) directly activates protein tyrosine kinase (PTK2) which phosphorylates serine and threonine residues in the tail of the chemokine receptor, causing its desensitization or inactivation. The initiated MAP kinase pathway activates specific cellular mechanisms involved in chemotaxis, degranulation, release of superoxide anions, and changes in the avidity of cell adhesion molecules called integrins. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a10f7577-58dd-4f15-accf-a3b2dc3d1ae4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-a10f7577-58dd-4f15-accf-a3b2dc3d1ae4 DHH+>GLI+>cornea differentiation uuid-a10f7577-58dd-4f15-accf-a3b2dc3d1ae4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a10f7577-58dd-4f15-accf-a3b2dc3d1ae4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1102ed0-e01f-40fc-8727-1e4057d5de3d NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: thymus gland Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-a1102ed0-e01f-40fc-8727-1e4057d5de3d Elevated Receptors -> Expression Targets in Thymus uuid-a1102ed0-e01f-40fc-8727-1e4057d5de3d PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1102ed0-e01f-40fc-8727-1e4057d5de3d PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ thymus gland PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1165786-0b63-4a0f-b83f-99c3bb075a4b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a1165786-0b63-4a0f-b83f-99c3bb075a4b tRNA charging template uuid-a1165786-0b63-4a0f-b83f-99c3bb075a4b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1165786-0b63-4a0f-b83f-99c3bb075a4b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a126e988-8daf-4e36-ab94-bfdce07d0ad0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-a126e988-8daf-4e36-ab94-bfdce07d0ad0 CO-|fibroblast <+ROS uuid-a126e988-8daf-4e36-ab94-bfdce07d0ad0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a126e988-8daf-4e36-ab94-bfdce07d0ad0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Double strand DNA breaks are common events in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a12aaa40-f6d8-4297-bfe5-301691cb77f0 NodeType: Pathway Notes: Headnote: Double strand DNA breaks are common events in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). NHEJ double strand repair recovers two broken DNA ends without using a homologous template. Signaling description: In NHEJ, XRCC6/XRCC5 heterodimer protein associates with free DNA ends and recruits other factors including DNA-dependent protein kinase (PRKDC). During DNA binding, PRKDC becomes activated and phosphorylates multiple proteins including DNA ligase IV (LIG4) cofactor XRCC4. Microhomology-mediated end joining (MMEJ) is XRCC6/XRCC5-independent NHEJ that makes use of short homologous sequences called microhomologies, existing in single-stranded overhangs on the ends of double-stranded gaps. MMEJ is based on ligating hung mismatched DNA ends that remove overhanging nucleotides and fills the gaps. MMEJ results in removing mutations from the genetic code. In most cases, MMEJ is used only when NHEJ is impossible. Outcome effects: The final step of NHEJ involves the ligation of DNA ends by LIG4. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-a12aaa40-f6d8-4297-bfe5-301691cb77f0 Double Strand DNA non-Homologous Repair uuid-a12aaa40-f6d8-4297-bfe5-301691cb77f0 PS:CellType generic PS:Description Double strand DNA breaks are common events in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a12aaa40-f6d8-4297-bfe5-301691cb77f0 PS:NodeType Pathway PS:Notes Headnote: Double strand DNA breaks are common events in eukaryotic cells and the two major pathways for repairing them are homologous recombination (HR) and non-homologous DNA end joining (NHEJ). NHEJ double strand repair recovers two broken DNA ends without using a homologous template. Signaling description: In NHEJ, XRCC6/XRCC5 heterodimer protein associates with free DNA ends and recruits other factors including DNA-dependent protein kinase (PRKDC). During DNA binding, PRKDC becomes activated and phosphorylates multiple proteins including DNA ligase IV (LIG4) cofactor XRCC4. Microhomology-mediated end joining (MMEJ) is XRCC6/XRCC5-independent NHEJ that makes use of short homologous sequences called microhomologies, existing in single-stranded overhangs on the ends of double-stranded gaps. MMEJ is based on ligating hung mismatched DNA ends that remove overhanging nucleotides and fills the gaps. MMEJ results in removing mutations from the genetic code. In most cases, MMEJ is used only when NHEJ is impossible. Outcome effects: The final step of NHEJ involves the ligation of DNA ends by LIG4. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a150b080-e111-4123-903e-b065bda5b73b NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-a150b080-e111-4123-903e-b065bda5b73b F2R/F2RL1 -> Expression Targets in Lymphoid System and Blood uuid-a150b080-e111-4123-903e-b065bda5b73b PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a150b080-e111-4123-903e-b065bda5b73b PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: FK506 binding protein 5 (FKBP5) is a protein that belongs to the immunophilin protein family. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a15988ea-ed36-4076-bba4-6c9dbcbbfcb4 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: FK506 binding protein 5 (FKBP5) is a protein that belongs to the immunophilin protein family. The protein is involved in immunosuppressant signaling, protein folding and trafficking. It has been shown that FKBP5 binds to heat shock protein 90 (HSP90AA1) and modulates the affinity of steroid receptors. Particularly, FKBP5 can influence androgen receptor (AR) stability through its binding to HSP90AA1. Another possible role of FKBP5 in AR signaling is the regulation of glucocorticoid action. Under physiological conditions, FKBP5 participates in the formation of the mature glucocorticoid receptor complex, NR3C1 (nuclear receptor subfamily 3, group C, member 1 also known as glucocorticoid receptor). However, overexpression of FKBP5 was found to reduce NR3C1 hormone binding affinity. Outcome effects: The reduced hormone binding affinity of NR3C1 may casue increased cell proliferation and inhibition of apoptosis since NR3C1 can regulate these processes through the mechanism of transrepression. In particular, NR3C1 can complex with NF-kB preventing them from regulating target genes. NR3C1can also inhibit the MAPK cascade. There is evidence that NR3C1serves as a tumor suppressor in prostate cells and is often downregulated or absent in prostate cancer specimens and cell lines. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ: prostate Organ_System: urinary tract PMID: 21565552 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a15988ea-ed36-4076-bba4-6c9dbcbbfcb4 Androgen Receptor/FKBP5 Signaling uuid-a15988ea-ed36-4076-bba4-6c9dbcbbfcb4 PS:CellType cancer cell PS:Description FK506 binding protein 5 (FKBP5) is a protein that belongs to the immunophilin protein family. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a15988ea-ed36-4076-bba4-6c9dbcbbfcb4 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: FK506 binding protein 5 (FKBP5) is a protein that belongs to the immunophilin protein family. The protein is involved in immunosuppressant signaling, protein folding and trafficking. It has been shown that FKBP5 binds to heat shock protein 90 (HSP90AA1) and modulates the affinity of steroid receptors. Particularly, FKBP5 can influence androgen receptor (AR) stability through its binding to HSP90AA1. Another possible role of FKBP5 in AR signaling is the regulation of glucocorticoid action. Under physiological conditions, FKBP5 participates in the formation of the mature glucocorticoid receptor complex, NR3C1 (nuclear receptor subfamily 3, group C, member 1 also known as glucocorticoid receptor). However, overexpression of FKBP5 was found to reduce NR3C1 hormone binding affinity. Outcome effects: The reduced hormone binding affinity of NR3C1 may casue increased cell proliferation and inhibition of apoptosis since NR3C1 can regulate these processes through the mechanism of transrepression. In particular, NR3C1 can complex with NF-kB preventing them from regulating target genes. NR3C1can also inhibit the MAPK cascade. There is evidence that NR3C1serves as a tumor suppressor in prostate cells and is often downregulated or absent in prostate cancer specimens and cell lines. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 21565552 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a163609b-560b-4fea-8f59-06eef0394d9c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a163609b-560b-4fea-8f59-06eef0394d9c Tryptophane degradation (bacteria) template uuid-a163609b-560b-4fea-8f59-06eef0394d9c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a163609b-560b-4fea-8f59-06eef0394d9c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1767bf7-04c3-470b-bbba-051d975208d9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-a1767bf7-04c3-470b-bbba-051d975208d9 Granulocytes->Neurons uuid-a1767bf7-04c3-470b-bbba-051d975208d9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1767bf7-04c3-470b-bbba-051d975208d9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: TGFB signaling plays a major role in epithelial-to-mesenchymal transition, a transformation process of non-mobile epithelial-like cells into mobile, making impact to metastatic dissemination. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a18088ca-35a5-4dbb-b36b-db1ea387ea58 NodeType: Pathway Notes: Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. TGFB signaling has a major role in EMT. Signaling description: TGFB activates several signaling routes, leading to EMT. The first is TGFBR/SMAD signaling activating specific embryonic transcription factors ZEB1/2 and SNAI1/2. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins inhibiting cell adhesion and activating cell migration (ex., CDH2, VIM, FN1, TNC, MMP2/9/15). The TGFBR/RAS/MAPK activation leads to SMADs regulation as well. The second is PI3K/AKT1/MTOR signaling which has it's own role in cell motility activation and invasion. The third signaling path involves TGFBR interaction with CDC42 and RHOA that activate cell migration through induction of actin polymerization. Outcome effects: Theses processes lead to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18539112 PMID: 19153598 PMID: 24556840 PMID: 25240174 PMID: 25249658 PMID: 25482613 PMID: 27340590 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a18088ca-35a5-4dbb-b36b-db1ea387ea58 TGFB Family in Epithelial to Mesenchymal Transition in Cancer uuid-a18088ca-35a5-4dbb-b36b-db1ea387ea58 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description TGFB signaling plays a major role in epithelial-to-mesenchymal transition, a transformation process of non-mobile epithelial-like cells into mobile, making impact to metastatic dissemination. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a18088ca-35a5-4dbb-b36b-db1ea387ea58 PS:NodeType Pathway PS:Notes Headnote: Epithelial-to-mesenchymal transition (EMT), the process first noted during embryogenesis, guides the transformation of non-mobile epithelial-like cells into mobile, mesenchymal-like cells that have the potential to travel to distant anatomical sites. This process has also been observed during tumor formation and may lead to the development of metastatic dissemination. TGFB signaling has a major role in EMT. Signaling description: TGFB activates several signaling routes, leading to EMT. The first is TGFBR/SMAD signaling activating specific embryonic transcription factors ZEB1/2 and SNAI1/2. These transcription factors down-regulate proteins responsible for cell adhesion and inhibiting cell motility (ex., CDH1, OCLN, CLDN1/7, TJP1, KRT18/19) and up-regulate proteins inhibiting cell adhesion and activating cell migration (ex., CDH2, VIM, FN1, TNC, MMP2/9/15). The TGFBR/RAS/MAPK activation leads to SMADs regulation as well. The second is PI3K/AKT1/MTOR signaling which has it's own role in cell motility activation and invasion. The third signaling path involves TGFBR interaction with CDC42 and RHOA that activate cell migration through induction of actin polymerization. Outcome effects: Theses processes lead to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18539112 PS:PMID 19153598 PS:PMID 24556840 PS:PMID 25240174 PS:PMID 25249658 PS:PMID 25482613 PS:PMID 27340590 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of PI3K/AKT/MTOR signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a190eeab-20fb-46e3-b7d2-35938d77d57e NodeType: Pathway Notes: Headnote: The PI3K/AKT/MTOR pathway is important for cell cycle regulation and is directly related to cellular quiescence, proliferation, longevity and is often dysregulated in cancer. Signaling description: Direct activation of PI3K by activated G protein-coupled receptors or receptor tyrosine kinase leads to phosphorylation and activation of AKT which, in turn, activates multiple downstream targets. Activating mutations of PIK3CA, PIK3R1, AKT1/2/3 contribute to cancer progression. Outcome effects: PI3K/AKT/MTOR signaling is switched-on which leads to uncontrolled cell proliferation, inhibition of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 15023437 PMID: 18794883 PMID: 18794884 PMID: 20582532 PMID: 24782981 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a190eeab-20fb-46e3-b7d2-35938d77d57e PI3K/AKT/MTOR Signaling Activation in Cancer uuid-a190eeab-20fb-46e3-b7d2-35938d77d57e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of PI3K/AKT/MTOR signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a190eeab-20fb-46e3-b7d2-35938d77d57e PS:NodeType Pathway PS:Notes Headnote: The PI3K/AKT/MTOR pathway is important for cell cycle regulation and is directly related to cellular quiescence, proliferation, longevity and is often dysregulated in cancer. Signaling description: Direct activation of PI3K by activated G protein-coupled receptors or receptor tyrosine kinase leads to phosphorylation and activation of AKT which, in turn, activates multiple downstream targets. Activating mutations of PIK3CA, PIK3R1, AKT1/2/3 contribute to cancer progression. Outcome effects: PI3K/AKT/MTOR signaling is switched-on which leads to uncontrolled cell proliferation, inhibition of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 15023437 PS:PMID 18794883 PS:PMID 18794884 PS:PMID 20582532 PS:PMID 24782981 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1a87aa4-c0b0-46b4-ba17-cc561952d255 NodeType: Pathway Notes: The molecular mechanisms underlying polycystic kidney disease development are not entirely understood. The pathogenesis of this disease results from cyst formation in the renal tubules and the subsequent tubule dysfunction. The cysts are probably formed as dilations in the renal tubules as a result of increased cellular proliferation and growth. An abnormal epithelial cell phenotype and extracellular matrix alterations result in spherical but not tubular structures. Disruption of the activity of the polycystins on renal epithelial cell membrane stimulates cell proliferation, growth, and the fluid secretion that cause cyst formation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-a1a87aa4-c0b0-46b4-ba17-cc561952d255 1_Formation of cysts in polycystic kidney disease uuid-a1a87aa4-c0b0-46b4-ba17-cc561952d255 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1a87aa4-c0b0-46b4-ba17-cc561952d255 PS:NodeType Pathway PS:Notes The molecular mechanisms underlying polycystic kidney disease development are not entirely understood. The pathogenesis of this disease results from cyst formation in the renal tubules and the subsequent tubule dysfunction. The cysts are probably formed as dilations in the renal tubules as a result of increased cellular proliferation and growth. An abnormal epithelial cell phenotype and extracellular matrix alterations result in spherical but not tubular structures. Disruption of the activity of the polycystins on renal epithelial cell membrane stimulates cell proliferation, growth, and the fluid secretion that cause cyst formation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1a9d4d1-c2ff-4f5d-aa54-dff2c7c9d7f9 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-a1a9d4d1-c2ff-4f5d-aa54-dff2c7c9d7f9 MTNR1 Signaling uuid-a1a9d4d1-c2ff-4f5d-aa54-dff2c7c9d7f9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1a9d4d1-c2ff-4f5d-aa54-dff2c7c9d7f9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1ab09f4-65b4-4029-b847-6fc9965e99d8 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a1ab09f4-65b4-4029-b847-6fc9965e99d8 Proteins Involved in Obesity uuid-a1ab09f4-65b4-4029-b847-6fc9965e99d8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1ab09f4-65b4-4029-b847-6fc9965e99d8 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: hepatocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1cb1247-fc89-40f3-881f-d46f56e84d0b NodeType: Pathway Organ: liver Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-a1cb1247-fc89-40f3-881f-d46f56e84d0b Proteins Involved in Hepatocellular Carcinoma uuid-a1cb1247-fc89-40f3-881f-d46f56e84d0b PS:CellType cancer cell PS:CellType hepatocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1cb1247-fc89-40f3-881f-d46f56e84d0b PS:NodeType Pathway PS:Organ liver PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1ce6e74-952f-40f1-a8fa-64ebc609b59c NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a1ce6e74-952f-40f1-a8fa-64ebc609b59c Proteins Involved in Hodgkin Lymphoma uuid-a1ce6e74-952f-40f1-a8fa-64ebc609b59c PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1ce6e74-952f-40f1-a8fa-64ebc609b59c PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1db82c4-4e60-4b02-b7ff-3beb727e85af NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-a1db82c4-4e60-4b02-b7ff-3beb727e85af Eat me Signal: Engulfment of Apoptotic Cell uuid-a1db82c4-4e60-4b02-b7ff-3beb727e85af PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1db82c4-4e60-4b02-b7ff-3beb727e85af PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1e09ae4-50ae-4740-bc11-48bbc4bf9030 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-a1e09ae4-50ae-4740-bc11-48bbc4bf9030 Genes with Mutations Associated with Cystic Kidney Disease uuid-a1e09ae4-50ae-4740-bc11-48bbc4bf9030 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1e09ae4-50ae-4740-bc11-48bbc4bf9030 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: Mutations in PRRT2 (ICCA) are strongly associated with hemiplegic migraine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1e4b822-4722-475b-8961-70d8b9154c15 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. Mutations in PRRT2 (ICCA) are strongly associated with hemiplegic migraine. Signaling description: The molecular mechanism for the effect of PRRT2 (ICCA) gene mutations on migrane pathogenesis has not yet been determined. One of the hypotheses which involves dysregulation of exocytosis is depicted on the pathway. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17691981 PMID: 19499287 PMID: 21458376 PMID: 22845787 PMID: 23077026 PMID: 23182655 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-a1e4b822-4722-475b-8961-70d8b9154c15 Glutamate Overdose and Aura Effect Caused by Mutations in PRRT2 Gene uuid-a1e4b822-4722-475b-8961-70d8b9154c15 PS:CellType astrocyte PS:CellType neuron PS:Description Mutations in PRRT2 (ICCA) are strongly associated with hemiplegic migraine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1e4b822-4722-475b-8961-70d8b9154c15 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. Mutations in PRRT2 (ICCA) are strongly associated with hemiplegic migraine. Signaling description: The molecular mechanism for the effect of PRRT2 (ICCA) gene mutations on migrane pathogenesis has not yet been determined. One of the hypotheses which involves dysregulation of exocytosis is depicted on the pathway. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17691981 PS:PMID 19499287 PS:PMID 21458376 PS:PMID 22845787 PS:PMID 23077026 PS:PMID 23182655 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Regulatory T cells (Tregs) are specialized population of T cells that are engaged in sustaining immunological self-tolerance and homeostasis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1f7c564-8474-4d92-8882-13bb5de7a7c9 NodeType: Pathway Notes: Headnote: Regulatory T-cells (Tregs) are specialized population of T cells that are engaged in sustaining immunological self-tolerance and homeostasis. Tregs are defined by expression of the transcription factor forkhead box protein 3 (FOXP3). Signaling description: TGFB1 plays a particularly important role in Tregs differentiation. Additionally, IL-2 and retinoic acid (RA) facilitate induction of FOXP3. The induction of functional FOXP3 Treg cells by the concurrent activation of TGFB1 and AHR signaling is mediated, at least partially, by the transcription factors SMAD1 and AIOLOS (IKZF3). SMAD1 alone or in combination with SMAD3/4 regulates FOXP3 expression. Dendritic cells (DCs), which produce RA and TGFB1, are potent inducers of Foxp3 expression in activated T-cells. Treatment of DCs with the AHR ligand promotes the expression of the retinal dehydrogenases ALDH1A1 that enhances RA secretion. Notably, RA forms a complex with the nuclear receptors, RA receptors (RARs) and retinoid X receptors (RXRs) that controls the transactivation of FOXP3 promoter in coordination with SMAD3, thereby promoting Treg differentiation. Kynurenine, which is produced when tryptophan is catabolized by indoleamine 2,3-dioxygenase (IDO), is an AHR agonist that is important for generating Tregs and inhibiting Th17 cell development. DCs produce IDO, and through the production of tryptophan metabolites preferentially induce Tregs. Dietary metabolites are another important environmental factor that influence Treg differentiation and function, especially in the gut. AHR ligands and promote Tregs include indole-3-carbanole and 3,3'-diindolylmethane, derived from cruciferous vegetables. Tryptophan metabolite, cinnabarinic acid, has been identified as a novel AHR ligand.Ouctome effects: Tregs produce IL-10 that oppose function of Th17 cells. IKZF3 interacts with FOXP3 and mediates the repression of IL-2 expression. Organ: generic Organ_System: lymphatic system PMID: 18362915 PMID: 19100241 PMID: 19464984 PMID: 19635913 PMID: 22653785 PMID: 23190340 PMID: 23580432 PMID: 24527450 PMID: 24905409 PMID: 25741338 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-a1f7c564-8474-4d92-8882-13bb5de7a7c9 AHR Signaling in Treg and Dendritic Cells Function uuid-a1f7c564-8474-4d92-8882-13bb5de7a7c9 PS:CellType T-cell PS:Description Regulatory T cells (Tregs) are specialized population of T cells that are engaged in sustaining immunological self-tolerance and homeostasis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a1f7c564-8474-4d92-8882-13bb5de7a7c9 PS:NodeType Pathway PS:Notes Headnote: Regulatory T-cells (Tregs) are specialized population of T cells that are engaged in sustaining immunological self-tolerance and homeostasis. Tregs are defined by expression of the transcription factor forkhead box protein 3 (FOXP3). Signaling description: TGFB1 plays a particularly important role in Tregs differentiation. Additionally, IL-2 and retinoic acid (RA) facilitate induction of FOXP3. The induction of functional FOXP3 Treg cells by the concurrent activation of TGFB1 and AHR signaling is mediated, at least partially, by the transcription factors SMAD1 and AIOLOS (IKZF3). SMAD1 alone or in combination with SMAD3/4 regulates FOXP3 expression. Dendritic cells (DCs), which produce RA and TGFB1, are potent inducers of Foxp3 expression in activated T-cells. Treatment of DCs with the AHR ligand promotes the expression of the retinal dehydrogenases ALDH1A1 that enhances RA secretion. Notably, RA forms a complex with the nuclear receptors, RA receptors (RARs) and retinoid X receptors (RXRs) that controls the transactivation of FOXP3 promoter in coordination with SMAD3, thereby promoting Treg differentiation. Kynurenine, which is produced when tryptophan is catabolized by indoleamine 2,3-dioxygenase (IDO), is an AHR agonist that is important for generating Tregs and inhibiting Th17 cell development. DCs produce IDO, and through the production of tryptophan metabolites preferentially induce Tregs. Dietary metabolites are another important environmental factor that influence Treg differentiation and function, especially in the gut. AHR ligands and promote Tregs include indole-3-carbanole and 3,3'-diindolylmethane, derived from cruciferous vegetables. Tryptophan metabolite, cinnabarinic acid, has been identified as a novel AHR ligand.Ouctome effects: Tregs produce IL-10 that oppose function of Th17 cells. IKZF3 interacts with FOXP3 and mediates the repression of IL-2 expression. PS:Organ generic PS:Organ_System lymphatic system PS:PMID 18362915 PS:PMID 19100241 PS:PMID 19464984 PS:PMID 19635913 PS:PMID 22653785 PS:PMID 23190340 PS:PMID 23580432 PS:PMID 24527450 PS:PMID 24905409 PS:PMID 25741338 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: OPTN is a multifunctional protein involved in regulating signal transduction, membrane vesicle trafficking, autophagy, NF-kB signaling, and cell survival. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a227dfb6-53a9-4f8c-844f-d609136875dd NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. OPTN is a multifunctional protein that may be mutated in normal-tension glaucoma and adult-onset primary open-angle glaucoma. Signaling description: Optineurin (OPTN) is involved in regulating various cellular functions including signal transduction, membrane vesicle trafficking, autophagy, NF-kB signaling, and cell survival. These functions are mediated through interactions with a variety of proteins. A glaucoma-causing mutant of OPTN, named E50K, selectively induces death in retinal ganglion cells. OPTN may function in vesicle trafficking and Golgi organization/biogenesis through its interactions with RAB8A, HTT, and MYO6. RAB8A recruits OPTN to link HTT and MYO6 to coordinate the movement of vesicles along microtubules and actin tracks. OPTN also interacts with TBC1D17, which does not bind directly to RAB8A and requires OPTN for this interaction, thereby leading to the inactivation of RAB8A. OPTN is localized in the Golgi apparatus and upon apoptotic stimuli, it translocates to the nucleus. This translocation is mediated by RAB8A. OPTN is involved in mitosis regulation through the interaction with PLK1. During mitosis, OPTN is phosphorylated by PLK1, which leads to its re-localization to the nucleus from the Golgi. In the nucleus, OPTN enhances phosphorylation of PPP1R12A by CDK1 leading to binding of PPP1R12A and PLK1 and, subsequently PLK1 inactivation. OPTN also inhibits GRM1/5 signaling. Outcome effects: The knockdown of OPTN leads to defects in chromosome separation and the formation of multinucleate cells. In addition, OPTN is involved in autophagy through the interaction with MAP1LC3A and GABARAP. Mutated OPTN may inhibit NF-kB signaling by acting as a competitive inhibitor of IKBKG and binding to ubiquitinated RIPK1 by displacing IKBKG. OPTN then recruits CYLD (a deubiquitinase) to the molecular complex, thus facilitating deubiquitination of polyubiquitinated RIPK1 by CYLD leading to the down regulation of downstream pathways causing cell apoptosis. Mutated OPTN triggers the release of cytochrome c (CYCS), loss of mitochondrial membrane potential, and activation of the mitochondrial pathway in neuronal cell apoptosis. The knockdown of endogenous OPTN has been shown to induce apoptotic cell death due to the reduced secretion of NTF3 and CNTF. Mutated proteins: Mutated gene is shown in white-out style. References: 1).Ghanshyam Swarup, Vipul Vaibhava, Ananthamurthy Nagabhushana (2013). Functional Defects Caused by Glaucoma - Associated Mutations in Optineurin, Glaucoma - Basic and Clinical Aspects, Dr Shimon Rumelt (Ed.), ISBN: 978-953-51-1064-4, InTech, DOI: 10.5772/52692.Available from: http://www.intechopen.com/books/glaucoma-basic-and-clinical-aspects/functional-defects-caused-by-glaucoma-associated-mutations-in-optineurin Organ: eye Organ_System: sensory system PMID: 15837803 PMID: 20431268 PMID: 20634958 PMID: 22173078 PMID: 22364875 PMID: 22801549 PMID: 22854040 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a227dfb6-53a9-4f8c-844f-d609136875dd OPTN Associated Glaucoma uuid-a227dfb6-53a9-4f8c-844f-d609136875dd PS:CellType retina cell PS:Description OPTN is a multifunctional protein involved in regulating signal transduction, membrane vesicle trafficking, autophagy, NF-kB signaling, and cell survival. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a227dfb6-53a9-4f8c-844f-d609136875dd PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. OPTN is a multifunctional protein that may be mutated in normal-tension glaucoma and adult-onset primary open-angle glaucoma. Signaling description: Optineurin (OPTN) is involved in regulating various cellular functions including signal transduction, membrane vesicle trafficking, autophagy, NF-kB signaling, and cell survival. These functions are mediated through interactions with a variety of proteins. A glaucoma-causing mutant of OPTN, named E50K, selectively induces death in retinal ganglion cells. OPTN may function in vesicle trafficking and Golgi organization/biogenesis through its interactions with RAB8A, HTT, and MYO6. RAB8A recruits OPTN to link HTT and MYO6 to coordinate the movement of vesicles along microtubules and actin tracks. OPTN also interacts with TBC1D17, which does not bind directly to RAB8A and requires OPTN for this interaction, thereby leading to the inactivation of RAB8A. OPTN is localized in the Golgi apparatus and upon apoptotic stimuli, it translocates to the nucleus. This translocation is mediated by RAB8A. OPTN is involved in mitosis regulation through the interaction with PLK1. During mitosis, OPTN is phosphorylated by PLK1, which leads to its re-localization to the nucleus from the Golgi. In the nucleus, OPTN enhances phosphorylation of PPP1R12A by CDK1 leading to binding of PPP1R12A and PLK1 and, subsequently PLK1 inactivation. OPTN also inhibits GRM1/5 signaling. Outcome effects: The knockdown of OPTN leads to defects in chromosome separation and the formation of multinucleate cells. In addition, OPTN is involved in autophagy through the interaction with MAP1LC3A and GABARAP. Mutated OPTN may inhibit NF-kB signaling by acting as a competitive inhibitor of IKBKG and binding to ubiquitinated RIPK1 by displacing IKBKG. OPTN then recruits CYLD (a deubiquitinase) to the molecular complex, thus facilitating deubiquitination of polyubiquitinated RIPK1 by CYLD leading to the down regulation of downstream pathways causing cell apoptosis. Mutated OPTN triggers the release of cytochrome c (CYCS), loss of mitochondrial membrane potential, and activation of the mitochondrial pathway in neuronal cell apoptosis. The knockdown of endogenous OPTN has been shown to induce apoptotic cell death due to the reduced secretion of NTF3 and CNTF. Mutated proteins: Mutated gene is shown in white-out style. References: 1).Ghanshyam Swarup, Vipul Vaibhava, Ananthamurthy Nagabhushana (2013). Functional Defects Caused by Glaucoma - Associated Mutations in Optineurin, Glaucoma - Basic and Clinical Aspects, Dr Shimon Rumelt (Ed.), ISBN: 978-953-51-1064-4, InTech, DOI: 10.5772/52692.Available from: http://www.intechopen.com/books/glaucoma-basic-and-clinical-aspects/functional-defects-caused-by-glaucoma-associated-mutations-in-optineurin PS:Organ eye PS:Organ_System sensory system PS:PMID 15837803 PS:PMID 20431268 PS:PMID 20634958 PS:PMID 22173078 PS:PMID 22364875 PS:PMID 22801549 PS:PMID 22854040 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: The most important events in pathogenesis of Alzheimer's disease (AD) are neurofibrillary tangles (NFTs) and amyloid plaques formation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a249b5e2-83c9-4caa-a9df-bb050fcdaeb7 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). About 5% of AD cases are the early-onset familial form, where a genetic predisposition leads to the disease. The genes involved are APP, PSEN1, and PSEN2. Signaling description: Abeta is derived from the amyloid precursor protein (APP) via sequential proteolysis by beta-secretase (BACE1) and gamma-secretase. MME, ACE, IDE, and ECE1 normally cleave Abeta, but become decreased in AD. The neurofibrillary tangles are formed when MAPT becomes hyper-phosphorylated with GSK3B being one of the major enzymes participating in this process. These processes are triggered and progressed by calcium (Ca2+) overload, which is provoked by the excessive ion influx into the neuron through specific ion channels, such as the voltage-gated calcium channels (VGCCs) and several ligand-gated ion channels (N-methyl-D-aspartate selective glutamate receptor or NMDAR, CHRM1, and CHRNA7). The channels open when Abeta binds to them. Abeta also interacts with TNFRSF1A promoting caspase cascade activation. Outcome effects: Caspase cascade activation directs the cells to apoptosis. Ca2+ also induces mitochondrial dysfunction by activating proapoptotic factors such as CYCS, ENDOG, and AIFM1. Finally,NFTs cause a disruption in intracellular transport and dendrite degradation triggering cell death. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 15910549 PMID: 16768248 PMID: 22257884 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a249b5e2-83c9-4caa-a9df-bb050fcdaeb7 Alzheimer's Disease uuid-a249b5e2-83c9-4caa-a9df-bb050fcdaeb7 PS:CellType neuron PS:Description The most important events in pathogenesis of Alzheimer's disease (AD) are neurofibrillary tangles (NFTs) and amyloid plaques formation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a249b5e2-83c9-4caa-a9df-bb050fcdaeb7 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). About 5% of AD cases are the early-onset familial form, where a genetic predisposition leads to the disease. The genes involved are APP, PSEN1, and PSEN2. Signaling description: Abeta is derived from the amyloid precursor protein (APP) via sequential proteolysis by beta-secretase (BACE1) and gamma-secretase. MME, ACE, IDE, and ECE1 normally cleave Abeta, but become decreased in AD. The neurofibrillary tangles are formed when MAPT becomes hyper-phosphorylated with GSK3B being one of the major enzymes participating in this process. These processes are triggered and progressed by calcium (Ca2+) overload, which is provoked by the excessive ion influx into the neuron through specific ion channels, such as the voltage-gated calcium channels (VGCCs) and several ligand-gated ion channels (N-methyl-D-aspartate selective glutamate receptor or NMDAR, CHRM1, and CHRNA7). The channels open when Abeta binds to them. Abeta also interacts with TNFRSF1A promoting caspase cascade activation. Outcome effects: Caspase cascade activation directs the cells to apoptosis. Ca2+ also induces mitochondrial dysfunction by activating proapoptotic factors such as CYCS, ENDOG, and AIFM1. Finally,NFTs cause a disruption in intracellular transport and dendrite degradation triggering cell death. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 15910549 PS:PMID 16768248 PS:PMID 22257884 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2561391-8687-4ea0-be93-cd279934d6f3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a2561391-8687-4ea0-be93-cd279934d6f3 VEGFA -> AP-1/CREBBP/MYC Expression Targets uuid-a2561391-8687-4ea0-be93-cd279934d6f3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2561391-8687-4ea0-be93-cd279934d6f3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a26712d7-ab25-4ad6-88d4-7bcad3f162df NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone tissue urn:agi-pathway:uuid-a26712d7-ab25-4ad6-88d4-7bcad3f162df Receptor Tyrosine Kinase Family -> Expression Targets in Bone uuid-a26712d7-ab25-4ad6-88d4-7bcad3f162df PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a26712d7-ab25-4ad6-88d4-7bcad3f162df PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Sterile inflammation is the result of trauma, ischemia-reperfusion injury, or chemically-induced injury and occurs in the absence of pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a27206fa-bab6-4af3-b289-3b5fa8219480 NodeType: Pathway Notes: Headnote: Sterile inflammation is the result of trauma, ischemia-reperfusion injury, or chemically-induced injury and occurs in the absence of pathogens. Sterile inflammation is induced in response to cell death by necrosis or injury. It is the main component of many disorders including pulmonary interstitial fibrosis, ischemia-reperfusion injury, atherosclerosis, Alzheimer's disease, and tumors. Signaling description: Under conditions of cellular stress or injury, different molecules including damage-associated molecular patterns (DAMPs) can be released into the extracellular environment by dying cells and trigger inflammation under sterile conditions. The most common DAMPs are HMGB1, heat shock proteins, SAP130, fragments of RNA and DNA, hyaluronic acid, VCAN, heparan sulfate, monosodium urate, IL33, and IL1A. Pattern recognition receptors such as NOD-like receptors (NLRs) have an important role in sterile inflammation development. NLRs form inflammasomes, which are multi-protein complexes required for the secretion of IL1B, a key mediator in the sterile inflammation process. There are two inflammasomes that can sense non-microbial molecules including NLRP3 and AIM2. There are three main pathways that have been proposed to mediate sterile activation of NLRP3 including ATP-, lysosomal damage- or ROS-mediated activation. IL1B is produced mainly by the macrophages and has many biological functions such as the upregulation of adhesion molecules on endothelial cells, which are important for the recruitment of neutrophils and monocytes and for the induction of additional proinflammatory mediators. In addition, IL1A and IL33 released from injured endothelial cells during necrosis, but not apoptosis also function to alert innate immune cells to tissue damage. IL1A is crucial for the production of CXCL1 through IL1R signaling by macrophages. IL1A and IL33 signaling results in the activation of NF-kB via TRAF6. AGER is a transmembrane receptor that is expressed by immune cells, endothelial cells, cardiomyocytes, and neurons. AGER recognizes HMGB1 and the S100 family members, which are released during cellular stress and necrotic cell death. The activation of AGER by its ligands results in inflammatory signaling pathways, which lead to the induction of proinflammatory cytokines such as TNF. The mechanism, by which AGER activates these proinflammatory signaling pathways is unclear. In certain cases, AGER may transduce signals by acting cooperatively with TLRs. Specifically, HMGB1-bound DNA can form a complex with TLR9 and AGER to induce proinflammatory cytokines. Following sterile inflammatory stimuli such as reactive oxygen species (ROS) and hydrolytic enzymes, native hyaluronic acid of intercellular matrix is degraded into small fragments. In the acute phase of inflammation, hyaluronic acid fragments may prime inflammation via TLR4 and CD44, by different pathways that finally both converge in NF-kB activation. The exact mechanism of CD44 signaling following hyaluronic acid stimuli is currently under investigation. One of the possible mechanisms is through SRC, Ras, and PKC activation. Conversely, the accumulation of high-molecular-weight (HMW) hyaluronan triggers the activation of a phosphatase which causes the formation of a growth-inhibitory complex. ERM (ezrin/radixin/moesin) proteins function as general cross-linkers between actin filaments and specific groups of integral membrane proteins such as CD44. Their carboxy- and amino- terminal halves bind to actin filaments and the cytoplasmic domains of integral membrane proteins, respectively. The amino- and carboxy-terminal halves of ERM proteins have been shown to bind each other and suppress the functions of both halves. This is a prerequisite for the replacement of ERM proteins bound to CD44 by the dephosphorylated active form of NF2. NF2 disrupts the local link to the actin cytoskeleton and blocks Ras activation and signaling. CLEC4E can detect SAP130, which is a component of Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-a27206fa-bab6-4af3-b289-3b5fa8219480 Toll-like Receptor Independent Sterile Inflammation uuid-a27206fa-bab6-4af3-b289-3b5fa8219480 PS:CellType generic PS:Description Sterile inflammation is the result of trauma, ischemia-reperfusion injury, or chemically-induced injury and occurs in the absence of pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a27206fa-bab6-4af3-b289-3b5fa8219480 PS:NodeType Pathway PS:Notes Headnote: Sterile inflammation is the result of trauma, ischemia-reperfusion injury, or chemically-induced injury and occurs in the absence of pathogens. Sterile inflammation is induced in response to cell death by necrosis or injury. It is the main component of many disorders including pulmonary interstitial fibrosis, ischemia-reperfusion injury, atherosclerosis, Alzheimer's disease, and tumors. Signaling description: Under conditions of cellular stress or injury, different molecules including damage-associated molecular patterns (DAMPs) can be released into the extracellular environment by dying cells and trigger inflammation under sterile conditions. The most common DAMPs are HMGB1, heat shock proteins, SAP130, fragments of RNA and DNA, hyaluronic acid, VCAN, heparan sulfate, monosodium urate, IL33, and IL1A. Pattern recognition receptors such as NOD-like receptors (NLRs) have an important role in sterile inflammation development. NLRs form inflammasomes, which are multi-protein complexes required for the secretion of IL1B, a key mediator in the sterile inflammation process. There are two inflammasomes that can sense non-microbial molecules including NLRP3 and AIM2. There are three main pathways that have been proposed to mediate sterile activation of NLRP3 including ATP-, lysosomal damage- or ROS-mediated activation. IL1B is produced mainly by the macrophages and has many biological functions such as the upregulation of adhesion molecules on endothelial cells, which are important for the recruitment of neutrophils and monocytes and for the induction of additional proinflammatory mediators. In addition, IL1A and IL33 released from injured endothelial cells during necrosis, but not apoptosis also function to alert innate immune cells to tissue damage. IL1A is crucial for the production of CXCL1 through IL1R signaling by macrophages. IL1A and IL33 signaling results in the activation of NF-kB via TRAF6. AGER is a transmembrane receptor that is expressed by immune cells, endothelial cells, cardiomyocytes, and neurons. AGER recognizes HMGB1 and the S100 family members, which are released during cellular stress and necrotic cell death. The activation of AGER by its ligands results in inflammatory signaling pathways, which lead to the induction of proinflammatory cytokines such as TNF. The mechanism, by which AGER activates these proinflammatory signaling pathways is unclear. In certain cases, AGER may transduce signals by acting cooperatively with TLRs. Specifically, HMGB1-bound DNA can form a complex with TLR9 and AGER to induce proinflammatory cytokines. Following sterile inflammatory stimuli such as reactive oxygen species (ROS) and hydrolytic enzymes, native hyaluronic acid of intercellular matrix is degraded into small fragments. In the acute phase of inflammation, hyaluronic acid fragments may prime inflammation via TLR4 and CD44, by different pathways that finally both converge in NF-kB activation. The exact mechanism of CD44 signaling following hyaluronic acid stimuli is currently under investigation. One of the possible mechanisms is through SRC, Ras, and PKC activation. Conversely, the accumulation of high-molecular-weight (HMW) hyaluronan triggers the activation of a phosphatase which causes the formation of a growth-inhibitory complex. ERM (ezrin/radixin/moesin) proteins function as general cross-linkers between actin filaments and specific groups of integral membrane proteins such as CD44. Their carboxy- and amino- terminal halves bind to actin filaments and the cytoplasmic domains of integral membrane proteins, respectively. The amino- and carboxy-terminal halves of ERM proteins have been shown to bind each other and suppress the functions of both halves. This is a prerequisite for the replacement of ERM proteins bound to CD44 by the dephosphorylated active form of NF2. NF2 disrupts the local link to the actin cytoskeleton and blocks Ras activation and signaling. CLEC4E can detect SAP130, which is a component of PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a27919f3-f5e3-4467-9b11-963b9d703e0b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a27919f3-f5e3-4467-9b11-963b9d703e0b Proteins genetically linked to SARS and ARDS uuid-a27919f3-f5e3-4467-9b11-963b9d703e0b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a27919f3-f5e3-4467-9b11-963b9d703e0b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2906e91-1de2-4432-b9b8-224fba7e1422 NodeType: Pathway Organ: generic Organ_System: generic PMID: 22981653 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-a2906e91-1de2-4432-b9b8-224fba7e1422 Estrogens/ESR1 non-Genomic Signaling uuid-a2906e91-1de2-4432-b9b8-224fba7e1422 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2906e91-1de2-4432-b9b8-224fba7e1422 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 22981653 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2d7f6c4-9e27-4a07-826c-87eb5cd34a35 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a2d7f6c4-9e27-4a07-826c-87eb5cd34a35 NSP10 inhibitors uuid-a2d7f6c4-9e27-4a07-826c-87eb5cd34a35 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2d7f6c4-9e27-4a07-826c-87eb5cd34a35 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2f58301-b903-4eaf-b9b2-eb1041822592 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a2f58301-b903-4eaf-b9b2-eb1041822592 ER->Golgi transport uuid-a2f58301-b903-4eaf-b9b2-eb1041822592 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a2f58301-b903-4eaf-b9b2-eb1041822592 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Graves disease (GD) is an autoimmune response to thyroid-specific antigens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a301ea31-8d5c-4549-8d7c-b8581ed729c3 NodeType: Pathway Notes: Headnote: Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. The disease is caused by an autoimmune response to thyroid antigens. As a result, the synthesis of thyroid hormones, metabolism, and the size of the thyroid increase. Signaling description: TSHR may act as an antigen that triggers the division and differentiation of lymphocytes and the production of antibodies. Occasionally, thyroid peroxidase (TPO) or thyroglobulin (TG) may also serve as antigens. Up to 90% of patients with GD have antibodies directed against TPO, while approximately 50% of patients have antibodies directed against TG. One of genetic causes for thyroid dysfunction may be single nucleotide polymorphisms (SNPs) in TSHR, MHC, CTLA4, and other genes. There are 3 main signaling pathways activated by TSHR including through G proteins-cAMP, G proteins-Ca2 activation, and STAT3 activation. Outcome effects: Activated by self-antigens, B cells produce immunoglobulins that enter the blood and bind to TSHR (in addition to TPO and TG). In GD patients, stimulatory, blocking, and neutral autoantibodies to TSHR present at the same time. Their degree of participation in GD progression varies significantly in different patients. When stimulatory antibodies prevail, the pathological effects on thyroid tissue are extensively produced. The TSHR signaling activation leads to the up-regulation of thyroid hormone synthesis and activation of thyroid cell proliferation. Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. Organ: thyroid gland Organ_System: endocrine system PMID: 14654350 PMID: 19258680 PMID: 20083159 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a301ea31-8d5c-4549-8d7c-b8581ed729c3 Thyroid Dysfunction uuid-a301ea31-8d5c-4549-8d7c-b8581ed729c3 PS:Description Graves disease (GD) is an autoimmune response to thyroid-specific antigens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a301ea31-8d5c-4549-8d7c-b8581ed729c3 PS:NodeType Pathway PS:Notes Headnote: Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. The disease is caused by an autoimmune response to thyroid antigens. As a result, the synthesis of thyroid hormones, metabolism, and the size of the thyroid increase. Signaling description: TSHR may act as an antigen that triggers the division and differentiation of lymphocytes and the production of antibodies. Occasionally, thyroid peroxidase (TPO) or thyroglobulin (TG) may also serve as antigens. Up to 90% of patients with GD have antibodies directed against TPO, while approximately 50% of patients have antibodies directed against TG. One of genetic causes for thyroid dysfunction may be single nucleotide polymorphisms (SNPs) in TSHR, MHC, CTLA4, and other genes. There are 3 main signaling pathways activated by TSHR including through G proteins-cAMP, G proteins-Ca2 activation, and STAT3 activation. Outcome effects: Activated by self-antigens, B cells produce immunoglobulins that enter the blood and bind to TSHR (in addition to TPO and TG). In GD patients, stimulatory, blocking, and neutral autoantibodies to TSHR present at the same time. Their degree of participation in GD progression varies significantly in different patients. When stimulatory antibodies prevail, the pathological effects on thyroid tissue are extensively produced. The TSHR signaling activation leads to the up-regulation of thyroid hormone synthesis and activation of thyroid cell proliferation. Highlighted proteins: Entities with increased expression or activity are highlighted in red and entities with decreased expression or activity are highlighted in blue. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 14654350 PS:PMID 19258680 PS:PMID 20083159 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a341849a-57c2-46d8-a32e-17553d1f6587 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-a341849a-57c2-46d8-a32e-17553d1f6587 IL1B Expression Targets -> Nociception uuid-a341849a-57c2-46d8-a32e-17553d1f6587 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a341849a-57c2-46d8-a32e-17553d1f6587 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a34c2f41-1f8e-4a85-a842-ab968f1946d2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a34c2f41-1f8e-4a85-a842-ab968f1946d2 DLL1 Expression Targets uuid-a34c2f41-1f8e-4a85-a842-ab968f1946d2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a34c2f41-1f8e-4a85-a842-ab968f1946d2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a352e010-1d7d-4bdc-8dd6-d542a8a3de11 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a352e010-1d7d-4bdc-8dd6-d542a8a3de11 Jasmonoyl-amino acid conjugates biosynthesis template uuid-a352e010-1d7d-4bdc-8dd6-d542a8a3de11 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a352e010-1d7d-4bdc-8dd6-d542a8a3de11 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3759b20-0f49-4207-8d27-403a84c62dd3 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a3759b20-0f49-4207-8d27-403a84c62dd3 FGF10 -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-a3759b20-0f49-4207-8d27-403a84c62dd3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3759b20-0f49-4207-8d27-403a84c62dd3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a38259c5-1e52-4dd6-bc21-f1a292460a3a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-a38259c5-1e52-4dd6-bc21-f1a292460a3a 1_cd_Amyloid-beta in Alzheimer's disease uuid-a38259c5-1e52-4dd6-bc21-f1a292460a3a PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a38259c5-1e52-4dd6-bc21-f1a292460a3a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3983e8b-c308-465c-8934-cac36ad11c69 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a3983e8b-c308-465c-8934-cac36ad11c69 Endometrial Cancer Clinical Trials uuid-a3983e8b-c308-465c-8934-cac36ad11c69 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3983e8b-c308-465c-8934-cac36ad11c69 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a4d3a2-b08d-49d4-a8a2-6d9363cd6100 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a3a4d3a2-b08d-49d4-a8a2-6d9363cd6100 Model of PPARG signaling in psoriasis (tested experimentally) uuid-a3a4d3a2-b08d-49d4-a8a2-6d9363cd6100 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a4d3a2-b08d-49d4-a8a2-6d9363cd6100 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a57c1e-1c66-465d-97aa-09623bc9a2c7 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-a3a57c1e-1c66-465d-97aa-09623bc9a2c7 Proteins Involved in Clear Cell Ovarian Carcinoma uuid-a3a57c1e-1c66-465d-97aa-09623bc9a2c7 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a57c1e-1c66-465d-97aa-09623bc9a2c7 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a98b2c-e41c-4dff-942f-bde254f1bf25 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a3a98b2c-e41c-4dff-942f-bde254f1bf25 Proteins Involved in Mantle Cell Lymphoma uuid-a3a98b2c-e41c-4dff-942f-bde254f1bf25 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3a98b2c-e41c-4dff-942f-bde254f1bf25 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3bcdaef-676d-4d59-845a-85d61aa3c748 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-a3bcdaef-676d-4d59-845a-85d61aa3c748 GABA(A)R -> Membrane Hyperpolarization uuid-a3bcdaef-676d-4d59-845a-85d61aa3c748 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3bcdaef-676d-4d59-845a-85d61aa3c748 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: leukocyte CellType: macrophage Description: This pathway illustrates the processes triggered by free hemoglobin and oxyhemoglobin that appear in subarachnoid space after lysis of erythrocytes in early Subarachnoid Hemorrhage. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3c2f99f-519c-4143-9175-71e53b67c583 NodeType: Pathway Notes: Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. Free hemoglobin and oxyhemoglobin bind to haptoglobin (HP) and the complex is absorbed and degraded by macrophages. In addition, free hemoglobin activates leukocyte adhesion. Free oxyhemoglobin is involved in a number of vital cell processes such as the formation of free radicals, lipid peroxidation, arrest of vasodilation, activation of vasoconstriction, and apoptotic cell death. Mutations that decrease the activity of HP lead to reduced amounts of hemoglobin absorbed by macrophages. This escalates the pathological effects of free hemoglobin and oxyhemoglobin, which increases the probability of a lethal outcome. Outcome effects: SAH and the formation of hematomas initiate several molecular and cellular processes that lead to cerebral vasospasm. The main pathological processes such as the formation of free radicals and activation of molecular pathways that lead to irreversible vascular spasm, which occurs within the first 10 minutes - 24 hours. Medical assistance is rarely sought at this point, which leads to a high death rate in cerebral vasospasm. According to various estimates, the mortality in progressive cerebral vasospasm after SAH is as high as 20-60% in the first 14 days. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PMID: 15795160 PMID: 20452866 PMID: 23050638 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-a3c2f99f-519c-4143-9175-71e53b67c583 Hemoglobin Reduction and Leukocyte Adhesion Initiate Vasospasm uuid-a3c2f99f-519c-4143-9175-71e53b67c583 PS:CellType endothelial cell PS:CellType leukocyte PS:CellType macrophage PS:Description This pathway illustrates the processes triggered by free hemoglobin and oxyhemoglobin that appear in subarachnoid space after lysis of erythrocytes in early Subarachnoid Hemorrhage. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3c2f99f-519c-4143-9175-71e53b67c583 PS:NodeType Pathway PS:Notes Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. Free hemoglobin and oxyhemoglobin bind to haptoglobin (HP) and the complex is absorbed and degraded by macrophages. In addition, free hemoglobin activates leukocyte adhesion. Free oxyhemoglobin is involved in a number of vital cell processes such as the formation of free radicals, lipid peroxidation, arrest of vasodilation, activation of vasoconstriction, and apoptotic cell death. Mutations that decrease the activity of HP lead to reduced amounts of hemoglobin absorbed by macrophages. This escalates the pathological effects of free hemoglobin and oxyhemoglobin, which increases the probability of a lethal outcome. Outcome effects: SAH and the formation of hematomas initiate several molecular and cellular processes that lead to cerebral vasospasm. The main pathological processes such as the formation of free radicals and activation of molecular pathways that lead to irreversible vascular spasm, which occurs within the first 10 minutes - 24 hours. Medical assistance is rarely sought at this point, which leads to a high death rate in cerebral vasospasm. According to various estimates, the mortality in progressive cerebral vasospasm after SAH is as high as 20-60% in the first 14 days. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 15795160 PS:PMID 20452866 PS:PMID 23050638 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3dc4b89-bf33-450e-b8a3-38e74f2f4c23 NodeType: Pathway Organ: kidney Organ: lung Organ: skin Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a3dc4b89-bf33-450e-b8a3-38e74f2f4c23 Genes with Mutations Associated with Cystic Fibrosis uuid-a3dc4b89-bf33-450e-b8a3-38e74f2f4c23 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3dc4b89-bf33-450e-b8a3-38e74f2f4c23 PS:NodeType Pathway PS:Organ kidney PS:Organ lung PS:Organ skin PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3e8fdf4-4571-4d8e-b004-34230cb3232d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a3e8fdf4-4571-4d8e-b004-34230cb3232d Noradrenaline/Gs Expression Targets uuid-a3e8fdf4-4571-4d8e-b004-34230cb3232d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3e8fdf4-4571-4d8e-b004-34230cb3232d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Leydig cell Description: Leydig cells are testicular cells responsible for production of testosterone in the presence of luteinizing hormone (LH). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3f0914a-fadf-4454-8945-4c01ca459b6b NodeType: Pathway Notes: Headnote: Leydig cells are testicular cells responsible for production of testosterone in the presence of luteinizing hormone (LH). Dysfunction of Leydig cells may result from mutations in luteinizing hormone / choriogonadotropin receptor (LHCGR) or enzymes, taking part in different stages of sex steroids biogenesis: cholesterol monooxygenase (P450SCC, CYP11A1); steroidogenic acute regulatory protein (STAR); 3 beta-hydroxysteroid dehydrogenase (HSD3B2); 17-alpha-hydroxylase (CYP17A1); 17,20-lyase (CYP17A1); and 17-beta-hydroxysteroid dehydrogenase III (HSD17B3). Signaling description: Leydig cell hypoplasia is caused by mutations in LHCGR. It is characterized by an inability of the body to respond to LH. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility. Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. This disorder is caused by mutations in CYP11A1 that converts cholesterol to pregnenolone and STAR that transports cholesterol into the mitochondria.HSD3B2 gene mutations result in the congenital adrenal hyperplasia and sex steroids deficiency. Males with the defect have hypospadias. This form of the adrenal hyperplasia can cause male pseudohermaphroditism. Organ: testis Organ_System: reproductive system PMID: 16103714 PMID: 18989307 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a3f0914a-fadf-4454-8945-4c01ca459b6b Leydig Cells Dysfunction in Testicular Male Infertility uuid-a3f0914a-fadf-4454-8945-4c01ca459b6b PS:CellType Leydig cell PS:Description Leydig cells are testicular cells responsible for production of testosterone in the presence of luteinizing hormone (LH). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a3f0914a-fadf-4454-8945-4c01ca459b6b PS:NodeType Pathway PS:Notes Headnote: Leydig cells are testicular cells responsible for production of testosterone in the presence of luteinizing hormone (LH). Dysfunction of Leydig cells may result from mutations in luteinizing hormone / choriogonadotropin receptor (LHCGR) or enzymes, taking part in different stages of sex steroids biogenesis: cholesterol monooxygenase (P450SCC, CYP11A1); steroidogenic acute regulatory protein (STAR); 3 beta-hydroxysteroid dehydrogenase (HSD3B2); 17-alpha-hydroxylase (CYP17A1); 17,20-lyase (CYP17A1); and 17-beta-hydroxysteroid dehydrogenase III (HSD17B3). Signaling description: Leydig cell hypoplasia is caused by mutations in LHCGR. It is characterized by an inability of the body to respond to LH. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility. Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. This disorder is caused by mutations in CYP11A1 that converts cholesterol to pregnenolone and STAR that transports cholesterol into the mitochondria.HSD3B2 gene mutations result in the congenital adrenal hyperplasia and sex steroids deficiency. Males with the defect have hypospadias. This form of the adrenal hyperplasia can cause male pseudohermaphroditism. PS:Organ testis PS:Organ_System reproductive system PS:PMID 16103714 PS:PMID 18989307 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a41071f1-46cb-4406-acbe-e40dca5f3ae2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a41071f1-46cb-4406-acbe-e40dca5f3ae2 Peptidoglycan biosynthesis template uuid-a41071f1-46cb-4406-acbe-e40dca5f3ae2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a41071f1-46cb-4406-acbe-e40dca5f3ae2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a44a6ac7-15bf-4cd3-b2b7-59f51afbb250 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-a44a6ac7-15bf-4cd3-b2b7-59f51afbb250 USP28-Mediated Epigenetic and Non-Epigenetic Effects uuid-a44a6ac7-15bf-4cd3-b2b7-59f51afbb250 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a44a6ac7-15bf-4cd3-b2b7-59f51afbb250 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: enterochromaffin-like cell Description: Activated ECL-cells of stomach stimulate stomach secretion by synthesis of histamine and pancreastatin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a44bd535-6192-43c4-ab6b-7633d140be0e NodeType: Pathway Notes: Headnote: Activation of enterochromaffin-like cells (ECL-cell) of the stomach is one of the major mechanisms of digestion. ECL-cells do not contact with the lumen and are activated by signals from other cells, as well as mechanical signals. Signaling description: Gastrins and PACAPs (products of adenylate cyclase activating polypeptide 1) activate signaling through phospholipase C: inositol-induced intra cellular calcium influx and PKA activation. Calcium influx also occurs by piezo type mechanosensitive ion channel (PIEZO2) which is sensitive to mechanical stretch. PACAPs also activate the ADCY/cAMP/PKA pathway through VIPR1. Activated PKA phosphorylates transcription factors CREB1 and SP1. CREB1 activates the transcription of CXCL8 and IL2 which are both are necessary for the immune response. In addition, CREB1 activates transcription of histidine decarboxylase (HDC) and pancreastatin precursor - chromogranin A (CHGA). HDC synthesizes histamine, which is loaded to vesicles by SLC18A2 and secreted following intracellular calcium overload. Secretion of histamine is necessary for stomach related secretion. Transcription of CHGA is under the control of SP1. Pancreastatin inhibits secretion of INS. Also, pancreastatin activates stomach acid secretion and inhibits pancreatic juice secretion. Outcome effects: Activated stomach ECL-cells stimulate stomach-dependent secretion through histamine and pancreastatin release. Organ: stomach Organ: stomach wall Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-a44bd535-6192-43c4-ab6b-7633d140be0e ECL-cell: CHGA and Histamine Synthesis uuid-a44bd535-6192-43c4-ab6b-7633d140be0e PS:CellType enterochromaffin-like cell PS:Description Activated ECL-cells of stomach stimulate stomach secretion by synthesis of histamine and pancreastatin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a44bd535-6192-43c4-ab6b-7633d140be0e PS:NodeType Pathway PS:Notes Headnote: Activation of enterochromaffin-like cells (ECL-cell) of the stomach is one of the major mechanisms of digestion. ECL-cells do not contact with the lumen and are activated by signals from other cells, as well as mechanical signals. Signaling description: Gastrins and PACAPs (products of adenylate cyclase activating polypeptide 1) activate signaling through phospholipase C: inositol-induced intra cellular calcium influx and PKA activation. Calcium influx also occurs by piezo type mechanosensitive ion channel (PIEZO2) which is sensitive to mechanical stretch. PACAPs also activate the ADCY/cAMP/PKA pathway through VIPR1. Activated PKA phosphorylates transcription factors CREB1 and SP1. CREB1 activates the transcription of CXCL8 and IL2 which are both are necessary for the immune response. In addition, CREB1 activates transcription of histidine decarboxylase (HDC) and pancreastatin precursor - chromogranin A (CHGA). HDC synthesizes histamine, which is loaded to vesicles by SLC18A2 and secreted following intracellular calcium overload. Secretion of histamine is necessary for stomach related secretion. Transcription of CHGA is under the control of SP1. Pancreastatin inhibits secretion of INS. Also, pancreastatin activates stomach acid secretion and inhibits pancreatic juice secretion. Outcome effects: Activated stomach ECL-cells stimulate stomach-dependent secretion through histamine and pancreastatin release. PS:Organ stomach PS:Organ stomach wall PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a45012f8-01a5-43a3-8764-f9fd590ddce3 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-a45012f8-01a5-43a3-8764-f9fd590ddce3 CD72 -> CREB/CREBBP Expression Targets uuid-a45012f8-01a5-43a3-8764-f9fd590ddce3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a45012f8-01a5-43a3-8764-f9fd590ddce3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4523222-98e6-4c80-9ce6-96f819308f85 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a4523222-98e6-4c80-9ce6-96f819308f85 FIGF -> NCOR2 Expression Target uuid-a4523222-98e6-4c80-9ce6-96f819308f85 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4523222-98e6-4c80-9ce6-96f819308f85 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a46d265a-abd8-450a-a581-a5436bd2cfa4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a46d265a-abd8-450a-a581-a5436bd2cfa4 mHTT-=>Sterol biosynthesis uuid-a46d265a-abd8-450a-a581-a5436bd2cfa4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a46d265a-abd8-450a-a581-a5436bd2cfa4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a487a5b6-0a38-499c-84ca-ccd2643f7ed4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a487a5b6-0a38-499c-84ca-ccd2643f7ed4 EGF -> TP53 Expression Targets uuid-a487a5b6-0a38-499c-84ca-ccd2643f7ed4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a487a5b6-0a38-499c-84ca-ccd2643f7ed4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a490ae3e-3fd8-47af-929a-d7bdd28589d4 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-a490ae3e-3fd8-47af-929a-d7bdd28589d4 Proteins/Ions Transporters -> Expression Targets in Lymphoid System and Blood uuid-a490ae3e-3fd8-47af-929a-d7bdd28589d4 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a490ae3e-3fd8-47af-929a-d7bdd28589d4 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4bad6a5-85a6-4455-b407-7757ae6a5477 NodeType: Pathway Notes: Headnote: Several drugs may increase PRL serum concentration. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. The second- and third generation antipsychotics have a weaker affinity for DRD2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. Other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Reference:Castan~o Lo'pez MA, Robles Rodri'guez JL, Garci'a MR (2013). Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice?, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/54758. Available from: http://www.intechopen.com/books/prolactin/physiological-and-pathological-hyperprolactinemia-can-we-minimize-errors-in-the-clinical-practice- Organ: brain Organ: pituitary gland Organ_System: endocrine system Organ_System: nervous system PMID: 18404390 PMID: 20521318 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a4bad6a5-85a6-4455-b407-7757ae6a5477 Drugs Induced Hyperprolactinemia uuid-a4bad6a5-85a6-4455-b407-7757ae6a5477 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4bad6a5-85a6-4455-b407-7757ae6a5477 PS:NodeType Pathway PS:Notes Headnote: Several drugs may increase PRL serum concentration. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. The second- and third generation antipsychotics have a weaker affinity for DRD2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. Other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Reference:Castan~o Lo'pez MA, Robles Rodri'guez JL, Garci'a MR (2013). Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice?, Prolactin, Prof. György M. Nagy (Ed.), ISBN: 978-953-51-0943-3, InTech, DOI: 10.5772/54758. Available from: http://www.intechopen.com/books/prolactin/physiological-and-pathological-hyperprolactinemia-can-we-minimize-errors-in-the-clinical-practice- PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:Organ_System nervous system PS:PMID 18404390 PS:PMID 20521318 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4c02052-16ee-46e6-bddc-070d052fed15 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a4c02052-16ee-46e6-bddc-070d052fed15 PDGFB -> AP-1/CREB/MYC Expression Target uuid-a4c02052-16ee-46e6-bddc-070d052fed15 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4c02052-16ee-46e6-bddc-070d052fed15 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: The mesenchymal subtype of glioblastoma is characterized by mutations in NF1 and PTEN genes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4f64e2c-55d4-401f-bdae-73d546c9ff27 NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The mesenchymal subtype is characterized by mutations in NF1 and PTEN genes and the overexpression of mesenchymal markers (CHI3L1 and MET), astrocytic markers (CD44 and MERTK), and members of NF-kB pathway (TRADD, RELB, and TNFRSF1A). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 20129251 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-a4f64e2c-55d4-401f-bdae-73d546c9ff27 Glioblastoma, Mesenchymal Subtype uuid-a4f64e2c-55d4-401f-bdae-73d546c9ff27 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description The mesenchymal subtype of glioblastoma is characterized by mutations in NF1 and PTEN genes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4f64e2c-55d4-401f-bdae-73d546c9ff27 PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The mesenchymal subtype is characterized by mutations in NF1 and PTEN genes and the overexpression of mesenchymal markers (CHI3L1 and MET), astrocytic markers (CD44 and MERTK), and members of NF-kB pathway (TRADD, RELB, and TNFRSF1A). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 20129251 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4fae6f2-8a1c-4de2-9fc0-119bad0902f8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a4fae6f2-8a1c-4de2-9fc0-119bad0902f8 EREG -> EP300/SP1 Expression Targets uuid-a4fae6f2-8a1c-4de2-9fc0-119bad0902f8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a4fae6f2-8a1c-4de2-9fc0-119bad0902f8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a503a08c-e0bd-4aab-964a-4d5b3a473f29 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-a503a08c-e0bd-4aab-964a-4d5b3a473f29 TNFRSF6 -> FOXO3A Signaling uuid-a503a08c-e0bd-4aab-964a-4d5b3a473f29 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a503a08c-e0bd-4aab-964a-4d5b3a473f29 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: The Familial Partial Lipodystrophies type 2 (FPL2, Dunnigan syndrome) is characterized by progressive lipoatrophy beginning at puberty. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a5058f5e-821d-4047-a7f6-d27cd603081f NodeType: Pathway Notes: Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. The most prevalent of these is FPL type 2 (Dunnigan syndrome), which is characterized by a normal distribution of body fat in childhood with a gradual and progressive lipoatrophy of the upper and lower extremities beginning at puberty, resulting in a muscular appearance. Some patients may gain excess fat in the face and chin as well as neck which leads to a cushingoid appearance. Fatty liver and acute pancreatitis may also occur. Metabolic complications may occur later in life, including diabetes mellitus, hypertriglyceridemia, low levels of high-density lipoprotein, and atherosclerotic disease. These are more common in women with Dunnigan syndrome than in affected men. Signaling description: FPL2 results from an autosomal dominant missense mutation in LMNA, which encodes lamin A and lamin C. LMNA regulates PPARG and SREBF1. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4 which increases glucose uptake. SREBF1 promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ_System: endocrine system Organ_System: integumentary system PMID: 20551664 PMID: 23272513 PMID: 24152769 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-a5058f5e-821d-4047-a7f6-d27cd603081f Familial Partial Lipodystrophy Type 2 Progression (Hypothesis) uuid-a5058f5e-821d-4047-a7f6-d27cd603081f PS:CellType adipocyte PS:Description The Familial Partial Lipodystrophies type 2 (FPL2, Dunnigan syndrome) is characterized by progressive lipoatrophy beginning at puberty. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a5058f5e-821d-4047-a7f6-d27cd603081f PS:NodeType Pathway PS:Notes Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. The most prevalent of these is FPL type 2 (Dunnigan syndrome), which is characterized by a normal distribution of body fat in childhood with a gradual and progressive lipoatrophy of the upper and lower extremities beginning at puberty, resulting in a muscular appearance. Some patients may gain excess fat in the face and chin as well as neck which leads to a cushingoid appearance. Fatty liver and acute pancreatitis may also occur. Metabolic complications may occur later in life, including diabetes mellitus, hypertriglyceridemia, low levels of high-density lipoprotein, and atherosclerotic disease. These are more common in women with Dunnigan syndrome than in affected men. Signaling description: FPL2 results from an autosomal dominant missense mutation in LMNA, which encodes lamin A and lamin C. LMNA regulates PPARG and SREBF1. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4 which increases glucose uptake. SREBF1 promotes FASN, ACACB, and ACACA which are involved in lipid metabolism. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System endocrine system PS:Organ_System integumentary system PS:PMID 20551664 PS:PMID 23272513 PS:PMID 24152769 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a50f25c7-3350-42b5-9b19-cc2d58b03457 NodeType: Pathway Notes: Headnote: Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord and generally does not affect other organs. Signaling description: Gliomas express antigens specific for neural stem and progenitor cells such as nestin (NES), CD133 (PROM1), MSI1, BMI1, OLIG2, and others. Sonic hedgehog homolog (SHH) and Notch are key regulators of neural progenitors and have been found to be overexpressed in gliomas. The binding of SHH ligands to their receptors activates transducers termed GLI1, 2, and 3 which translocate into the nucleus and activate downstream targets. In addition, BMP2, 4, and 7 elicit their actions through binding to cell-surface receptor kinases (BMPRs). BMPRs, acting through SMAD1, 5, and 9 and co-activator SMAD4, translocate into the nucleus and regulate transcription. Furthermore, IL6 activates JAK/STAT3 cascade and thereby the downstream targets. FOXM1 is a downstream component of WNT signaling and is critical for beta-catenin (CTNNB1) transcription in tumor cells. WNT3A increases the level and nuclear translocation of FOXM1, which binds directly to CTNNB1 and enhances CTNNB1 nuclear localization and transcriptional activity. In addition, ASCL1 activates WNT signaling by repressing the negative regulator, DKK1. ASCL1 is essential for the maintenance and tumorigenicity of glioma stem cells. ASCL1 also induces AXIN2, TCF7, and TCF7L1. TGFB1 signaling plays an essential role in the retention of stemness of glioma-initiating cells. TGFB1-induced SOX4-SOX2 maintains tumorigenicity of glioma stem cells. Finally, EZH2 plays a crucial role in tissue-specific stem cell maintenance and tumor development. MYC is a direct target of EZH2 in glioma progenitor cells. Outcome effects: Taken together the resulting signaling events activate downstream targets ultimately leading to increased proliferation, dedifferentiation and gliogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 19286664 PMID: 19896441 PMID: 19934302 PMID: 20470003 PMID: 21516289 PMID: 22677165 PMID: 24212955 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-a50f25c7-3350-42b5-9b19-cc2d58b03457 Glioma Stem Cell Program Activation uuid-a50f25c7-3350-42b5-9b19-cc2d58b03457 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a50f25c7-3350-42b5-9b19-cc2d58b03457 PS:NodeType Pathway PS:Notes Headnote: Glioma is a broad category of brain and spinal cord tumors that arise from glial cells, the most abundant cell type in the central nervous system. Glioma is highly invasive by nature but does not typically spread outside the brain and spinal cord and generally does not affect other organs. Signaling description: Gliomas express antigens specific for neural stem and progenitor cells such as nestin (NES), CD133 (PROM1), MSI1, BMI1, OLIG2, and others. Sonic hedgehog homolog (SHH) and Notch are key regulators of neural progenitors and have been found to be overexpressed in gliomas. The binding of SHH ligands to their receptors activates transducers termed GLI1, 2, and 3 which translocate into the nucleus and activate downstream targets. In addition, BMP2, 4, and 7 elicit their actions through binding to cell-surface receptor kinases (BMPRs). BMPRs, acting through SMAD1, 5, and 9 and co-activator SMAD4, translocate into the nucleus and regulate transcription. Furthermore, IL6 activates JAK/STAT3 cascade and thereby the downstream targets. FOXM1 is a downstream component of WNT signaling and is critical for beta-catenin (CTNNB1) transcription in tumor cells. WNT3A increases the level and nuclear translocation of FOXM1, which binds directly to CTNNB1 and enhances CTNNB1 nuclear localization and transcriptional activity. In addition, ASCL1 activates WNT signaling by repressing the negative regulator, DKK1. ASCL1 is essential for the maintenance and tumorigenicity of glioma stem cells. ASCL1 also induces AXIN2, TCF7, and TCF7L1. TGFB1 signaling plays an essential role in the retention of stemness of glioma-initiating cells. TGFB1-induced SOX4-SOX2 maintains tumorigenicity of glioma stem cells. Finally, EZH2 plays a crucial role in tissue-specific stem cell maintenance and tumor development. MYC is a direct target of EZH2 in glioma progenitor cells. Outcome effects: Taken together the resulting signaling events activate downstream targets ultimately leading to increased proliferation, dedifferentiation and gliogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 19286664 PS:PMID 19896441 PS:PMID 19934302 PS:PMID 20470003 PS:PMID 21516289 PS:PMID 22677165 PS:PMID 24212955 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a51e5d5a-dc39-495c-a770-51c78ec5b08c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a51e5d5a-dc39-495c-a770-51c78ec5b08c Epicuticular wax biosynthesis template uuid-a51e5d5a-dc39-495c-a770-51c78ec5b08c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a51e5d5a-dc39-495c-a770-51c78ec5b08c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Lactate is the end-product of aerobic glycolysis in cancer cells. It may serve as an important signaling molecule and promote cancer progression Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a52668c9-0040-4668-9e52-0f114a154fc8 NodeType: Pathway Notes: Headnote: Lactate is the end-product of aerobic glycolysis in cancer cells. It may serve as an important signaling molecule and promote cancer progression. Signaling description: Lactate is the end-product of aerobic glycolysis obtained from pyruvate by over-expressed LDHA (activated by MYC, HIF1A and HSF1). Also, lactate can be shuttled from catabolic/stromal cancer cells to anabolic cancer cells (this phenomena is called the reverse Warburg effect). Lactate import is performed by multiple transporters (SLC16A1/3/4/7). The activity of transporters is regulated by MYC, BSG and AMPK. In addition, lactate may be converted back to pyruvate by LDHB and enter the Krebs cycle. Lactate serves as an important signaling molecule and promotes cancer progression by regulating cell migration, angiogenesis and the immune escape. Lactate activates HIF1A through EGLN1 inhibition. Further, lactate inhibits NFKBIA thereby activating NFKB. Lactate regulates TGFB2 expression via induction of THBS-1, controls hyaluronic acid synthesis and activates it's receptor CD44. NDRG3 is degraded in an EGLN1/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates in hypoxia. NDRG3 activates angiogenesis and cell migration through RAF1/MAPK signaling. Outcome effects: Overexpressed CD44, TGFB1, CXCL8, KDR, VEGFA and PECAM1 promote cancer cell migration and angiogenesis. CD44 may also potentiate glycolysis. Lactate promotes the immune escape by inhibiting monocyte migration and NK cell mediated cytotoxicity. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" and for details. Organ: oncogenic Organ_System: oncogenic PMID: 22065843 PMID: 23817426 PMID: 23999443 PMID: 25892225 PMID: 26099350 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a52668c9-0040-4668-9e52-0f114a154fc8 Lactate as a Signaling Molecule in Cancer Cells uuid-a52668c9-0040-4668-9e52-0f114a154fc8 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Lactate is the end-product of aerobic glycolysis in cancer cells. It may serve as an important signaling molecule and promote cancer progression PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a52668c9-0040-4668-9e52-0f114a154fc8 PS:NodeType Pathway PS:Notes Headnote: Lactate is the end-product of aerobic glycolysis in cancer cells. It may serve as an important signaling molecule and promote cancer progression. Signaling description: Lactate is the end-product of aerobic glycolysis obtained from pyruvate by over-expressed LDHA (activated by MYC, HIF1A and HSF1). Also, lactate can be shuttled from catabolic/stromal cancer cells to anabolic cancer cells (this phenomena is called the reverse Warburg effect). Lactate import is performed by multiple transporters (SLC16A1/3/4/7). The activity of transporters is regulated by MYC, BSG and AMPK. In addition, lactate may be converted back to pyruvate by LDHB and enter the Krebs cycle. Lactate serves as an important signaling molecule and promotes cancer progression by regulating cell migration, angiogenesis and the immune escape. Lactate activates HIF1A through EGLN1 inhibition. Further, lactate inhibits NFKBIA thereby activating NFKB. Lactate regulates TGFB2 expression via induction of THBS-1, controls hyaluronic acid synthesis and activates it's receptor CD44. NDRG3 is degraded in an EGLN1/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates in hypoxia. NDRG3 activates angiogenesis and cell migration through RAF1/MAPK signaling. Outcome effects: Overexpressed CD44, TGFB1, CXCL8, KDR, VEGFA and PECAM1 promote cancer cell migration and angiogenesis. CD44 may also potentiate glycolysis. Lactate promotes the immune escape by inhibiting monocyte migration and NK cell mediated cytotoxicity. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" and for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 22065843 PS:PMID 23817426 PS:PMID 23999443 PS:PMID 25892225 PS:PMID 26099350 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a54edeb6-6ec1-4a0c-b233-01db5d68c5a4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-a54edeb6-6ec1-4a0c-b233-01db5d68c5a4 HRH1/2 -> Membrane Polarization uuid-a54edeb6-6ec1-4a0c-b233-01db5d68c5a4 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a54edeb6-6ec1-4a0c-b233-01db5d68c5a4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a54fb7f4-d96b-44f4-b169-54d4b694ef04 NodeType: Pathway Notes: Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone which regulates circadian rhythms, and has an antioxidant potential. Melatonin level declines with aging. Organ: brain Organ_System: nervous system PMID: 23985544 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-a54fb7f4-d96b-44f4-b169-54d4b694ef04 Melatonin Effects on Circadian Cycle uuid-a54fb7f4-d96b-44f4-b169-54d4b694ef04 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a54fb7f4-d96b-44f4-b169-54d4b694ef04 PS:NodeType Pathway PS:Notes Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone which regulates circadian rhythms, and has an antioxidant potential. Melatonin level declines with aging. PS:Organ brain PS:Organ_System nervous system PS:PMID 23985544 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage CellType: mast cell Description: PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome (MIM 604416) is an autosomal dominant disease caused by mutations in PSTPIP1 gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a565fb09-510e-43d5-8a28-07f03aa31647 NodeType: Pathway Notes: Headnote: PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome (MIM 604416) is an autosomal dominant disease caused by mutations in the PSTPIP1 gene encoding CD2-binding protein 1 (CD2BP1). The disease appears in early childhood and is characterized by joint involvement manifested by severe self-limiting pyogenic arthritis. In terms of skin involvement, the appearance of pyoderma gangrenosum and nodular-cystic acne are also described in early childhood. Signaling description: CD2BP1 is involved in the proper assembly of the cytoskeleton and normally inhibits pyrin-mediated inflammatory signals and the activation of CASP1. Outcome effects: Increased IL1B production has been demonstrated in a patient with clinically active PAPA syndrome caused by Ala230Thr PSTPIP1 mutation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 14595024 PMID: 24282415 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone tissue Tissue: epidermis urn:agi-pathway:uuid-a565fb09-510e-43d5-8a28-07f03aa31647 PAPA Syndrome uuid-a565fb09-510e-43d5-8a28-07f03aa31647 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome (MIM 604416) is an autosomal dominant disease caused by mutations in PSTPIP1 gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a565fb09-510e-43d5-8a28-07f03aa31647 PS:NodeType Pathway PS:Notes Headnote: PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome (MIM 604416) is an autosomal dominant disease caused by mutations in the PSTPIP1 gene encoding CD2-binding protein 1 (CD2BP1). The disease appears in early childhood and is characterized by joint involvement manifested by severe self-limiting pyogenic arthritis. In terms of skin involvement, the appearance of pyoderma gangrenosum and nodular-cystic acne are also described in early childhood. Signaling description: CD2BP1 is involved in the proper assembly of the cytoskeleton and normally inhibits pyrin-mediated inflammatory signals and the activation of CASP1. Outcome effects: Increased IL1B production has been demonstrated in a patient with clinically active PAPA syndrome caused by Ala230Thr PSTPIP1 mutation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 14595024 PS:PMID 24282415 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone tissue PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: keratinocyte Description: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a5680a06-5b4d-4e2e-954f-754ccd2babd0 NodeType: Pathway Notes: Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Cholesteatoma growing in a space-limited area of the middle ear can exceed the capacity of the existing vessel supply. This might result in molecular changes such as apoptosis or hypoxia and necrotic cell death within the cholesteatoma tissue, followed by release of HMGB1. HMGB1 is released extracellularly in response to stress or necrosis and behaves as a cytokine, promoting inflammation. Higher expression of RAGE within cholesteatoma perimatrix, which is adjacent to ossicle surface or to other parts of the temporal bone, might be interpreted as indicative of the RAGE/HMGB1 involvement in this process. HMGB1 triggers paracrine activation of RAGE expressed in the cholesteatoma matrix but not in normal skin. It is possible that keratinocyte proliferation is promoted and sustained by HMGB1 via its interaction with RAGE on keratinocytes. It is also plausible that RAGE/HMGB1 interactions may trigger the signaling pathways involved in the regulation of chronic inflammation as well as bone resorption in cholesteatoma. The cholesteatoma might be related to the co-expression and functional interactions between HMGB1 and RAGE.The PI3K/Akt/NF-kB pathway is now recognized as one of the critical pathways in regulating cell survival/apoptosis, migration, and proliferation in pathological conditions such as chronic inflammation. It was shown that triggering of RAGE by HMGB1 activated Akt, induced NF-kB p65 translocation, and resulted in increased proliferation and decreased sensitivity to drug-induced apoptosis in keratinocytes. Levels of pAkt and pNF-kB molecules were significantly increased and the phosphorylated forms of c-Jun, MEK1, MEK2, MAPKp44/p42 (Erk1/2), and STAT3 were overexpressed in cholesteatoma tissue vs. normal skin epithelium. Furthermore, phosphorylation of all the above-listed molecules was triggered by HMGB1/RAGE interactions in cell lines and correspondingly also in cholesteatoma tissues. The abnormal behavior of cholesteatoma epithelium seems to be related to the presence of infiltrating immune cells releasing high levels of various cytokines and growth factors. Although IL1b and TNFa were not secreted by cells induced HMGB1, HMGB1 triggered IL8 production in these cells, confirming reports that HMGB1/RAGE interactions can induce IL8, a cytokine best known for its pro-inflammatory effects on immune cells. There is speculation that RAGE and HMGB1 regulate bone remodeling in chronic inflammation via up-regulation of the IL8 production, a mediator of bone destruction, in tissue samples of cholesteatoma. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 25385222 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-a5680a06-5b4d-4e2e-954f-754ccd2babd0 HMGB1/RAGE Signaling in Middle Ear Cholesteatoma uuid-a5680a06-5b4d-4e2e-954f-754ccd2babd0 PS:CellType cancer cell PS:CellType keratinocyte PS:Description Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a5680a06-5b4d-4e2e-954f-754ccd2babd0 PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Cholesteatoma growing in a space-limited area of the middle ear can exceed the capacity of the existing vessel supply. This might result in molecular changes such as apoptosis or hypoxia and necrotic cell death within the cholesteatoma tissue, followed by release of HMGB1. HMGB1 is released extracellularly in response to stress or necrosis and behaves as a cytokine, promoting inflammation. Higher expression of RAGE within cholesteatoma perimatrix, which is adjacent to ossicle surface or to other parts of the temporal bone, might be interpreted as indicative of the RAGE/HMGB1 involvement in this process. HMGB1 triggers paracrine activation of RAGE expressed in the cholesteatoma matrix but not in normal skin. It is possible that keratinocyte proliferation is promoted and sustained by HMGB1 via its interaction with RAGE on keratinocytes. It is also plausible that RAGE/HMGB1 interactions may trigger the signaling pathways involved in the regulation of chronic inflammation as well as bone resorption in cholesteatoma. The cholesteatoma might be related to the co-expression and functional interactions between HMGB1 and RAGE.The PI3K/Akt/NF-kB pathway is now recognized as one of the critical pathways in regulating cell survival/apoptosis, migration, and proliferation in pathological conditions such as chronic inflammation. It was shown that triggering of RAGE by HMGB1 activated Akt, induced NF-kB p65 translocation, and resulted in increased proliferation and decreased sensitivity to drug-induced apoptosis in keratinocytes. Levels of pAkt and pNF-kB molecules were significantly increased and the phosphorylated forms of c-Jun, MEK1, MEK2, MAPKp44/p42 (Erk1/2), and STAT3 were overexpressed in cholesteatoma tissue vs. normal skin epithelium. Furthermore, phosphorylation of all the above-listed molecules was triggered by HMGB1/RAGE interactions in cell lines and correspondingly also in cholesteatoma tissues. The abnormal behavior of cholesteatoma epithelium seems to be related to the presence of infiltrating immune cells releasing high levels of various cytokines and growth factors. Although IL1b and TNFa were not secreted by cells induced HMGB1, HMGB1 triggered IL8 production in these cells, confirming reports that HMGB1/RAGE interactions can induce IL8, a cytokine best known for its pro-inflammatory effects on immune cells. There is speculation that RAGE and HMGB1 regulate bone remodeling in chronic inflammation via up-regulation of the IL8 production, a mediator of bone destruction, in tissue samples of cholesteatoma. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 25385222 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a58d9efe-5d6b-4734-86c3-20f2a3b3e8c8 NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-a58d9efe-5d6b-4734-86c3-20f2a3b3e8c8 TGFb+>Translation uuid-a58d9efe-5d6b-4734-86c3-20f2a3b3e8c8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a58d9efe-5d6b-4734-86c3-20f2a3b3e8c8 PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: Metalloproteinase-mediated degradation of extracellular matrix (ECM) proteins resulting in cartilage destruction occurs in osteoarthritis (OA). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a58df364-ee78-4a1c-9622-d6f92c1167bf NodeType: Pathway Notes: Headnote: Metalloproteinase-mediated degradation of extracellular matrix (ECM) proteins resulting in cartilage destruction occurs in osteoarthritis (OA) and is a strong attribute of the pathology. The excessive mechanical loading of cartilage, which causes TNF and IL1B synthesis, is a proven trigger of OA. Signaling description: The cytokines bind to their receptors on the chondrocyte surface and lead to JUN-FOS activation through MAPK8, MAPK p38, and MAPK1 pathways. The release of NF-kB from its inhibitor, NFKBIA is also provoked by these cytokines. JUN, FOS, and NF-kB bind to the promoter regions of metalloproteinases including MMP1, MMP3, and MMP13 and cause their synthesis. Outcome effects: The metalloproteinases released into the ECM cleave collagens, thereby impairing cartilage function. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 12010565 PMID: 12082286 PMID: 22179031 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a58df364-ee78-4a1c-9622-d6f92c1167bf TNF and IL1B Induce Metalloproteinase Synthesis in Osteoarthritis uuid-a58df364-ee78-4a1c-9622-d6f92c1167bf PS:CellType chondrocyte PS:Description Metalloproteinase-mediated degradation of extracellular matrix (ECM) proteins resulting in cartilage destruction occurs in osteoarthritis (OA). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a58df364-ee78-4a1c-9622-d6f92c1167bf PS:NodeType Pathway PS:Notes Headnote: Metalloproteinase-mediated degradation of extracellular matrix (ECM) proteins resulting in cartilage destruction occurs in osteoarthritis (OA) and is a strong attribute of the pathology. The excessive mechanical loading of cartilage, which causes TNF and IL1B synthesis, is a proven trigger of OA. Signaling description: The cytokines bind to their receptors on the chondrocyte surface and lead to JUN-FOS activation through MAPK8, MAPK p38, and MAPK1 pathways. The release of NF-kB from its inhibitor, NFKBIA is also provoked by these cytokines. JUN, FOS, and NF-kB bind to the promoter regions of metalloproteinases including MMP1, MMP3, and MMP13 and cause their synthesis. Outcome effects: The metalloproteinases released into the ECM cleave collagens, thereby impairing cartilage function. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 12010565 PS:PMID 12082286 PS:PMID 22179031 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Anthracycline antibiotics such as doxorubicin, daunorubicin, epirubicin, and idarubicin are some of the most effective chemotherapeutic agents used in the treatment of cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a61f64ea-ab96-40cb-8a62-2400bc55ddb8 NodeType: Pathway Notes: Headnote: Anthracycline antibiotics such as doxorubicin, daunorubicin, epirubicin, and idarubicin are some of the most effective chemotherapeutic agents used in the treatment of cancer. Signaling description: Anthracycline molecules contain aglyconic and sugar moieties. The aglycone consists of a tetracyclic ring with adjacent quinone-hydroquinone groups. One-electron addition to the quinone moiety results in the formation of a semiquinone that quickly regenerates its parent quinine by reducing oxygen (O2) to reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2). During this cycle, the semiquinone can also oxidize resulting in reductive deglycosidation and the formation of 7-deoxyaglycone. Aglycones intercalate into biologic membranes due to their increased lipid solubility and form ROS in the closest proximity to sensitive targets. The accumulation of the more lipophilic 7-deoxyaglycone in the inner mitochondrial membrane greatly enhances electron deviation from the regular pathway of respiratory chain to O2, leading to an increased formation of superoxide radical and consequent amplification of mitochondrial dysfunction. One-electron redox cycling of doxorubicin is also accompanied by the release of iron (Fe2+) from intracellular stores which results in the formation of drug-iron complexes that convert superoxide radical and H2O2 into more potent hydroxyl radicals. The clinical use of anthracyclines is hindered by serious problems such as the development of resistance in tumor cells or toxicity in healthy tissues, particularly in the form of chronic cardiomyopathy and congestive heart failure. The ultrastructural features of anthracycline-induced cardiomyopathy include the loss of myofibrils, dilation of the sarcoplasmic reticulum, cytoplasmic vacuolization, swelling of mitochondria, and increased number of lysosomes. Cardiomyocytes are more susceptible to apoptosis induced by anthracyclines than other tissues since they exhibit low levels of catalase and readily undergo inactivation of glutathione peroxidase following exposure to doxorubicin. The reduction of diverse antioxidant enzymes represents a common response to anthracycline treatment. Mitochondrial death pathway in cardiac myocytes is triggered by oxidative stress. Doxorubicin-induced apoptosis of cardiomyocytes proceeds through redox cycling of anthracycline, consequent formation of ROS, and activation of NF-kB. In contrast, NF-kB activation usually inhibits apoptosis induced by doxorubicin in cancer cells. Chronic cardiomyopathy develops after the summation and mutual feedback of diverse processes such as increased membrane lipid peroxidation, inhibition of nucleic acid and protein synthesis, changes in adrenergic function and adenylate cyclase (ADCY), abnormalities in Ca2+ handling, reduced expression of specific genes, and induction of nitric oxide synthase (NOS2), which leads to nitric oxide (NO), peroxynitrite, and converse nitration/activation of metalloproteinases. Compound with elevated level is highlighted in red. Highlighted proteins: Entities with elevated level are highlighted in red. Organ: heart Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-a61f64ea-ab96-40cb-8a62-2400bc55ddb8 Doxorubicin Induced Cardiotoxicity uuid-a61f64ea-ab96-40cb-8a62-2400bc55ddb8 PS:Description Anthracycline antibiotics such as doxorubicin, daunorubicin, epirubicin, and idarubicin are some of the most effective chemotherapeutic agents used in the treatment of cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a61f64ea-ab96-40cb-8a62-2400bc55ddb8 PS:NodeType Pathway PS:Notes Headnote: Anthracycline antibiotics such as doxorubicin, daunorubicin, epirubicin, and idarubicin are some of the most effective chemotherapeutic agents used in the treatment of cancer. Signaling description: Anthracycline molecules contain aglyconic and sugar moieties. The aglycone consists of a tetracyclic ring with adjacent quinone-hydroquinone groups. One-electron addition to the quinone moiety results in the formation of a semiquinone that quickly regenerates its parent quinine by reducing oxygen (O2) to reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2). During this cycle, the semiquinone can also oxidize resulting in reductive deglycosidation and the formation of 7-deoxyaglycone. Aglycones intercalate into biologic membranes due to their increased lipid solubility and form ROS in the closest proximity to sensitive targets. The accumulation of the more lipophilic 7-deoxyaglycone in the inner mitochondrial membrane greatly enhances electron deviation from the regular pathway of respiratory chain to O2, leading to an increased formation of superoxide radical and consequent amplification of mitochondrial dysfunction. One-electron redox cycling of doxorubicin is also accompanied by the release of iron (Fe2+) from intracellular stores which results in the formation of drug-iron complexes that convert superoxide radical and H2O2 into more potent hydroxyl radicals. The clinical use of anthracyclines is hindered by serious problems such as the development of resistance in tumor cells or toxicity in healthy tissues, particularly in the form of chronic cardiomyopathy and congestive heart failure. The ultrastructural features of anthracycline-induced cardiomyopathy include the loss of myofibrils, dilation of the sarcoplasmic reticulum, cytoplasmic vacuolization, swelling of mitochondria, and increased number of lysosomes. Cardiomyocytes are more susceptible to apoptosis induced by anthracyclines than other tissues since they exhibit low levels of catalase and readily undergo inactivation of glutathione peroxidase following exposure to doxorubicin. The reduction of diverse antioxidant enzymes represents a common response to anthracycline treatment. Mitochondrial death pathway in cardiac myocytes is triggered by oxidative stress. Doxorubicin-induced apoptosis of cardiomyocytes proceeds through redox cycling of anthracycline, consequent formation of ROS, and activation of NF-kB. In contrast, NF-kB activation usually inhibits apoptosis induced by doxorubicin in cancer cells. Chronic cardiomyopathy develops after the summation and mutual feedback of diverse processes such as increased membrane lipid peroxidation, inhibition of nucleic acid and protein synthesis, changes in adrenergic function and adenylate cyclase (ADCY), abnormalities in Ca2+ handling, reduced expression of specific genes, and induction of nitric oxide synthase (NOS2), which leads to nitric oxide (NO), peroxynitrite, and converse nitration/activation of metalloproteinases. Compound with elevated level is highlighted in red. Highlighted proteins: Entities with elevated level are highlighted in red. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a626e163-d787-4de3-8ce0-76b89c906de3 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-a626e163-d787-4de3-8ce0-76b89c906de3 Irinotecan Metabolism uuid-a626e163-d787-4de3-8ce0-76b89c906de3 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a626e163-d787-4de3-8ce0-76b89c906de3 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: MTOR plays important role in the regulation of tumor cell motility, invasion and cancer metastasis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a630388e-7cd3-4b8a-b260-f04425a0b554 NodeType: Pathway Notes: Headnote: The mammalian target of rapamycin (MTOR), a highly conserved and ubiquitously expressed kinase, is a central regulator of cell growth, proliferation, differentiation and survival. MTOR has a central role in the regulation of tumor cell motility, invasion and cancer metastasis. Signaling description: MTOR is activated through growth factor receptor/PI3K/AKT1 signaling and functions as two distinct complexes, TORC1 and mTORC2. TORC1 acts through interaction with TORC2 and through PP2A/MAPK/JUN-FOS signaling. TORC2 phosphorylates AKT1, protein kinase PRKCA, controls the activity of CDC42 and RHOA and thereby regulates F-actin polymerization. Outcome effects: TORC activation induces F-actin polymerization and transcriptional activation of some factors (MMPs, PLAU, SERPINE1) implicated in tumor invasion. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21190521 PMID: 22408430 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a630388e-7cd3-4b8a-b260-f04425a0b554 MTOR/TORC in Cancer Cell Motility and Invasion uuid-a630388e-7cd3-4b8a-b260-f04425a0b554 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description MTOR plays important role in the regulation of tumor cell motility, invasion and cancer metastasis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a630388e-7cd3-4b8a-b260-f04425a0b554 PS:NodeType Pathway PS:Notes Headnote: The mammalian target of rapamycin (MTOR), a highly conserved and ubiquitously expressed kinase, is a central regulator of cell growth, proliferation, differentiation and survival. MTOR has a central role in the regulation of tumor cell motility, invasion and cancer metastasis. Signaling description: MTOR is activated through growth factor receptor/PI3K/AKT1 signaling and functions as two distinct complexes, TORC1 and mTORC2. TORC1 acts through interaction with TORC2 and through PP2A/MAPK/JUN-FOS signaling. TORC2 phosphorylates AKT1, protein kinase PRKCA, controls the activity of CDC42 and RHOA and thereby regulates F-actin polymerization. Outcome effects: TORC activation induces F-actin polymerization and transcriptional activation of some factors (MMPs, PLAU, SERPINE1) implicated in tumor invasion. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21190521 PS:PMID 22408430 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a64acaed-3838-46be-8ad1-f577cb73dd2d NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-a64acaed-3838-46be-8ad1-f577cb73dd2d Pyrimidine metabolism template uuid-a64acaed-3838-46be-8ad1-f577cb73dd2d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a64acaed-3838-46be-8ad1-f577cb73dd2d PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a65b2929-b065-4d3a-a0a8-ba6c332710a9 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: seminal vesicle Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-a65b2929-b065-4d3a-a0a8-ba6c332710a9 Elevated Receptors -> Expression Targets in Seminal Vesicle uuid-a65b2929-b065-4d3a-a0a8-ba6c332710a9 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a65b2929-b065-4d3a-a0a8-ba6c332710a9 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ seminal vesicle PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6952950-5ca3-4985-a907-07aa0cfe06e4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a6952950-5ca3-4985-a907-07aa0cfe06e4 mHTT effects in Striatal Neuron uuid-a6952950-5ca3-4985-a907-07aa0cfe06e4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6952950-5ca3-4985-a907-07aa0cfe06e4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sperm cell Description: Mutations in CFTR cause cystic fibrosis (CF) which is a disease with a multitude of clinical manifestations including infertility and subfertility in both sexes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6996ed5-2df6-464f-a8d4-00d9915868ab NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. CF is a disease with a multitude of clinical manifestations including infertility and subfertility in both sexes. Signaling description: About 97 percent of men with CF are infertile due to congenital bilateral absence of the vas deferens (CBAVD) with resultant obstructive azoospermia. CFTR mutations may also result in other forms of male infertility. CFTR mediates the uterine HCO3- secretion and is necessary for HCO3-related sperm capacitation. Therefore, mutant CFTR may lead to impaired sperm fertilizing capacity and thus reduced fertility in women with CF. The detailed mechanisms of CFTR participation in reproduction remain largely unknown. Capacitation is the final step in the maturation of mammalian spermatozoa and is required for the fertilization of oocytes. This step occurs in the female reproductive tract following ejaculation. Capacitation results in membrane fluidity due to lipid modifications, an influx of calcium (Ca2+) in the sperm head and flagellum, and the phosphorylation of proteins on serine (Ser), threonine (Thr), and the oocyte tyrosine (Tyr) residues. Firstly, the influx of HCO3- and Ca2+ stimulates ADCY10 and increases intracellular cAMP concentrations. HCO3- entry is mediated by SLC26A3. CFTR may act as a Cl- channel to provide a recycling pathway for Cl-, which is required for the operation of SLC26A3. High cAMP levels activate protein kinase A (PKA) and AKAP6. Outcome effects: AKAP6, AKAP3, and CABYR all participate in PKA activation. The phosphorylation of PKA substrates is subjected to regulation by a protein phosphatase, likely PP2A. PKA and PP2A lead to Tyr residue phosphorylation of sperm proteins. In addition, the increase in intracellular Ca2+ may affect the axoneme directly, through phospholipids or selective regulation of dyneins. Ca2+ also up-regulates CAMK4, which results in hyperactivation. Furthermore, G-actin is polymerized to F-actin during sperm capacitation and the fibers must undergo depolymerization in order to achieve the acrosome reaction. Actin polymerization is influenced by PLD1 activation, which occurs via the HCO3-/cAMP/PKA pathway or via the G-protein coupled receptor (GPCR). External albumin (ALB) activates capacitation through the interaction with phospholipids. Additionally, capacitated spermatozoa undergo the acrosome reaction when they come in contact with zona pellucida. The acrosome reaction is normally triggered by ACR. In conclusion, capacitation and acrosome reaction are complex processes that appear to be controlled by several kinases and pathways since they are blocked by inhibitors of PKC, PKA, PTK, PI3K, AKT1, and ERK (MAPK), however, the details of these processes are still incomplete. Mutated proteins: Mutated gene is shown in white-out style. Organ: testis Organ_System: reproductive system PMID: 17920343 PMID: 19015188 PMID: 21540868 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a6996ed5-2df6-464f-a8d4-00d9915868ab CFTR in Sperm Capacitation and Acrosome Reaction uuid-a6996ed5-2df6-464f-a8d4-00d9915868ab PS:CellType sperm cell PS:Description Mutations in CFTR cause cystic fibrosis (CF) which is a disease with a multitude of clinical manifestations including infertility and subfertility in both sexes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6996ed5-2df6-464f-a8d4-00d9915868ab PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. CF is a disease with a multitude of clinical manifestations including infertility and subfertility in both sexes. Signaling description: About 97 percent of men with CF are infertile due to congenital bilateral absence of the vas deferens (CBAVD) with resultant obstructive azoospermia. CFTR mutations may also result in other forms of male infertility. CFTR mediates the uterine HCO3- secretion and is necessary for HCO3-related sperm capacitation. Therefore, mutant CFTR may lead to impaired sperm fertilizing capacity and thus reduced fertility in women with CF. The detailed mechanisms of CFTR participation in reproduction remain largely unknown. Capacitation is the final step in the maturation of mammalian spermatozoa and is required for the fertilization of oocytes. This step occurs in the female reproductive tract following ejaculation. Capacitation results in membrane fluidity due to lipid modifications, an influx of calcium (Ca2+) in the sperm head and flagellum, and the phosphorylation of proteins on serine (Ser), threonine (Thr), and the oocyte tyrosine (Tyr) residues. Firstly, the influx of HCO3- and Ca2+ stimulates ADCY10 and increases intracellular cAMP concentrations. HCO3- entry is mediated by SLC26A3. CFTR may act as a Cl- channel to provide a recycling pathway for Cl-, which is required for the operation of SLC26A3. High cAMP levels activate protein kinase A (PKA) and AKAP6. Outcome effects: AKAP6, AKAP3, and CABYR all participate in PKA activation. The phosphorylation of PKA substrates is subjected to regulation by a protein phosphatase, likely PP2A. PKA and PP2A lead to Tyr residue phosphorylation of sperm proteins. In addition, the increase in intracellular Ca2+ may affect the axoneme directly, through phospholipids or selective regulation of dyneins. Ca2+ also up-regulates CAMK4, which results in hyperactivation. Furthermore, G-actin is polymerized to F-actin during sperm capacitation and the fibers must undergo depolymerization in order to achieve the acrosome reaction. Actin polymerization is influenced by PLD1 activation, which occurs via the HCO3-/cAMP/PKA pathway or via the G-protein coupled receptor (GPCR). External albumin (ALB) activates capacitation through the interaction with phospholipids. Additionally, capacitated spermatozoa undergo the acrosome reaction when they come in contact with zona pellucida. The acrosome reaction is normally triggered by ACR. In conclusion, capacitation and acrosome reaction are complex processes that appear to be controlled by several kinases and pathways since they are blocked by inhibitors of PKC, PKA, PTK, PI3K, AKT1, and ERK (MAPK), however, the details of these processes are still incomplete. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ testis PS:Organ_System reproductive system PS:PMID 17920343 PS:PMID 19015188 PS:PMID 21540868 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6a03cee-f651-481c-99fd-cae25ac666fc NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-a6a03cee-f651-481c-99fd-cae25ac666fc Achondroplasia_Mutated Genes uuid-a6a03cee-f651-481c-99fd-cae25ac666fc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6a03cee-f651-481c-99fd-cae25ac666fc PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6de9c4b-047c-451d-bd7f-4b667de191e5 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-a6de9c4b-047c-451d-bd7f-4b667de191e5 Acetylcholine Release in Nociception uuid-a6de9c4b-047c-451d-bd7f-4b667de191e5 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6de9c4b-047c-451d-bd7f-4b667de191e5 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: keratinocyte Description: Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6f55397-0d33-4e1a-9273-42ef28ffde37 NodeType: Pathway Notes: Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 11568623 PMID: 12218613 PMID: 16513304 PMID: 23463347 PMID: 23826119 PMID: 24311896 PMID: 24321752 PMID: 24551293 PMID: 9655214 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-a6f55397-0d33-4e1a-9273-42ef28ffde37 Cholesteatoma uuid-a6f55397-0d33-4e1a-9273-42ef28ffde37 PS:CellType cancer cell PS:CellType keratinocyte PS:Description Cholesteatoma is a benign keratinizing and hyperproliferative squamous epithelial lesion of the temporal bone which gradually expands and causes serious complications. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6f55397-0d33-4e1a-9273-42ef28ffde37 PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 11568623 PS:PMID 12218613 PS:PMID 16513304 PS:PMID 23463347 PS:PMID 23826119 PS:PMID 24311896 PS:PMID 24321752 PS:PMID 24551293 PS:PMID 9655214 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6f7be8e-b82c-4619-aaca-1ee34e6a9898 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-a6f7be8e-b82c-4619-aaca-1ee34e6a9898 DRD1/5 Expression Targets uuid-a6f7be8e-b82c-4619-aaca-1ee34e6a9898 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6f7be8e-b82c-4619-aaca-1ee34e6a9898 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Endometrial carcinoma (EC) is the most common gynecological malignant tumor. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6fb71ab-7ba8-44d2-8bff-a548522abca4 NodeType: Pathway Notes: Headnote: Endometrial carcinoma (EC) is the most common gynecological malignant tumor. Overall, approximately 2-3% of women develop EC. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma (EEC) and type II estrogen-independent EC. EECs usually develop in perimenopausal women and are characterized by atypical endometrial hyperplasia. In contrast, type II tumors are aggressive estrogen-independent endometrial carcinomas which include clear-cell endometrial cancer and papillary serous endometrial cancer. Signaling description: The clinicopathological differences between the two EC types are correlated by specific genetic features. Type I demonstrates microsatellite instability, mutations in PTEN, PIK3CA, KRAS, ARID1A, and CTNNB1 genes as well as mutations in mismatch repair genes such as MLH1, MSH2, MSH3, and MSH6. In addition, type I EC is characterized by the reduced expression of PGR (progesterone receptor), overexpression of growth factor receptors and their ligands such as EGFR, FGF2, TGFA, IGF1R, IGF1/2, INS, and FGFR2 in addition to the overexpression of WNT, ESR1 (estrogen receptor), and CTNNB1 (beta-catenin). Type II EC exhibits mutations in TP53 as well as overexpression of ERBB2, CLDN3/4, EPCAM, and CDKN2A with the reduced expression of CDH1 (E-cadherin). Outcome effects: The overexpression of growth factor receptors and mutations in PTEN and KRAS genes cause the constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, increased proliferation, and migration of endometrial epithelial cells. Mutations in mismatch repair genes cause block of DNA repair. The overexpression of CLDN3/4 and EPCAM proteins, which form tight junctions, may increase cell motility and contribute to the aggressive phenotype of EC of serous papillary or clear-cell histology. The WNT/CTNNB1 signaling pathway controls various cellular functions. The overexpression of WNT induces the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. The role of ESR1 in promoting EC is related to its function as a transcription factor that induces the proliferation of endometrial cells. Mutations in ARID1A result in a dysfunction of chromatin remodeling. Danazol, Megace (megestrol), Provera (medroxyprogesterone), and progesterone are used for the specific treatment of EC. These drugs may directly inhibit steroidogenesis via binding to PGRs. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: uterus Organ_System: reproductive system PMID: 18061438 PMID: 21317462 PMID: 22653804 PMID: 22888282 PMID: 23240673 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: endometrium Tissue: epithelium urn:agi-pathway:uuid-a6fb71ab-7ba8-44d2-8bff-a548522abca4 Endometrial Cancer uuid-a6fb71ab-7ba8-44d2-8bff-a548522abca4 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Endometrial carcinoma (EC) is the most common gynecological malignant tumor. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6fb71ab-7ba8-44d2-8bff-a548522abca4 PS:NodeType Pathway PS:Notes Headnote: Endometrial carcinoma (EC) is the most common gynecological malignant tumor. Overall, approximately 2-3% of women develop EC. The two major categories of EC include type I estrogen-dependent endometrioid endometrial carcinoma (EEC) and type II estrogen-independent EC. EECs usually develop in perimenopausal women and are characterized by atypical endometrial hyperplasia. In contrast, type II tumors are aggressive estrogen-independent endometrial carcinomas which include clear-cell endometrial cancer and papillary serous endometrial cancer. Signaling description: The clinicopathological differences between the two EC types are correlated by specific genetic features. Type I demonstrates microsatellite instability, mutations in PTEN, PIK3CA, KRAS, ARID1A, and CTNNB1 genes as well as mutations in mismatch repair genes such as MLH1, MSH2, MSH3, and MSH6. In addition, type I EC is characterized by the reduced expression of PGR (progesterone receptor), overexpression of growth factor receptors and their ligands such as EGFR, FGF2, TGFA, IGF1R, IGF1/2, INS, and FGFR2 in addition to the overexpression of WNT, ESR1 (estrogen receptor), and CTNNB1 (beta-catenin). Type II EC exhibits mutations in TP53 as well as overexpression of ERBB2, CLDN3/4, EPCAM, and CDKN2A with the reduced expression of CDH1 (E-cadherin). Outcome effects: The overexpression of growth factor receptors and mutations in PTEN and KRAS genes cause the constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, increased proliferation, and migration of endometrial epithelial cells. Mutations in mismatch repair genes cause block of DNA repair. The overexpression of CLDN3/4 and EPCAM proteins, which form tight junctions, may increase cell motility and contribute to the aggressive phenotype of EC of serous papillary or clear-cell histology. The WNT/CTNNB1 signaling pathway controls various cellular functions. The overexpression of WNT induces the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. The role of ESR1 in promoting EC is related to its function as a transcription factor that induces the proliferation of endometrial cells. Mutations in ARID1A result in a dysfunction of chromatin remodeling. Danazol, Megace (megestrol), Provera (medroxyprogesterone), and progesterone are used for the specific treatment of EC. These drugs may directly inhibit steroidogenesis via binding to PGRs. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 18061438 PS:PMID 21317462 PS:PMID 22653804 PS:PMID 22888282 PS:PMID 23240673 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue endometrium PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6fbbcb0-09ee-426d-9e86-f8754869a4d2 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-a6fbbcb0-09ee-426d-9e86-f8754869a4d2 Proteins Involed in Timothy Syndrome uuid-a6fbbcb0-09ee-426d-9e86-f8754869a4d2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a6fbbcb0-09ee-426d-9e86-f8754869a4d2 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: It is evident that endothelial dysfunction disturbs the physiological protective regulatory balance, which is a critical factor in atherosclerotic disease progression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a708002a-f2a4-4f76-8baa-c66e54c1a7c0 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The endothelial dysfunction disturbs the physiological protective regulatory balance, which is a critical factor in atherosclerotic disease progression and diseases/disorders associated with an increased cardiovascular risk including hypertension, dyslipidemia, smoking, and mental stress. Endothelial dysfunction is associated with the inability of arteries and arterioles to fully dilate in response to a number of vasoactive substances including nitric oxide (NO). The decrease in NO levels is a hallmark of endothelial dysfunction. During endothelial dysfunction, the endothelium reduces anticoagulant properties while increasing the expression of adhesion molecules, chemokines, and reactive oxygen species (ROS) production. Under oxidative stress, oxidized LDL (oxLDL) in the vessel wall causes activation followed by endothelial dysfunction. OLR1 (also known as LOX-1) is the main receptor for oxLDL in endothelial cells. In normal endothelium, OLR1 is expressed at low levels, whereas pathological states such as dyslipidemia, inflammation, and oxidative stress dramatically increase OLR1 expression. In vitro, OLR1 expression is induced by several stimuli including pro-inflammatory cytokines (TNF, IL1, and IFNG), angiotensin II, EDN1, and free radicals. Moreover, oxLDL can upregulate the expression of its own receptor, OLR1 in a dose-dependent manner. OxLDL, through OLR1, contributes to the induction of endothelial dysfunction by several mechanisms. In vascular endothelial cells, OLR1 activation triggers a major source of intracellular ROS-NAD(P)H oxidase on the cell membrane, which results in the rapid increase of intracellular ROS such as O2 and H2O2. NAD(P)H oxidase consists of four major subunits including CYBB, CYBA, NCF1, and NCF2 and several isoforms of NAD(P)H subunits have been detected in endothelial cells. The exact mechanism of OLR1-dependent NAD(P)H oxidase activation is unknown. OxLDL/OLR1 may induce RAC1 activation via MMP14 axis to modulate RAC1-mediated NAD(P)H oxidase activity and ROS generation. OLR1 forms a complex with MMP14, which is a cellular receptor and activator for MMP2, but is also a potent matrix-degrading enzyme. Human endothelial cells increase the expression of MMP14, when treated with oxLDL, possibly through an EGFR-dependent mechanism. In addition, OLR1 may directly activate the assembly of NAD(P)H oxidase complex via RAC1 regulation. ROS triggers NF-kB activation and the production of chemokines and adhesion molecules including CCL2, IL8, CXCL2, VCAM1, ICAM1, SELE, and SELP, which leads to the recruitment and adhesion of leukocytes to the endothelium. Furthermore, oxLDL, via OLR1 activation, modulates the expression and activity of MMP1 and MMP3 in human coronary artery endothelial cells (HCAECs). In this process, the activation of PRKCB subunit has an important signaling role. The precise mechanism of this signaling has yet to be determined. NO reduction is considered a hallmark of endothelial dysfunction. Outcome effects: The decrease of intracellular NO results in increased levels of O2. In addition, oxLDL/OLR1 may induce RHOA activation, via MMP1 axis, to modulate RHOA-dependent NOS3 protein downregulation. ARHGEF1 and ROCK2 may be involved in RHOA-dependent NOS3 protein downregulation downstream from the OLR1 receptor complex. OxLDL can inhibit NO generation by displacing NOS3 from its caveolae membrane localization by depleting caveolae of cholesterol. This suggests that DNM2 is involved in scavenger receptor-mediated oxLDL endocytosis. Furthermore, oxLDL activates endothelial ARG2, which regulates NO production by competing with NOS3 for the common substrate L-arginine, through the dissociation of ar Organ: blood vessel Organ_System: cardiovascular system PMID: 12163130 PMID: 12694307 PMID: 15838273 PMID: 18796547 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-a708002a-f2a4-4f76-8baa-c66e54c1a7c0 Scavenger Receptor OLR1 in Inflammation Related Endothelial Dysfunction uuid-a708002a-f2a4-4f76-8baa-c66e54c1a7c0 PS:CellType endothelial cell PS:Description It is evident that endothelial dysfunction disturbs the physiological protective regulatory balance, which is a critical factor in atherosclerotic disease progression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a708002a-f2a4-4f76-8baa-c66e54c1a7c0 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The endothelial dysfunction disturbs the physiological protective regulatory balance, which is a critical factor in atherosclerotic disease progression and diseases/disorders associated with an increased cardiovascular risk including hypertension, dyslipidemia, smoking, and mental stress. Endothelial dysfunction is associated with the inability of arteries and arterioles to fully dilate in response to a number of vasoactive substances including nitric oxide (NO). The decrease in NO levels is a hallmark of endothelial dysfunction. During endothelial dysfunction, the endothelium reduces anticoagulant properties while increasing the expression of adhesion molecules, chemokines, and reactive oxygen species (ROS) production. Under oxidative stress, oxidized LDL (oxLDL) in the vessel wall causes activation followed by endothelial dysfunction. OLR1 (also known as LOX-1) is the main receptor for oxLDL in endothelial cells. In normal endothelium, OLR1 is expressed at low levels, whereas pathological states such as dyslipidemia, inflammation, and oxidative stress dramatically increase OLR1 expression. In vitro, OLR1 expression is induced by several stimuli including pro-inflammatory cytokines (TNF, IL1, and IFNG), angiotensin II, EDN1, and free radicals. Moreover, oxLDL can upregulate the expression of its own receptor, OLR1 in a dose-dependent manner. OxLDL, through OLR1, contributes to the induction of endothelial dysfunction by several mechanisms. In vascular endothelial cells, OLR1 activation triggers a major source of intracellular ROS-NAD(P)H oxidase on the cell membrane, which results in the rapid increase of intracellular ROS such as O2 and H2O2. NAD(P)H oxidase consists of four major subunits including CYBB, CYBA, NCF1, and NCF2 and several isoforms of NAD(P)H subunits have been detected in endothelial cells. The exact mechanism of OLR1-dependent NAD(P)H oxidase activation is unknown. OxLDL/OLR1 may induce RAC1 activation via MMP14 axis to modulate RAC1-mediated NAD(P)H oxidase activity and ROS generation. OLR1 forms a complex with MMP14, which is a cellular receptor and activator for MMP2, but is also a potent matrix-degrading enzyme. Human endothelial cells increase the expression of MMP14, when treated with oxLDL, possibly through an EGFR-dependent mechanism. In addition, OLR1 may directly activate the assembly of NAD(P)H oxidase complex via RAC1 regulation. ROS triggers NF-kB activation and the production of chemokines and adhesion molecules including CCL2, IL8, CXCL2, VCAM1, ICAM1, SELE, and SELP, which leads to the recruitment and adhesion of leukocytes to the endothelium. Furthermore, oxLDL, via OLR1 activation, modulates the expression and activity of MMP1 and MMP3 in human coronary artery endothelial cells (HCAECs). In this process, the activation of PRKCB subunit has an important signaling role. The precise mechanism of this signaling has yet to be determined. NO reduction is considered a hallmark of endothelial dysfunction. Outcome effects: The decrease of intracellular NO results in increased levels of O2. In addition, oxLDL/OLR1 may induce RHOA activation, via MMP1 axis, to modulate RHOA-dependent NOS3 protein downregulation. ARHGEF1 and ROCK2 may be involved in RHOA-dependent NOS3 protein downregulation downstream from the OLR1 receptor complex. OxLDL can inhibit NO generation by displacing NOS3 from its caveolae membrane localization by depleting caveolae of cholesterol. This suggests that DNM2 is involved in scavenger receptor-mediated oxLDL endocytosis. Furthermore, oxLDL activates endothelial ARG2, which regulates NO production by competing with NOS3 for the common substrate L-arginine, through the dissociation of ar PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 12163130 PS:PMID 12694307 PS:PMID 15838273 PS:PMID 18796547 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a72f6ccc-b61d-4781-be6a-e158822716ab NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-a72f6ccc-b61d-4781-be6a-e158822716ab Drugs for SARS and MERS uuid-a72f6ccc-b61d-4781-be6a-e158822716ab PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a72f6ccc-b61d-4781-be6a-e158822716ab PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7a728c1-7a9f-405c-9004-3bf3fdae96b3 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-a7a728c1-7a9f-405c-9004-3bf3fdae96b3 Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death uuid-a7a728c1-7a9f-405c-9004-3bf3fdae96b3 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7a728c1-7a9f-405c-9004-3bf3fdae96b3 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7c131b2-b705-4d1e-9696-3c913cce54a6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a7c131b2-b705-4d1e-9696-3c913cce54a6 ANGPT1 -> CREB/CREBBP Expression Targets uuid-a7c131b2-b705-4d1e-9696-3c913cce54a6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7c131b2-b705-4d1e-9696-3c913cce54a6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7e6949a-0c2a-4b8b-b222-cc2b6e92b56f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-a7e6949a-0c2a-4b8b-b222-cc2b6e92b56f TLR1/2/6 -> NF-kB Signaling uuid-a7e6949a-0c2a-4b8b-b222-cc2b6e92b56f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7e6949a-0c2a-4b8b-b222-cc2b6e92b56f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7f14f09-85c0-441b-9013-1efd56937eb2 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-a7f14f09-85c0-441b-9013-1efd56937eb2 InsulinR -> ELK/SRF/SREBF Signaling uuid-a7f14f09-85c0-441b-9013-1efd56937eb2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7f14f09-85c0-441b-9013-1efd56937eb2 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7f99c28-6151-40d5-8457-e06a45e774b6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-a7f99c28-6151-40d5-8457-e06a45e774b6 ProlactinR -> STAT Signaling uuid-a7f99c28-6151-40d5-8457-e06a45e774b6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a7f99c28-6151-40d5-8457-e06a45e774b6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a803a466-df85-492a-b768-57657ab201b5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-a803a466-df85-492a-b768-57657ab201b5 microRNAs-|ZEB1/2 uuid-a803a466-df85-492a-b768-57657ab201b5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a803a466-df85-492a-b768-57657ab201b5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a81708ad-c47a-445b-ba7a-52959f01a66e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-a81708ad-c47a-445b-ba7a-52959f01a66e Tricarboxylic Acid Cycle uuid-a81708ad-c47a-445b-ba7a-52959f01a66e PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a81708ad-c47a-445b-ba7a-52959f01a66e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a81f5abe-d3ea-4cf7-a84a-e5d612f169cc NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-a81f5abe-d3ea-4cf7-a84a-e5d612f169cc Vascular Smooth Muscle Cell Vasodilation in Brain uuid-a81f5abe-d3ea-4cf7-a84a-e5d612f169cc PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a81f5abe-d3ea-4cf7-a84a-e5d612f169cc PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a83c3fef-b675-4fe0-8c63-406924948166 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a83c3fef-b675-4fe0-8c63-406924948166 Noreadrenaline/Gq Expression Targets uuid-a83c3fef-b675-4fe0-8c63-406924948166 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a83c3fef-b675-4fe0-8c63-406924948166 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8479dbc-9d9d-4a57-8db9-4276fcf5721e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a8479dbc-9d9d-4a57-8db9-4276fcf5721e AREG -> AP-1 Expression Targets uuid-a8479dbc-9d9d-4a57-8db9-4276fcf5721e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8479dbc-9d9d-4a57-8db9-4276fcf5721e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a861a6aa-e461-4d2d-b15d-4342f4d368a3 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a861a6aa-e461-4d2d-b15d-4342f4d368a3 Wiskott-Aldrich syndrome Anatomy and Molecular Biomarkers uuid-a861a6aa-e461-4d2d-b15d-4342f4d368a3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a861a6aa-e461-4d2d-b15d-4342f4d368a3 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: The E6 and E7 are early HPV proteins. Viral infection leads to activation of TLR and TNF pathways, which must lead to apoptosis of infected cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a862cc5d-50bf-4178-bcac-4c12865754e0 NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). The expression of E6 and E7 is required for cell transformation. Viral infection leads to the activation of TLR and TNF pathways, which leads to the apoptosis of infected cells. In the course of the TLR-mediated cellular response to the virus, interferon regulatory factors (IRF7 and IRF3) and TRAF6 are activated. The increased activity of TRAF6 increases the phosphorylation of NFKBIA, which is an inhibitor of NF-kB. In parallel, there is an activation of protein ubiquitination by the TNF pathway, particularly by the CUL1/SKP1/BTRC/RBX1 complex. This complex activates the ubiquitination of phosphorylated NFKBIA. The degradation of NFKBIA leads to the nuclear translocation of NF-kB. CpG islands of viral DNA are ligands for endosomal toll-like receptors including TLR9. HPV proteins E6 and E7 have been implicated in the direct inhibition of TLR9-mediated pathways by the down-regulation of the TLR9 gene transcription. Outcome effects: The down-regulation of TLR9 gene transcription leads to a reduction of cell response to viral infection. In addition, the activation of NF-kB leads to the transcription activity of various genes including those coding for cytokines, activators of vascularization, negative regulators of apoptosis, CCND1, MYC, CASP8, and CFLAR. The CFLAR protein can inhibit both FADD and CASP8. This leads to block of apoptosis, genome instability, cell survival, and vascularization of transformed tissues. Additionally, E6 protein acticvates FADD degradation, with the decrease of cellular FADD level proportional to the amount of E6 expressed. These results support a model in which E6-mediated degradation of FADD prevents transmission of apoptotic signals via the FAS pathway. In the FAS pathway, FADD activates CASP8 which does not occur in the presence of E6, which can also inhibit TP53 resulting in loss of CASP8 transcription. NF-kB-dependent proliferation and protection from apoptosis are likely to be important in the pathogenesis of HPV-related diseases. Thus, viral infection activates protective TLR and TNF pathways. However, viral proteins E6 and E7 modify these pathways for the survival of infected cells and for the protection of viral reproduction. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Exogenous proteins are shown in grey. Organ: skin PMID: 19007434 PMID: 19081593 PMID: 21400034 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-a862cc5d-50bf-4178-bcac-4c12865754e0 HPV E6 and E7 Induced Disruption of TNFR/NF-kB Signaling in Keratinocytes uuid-a862cc5d-50bf-4178-bcac-4c12865754e0 PS:CellType cancer cell PS:CellType keratinocyte PS:Description The E6 and E7 are early HPV proteins. Viral infection leads to activation of TLR and TNF pathways, which must lead to apoptosis of infected cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a862cc5d-50bf-4178-bcac-4c12865754e0 PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). The expression of E6 and E7 is required for cell transformation. Viral infection leads to the activation of TLR and TNF pathways, which leads to the apoptosis of infected cells. In the course of the TLR-mediated cellular response to the virus, interferon regulatory factors (IRF7 and IRF3) and TRAF6 are activated. The increased activity of TRAF6 increases the phosphorylation of NFKBIA, which is an inhibitor of NF-kB. In parallel, there is an activation of protein ubiquitination by the TNF pathway, particularly by the CUL1/SKP1/BTRC/RBX1 complex. This complex activates the ubiquitination of phosphorylated NFKBIA. The degradation of NFKBIA leads to the nuclear translocation of NF-kB. CpG islands of viral DNA are ligands for endosomal toll-like receptors including TLR9. HPV proteins E6 and E7 have been implicated in the direct inhibition of TLR9-mediated pathways by the down-regulation of the TLR9 gene transcription. Outcome effects: The down-regulation of TLR9 gene transcription leads to a reduction of cell response to viral infection. In addition, the activation of NF-kB leads to the transcription activity of various genes including those coding for cytokines, activators of vascularization, negative regulators of apoptosis, CCND1, MYC, CASP8, and CFLAR. The CFLAR protein can inhibit both FADD and CASP8. This leads to block of apoptosis, genome instability, cell survival, and vascularization of transformed tissues. Additionally, E6 protein acticvates FADD degradation, with the decrease of cellular FADD level proportional to the amount of E6 expressed. These results support a model in which E6-mediated degradation of FADD prevents transmission of apoptotic signals via the FAS pathway. In the FAS pathway, FADD activates CASP8 which does not occur in the presence of E6, which can also inhibit TP53 resulting in loss of CASP8 transcription. NF-kB-dependent proliferation and protection from apoptosis are likely to be important in the pathogenesis of HPV-related diseases. Thus, viral infection activates protective TLR and TNF pathways. However, viral proteins E6 and E7 modify these pathways for the survival of infected cells and for the protection of viral reproduction. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Exogenous proteins are shown in grey. PS:Organ skin PS:PMID 19007434 PS:PMID 19081593 PS:PMID 21400034 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: macrophage CellType: monocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a86532ee-58eb-44b8-b0ac-5730f11fb6ce NodeType: Pathway Notes: During the initial stages in the development of atherosclerosis, the passage of low-density lipoprotein (LDL) into the arterial wall leads to lipid deposition and visible plague development. First, LDL becomes oxidized and then attracts monocytes and macrophages to the site of deposition to induce the formation of lipid-laden foam cells in the vessel wall. Cholesterol-laden foam cells and macrophages lose their mobility, release proinflammatory cytokines and proteases (not shown) that together recruit more monocytes to the site, and launch the inflammation. In atherosclerotic lesions, oxidized LDLs are connected with insoluble crystals of ceroids/lipofuscin aggregates. Cholesterol crystals and lipofuscin induce lysosome destabilization and cell death. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: Blood Vessels Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-a86532ee-58eb-44b8-b0ac-5730f11fb6ce 1_Low-density lipoprotein internalization and the accumulation of lipids in atherosclerosis uuid-a86532ee-58eb-44b8-b0ac-5730f11fb6ce PS:CellType endothelial cell PS:CellType macrophage PS:CellType monocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a86532ee-58eb-44b8-b0ac-5730f11fb6ce PS:NodeType Pathway PS:Notes During the initial stages in the development of atherosclerosis, the passage of low-density lipoprotein (LDL) into the arterial wall leads to lipid deposition and visible plague development. First, LDL becomes oxidized and then attracts monocytes and macrophages to the site of deposition to induce the formation of lipid-laden foam cells in the vessel wall. Cholesterol-laden foam cells and macrophages lose their mobility, release proinflammatory cytokines and proteases (not shown) that together recruit more monocytes to the site, and launch the inflammation. In atherosclerotic lesions, oxidized LDLs are connected with insoluble crystals of ceroids/lipofuscin aggregates. Cholesterol crystals and lipofuscin induce lysosome destabilization and cell death. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ Blood Vessels PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8687b38-0d3b-4c2a-a46a-7af1e887ccbe NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-a8687b38-0d3b-4c2a-a46a-7af1e887ccbe P2RX7 -> Expression Targets in Nerve Tissue uuid-a8687b38-0d3b-4c2a-a46a-7af1e887ccbe PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8687b38-0d3b-4c2a-a46a-7af1e887ccbe PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a86b98b2-ad1a-409e-8aa6-7a2cd6bf33db NodeType: Pathway Organ: generic Organ_System: generic PMID: 18267068 PMID: 20685151 PMID: 2391518 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-a86b98b2-ad1a-409e-8aa6-7a2cd6bf33db NF-kB non-Canonical Signaling uuid-a86b98b2-ad1a-409e-8aa6-7a2cd6bf33db PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a86b98b2-ad1a-409e-8aa6-7a2cd6bf33db PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 18267068 PS:PMID 20685151 PS:PMID 2391518 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a883149f-ebd3-49fb-b294-e7bc29317e74 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a883149f-ebd3-49fb-b294-e7bc29317e74 BTC -> STAT Expression Targets uuid-a883149f-ebd3-49fb-b294-e7bc29317e74 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a883149f-ebd3-49fb-b294-e7bc29317e74 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Approximately 4? of cases of adult-onset primary open-angle glaucoma and more than 10? of juvenile-onset cases are associated with myocilin (MYOC) mutations. The exact function of MYOC is unknown. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a89d6a47-a9cf-42b7-bd6a-10b37817aef7 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Approximately 4% of adult-onset primary open-angle glaucoma cases and more than 10% of juvenile-onset cases are associated with myocilin (MYOC) mutations. Signaling description: MYOC is a secreted glycoprotein of unknown function. Most likely, mutations in MYOC have a pathogenic effect due to the inability of the protein to fold properly. When misfolded, this mutated protein forms aggregates in the endoplasmic reticulum (ER) as well as in the cytoplasm. The misfolded protein ultimately results in unfolded protein response (UPR) and activates mitochondria-independent apoptosis pathway. In addition, MYOC mutations greatly reduce the quantity of MYOC that is secreted into the AH which supports the idea that failure to secrete MYOC is one of the central events in the pathogenesis of MYOC-associated glaucoma. Normally, MYOC is cleaved by CAPN2 into two fragments: a 20 kDa N-terminal fragment and a 35 kDa C-terminal olfactomedin-containing fragment. The 35-kDa fragment and full length MYOC have been shown to be excreted into the extracellular matrix (ECM), and thus hypothesized to maintain a normal ECM structure. Furthermore, data suggests that MYOC can control the adhesive properties of the cell. MYOC was shown to be a modulator of WNT signaling pathway, and the protein also affects the TM adhesion properties through RHOA. MYOC interacts with the components of the WNT signaling pathways, including WNT receptors of the Frizzled (FZD) family, WNT antagonists of the secreted FZD-related protein (SFRP1) family, and WNT inhibitory factor 1 (WIF1), which modulate the organization of actin cytoskeleton and stimulate the formation of stress fibers critical for the contractility of TM and IOP regulation. MYOC expression is known to be upregulated by glucocorticoids in TM cells and altered MYOC levels may be the culprit in conditions such as corticosteroid glaucoma. The expression of MYOC may also be induced by TGFB1, OPTN, and mechanical stress. Outcome effects: Mutations in MYOC disturb its normal cleavage by CAPN2, and thus cause the breakdown of ECM structure in TM which ultimately results in higher intraocular pressure (IOP) and glaucoma. In addition, the mitochondria-independent apoptosis pathway caused by misfolded MYOC leads to cell death and the breakdown of the trabecular meshwork (TM) cell structure, obstruction of aqueous humor (AH) outflow pathway, and also leads to ocular hypertension and glaucoma. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ: trabecular meshwork Organ_System: sensory system PMID: 17984096 PMID: 19188438 PMID: 20431268 PMID: 21709622 PMID: 22173078 PMID: 22216020 PMID: 23876925 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a89d6a47-a9cf-42b7-bd6a-10b37817aef7 MYOC Associated Glaucoma uuid-a89d6a47-a9cf-42b7-bd6a-10b37817aef7 PS:Description Approximately 4? of cases of adult-onset primary open-angle glaucoma and more than 10? of juvenile-onset cases are associated with myocilin (MYOC) mutations. The exact function of MYOC is unknown. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a89d6a47-a9cf-42b7-bd6a-10b37817aef7 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Approximately 4% of adult-onset primary open-angle glaucoma cases and more than 10% of juvenile-onset cases are associated with myocilin (MYOC) mutations. Signaling description: MYOC is a secreted glycoprotein of unknown function. Most likely, mutations in MYOC have a pathogenic effect due to the inability of the protein to fold properly. When misfolded, this mutated protein forms aggregates in the endoplasmic reticulum (ER) as well as in the cytoplasm. The misfolded protein ultimately results in unfolded protein response (UPR) and activates mitochondria-independent apoptosis pathway. In addition, MYOC mutations greatly reduce the quantity of MYOC that is secreted into the AH which supports the idea that failure to secrete MYOC is one of the central events in the pathogenesis of MYOC-associated glaucoma. Normally, MYOC is cleaved by CAPN2 into two fragments: a 20 kDa N-terminal fragment and a 35 kDa C-terminal olfactomedin-containing fragment. The 35-kDa fragment and full length MYOC have been shown to be excreted into the extracellular matrix (ECM), and thus hypothesized to maintain a normal ECM structure. Furthermore, data suggests that MYOC can control the adhesive properties of the cell. MYOC was shown to be a modulator of WNT signaling pathway, and the protein also affects the TM adhesion properties through RHOA. MYOC interacts with the components of the WNT signaling pathways, including WNT receptors of the Frizzled (FZD) family, WNT antagonists of the secreted FZD-related protein (SFRP1) family, and WNT inhibitory factor 1 (WIF1), which modulate the organization of actin cytoskeleton and stimulate the formation of stress fibers critical for the contractility of TM and IOP regulation. MYOC expression is known to be upregulated by glucocorticoids in TM cells and altered MYOC levels may be the culprit in conditions such as corticosteroid glaucoma. The expression of MYOC may also be induced by TGFB1, OPTN, and mechanical stress. Outcome effects: Mutations in MYOC disturb its normal cleavage by CAPN2, and thus cause the breakdown of ECM structure in TM which ultimately results in higher intraocular pressure (IOP) and glaucoma. In addition, the mitochondria-independent apoptosis pathway caused by misfolded MYOC leads to cell death and the breakdown of the trabecular meshwork (TM) cell structure, obstruction of aqueous humor (AH) outflow pathway, and also leads to ocular hypertension and glaucoma. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ trabecular meshwork PS:Organ_System sensory system PS:PMID 17984096 PS:PMID 19188438 PS:PMID 20431268 PS:PMID 21709622 PS:PMID 22173078 PS:PMID 22216020 PS:PMID 23876925 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: In human epidermal keratinocytes, the antifungal agent ketoconazole in addition to its inhibitory effects against fungi activates NF erythroid 2-related factor-2 (NFE2L2) via AHR signaling. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8a28428-8672-4561-94d5-6715361bca85 NodeType: Pathway Notes: Headnote: Ketoconazole is an antifungal agent. Signaling description: In human epidermal keratinocytes, ketoconazole in addition to its inhibitory effects against fungi activates NF erythroid 2-related factor-2 (NFE2L2) via AHR signaling. AHR initiates dissociation of inhibitory KEAP1 from NFE2L2 and nuclear translocation of NFE2L2. This leads to activation of the target gene NQO1 with subsequent elimination of ROS. Outcome effects: Cynaropicrin is a natural component of artichoke (Cynara scolymus) used as folk medicine due to its antioxidant and anti-inflammatory activities. Cynaropicrin was shown to attenuate UVB-induced oxidative stress via the AHR- NFE2L2-NQO1 pathway. Ligustilide, an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba was shown to induce the NFE2L2-NQO1 axis. Organ: skin Organ_System: integumentary system PMID: 21753779 PMID: 22158605 PMID: 24588654 PMID: 24966027 PMID: 25680693 PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-a8a28428-8672-4561-94d5-6715361bca85 Oxidative Stress Protection via AHR-NFE2L2-NQO1 Signaling in Keratinocytes uuid-a8a28428-8672-4561-94d5-6715361bca85 PS:CellType keratinocyte PS:Description In human epidermal keratinocytes, the antifungal agent ketoconazole in addition to its inhibitory effects against fungi activates NF erythroid 2-related factor-2 (NFE2L2) via AHR signaling. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8a28428-8672-4561-94d5-6715361bca85 PS:NodeType Pathway PS:Notes Headnote: Ketoconazole is an antifungal agent. Signaling description: In human epidermal keratinocytes, ketoconazole in addition to its inhibitory effects against fungi activates NF erythroid 2-related factor-2 (NFE2L2) via AHR signaling. AHR initiates dissociation of inhibitory KEAP1 from NFE2L2 and nuclear translocation of NFE2L2. This leads to activation of the target gene NQO1 with subsequent elimination of ROS. Outcome effects: Cynaropicrin is a natural component of artichoke (Cynara scolymus) used as folk medicine due to its antioxidant and anti-inflammatory activities. Cynaropicrin was shown to attenuate UVB-induced oxidative stress via the AHR- NFE2L2-NQO1 pathway. Ligustilide, an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba was shown to induce the NFE2L2-NQO1 axis. PS:Organ skin PS:Organ_System integumentary system PS:PMID 21753779 PS:PMID 22158605 PS:PMID 24588654 PS:PMID 24966027 PS:PMID 25680693 PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8b40150-e1c4-4834-8d3d-19b291b4a2a6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-a8b40150-e1c4-4834-8d3d-19b291b4a2a6 IL5R -> STAT Signaling uuid-a8b40150-e1c4-4834-8d3d-19b291b4a2a6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8b40150-e1c4-4834-8d3d-19b291b4a2a6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8c8ea9e-9ad4-4753-9305-04631e004ef6 NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-a8c8ea9e-9ad4-4753-9305-04631e004ef6 Genes with Mutations Associated with Endometrial Cancer uuid-a8c8ea9e-9ad4-4753-9305-04631e004ef6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8c8ea9e-9ad4-4753-9305-04631e004ef6 PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8df3b53-b0b1-429a-8873-2849eac8acd0 NodeType: Pathway Organ: testis Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a8df3b53-b0b1-429a-8873-2849eac8acd0 Proteins Involved in Cryptorchidism uuid-a8df3b53-b0b1-429a-8873-2849eac8acd0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8df3b53-b0b1-429a-8873-2849eac8acd0 PS:NodeType Pathway PS:Organ testis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8e815cc-c83c-479c-93c0-9cd79d2af4ba NodeType: Pathway Organ: colon Organ: intestine Organ_System: digestive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a8e815cc-c83c-479c-93c0-9cd79d2af4ba Proteins Involved in Colorectal Neoplasms uuid-a8e815cc-c83c-479c-93c0-9cd79d2af4ba PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8e815cc-c83c-479c-93c0-9cd79d2af4ba PS:NodeType Pathway PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is the most common cancer in women. WNT/CTNNB1 signaling is implicated in different stages of mammary gland development and mammary oncogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8ef89bf-bc28-40f3-85ff-490440dea5fb NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: The WNT/beta-catenin (WNT/CTNNB1) signaling pathway controls various cellular functions including proliferation, differentiation, and migration. In particular, WNT/CTNNB1 signaling was shown to be involved in mammary gland development and mammary oncogenesis. In the absence of WNT proteins, CTNNB1 is associated with a complex which comprises AXIN1, GSK3B, and CSNK1A1. The formation of this complex induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B leading to CTNNB1 protein ubiquitination and degradation by the proteasome. When WNT proteins bind to LRP5/6 and FZD7, DVL1 is activated and inhibits GSK3B, which results in the stabilization of cytosolic CTNNB1 protein. Outcome effects: Further, activated CTNNB1 protein translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. It has been demonstrated that FZD7 and LRP6 overexpression plays an essential role in triple-negative breast cancer (TNBC). The overexpression of FZD7 and LRP6 causes the constitutive activation of WNT/CTNNB1 signaling pathway causing loss of differentiation, redundant proliferation, and migration of mammary epithelial cells. In addition, WNT/FZD7 induces breast cancer cell migration and growth via the MAPK-cascade: WNT/FZD7 activates the DVL1/DAAM1 complex, which in turn activates RAC1 and RHOA, which induce the MAPK-cascade. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: breast Organ_System: integumentary system PMID: 16465433 PMID: 21898546 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-a8ef89bf-bc28-40f3-85ff-490440dea5fb WNT Signaling in Breast Cancer uuid-a8ef89bf-bc28-40f3-85ff-490440dea5fb PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is the most common cancer in women. WNT/CTNNB1 signaling is implicated in different stages of mammary gland development and mammary oncogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a8ef89bf-bc28-40f3-85ff-490440dea5fb PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: The WNT/beta-catenin (WNT/CTNNB1) signaling pathway controls various cellular functions including proliferation, differentiation, and migration. In particular, WNT/CTNNB1 signaling was shown to be involved in mammary gland development and mammary oncogenesis. In the absence of WNT proteins, CTNNB1 is associated with a complex which comprises AXIN1, GSK3B, and CSNK1A1. The formation of this complex induces the phosphorylation of CTNNB1 by CSNK1A1 and GSK3B leading to CTNNB1 protein ubiquitination and degradation by the proteasome. When WNT proteins bind to LRP5/6 and FZD7, DVL1 is activated and inhibits GSK3B, which results in the stabilization of cytosolic CTNNB1 protein. Outcome effects: Further, activated CTNNB1 protein translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. It has been demonstrated that FZD7 and LRP6 overexpression plays an essential role in triple-negative breast cancer (TNBC). The overexpression of FZD7 and LRP6 causes the constitutive activation of WNT/CTNNB1 signaling pathway causing loss of differentiation, redundant proliferation, and migration of mammary epithelial cells. In addition, WNT/FZD7 induces breast cancer cell migration and growth via the MAPK-cascade: WNT/FZD7 activates the DVL1/DAAM1 complex, which in turn activates RAC1 and RHOA, which induce the MAPK-cascade. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ breast PS:Organ_System integumentary system PS:PMID 16465433 PS:PMID 21898546 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9046ef3-36c3-4b97-9275-c10623f54214 NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-a9046ef3-36c3-4b97-9275-c10623f54214 H4 Modification Sites uuid-a9046ef3-36c3-4b97-9275-c10623f54214 PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9046ef3-36c3-4b97-9275-c10623f54214 PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: gonadotroph CellType: lactotroph Description: The hyperprolactinemia of hypothyroidism is related to several mechanisms. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a905d687-500c-4ce1-9394-30fc809634ba NodeType: Pathway Notes: The hyperprolactinemia of hypothyroidism is associated to several mechanisms. Thyrotropin releasing hormone (TRH) is a well-known positive regulator of prolactin (PRL) production and release. In response to the hypothyroid state (low level of thyroid hormones), a compensatory increase in hypothalamic TRH results in increased stimulation of PRL secretion. Also in hypothyroid state thyroid hormones stop to inhibit the expression of PRL gene (the proximal promoter of PRL gene contains an inhibitory region that responds to thyroid hormones). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 20938100 PMID: 23776802 PMID: 25737975 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a905d687-500c-4ce1-9394-30fc809634ba Hypothyrodism Associated Hyperprolactinemia uuid-a905d687-500c-4ce1-9394-30fc809634ba PS:CellType gonadotroph PS:CellType lactotroph PS:Description The hyperprolactinemia of hypothyroidism is related to several mechanisms. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a905d687-500c-4ce1-9394-30fc809634ba PS:NodeType Pathway PS:Notes The hyperprolactinemia of hypothyroidism is associated to several mechanisms. Thyrotropin releasing hormone (TRH) is a well-known positive regulator of prolactin (PRL) production and release. In response to the hypothyroid state (low level of thyroid hormones), a compensatory increase in hypothalamic TRH results in increased stimulation of PRL secretion. Also in hypothyroid state thyroid hormones stop to inhibit the expression of PRL gene (the proximal promoter of PRL gene contains an inhibitory region that responds to thyroid hormones). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 20938100 PS:PMID 23776802 PS:PMID 25737975 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a91e5a43-5a0d-4cda-979a-5e686bed82de NodeType: Pathway Notes: Low expression of pattern recognition receptors leads to insufficient immune response in the middle ear epithelium cells in otitis media. The downregulation of TLRs, NODs, and other pattern recognition receptor expression in otitis media leads to an inefficient defense in the middle ear, which in turn causes repeated infections and persistent inflammations. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-a91e5a43-5a0d-4cda-979a-5e686bed82de 1_Insufficient activation of immune response in the middle ear epithelium cells in otitis media uuid-a91e5a43-5a0d-4cda-979a-5e686bed82de PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a91e5a43-5a0d-4cda-979a-5e686bed82de PS:NodeType Pathway PS:Notes Low expression of pattern recognition receptors leads to insufficient immune response in the middle ear epithelium cells in otitis media. The downregulation of TLRs, NODs, and other pattern recognition receptor expression in otitis media leads to an inefficient defense in the middle ear, which in turn causes repeated infections and persistent inflammations. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a92d0a8c-9468-48d9-8054-99c9e898a805 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a92d0a8c-9468-48d9-8054-99c9e898a805 EGF -> CTNN Expression Targets uuid-a92d0a8c-9468-48d9-8054-99c9e898a805 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a92d0a8c-9468-48d9-8054-99c9e898a805 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Inflammation in adipose tissue can cause insulin resistance. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a92db538-1482-4b8e-a835-dbfba80d5044 NodeType: Pathway Notes: Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Inflammation in adipose tissue can cause insulin resistance. Signaling description: The excess of triglycerides in adipose tissue caused by a high-fat diet provokes inflammation. Triglycerides facilitate MCP-1 (CCL2) expression; however the precise molecular mechanism remains unclear. CCL2 is a chemoattractant recruiting macrophages to adipose tissue. Triglycerides also activate NF-kB triggering TNF synthesis and secretion. The binding of this proinflammatory cytokine to its receptor, TNFRSF1A on the surface of macrophages and adipocytes leads to IL6 and CXCL5 synthesis. The excessive amount of triglycerides in adipose tissue undergoes lysis by the PNPLA2 and LIPE proteins. The released free fatty acids (FFA) are transported via FABP4 to the cell membrane and transported across the cell membrane via SLC27A1. Outcome effects: The released IL6 provokes insulin resistance in the liver; whereas CXCL5 acts on the muscles. The increased FFA in the blood is exposed to peripheral tissues provoking insulin resistance in these tissues. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ_System: endocrine system PMID: 16613757 PMID: 20157549 PMID: 21104928 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-a92db538-1482-4b8e-a835-dbfba80d5044 Adipose Tissue Inflammation Provokes Insulin Resistance uuid-a92db538-1482-4b8e-a835-dbfba80d5044 PS:CellType adipocyte PS:Description Inflammation in adipose tissue can cause insulin resistance. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a92db538-1482-4b8e-a835-dbfba80d5044 PS:NodeType Pathway PS:Notes Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Inflammation in adipose tissue can cause insulin resistance. Signaling description: The excess of triglycerides in adipose tissue caused by a high-fat diet provokes inflammation. Triglycerides facilitate MCP-1 (CCL2) expression; however the precise molecular mechanism remains unclear. CCL2 is a chemoattractant recruiting macrophages to adipose tissue. Triglycerides also activate NF-kB triggering TNF synthesis and secretion. The binding of this proinflammatory cytokine to its receptor, TNFRSF1A on the surface of macrophages and adipocytes leads to IL6 and CXCL5 synthesis. The excessive amount of triglycerides in adipose tissue undergoes lysis by the PNPLA2 and LIPE proteins. The released free fatty acids (FFA) are transported via FABP4 to the cell membrane and transported across the cell membrane via SLC27A1. Outcome effects: The released IL6 provokes insulin resistance in the liver; whereas CXCL5 acts on the muscles. The increased FFA in the blood is exposed to peripheral tissues provoking insulin resistance in these tissues. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ_System endocrine system PS:PMID 16613757 PS:PMID 20157549 PS:PMID 21104928 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9778467-a5c2-43a1-9798-3eb23dbb2ae7 NodeType: Pathway Organ: ear Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a9778467-a5c2-43a1-9798-3eb23dbb2ae7 Proteins Involved in Congenital Deafness uuid-a9778467-a5c2-43a1-9798-3eb23dbb2ae7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9778467-a5c2-43a1-9798-3eb23dbb2ae7 PS:NodeType Pathway PS:Organ ear PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a97ac062-8753-4ba3-afc5-3caa86b6ca97 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. This pathway describes the signaling cascades that could potentially exist in cancer cells, but may not necessarily occur in every case. Signaling description: It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. This may be due to changes in either the receptor itself (e.g., mutations or amplifications) or in coregulators influencing AR activity (e.g., NCOA2, NCOA3, NCOA4, CCND1, and ARA55). However, in primary tumors AR activity is strongly dependent on androgens (testosterone and DHT) and antiandrogen therapy is used successfully to stop the progression of the cancer. Nevertheless, during this therapy the disease acquires androgen-refractory status characterized by deregulation of many signaling pathways. One of the deregulated signaling cascades in prostate cancer cells is the PI3K/Akt pathway that is found to be highly activated in advanced cases of the disease. The main cause of constitutive activation of Akt (AKT1) is the loss of PTEN function in advanced cancer since PI3K pathway inhibition is primarily performed by the tumor suppressor, PTEN. Another signaling cascade that is deregulated in prostate cancer is MAP kinase (MAPK) pathway. The main probable cause for permanent activation of the MAPK cascade in prostate cancer cells is increased levels of autocrine and paracrine growth factors. Additionally, prostate cancer cells are characterized by the overexpression of some growth factor receptors (e.g., ERBB2), that also activate growth factor pathways. Multiple growth factors and cytokines such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF1), and interleukin-6 (IL6) stimulate cell growth through the activation of small G-protein Ras and MAPK cascade. The phosphorylation of ERK1/2 (MAPK1/2) leads to the activation of various transcription factors such as MYC, ETS1, EGR1, SP1, and Jun/Fos and the modulation of downstream cell processes. In addition, the transmembrane receptor tyrosine kinase, c-Met (MET) plays an important role in prostate cancer. MET is activated by the hepatocyte growth factor/scatter factor (HGF/SF), which is a multifunctional growth factor that regulates various cell processes such as cell motility, invasive growth, and angiogenesis. AR inhibits the expression of MET by competing with another transcription factor, SP1 for binding to the promoter of MET gene. Lastly, there are several microRNAs (miRNAs) that play a major role in the pathogenesis and prognosis of prostate cancer. Several miRNAs and their targets have been discovered to express abnormally in some prostate cancer cases, including some that are oncogenic (MIR106B and MIR221) and tumor suppressive (MIR15A, MIR145, and MIR101-1). Outcome effects: AKT1 regulates cell survival and cell cycle. For example, AKT1 negatively regulates apoptosis by inhibiting procaspase-9 (CASP9) and BAD, while positively regulating the cell cycle by inhibiting p21 and p27, thus enabling cell cycle progression. Furthermore, AKT1 can also regulate AR activity. In the normal prostate, AR seems to balance proliferative and proapoptotic programs, while in cancerous tissue AKT1 can phosphorylate and inactivate AR, thereby permanently switching on a pro-survival program. Another target of AKT1 is enhancer of zeste homolog 2 (EZH2), which is a transcriptional repressor whose expression in prostate cancer is associated with hormone-refractory status and metastasis. Further, the MAPK pathway controls such processes as proliferation, metastasis, and angiogenesis as well as resistance to antitumor drugs. One of the transcriptional targets of MAPK signaling is interleukin-6 which can play a role in the progression of prostate cancer through sev Organ: prostate Organ_System: urinary tract PMID: 16741972 PMID: 17297502 PMID: 18667687 PMID: 21475371 PMID: 21956922 PMID: 22417299 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a97ac062-8753-4ba3-afc5-3caa86b6ca97 Prostate Cancer uuid-a97ac062-8753-4ba3-afc5-3caa86b6ca97 PS:CellType cancer cell PS:Description Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a97ac062-8753-4ba3-afc5-3caa86b6ca97 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. This pathway describes the signaling cascades that could potentially exist in cancer cells, but may not necessarily occur in every case. Signaling description: It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. This may be due to changes in either the receptor itself (e.g., mutations or amplifications) or in coregulators influencing AR activity (e.g., NCOA2, NCOA3, NCOA4, CCND1, and ARA55). However, in primary tumors AR activity is strongly dependent on androgens (testosterone and DHT) and antiandrogen therapy is used successfully to stop the progression of the cancer. Nevertheless, during this therapy the disease acquires androgen-refractory status characterized by deregulation of many signaling pathways. One of the deregulated signaling cascades in prostate cancer cells is the PI3K/Akt pathway that is found to be highly activated in advanced cases of the disease. The main cause of constitutive activation of Akt (AKT1) is the loss of PTEN function in advanced cancer since PI3K pathway inhibition is primarily performed by the tumor suppressor, PTEN. Another signaling cascade that is deregulated in prostate cancer is MAP kinase (MAPK) pathway. The main probable cause for permanent activation of the MAPK cascade in prostate cancer cells is increased levels of autocrine and paracrine growth factors. Additionally, prostate cancer cells are characterized by the overexpression of some growth factor receptors (e.g., ERBB2), that also activate growth factor pathways. Multiple growth factors and cytokines such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF1), and interleukin-6 (IL6) stimulate cell growth through the activation of small G-protein Ras and MAPK cascade. The phosphorylation of ERK1/2 (MAPK1/2) leads to the activation of various transcription factors such as MYC, ETS1, EGR1, SP1, and Jun/Fos and the modulation of downstream cell processes. In addition, the transmembrane receptor tyrosine kinase, c-Met (MET) plays an important role in prostate cancer. MET is activated by the hepatocyte growth factor/scatter factor (HGF/SF), which is a multifunctional growth factor that regulates various cell processes such as cell motility, invasive growth, and angiogenesis. AR inhibits the expression of MET by competing with another transcription factor, SP1 for binding to the promoter of MET gene. Lastly, there are several microRNAs (miRNAs) that play a major role in the pathogenesis and prognosis of prostate cancer. Several miRNAs and their targets have been discovered to express abnormally in some prostate cancer cases, including some that are oncogenic (MIR106B and MIR221) and tumor suppressive (MIR15A, MIR145, and MIR101-1). Outcome effects: AKT1 regulates cell survival and cell cycle. For example, AKT1 negatively regulates apoptosis by inhibiting procaspase-9 (CASP9) and BAD, while positively regulating the cell cycle by inhibiting p21 and p27, thus enabling cell cycle progression. Furthermore, AKT1 can also regulate AR activity. In the normal prostate, AR seems to balance proliferative and proapoptotic programs, while in cancerous tissue AKT1 can phosphorylate and inactivate AR, thereby permanently switching on a pro-survival program. Another target of AKT1 is enhancer of zeste homolog 2 (EZH2), which is a transcriptional repressor whose expression in prostate cancer is associated with hormone-refractory status and metastasis. Further, the MAPK pathway controls such processes as proliferation, metastasis, and angiogenesis as well as resistance to antitumor drugs. One of the transcriptional targets of MAPK signaling is interleukin-6 which can play a role in the progression of prostate cancer through sev PS:Organ prostate PS:Organ_System urinary tract PS:PMID 16741972 PS:PMID 17297502 PS:PMID 18667687 PS:PMID 21475371 PS:PMID 21956922 PS:PMID 22417299 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: MBP, MOG and PLP proteins or their fragments may serve as antigens and interact with the MHC protein complex, HLA-DRB1 and T cell receptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9c45968-7f55-4596-b0c2-0ed6c49de8d6 NodeType: Pathway Notes: MBP, MOG and PLP proteins or their fragments may serve as antigens and interact with the MHC protein complex, HLA-DRB1 and T cell receptors. Organ_System: lymphatic system PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-a9c45968-7f55-4596-b0c2-0ed6c49de8d6 MBP/MOG/PLP in Immune System Activation uuid-a9c45968-7f55-4596-b0c2-0ed6c49de8d6 PS:CellType T-cell PS:Description MBP, MOG and PLP proteins or their fragments may serve as antigens and interact with the MHC protein complex, HLA-DRB1 and T cell receptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9c45968-7f55-4596-b0c2-0ed6c49de8d6 PS:NodeType Pathway PS:Notes MBP, MOG and PLP proteins or their fragments may serve as antigens and interact with the MHC protein complex, HLA-DRB1 and T cell receptors. PS:Organ_System lymphatic system PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9c60afa-b1e2-4a43-846e-29c8dc9ef2ae NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-a9c60afa-b1e2-4a43-846e-29c8dc9ef2ae Bile Acids Metabolism uuid-a9c60afa-b1e2-4a43-846e-29c8dc9ef2ae PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9c60afa-b1e2-4a43-846e-29c8dc9ef2ae PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Myocardial Ischemia is a restriction in blood supply causes a deficit of oxygen needed for cellular metabolism. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9cf3df2-92f8-404a-ab10-41eae3c81335 NodeType: Pathway Notes: Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: The lack of oxygen leads to the degradation of pyruvic acid to lactic acid (anaerobic glycolysis) and bloackage of tricarboxylic acid cycle (Krebs cycle) and fatty acid oxidation (beta-oxidation of fatty acids). During the initial minutes of ischemia, anaerobic glycolysis and H+ release produce a progressive decline of the intracellular pH and ATP. These initial changes are associated with the activation of the Na+/H+-exchanger (SLC9A6) and a sustained rise of intracellular Na+, which requires Na+ exchange through the activation of the Na+/K+-ATPase (ATP1A1) and Na+/Ca2+ exchanger (SLC8A1). During ischemia, ATP is progressively depleted and energy-dependent ion pumps such as the Na+/K+-ATPase cannot function. Outcome effects: Cytosolic Na+ overload provides a large driving force for Ca2+ influx through the reverse mode of Na+/Ca2+ exchanger. In addition, Ca2+ entry through CACNs results in substantial Ca2+-induced Ca2+ release via RYR2 in sarcoplasmic reticulum. Ca2+ is a highly versatile intracellular signal that regulates many different cellular processes and cytosolic Ca2+ overload is a key component of cardiomyocyte death. The increase of Ca2+ leads to mitochondrial Ca2+ accumulation, which may result in the opening of mitochondrial permeability transition pore (mPTP), and the later participates in cardiomyocyte apoptosis and necrosis. Low ATP and altered ion homeostasis result in the plasma membrane rupture and cell death. Cytosolic Ca2+ damages the organelles that regulate the contractile cycle, which subsequently results in a defective functioning of the myocardial contractile apparatus. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. Organ: heart Organ_System: cardiovascular system PMID: 19640931 PMID: 22499772 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-a9cf3df2-92f8-404a-ab10-41eae3c81335 Oxygen Shortage in Myocardial Ischemia uuid-a9cf3df2-92f8-404a-ab10-41eae3c81335 PS:CellType cardiac myocyte PS:Description Myocardial Ischemia is a restriction in blood supply causes a deficit of oxygen needed for cellular metabolism. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9cf3df2-92f8-404a-ab10-41eae3c81335 PS:NodeType Pathway PS:Notes Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: The lack of oxygen leads to the degradation of pyruvic acid to lactic acid (anaerobic glycolysis) and bloackage of tricarboxylic acid cycle (Krebs cycle) and fatty acid oxidation (beta-oxidation of fatty acids). During the initial minutes of ischemia, anaerobic glycolysis and H+ release produce a progressive decline of the intracellular pH and ATP. These initial changes are associated with the activation of the Na+/H+-exchanger (SLC9A6) and a sustained rise of intracellular Na+, which requires Na+ exchange through the activation of the Na+/K+-ATPase (ATP1A1) and Na+/Ca2+ exchanger (SLC8A1). During ischemia, ATP is progressively depleted and energy-dependent ion pumps such as the Na+/K+-ATPase cannot function. Outcome effects: Cytosolic Na+ overload provides a large driving force for Ca2+ influx through the reverse mode of Na+/Ca2+ exchanger. In addition, Ca2+ entry through CACNs results in substantial Ca2+-induced Ca2+ release via RYR2 in sarcoplasmic reticulum. Ca2+ is a highly versatile intracellular signal that regulates many different cellular processes and cytosolic Ca2+ overload is a key component of cardiomyocyte death. The increase of Ca2+ leads to mitochondrial Ca2+ accumulation, which may result in the opening of mitochondrial permeability transition pore (mPTP), and the later participates in cardiomyocyte apoptosis and necrosis. Low ATP and altered ion homeostasis result in the plasma membrane rupture and cell death. Cytosolic Ca2+ damages the organelles that regulate the contractile cycle, which subsequently results in a defective functioning of the myocardial contractile apparatus. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 19640931 PS:PMID 22499772 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9d2db3d-3875-4f54-8389-de0aff89d2c6 NodeType: Pathway Organ: generic Organ_System: generic PMID: 21102635 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-a9d2db3d-3875-4f54-8389-de0aff89d2c6 Ras-GRF Regulation Signaling uuid-a9d2db3d-3875-4f54-8389-de0aff89d2c6 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9d2db3d-3875-4f54-8389-de0aff89d2c6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21102635 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9d78469-a768-406b-9b64-4cfe918909a9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-a9d78469-a768-406b-9b64-4cfe918909a9 CSF1 -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-a9d78469-a768-406b-9b64-4cfe918909a9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9d78469-a768-406b-9b64-4cfe918909a9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Key regulators of apoptosis are frequently mutated as secondary genetic events in mantle cell lymphoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9e1e5fa-5bef-46c8-bd5d-105c464c8b24 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: Key regulators of apoptosis are frequently mutated as secondary genetic events in MCL. TP53 and BCL2L11 are inactivated by point mutations or gene deletions, while BCL2 and MDM2 are activated by gene amplifications. The constitutive activation of NF-kB has been detected in MCL with the overexpression of antiapoptotic proteins including CFLAR, BCL2L1, and XIAP. Outcome effects: The described events lead to block of apoptosis and tumor survival. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 18410453 PMID: 20940415 PMID: 23023712 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-a9e1e5fa-5bef-46c8-bd5d-105c464c8b24 Apoptosis of Mantle Cell Deregulation uuid-a9e1e5fa-5bef-46c8-bd5d-105c464c8b24 PS:CellType B-cell PS:CellType cancer cell PS:Description Key regulators of apoptosis are frequently mutated as secondary genetic events in mantle cell lymphoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9e1e5fa-5bef-46c8-bd5d-105c464c8b24 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: Key regulators of apoptosis are frequently mutated as secondary genetic events in MCL. TP53 and BCL2L11 are inactivated by point mutations or gene deletions, while BCL2 and MDM2 are activated by gene amplifications. The constitutive activation of NF-kB has been detected in MCL with the overexpression of antiapoptotic proteins including CFLAR, BCL2L1, and XIAP. Outcome effects: The described events lead to block of apoptosis and tumor survival. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 18410453 PS:PMID 20940415 PS:PMID 23023712 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9ff949f-de10-4f1c-9cc0-36cb94ed23b2 NodeType: Pathway Organ_System: hematological system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-a9ff949f-de10-4f1c-9cc0-36cb94ed23b2 Proteins Involved in Hereditary Hemorrhagic Telangiectasia uuid-a9ff949f-de10-4f1c-9cc0-36cb94ed23b2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-a9ff949f-de10-4f1c-9cc0-36cb94ed23b2 PS:NodeType Pathway PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa2a2393-53c7-40df-9cb8-b97c849975a4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-aa2a2393-53c7-40df-9cb8-b97c849975a4 Sucrose degradation template uuid-aa2a2393-53c7-40df-9cb8-b97c849975a4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa2a2393-53c7-40df-9cb8-b97c849975a4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa2cf760-7dc4-4f5a-97e8-ba8c5c6f5070 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19948493 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: generic urn:agi-pathway:uuid-aa2cf760-7dc4-4f5a-97e8-ba8c5c6f5070 Golgi Transport uuid-aa2cf760-7dc4-4f5a-97e8-ba8c5c6f5070 PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa2cf760-7dc4-4f5a-97e8-ba8c5c6f5070 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19948493 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa3d46be-e354-420c-a16a-5cf758beeb2f NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-aa3d46be-e354-420c-a16a-5cf758beeb2f Hedgehog Family -> ARRB1/ARRB2 Canonical Signaling uuid-aa3d46be-e354-420c-a16a-5cf758beeb2f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa3d46be-e354-420c-a16a-5cf758beeb2f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Most proteins need to be folded into a certain three-dimensional structure to fulfill their biological functions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa559429-3701-4071-ad0c-6086182e5cc0 NodeType: Pathway Notes: Headnote: Most proteins need to be folded into a certain three-dimensional structure to fulfill their biological functions. Some proteins have been shown to fold spontaneously, but many newly synthesized proteins require the assistance of molecular chaperones to reach their folded states efficiently. Signaling description: The role of chaperones is largely to optimize the efficiency of folding rather than to deliver steric information to the folding process. The chaperone pathways operate in the endoplasmic reticulum. Heat shock proteins HSPA8, HSPA1A, and HSPA14 are the central organizers of the chaperone network and distribute subsets of proteins to chaperones that act downstream including chaperonins (TRiC) and HSP90AA1. ATP binding causes the release of the substrate which allows folding toward the native state to proceed. Approximately 20% of chains reach their native states in a reaction assisted by HSPA14 and DnaJ family proteins. Initially, ribosome-bound chaperones HSPA14 directly bind to the large ribosomal subunit in close proximity to the polypeptide exit site. The DnaJ family interacts directly with unfolded polypeptides and can recruit heat shock 70kDa proteins to protein substrates. Several polypeptides fold with the assistance of HSPA14, whereas others are passed to HSP90AA1. Around 10% of the chains are passed on to the TRiC co- or post-translationally. The chaperonins are large, cylindrical complexes that function by enclosing protein molecules so that folding can occur unimpaired by aggregation. TRiC interacts directly with HSPA8 and other upstream factors such as prefoldin. The family of co-chaperones containing modular TPR clamp domains, including ST13, FKBP4, and UNC45A, organize the transfer of proteins from HSPA14 to HSP90AA1. Some mitochondrial precursor proteins are delivered by HSPA1A and HSP90AA1 to TOMM70A for import into the mitochondria. Outcome effects: The ubiquitin-ligase STUB1 contacts heat shock 70kDa and 90kDa proteins to attach polyubiquitin onto substrate polypeptides for degradation. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-aa559429-3701-4071-ad0c-6086182e5cc0 Protein Folding uuid-aa559429-3701-4071-ad0c-6086182e5cc0 PS:CellType generic PS:Description Most proteins need to be folded into a certain three-dimensional structure to fulfill their biological functions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa559429-3701-4071-ad0c-6086182e5cc0 PS:NodeType Pathway PS:Notes Headnote: Most proteins need to be folded into a certain three-dimensional structure to fulfill their biological functions. Some proteins have been shown to fold spontaneously, but many newly synthesized proteins require the assistance of molecular chaperones to reach their folded states efficiently. Signaling description: The role of chaperones is largely to optimize the efficiency of folding rather than to deliver steric information to the folding process. The chaperone pathways operate in the endoplasmic reticulum. Heat shock proteins HSPA8, HSPA1A, and HSPA14 are the central organizers of the chaperone network and distribute subsets of proteins to chaperones that act downstream including chaperonins (TRiC) and HSP90AA1. ATP binding causes the release of the substrate which allows folding toward the native state to proceed. Approximately 20% of chains reach their native states in a reaction assisted by HSPA14 and DnaJ family proteins. Initially, ribosome-bound chaperones HSPA14 directly bind to the large ribosomal subunit in close proximity to the polypeptide exit site. The DnaJ family interacts directly with unfolded polypeptides and can recruit heat shock 70kDa proteins to protein substrates. Several polypeptides fold with the assistance of HSPA14, whereas others are passed to HSP90AA1. Around 10% of the chains are passed on to the TRiC co- or post-translationally. The chaperonins are large, cylindrical complexes that function by enclosing protein molecules so that folding can occur unimpaired by aggregation. TRiC interacts directly with HSPA8 and other upstream factors such as prefoldin. The family of co-chaperones containing modular TPR clamp domains, including ST13, FKBP4, and UNC45A, organize the transfer of proteins from HSPA14 to HSP90AA1. Some mitochondrial precursor proteins are delivered by HSPA1A and HSP90AA1 to TOMM70A for import into the mitochondria. Outcome effects: The ubiquitin-ligase STUB1 contacts heat shock 70kDa and 90kDa proteins to attach polyubiquitin onto substrate polypeptides for degradation. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa6ac326-59e4-4859-8a14-9396e28da006 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-aa6ac326-59e4-4859-8a14-9396e28da006 NRAS-RAFs-MAPK1/3 uuid-aa6ac326-59e4-4859-8a14-9396e28da006 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa6ac326-59e4-4859-8a14-9396e28da006 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Germinal center B-cell-like diffuse large B-cell lymphoma (GCB DLBCL) is a subtype of DLBCL identified by gene-expression profile. It has an expression profile typical for germinal center cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa709803-6a6d-4be6-a026-98ded180d0fd NodeType: Pathway Notes: Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization. Germinal center B-cell-like DLBCL (GCB DLBCL) is a subtype of DLBCL identified by gene-expression profile. It has an expression profile typical for germinal center cells. Signaling description: There are several oncogenic mechanisms distinguishing GCB DLBCL from other types of DLBCL. A significant fraction of GCB DLBCL have a translocation, t(14;18) (q32; q21), which activates the antiapoptotic BCL2 gene. PTEN deletions are also detected in approximately 15% of GCB DLBCL cases. As an alternative mechanism for deregulating PTEN nearly 15% of GCB DLBCL cases have amplifications of the miR-17-92 microRNA (miRNA) cluster resulting in PTEN suppression. The inactivation of PTEN leads to the constitutive activation of PI3K/Akt signaling pathway. In more than 10% of samples of GCB DLBCLs, amplification of the nuclear-localized E3 ubiquitin ligase MDM2 is also observed. The MDM2 gene is transcriptionally regulated by TP53. In addition, genetic aberrations affecting CREBBP and EP300 have also been identified. TP53 mutations are also revealed in GCB DLBCL. The REL locus is recurrently amplified in approximately 30% of GCB DLBCL cases. REL is a transcription factor that is a member of the REL/NF-kB family which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NF-kB inhibitor. However, in contrast to ABC DLBCL in which the NF-kB pathway is constitutively activated in virtually all cases, GCB DLBCL does not seem to depend on NF-kB signaling. Thus, the functional role of this aberration in the biology of GCB DLBCL needs to be functionally clarified. In conclusion, GCB DLBCL has a more favorable prognosis when compared to ABC DLBCL. It may be successfully treated with conventional chemotherapy plus rituximab. Outcome effects: MDM2 can promote tumor formation by targeting tumor suppressor proteins, such as TP53 for proteasomal degradation. Mutant CREBBP and EP300 proteins are deficient in acetylating BCL6 and TP53 which leads to the constitutive activation of BCL6 and to decreased TP53 tumor suppressor activity. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 19577170 PMID: 20393178 PMID: 22224767 PMID: 22409819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-aa709803-6a6d-4be6-a026-98ded180d0fd Lymphoma, GCB Subtype uuid-aa709803-6a6d-4be6-a026-98ded180d0fd PS:CellType B-cell PS:CellType cancer cell PS:Description Germinal center B-cell-like diffuse large B-cell lymphoma (GCB DLBCL) is a subtype of DLBCL identified by gene-expression profile. It has an expression profile typical for germinal center cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa709803-6a6d-4be6-a026-98ded180d0fd PS:NodeType Pathway PS:Notes Headnote: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large transformed B-cells and accounts for 30-40% of all adult non-Hodgkin lymphomas, making it the most common type. DLBCL is subdivided into many categories based on biological properties and localization. Germinal center B-cell-like DLBCL (GCB DLBCL) is a subtype of DLBCL identified by gene-expression profile. It has an expression profile typical for germinal center cells. Signaling description: There are several oncogenic mechanisms distinguishing GCB DLBCL from other types of DLBCL. A significant fraction of GCB DLBCL have a translocation, t(14;18) (q32; q21), which activates the antiapoptotic BCL2 gene. PTEN deletions are also detected in approximately 15% of GCB DLBCL cases. As an alternative mechanism for deregulating PTEN nearly 15% of GCB DLBCL cases have amplifications of the miR-17-92 microRNA (miRNA) cluster resulting in PTEN suppression. The inactivation of PTEN leads to the constitutive activation of PI3K/Akt signaling pathway. In more than 10% of samples of GCB DLBCLs, amplification of the nuclear-localized E3 ubiquitin ligase MDM2 is also observed. The MDM2 gene is transcriptionally regulated by TP53. In addition, genetic aberrations affecting CREBBP and EP300 have also been identified. TP53 mutations are also revealed in GCB DLBCL. The REL locus is recurrently amplified in approximately 30% of GCB DLBCL cases. REL is a transcription factor that is a member of the REL/NF-kB family which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NF-kB inhibitor. However, in contrast to ABC DLBCL in which the NF-kB pathway is constitutively activated in virtually all cases, GCB DLBCL does not seem to depend on NF-kB signaling. Thus, the functional role of this aberration in the biology of GCB DLBCL needs to be functionally clarified. In conclusion, GCB DLBCL has a more favorable prognosis when compared to ABC DLBCL. It may be successfully treated with conventional chemotherapy plus rituximab. Outcome effects: MDM2 can promote tumor formation by targeting tumor suppressor proteins, such as TP53 for proteasomal degradation. Mutant CREBBP and EP300 proteins are deficient in acetylating BCL6 and TP53 which leads to the constitutive activation of BCL6 and to decreased TP53 tumor suppressor activity. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 19577170 PS:PMID 20393178 PS:PMID 22224767 PS:PMID 22409819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7253d2-4cfd-45ed-b105-1a82ed13eedc NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-aa7253d2-4cfd-45ed-b105-1a82ed13eedc Proteins Involved in Atopic Dermatitis uuid-aa7253d2-4cfd-45ed-b105-1a82ed13eedc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7253d2-4cfd-45ed-b105-1a82ed13eedc PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa732b21-309f-4681-9bdd-164150926b09 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-aa732b21-309f-4681-9bdd-164150926b09 Proteins Involved in Usher Syndromes uuid-aa732b21-309f-4681-9bdd-164150926b09 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa732b21-309f-4681-9bdd-164150926b09 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7db09d-b617-4425-9bf4-7e81c51cae44 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-aa7db09d-b617-4425-9bf4-7e81c51cae44 GA12 biosynthesis template uuid-aa7db09d-b617-4425-9bf4-7e81c51cae44 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7db09d-b617-4425-9bf4-7e81c51cae44 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: kidney tubule cell Description: Osteopetrosis with renal tubular acidosis is caused by mutations in carbonic anhydrase II (CA2). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7df9d4-9471-4a66-b659-2168a4bf9af2 NodeType: Pathway Notes: Headnote: Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis, renal tubular acidosis (RTA), and neurological symptoms related to cerebral calcifications. Osteopetrosis can be caused by mutations in the carbonic anhydrase II (CA2) gene. Signaling description: Normally, renal CA2 plays an important role in blood acid-base balance maintenance. CA2 catalizes the reversible hydration of carbon dioxide to form bicarbonate and a proton. Outcome effects: When CA2 is mutated, blood acid-base balance is impaired leading to systemic acidosis. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 15300855 PMID: 17936098 PMID: 19232111 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-aa7df9d4-9471-4a66-b659-2168a4bf9af2 Renal Tubular Acidosis Associated with Carbonic Anhydrase II Mutation and Osteopetrosis uuid-aa7df9d4-9471-4a66-b659-2168a4bf9af2 PS:CellType kidney tubule cell PS:Description Osteopetrosis with renal tubular acidosis is caused by mutations in carbonic anhydrase II (CA2). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa7df9d4-9471-4a66-b659-2168a4bf9af2 PS:NodeType Pathway PS:Notes Headnote: Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis, renal tubular acidosis (RTA), and neurological symptoms related to cerebral calcifications. Osteopetrosis can be caused by mutations in the carbonic anhydrase II (CA2) gene. Signaling description: Normally, renal CA2 plays an important role in blood acid-base balance maintenance. CA2 catalizes the reversible hydration of carbon dioxide to form bicarbonate and a proton. Outcome effects: When CA2 is mutated, blood acid-base balance is impaired leading to systemic acidosis. Highlighted proteins: Entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 15300855 PS:PMID 17936098 PS:PMID 19232111 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activation of RAS/RAF/MAPK signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa9c46f3-bfcb-43af-b4fb-db194ef52137 NodeType: Pathway Notes: Headnote: RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation. Signaling description: In cancer, RAS/RAF/MAPK signaling may be constitutively activated due to mutations in RAS (KRAS, HRAS, NRAS) or RAF (BRAF1) or MAPK (MAP2K1). Outcome effects: Constant activation of RAS/RAF/MAPK signaling leads to uncontrolled cell proliferation and inhibition of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17496922 PMID: 17496923 PMID: 21779504 PMID: 21993244 PMID: 22239440 PMID: 22589270 PMID: 24948110 PMID: 24957944 PMID: 26858988 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-aa9c46f3-bfcb-43af-b4fb-db194ef52137 RAS/RAF/MAPK Signaling Activation in Cancer uuid-aa9c46f3-bfcb-43af-b4fb-db194ef52137 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activation of RAS/RAF/MAPK signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aa9c46f3-bfcb-43af-b4fb-db194ef52137 PS:NodeType Pathway PS:Notes Headnote: RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation. Signaling description: In cancer, RAS/RAF/MAPK signaling may be constitutively activated due to mutations in RAS (KRAS, HRAS, NRAS) or RAF (BRAF1) or MAPK (MAP2K1). Outcome effects: Constant activation of RAS/RAF/MAPK signaling leads to uncontrolled cell proliferation and inhibition of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17496922 PS:PMID 17496923 PS:PMID 21779504 PS:PMID 21993244 PS:PMID 22239440 PS:PMID 22589270 PS:PMID 24948110 PS:PMID 24957944 PS:PMID 26858988 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: eosinophil Description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 - 6 percent of all white blood cells and circulate in blood for several hours. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aaa0294e-0296-4211-a70b-e90a5e0449ff NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 to 6 percent of the entire population of white blood cells, and they circulate in blood for several hours. In lung, eosinophils appear only in case of disease (such as asthma) and survive for up to 12 days. The effector function of eosinophils is related to their cytotoxic properties. Allergic asthma is associated with eosinophilic inflammation in the airways. The proinflammatory mediators derived by eosinophils are the major contributors to inflammation in asthma, mucus hypersecretion, and fibrosis. High levels of circulating IL5, IL25 and BDNF have been detected in acute allergic asthmatics. Outcome effects: The effects of IL25 in eosinophils activation are mediated by the IL25 receptor, composed of two subunits, IL-17RA and IL-17RB. IL5 and GM-CSF promote the local survival of tissue eosinophils during allergic airway inflammation for longer periods. BDNF has been described to modulate airway hyper-responsiveness and was involved in late allergic reaction in asthma. Locally generated IL4 and IL13 promote increased eosinophil adhesion to the airway vasculature. IL5 positively regulates phosphorylation of JAK2, as well as Lyn kinases, decreases BAX translocation and ultimately down-regulates apoptosis, and provokes eosinophil surviving. CSF appears to have a strong role in inhibiting eosinophil apoptosis at the tissue level (via STAT3 depended BAD inhibition). It is possible that IL5 triggers eosinophil differentiation through the activation of SOX4 transcription factor. Siglec8 is selectively expressed on human eosinophils at a higher level and mediates eosinophil apoptosis. Siglec8-induced eosinophils death was enhanced by IL5 and GM-CSF cytokines. The exact biochemical identity of natural tissue ligands for Siglec8 and its signaling in eosinophils remains unknown. A significant association between sequence variants of Siglec8 and asthma was observed for various SNPs among African American, Japanese and Brazilian populations. Highlighted proteins: Proteins with increased expression are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 15113433 PMID: 22379601 PMID: 22884075 PMID: 23616768 PMID: 23921745 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-aaa0294e-0296-4211-a70b-e90a5e0449ff Eosinophil Survival in Asthma uuid-aaa0294e-0296-4211-a70b-e90a5e0449ff PS:CellType eosinophil PS:Description Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 - 6 percent of all white blood cells and circulate in blood for several hours. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aaa0294e-0296-4211-a70b-e90a5e0449ff PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 to 6 percent of the entire population of white blood cells, and they circulate in blood for several hours. In lung, eosinophils appear only in case of disease (such as asthma) and survive for up to 12 days. The effector function of eosinophils is related to their cytotoxic properties. Allergic asthma is associated with eosinophilic inflammation in the airways. The proinflammatory mediators derived by eosinophils are the major contributors to inflammation in asthma, mucus hypersecretion, and fibrosis. High levels of circulating IL5, IL25 and BDNF have been detected in acute allergic asthmatics. Outcome effects: The effects of IL25 in eosinophils activation are mediated by the IL25 receptor, composed of two subunits, IL-17RA and IL-17RB. IL5 and GM-CSF promote the local survival of tissue eosinophils during allergic airway inflammation for longer periods. BDNF has been described to modulate airway hyper-responsiveness and was involved in late allergic reaction in asthma. Locally generated IL4 and IL13 promote increased eosinophil adhesion to the airway vasculature. IL5 positively regulates phosphorylation of JAK2, as well as Lyn kinases, decreases BAX translocation and ultimately down-regulates apoptosis, and provokes eosinophil surviving. CSF appears to have a strong role in inhibiting eosinophil apoptosis at the tissue level (via STAT3 depended BAD inhibition). It is possible that IL5 triggers eosinophil differentiation through the activation of SOX4 transcription factor. Siglec8 is selectively expressed on human eosinophils at a higher level and mediates eosinophil apoptosis. Siglec8-induced eosinophils death was enhanced by IL5 and GM-CSF cytokines. The exact biochemical identity of natural tissue ligands for Siglec8 and its signaling in eosinophils remains unknown. A significant association between sequence variants of Siglec8 and asthma was observed for various SNPs among African American, Japanese and Brazilian populations. Highlighted proteins: Proteins with increased expression are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 15113433 PS:PMID 22379601 PS:PMID 22884075 PS:PMID 23616768 PS:PMID 23921745 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aac7f719-98df-49e3-ae2a-5652456b6190 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-aac7f719-98df-49e3-ae2a-5652456b6190 Lysine biosynthesis template uuid-aac7f719-98df-49e3-ae2a-5652456b6190 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aac7f719-98df-49e3-ae2a-5652456b6190 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: The energy uptake is controlled by leptin and insulin. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aac85c0a-7504-473f-ac75-6e358f9f432c NodeType: Pathway Notes: Headnote: The energy uptake is controlled by leptin and insulin that act on specific neuronal populations in CNS. Hypothalamic LEP resistance is associated with impairment of LEP transport across the blood-brain-barrier, reduction JAK-STAT signaling, and induction of signaling suppressors SOCS-3 and PTPN1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ_System: endocrine system PMID: 16166564 PMID: 16782141 PMID: 20846876 PMID: 24058813 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-aac85c0a-7504-473f-ac75-6e358f9f432c SOCS3 and PTPN1 in Hypothalamic Neuron Insensitivity to Insulin and Leptin uuid-aac85c0a-7504-473f-ac75-6e358f9f432c PS:CellType neuron PS:Description The energy uptake is controlled by leptin and insulin. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aac85c0a-7504-473f-ac75-6e358f9f432c PS:NodeType Pathway PS:Notes Headnote: The energy uptake is controlled by leptin and insulin that act on specific neuronal populations in CNS. Hypothalamic LEP resistance is associated with impairment of LEP transport across the blood-brain-barrier, reduction JAK-STAT signaling, and induction of signaling suppressors SOCS-3 and PTPN1. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ_System endocrine system PS:PMID 16166564 PS:PMID 16782141 PS:PMID 20846876 PS:PMID 24058813 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aadcf86d-1f16-46b7-b7a7-1ccd1f30a47a NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-aadcf86d-1f16-46b7-b7a7-1ccd1f30a47a Proteins Involved in Vitiligo uuid-aadcf86d-1f16-46b7-b7a7-1ccd1f30a47a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aadcf86d-1f16-46b7-b7a7-1ccd1f30a47a PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aae65d2e-2333-4f9b-ae47-4bff63bd9ee0 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-aae65d2e-2333-4f9b-ae47-4bff63bd9ee0 FGFR3 -> STAT Signaling uuid-aae65d2e-2333-4f9b-ae47-4bff63bd9ee0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aae65d2e-2333-4f9b-ae47-4bff63bd9ee0 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aafed2b1-008e-475f-9f1c-36f36dcf9f6c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-aafed2b1-008e-475f-9f1c-36f36dcf9f6c Tropane biosynthesis template uuid-aafed2b1-008e-475f-9f1c-36f36dcf9f6c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aafed2b1-008e-475f-9f1c-36f36dcf9f6c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0082a4-4dbc-48dd-ba3c-1c34615dcb81 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-ab0082a4-4dbc-48dd-ba3c-1c34615dcb81 N protein interactions uuid-ab0082a4-4dbc-48dd-ba3c-1c34615dcb81 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0082a4-4dbc-48dd-ba3c-1c34615dcb81 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0430df-101f-40f5-a93b-5b7e66fbdcfd NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ab0430df-101f-40f5-a93b-5b7e66fbdcfd EGFR -> NCOR2 Signaling uuid-ab0430df-101f-40f5-a93b-5b7e66fbdcfd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0430df-101f-40f5-a93b-5b7e66fbdcfd PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0ba28a-cfea-44b0-9f14-393c6dbcfb20 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ab0ba28a-cfea-44b0-9f14-393c6dbcfb20 Proteins Involved in Parkinson's Disease uuid-ab0ba28a-cfea-44b0-9f14-393c6dbcfb20 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab0ba28a-cfea-44b0-9f14-393c6dbcfb20 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Etroposon that inserts itself into a functional gene will most likely disable that gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab3673a7-2dec-4898-9272-bc65ea363dcd NodeType: Pathway Notes: Headnote: About 50% of mammalian genome composed of repetitive sequences. Multiple copies of the same sequence can hinder precise chromosomal pairing during mitosis. A transposon or a retroposon that inserts itself into a functional gene will most likely disable that gene. Signaling description: The most abundant repeats in mammals are the retrotransposons, which self-replicate through the reverse transcription of RNA intermediates.The retrotransposon class includes two subgroups: the LTR (long terminal repeat) type, which is flanked by direct repeats, and the non-LTR type, which includes LINEs (long interspersed elements) and SINEs (short interspersed elements). Mechanisms for the suppression of retrotransposon transcription include cooperation of de novo CpG methylation, histone modification and RNA-based silencing pathways - piRNA and endo-siRNA. The piRNA pathway relies on the specificity to recognize complementary transposable element targets; piRNAs are generated either from RNA transcripts of active transposable elements or from transcripts originating from specialized loci in the genome called piRNA clusters. Outcome effects: PIWI proteins function at the chromatin level in the nucleus to silence transposable elements transcription by directing deposition of repressive histone marks and DNA methylation to copies of transposable elements. Animal data: mouse model. Organ: generic Organ_System: generic PMID: 26659487 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-ab3673a7-2dec-4898-9272-bc65ea363dcd Retrotransposons Regulation (Mouse Model) uuid-ab3673a7-2dec-4898-9272-bc65ea363dcd PS:CellType generic PS:Description Etroposon that inserts itself into a functional gene will most likely disable that gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab3673a7-2dec-4898-9272-bc65ea363dcd PS:NodeType Pathway PS:Notes Headnote: About 50% of mammalian genome composed of repetitive sequences. Multiple copies of the same sequence can hinder precise chromosomal pairing during mitosis. A transposon or a retroposon that inserts itself into a functional gene will most likely disable that gene. Signaling description: The most abundant repeats in mammals are the retrotransposons, which self-replicate through the reverse transcription of RNA intermediates.The retrotransposon class includes two subgroups: the LTR (long terminal repeat) type, which is flanked by direct repeats, and the non-LTR type, which includes LINEs (long interspersed elements) and SINEs (short interspersed elements). Mechanisms for the suppression of retrotransposon transcription include cooperation of de novo CpG methylation, histone modification and RNA-based silencing pathways - piRNA and endo-siRNA. The piRNA pathway relies on the specificity to recognize complementary transposable element targets; piRNAs are generated either from RNA transcripts of active transposable elements or from transcripts originating from specialized loci in the genome called piRNA clusters. Outcome effects: PIWI proteins function at the chromatin level in the nucleus to silence transposable elements transcription by directing deposition of repressive histone marks and DNA methylation to copies of transposable elements. Animal data: mouse model. PS:Organ generic PS:Organ_System generic PS:PMID 26659487 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab45bf52-a823-4341-afd8-c11a4f7aa4e2 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ab45bf52-a823-4341-afd8-c11a4f7aa4e2 Proteins Involved in Autistic Disorder uuid-ab45bf52-a823-4341-afd8-c11a4f7aa4e2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab45bf52-a823-4341-afd8-c11a4f7aa4e2 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab5744ca-006b-4843-8f49-aed05e5e56cc NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ab5744ca-006b-4843-8f49-aed05e5e56cc NRG1 -> STAT Expression Targets uuid-ab5744ca-006b-4843-8f49-aed05e5e56cc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab5744ca-006b-4843-8f49-aed05e5e56cc PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab5777b9-5bf4-414b-b944-e338654b49c6 NodeType: Pathway Notes: PCOS is a heterogeneous condition with various phenotypes. Hyperandrogenism and insulin resistance are thought to be the two main features of the PCOS-related conditions. Hyperandrogenism can be a consequence of the disruption of pituitary and hypothalamus function, which in turn impairs the production of luteinizing and follicle-stimulating hormones. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ab5777b9-5bf4-414b-b944-e338654b49c6 1_Disruption of luteinizing hormone and follicle-stimulating hormone secretion in PCOS uuid-ab5777b9-5bf4-414b-b944-e338654b49c6 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab5777b9-5bf4-414b-b944-e338654b49c6 PS:NodeType Pathway PS:Notes PCOS is a heterogeneous condition with various phenotypes. Hyperandrogenism and insulin resistance are thought to be the two main features of the PCOS-related conditions. Hyperandrogenism can be a consequence of the disruption of pituitary and hypothalamus function, which in turn impairs the production of luteinizing and follicle-stimulating hormones. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: A centriole is a cylinder shaped cell structure found in most eukaryotic cells that is comprised of nine triplets of microtubules in the cytoplasm. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab581f90-c839-46f5-937a-97a70efa2779 NodeType: Pathway Notes: Headnote: A centriole is a cylinder shaped cell structure found in most eukaryotic cells that is comprised of nine triplets of microtubules in the cytoplasm. A centrosome consists of an associated pair of centrioles which are arranged perpendicularly and surrounded by an amorphous mass of pericentriolar material (PCM). Signaling description: In the centrosome, subdistal appendages anchor microtubule minus ends, while distal appendages are required to attach the centriole to the plasma membrane (such as CEP170, PCNT, and NIN). The PCM contains a number of proteinaceous complexes, such as DCTN1, dynactin complex, MAPRE1, and centrin, which are responsible for microtubule nucleation (gamma tubulin ring complex) and the anchoring of microtubule minus ends to PCM. Cells begin the cell cycle with a single centrosome containing a pair of centrioles. The older centriole in a pair is termed mother centriole, whereas the younger one is termed daughter centriole. A new centriole grows from the side of each mother centriole. The replication of centrioles proceeds through G1/S transition until the onset of mitosis. The phosphorylation of NPM1, TTK, and PLK4 by CDK2 results in percentriole formation. The activation of PLK4 on the centrosome is required for the sequential recruitment of SASS6 and CENPJ. Outcome effects: The distance between mother and daughter centrioles increases early in mitosis and NEK2 induces centrosome separation. In anaphase, the mother and daughter centrioles lose their orthogonal relationship and disengage. From this point onward, each centriole is surrounded by its own cloud of PCM. The molecular mechanisms responsible for centriole disengagement are poorly understood, however the cleavage may be mediated by separase ESPL1. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-ab581f90-c839-46f5-937a-97a70efa2779 Centriole Duplication and Separation uuid-ab581f90-c839-46f5-937a-97a70efa2779 PS:CellType generic PS:Description A centriole is a cylinder shaped cell structure found in most eukaryotic cells that is comprised of nine triplets of microtubules in the cytoplasm. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab581f90-c839-46f5-937a-97a70efa2779 PS:NodeType Pathway PS:Notes Headnote: A centriole is a cylinder shaped cell structure found in most eukaryotic cells that is comprised of nine triplets of microtubules in the cytoplasm. A centrosome consists of an associated pair of centrioles which are arranged perpendicularly and surrounded by an amorphous mass of pericentriolar material (PCM). Signaling description: In the centrosome, subdistal appendages anchor microtubule minus ends, while distal appendages are required to attach the centriole to the plasma membrane (such as CEP170, PCNT, and NIN). The PCM contains a number of proteinaceous complexes, such as DCTN1, dynactin complex, MAPRE1, and centrin, which are responsible for microtubule nucleation (gamma tubulin ring complex) and the anchoring of microtubule minus ends to PCM. Cells begin the cell cycle with a single centrosome containing a pair of centrioles. The older centriole in a pair is termed mother centriole, whereas the younger one is termed daughter centriole. A new centriole grows from the side of each mother centriole. The replication of centrioles proceeds through G1/S transition until the onset of mitosis. The phosphorylation of NPM1, TTK, and PLK4 by CDK2 results in percentriole formation. The activation of PLK4 on the centrosome is required for the sequential recruitment of SASS6 and CENPJ. Outcome effects: The distance between mother and daughter centrioles increases early in mitosis and NEK2 induces centrosome separation. In anaphase, the mother and daughter centrioles lose their orthogonal relationship and disengage. From this point onward, each centriole is surrounded by its own cloud of PCM. The molecular mechanisms responsible for centriole disengagement are poorly understood, however the cleavage may be mediated by separase ESPL1. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab65e18c-b42a-4d50-a4b4-7e0ad33cd16f NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ab65e18c-b42a-4d50-a4b4-7e0ad33cd16f Genes with Mutations Associated with Asthma uuid-ab65e18c-b42a-4d50-a4b4-7e0ad33cd16f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab65e18c-b42a-4d50-a4b4-7e0ad33cd16f PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: leukocyte CellType: myeloblast Description: Chronic myeloid leukemia is a hematological cancer characterized by the increased and deregulated proliferation of myeloid cells. BCR/ABL is believed to be the primary cause of the chronic phase of CML. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab743729-c9ec-43bb-bd97-342b684942df NodeType: Pathway Notes: Headnote: Chronic myeloid or myelogenous leukemia (CML) is a clonal bone marrow stem cell disorder characterized by the increased and unregulated proliferation of predominantly myeloid cells. The main finding in this disease is an elevated level of mature granulocytes and their precursors in bone marrow and blood. Signaling description: CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation, that forms the Philadelphia (Ph) chromosome. The resulting BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which has constitutive tyrosine kinase activity. BCR/ABL activates PI3K/Akt/MTOR, NF-kB, and RAS/MAPK pathways. BCR/ABL also directly activates STAT5A and MYC. In CML cells, the BCR/ABL fusion protein can increase the activity of SMAD3 and 4 promoters and enhance TGFB signaling. The main target in CML is BCR/ABL which can be inactivated by target therapy such as Imatinib, Dasatinib, and Nilotinib (AMN-107). While BCR/ABL is believed to be the primary cause of the chronic phase of CML, the progression to blast crisis requires other molecular changes such as mutations in GATA2, CDKN2A, RUNX1, and TP53. Additional chromosome translocations may be found which generate AML1-EVI1 and AML1-ETO fusion proteins. Consistent with the early stem cell nature of CML, blastic transformation may be myeloid, lymphoid, or undifferentiated/mixed, with myeloid blast crisis being about two times more common than lymphoid. These secondary genetic abnormalities are regarded as probable reasons for drug resistance and are potential therapeutic targets. Outcome effects: As a result, oncogenic signaling leads to block of apoptosis, increased proliferation, and oncogenic protein translation as well as the disruption of DNA repair. TGFB signaling leads to the inhibition of hematopoietic progenitor cell differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: hematological system PMID: 15271392 PMID: 16484590 PMID: 17288299 PMID: 18024655 PMID: 18827185 PMID: 20592475 PMID: 21098337 PMID: 21302608 PMID: 22632137 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-ab743729-c9ec-43bb-bd97-342b684942df Chronic Myeloid Leukemia uuid-ab743729-c9ec-43bb-bd97-342b684942df PS:CellType cancer cell PS:CellType leukocyte PS:CellType myeloblast PS:Description Chronic myeloid leukemia is a hematological cancer characterized by the increased and deregulated proliferation of myeloid cells. BCR/ABL is believed to be the primary cause of the chronic phase of CML. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab743729-c9ec-43bb-bd97-342b684942df PS:NodeType Pathway PS:Notes Headnote: Chronic myeloid or myelogenous leukemia (CML) is a clonal bone marrow stem cell disorder characterized by the increased and unregulated proliferation of predominantly myeloid cells. The main finding in this disease is an elevated level of mature granulocytes and their precursors in bone marrow and blood. Signaling description: CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation, that forms the Philadelphia (Ph) chromosome. The resulting BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which has constitutive tyrosine kinase activity. BCR/ABL activates PI3K/Akt/MTOR, NF-kB, and RAS/MAPK pathways. BCR/ABL also directly activates STAT5A and MYC. In CML cells, the BCR/ABL fusion protein can increase the activity of SMAD3 and 4 promoters and enhance TGFB signaling. The main target in CML is BCR/ABL which can be inactivated by target therapy such as Imatinib, Dasatinib, and Nilotinib (AMN-107). While BCR/ABL is believed to be the primary cause of the chronic phase of CML, the progression to blast crisis requires other molecular changes such as mutations in GATA2, CDKN2A, RUNX1, and TP53. Additional chromosome translocations may be found which generate AML1-EVI1 and AML1-ETO fusion proteins. Consistent with the early stem cell nature of CML, blastic transformation may be myeloid, lymphoid, or undifferentiated/mixed, with myeloid blast crisis being about two times more common than lymphoid. These secondary genetic abnormalities are regarded as probable reasons for drug resistance and are potential therapeutic targets. Outcome effects: As a result, oncogenic signaling leads to block of apoptosis, increased proliferation, and oncogenic protein translation as well as the disruption of DNA repair. TGFB signaling leads to the inhibition of hematopoietic progenitor cell differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System hematological system PS:PMID 15271392 PS:PMID 16484590 PS:PMID 17288299 PS:PMID 18024655 PS:PMID 18827185 PS:PMID 20592475 PS:PMID 21098337 PS:PMID 21302608 PS:PMID 22632137 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Neovascular glaucoma is a secondary glaucoma. Retinal ischemia triggers the production of HIF1A which in turn leads to the expression of different factors such as VEGFA. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab808359-9293-4008-8f8a-3e60bbdc1ac0 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Neovascular glaucoma (NVG) is a secondary glaucoma and can present through either secondary open-angle or secondary closed-angle mechanisms contingent on the extent of neovascularization. Signaling description: NVG is associated with a wide range of conditions including retinal ischemia, which accounts for the majority of the cases, and central retinal vein occlusion and diabetes retinopathy, which produces nearly two thirds of all cases. Neovascularization is a growth of vessels into tissues normally not vascularized. In NVG, neovascularization is localized in the iris and anterior angle of the eye. Retinal ischemia triggers the production of HIF1A, which in turn leads to the expression of different factors such as VEGFA, which has been shown to play a major role in NVG pathogenesis. Outcome effects: VEGFA induces different signaling pathways, resulting in the upregulation of genes involved in proliferation, migration, and survival of endothelial cells and vascular permeability. All of these events contribute to neovascularization. Anti-VEGFA therapy (bevacizumab) has been demonstrated as being beneficial in NVG. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1) Kurt Spiteri Cornish (2011). Neovascular Glaucoma, Glaucoma - Current Clinical and Research Aspects, Dr. Pinakin Gunvant (Ed.), ISBN: 978-953-307-263-0, InTech, DOI: 10.5772/18497.Available from: http://www.intechopen.com/books/glaucoma-current-clinical-and-research-aspects/neovascular-glaucoma 4) Organ: eye Organ_System: sensory system PMID: 18369162 PMID: 21633236 PMID: 23329331 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ab808359-9293-4008-8f8a-3e60bbdc1ac0 VEGFA in Neovascular Glaucoma uuid-ab808359-9293-4008-8f8a-3e60bbdc1ac0 PS:CellType endothelial cell PS:Description Neovascular glaucoma is a secondary glaucoma. Retinal ischemia triggers the production of HIF1A which in turn leads to the expression of different factors such as VEGFA. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab808359-9293-4008-8f8a-3e60bbdc1ac0 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Neovascular glaucoma (NVG) is a secondary glaucoma and can present through either secondary open-angle or secondary closed-angle mechanisms contingent on the extent of neovascularization. Signaling description: NVG is associated with a wide range of conditions including retinal ischemia, which accounts for the majority of the cases, and central retinal vein occlusion and diabetes retinopathy, which produces nearly two thirds of all cases. Neovascularization is a growth of vessels into tissues normally not vascularized. In NVG, neovascularization is localized in the iris and anterior angle of the eye. Retinal ischemia triggers the production of HIF1A, which in turn leads to the expression of different factors such as VEGFA, which has been shown to play a major role in NVG pathogenesis. Outcome effects: VEGFA induces different signaling pathways, resulting in the upregulation of genes involved in proliferation, migration, and survival of endothelial cells and vascular permeability. All of these events contribute to neovascularization. Anti-VEGFA therapy (bevacizumab) has been demonstrated as being beneficial in NVG. Highlighted proteins: Protein with increased expression or activity is highlighted in red, and protein with decreased expression or activity is highlighted in blue. References: 1) Kurt Spiteri Cornish (2011). Neovascular Glaucoma, Glaucoma - Current Clinical and Research Aspects, Dr. Pinakin Gunvant (Ed.), ISBN: 978-953-307-263-0, InTech, DOI: 10.5772/18497.Available from: http://www.intechopen.com/books/glaucoma-current-clinical-and-research-aspects/neovascular-glaucoma 4) PS:Organ eye PS:Organ_System sensory system PS:PMID 18369162 PS:PMID 21633236 PS:PMID 23329331 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab84e616-c73c-46e5-b931-27a4927c0d05 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-ab84e616-c73c-46e5-b931-27a4927c0d05 DRD2 -> TRPC1 Transcription uuid-ab84e616-c73c-46e5-b931-27a4927c0d05 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab84e616-c73c-46e5-b931-27a4927c0d05 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab89dc12-aaf6-48bf-8b8b-1dafdca42e36 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-ab89dc12-aaf6-48bf-8b8b-1dafdca42e36 Collagen biosynthesis in myofibroblats uuid-ab89dc12-aaf6-48bf-8b8b-1dafdca42e36 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab89dc12-aaf6-48bf-8b8b-1dafdca42e36 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab8e0814-7f83-4b4a-b0aa-d1fcbe51a8fa NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ab8e0814-7f83-4b4a-b0aa-d1fcbe51a8fa HBEGF -> FOXO3A Expression Target uuid-ab8e0814-7f83-4b4a-b0aa-d1fcbe51a8fa PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab8e0814-7f83-4b4a-b0aa-d1fcbe51a8fa PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Pathway_Author PS:Source Description: Eukaryotic translation is the process by which messenger RNA (mRNA) is translated into polypeptides. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab94dfe1-ea6e-4234-9ebe-bd2febb8ea06 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Cell Process urn:agi-pathway:uuid-ab94dfe1-ea6e-4234-9ebe-bd2febb8ea06 Stress Granule Formation uuid-ab94dfe1-ea6e-4234-9ebe-bd2febb8ea06 PS:Description Eukaryotic translation is the process by which messenger RNA (mRNA) is translated into polypeptides. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab94dfe1-ea6e-4234-9ebe-bd2febb8ea06 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Cell Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab9e8550-2fea-45e4-9806-d1888467bab5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ab9e8550-2fea-45e4-9806-d1888467bab5 BTC -> NFATC Expression Targets uuid-ab9e8550-2fea-45e4-9806-d1888467bab5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ab9e8550-2fea-45e4-9806-d1888467bab5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: There are several mechanisms of transcriptional activation of immunoglobulin genes following the different types of rearrangement such as V(D)J recombination or immunoglobulin class-switch recombination. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abbc0a42-d89f-44cd-9b09-0d26cb98af99 NodeType: Pathway Notes: Headnote: There are several mechanisms of transcriptional activation of immunoglobulin genes following different types of rearrangement processes, such as V(D)J recombination or immunoglobulin class-switch recombination. Signaling description: The key transcription factors that bind to sequences in the promoters of immunoglobulin genes are POU2AF1 (BOB-1), POU2F2 (OCT-2), and SPI1 (PU.1). The activation of these transcription factors is initiated by the binding of interleukin 21 receptor (IL21R) and interleukin 13 receptor, alpha 1 (IL13RA1) to their ligands (IL21 and IL13). The suppression of immunoglobulin gene transcription occurs through the NOTCH1 receptor. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-abbc0a42-d89f-44cd-9b09-0d26cb98af99 Immunoglobulin Genes Transcriptional Activation uuid-abbc0a42-d89f-44cd-9b09-0d26cb98af99 PS:CellType B-cell PS:Description There are several mechanisms of transcriptional activation of immunoglobulin genes following the different types of rearrangement such as V(D)J recombination or immunoglobulin class-switch recombination. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abbc0a42-d89f-44cd-9b09-0d26cb98af99 PS:NodeType Pathway PS:Notes Headnote: There are several mechanisms of transcriptional activation of immunoglobulin genes following different types of rearrangement processes, such as V(D)J recombination or immunoglobulin class-switch recombination. Signaling description: The key transcription factors that bind to sequences in the promoters of immunoglobulin genes are POU2AF1 (BOB-1), POU2F2 (OCT-2), and SPI1 (PU.1). The activation of these transcription factors is initiated by the binding of interleukin 21 receptor (IL21R) and interleukin 13 receptor, alpha 1 (IL13RA1) to their ligands (IL21 and IL13). The suppression of immunoglobulin gene transcription occurs through the NOTCH1 receptor. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abcf7a10-c562-4cc0-86db-0fba79d58e7d NodeType: Pathway Organ: generic Organ_System: generic PMID: 19696797 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: generic urn:agi-pathway:uuid-abcf7a10-c562-4cc0-86db-0fba79d58e7d Endosomal Recycling uuid-abcf7a10-c562-4cc0-86db-0fba79d58e7d PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abcf7a10-c562-4cc0-86db-0fba79d58e7d PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19696797 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abf29993-8939-4dd2-a4cc-8759fa4ab5a3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-abf29993-8939-4dd2-a4cc-8759fa4ab5a3 NSP11 interactions uuid-abf29993-8939-4dd2-a4cc-8759fa4ab5a3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-abf29993-8939-4dd2-a4cc-8759fa4ab5a3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac2ff37a-ffe5-4092-88f3-7da4f61a1403 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ac2ff37a-ffe5-4092-88f3-7da4f61a1403 Proteins with Altered Expression in Osteoporosis uuid-ac2ff37a-ffe5-4092-88f3-7da4f61a1403 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac2ff37a-ffe5-4092-88f3-7da4f61a1403 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac48a589-9b47-4808-81e5-52ec56bf3c21 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-ac48a589-9b47-4808-81e5-52ec56bf3c21 DRD2/4 -> Membrane Transport uuid-ac48a589-9b47-4808-81e5-52ec56bf3c21 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac48a589-9b47-4808-81e5-52ec56bf3c21 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac49c69a-ac28-42d9-a2a9-bb5d6ee5e41f NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones, and a multitude of other proteins. Inositol requiring 80 (INO80) chromatin remodeling complex regulates the expression of a subset of genes through its ATP-dependent chromatin remodeling activity. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling, can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. In addition to its function in transcriptional regulation, the INO80 complex participates in multiple DNA repair pathways by its nucleosome remodeling ability and by regulating the accessibility of DNA repair proteins around the double strand DNA break site. The INO80 complex is enriched at stalled replication forks, where it promotes the resumption of replication upon recovery from the replication arrest. Outcome effects: Ubiquitously expressed transcription factor YY1 controls the expression of many genes. YY1 is tightly associated with INO80 which recruited by YY1 to YY1-activated genes where it functions as an essential coactivator. RUVBL1 and RUVBL2, which have ATPase and DNA helicase activities, are also proposed core components of the INO80 complex. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-ac49c69a-ac28-42d9-a2a9-bb5d6ee5e41f INO80 in Chromatin Remodeling uuid-ac49c69a-ac28-42d9-a2a9-bb5d6ee5e41f PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac49c69a-ac28-42d9-a2a9-bb5d6ee5e41f PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones, and a multitude of other proteins. Inositol requiring 80 (INO80) chromatin remodeling complex regulates the expression of a subset of genes through its ATP-dependent chromatin remodeling activity. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling, can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. In addition to its function in transcriptional regulation, the INO80 complex participates in multiple DNA repair pathways by its nucleosome remodeling ability and by regulating the accessibility of DNA repair proteins around the double strand DNA break site. The INO80 complex is enriched at stalled replication forks, where it promotes the resumption of replication upon recovery from the replication arrest. Outcome effects: Ubiquitously expressed transcription factor YY1 controls the expression of many genes. YY1 is tightly associated with INO80 which recruited by YY1 to YY1-activated genes where it functions as an essential coactivator. RUVBL1 and RUVBL2, which have ATPase and DNA helicase activities, are also proposed core components of the INO80 complex. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac54acdd-320f-42cc-a2f3-1d4866e3610d NodeType: Pathway Notes: Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway displays thyroid gland development and cleft palate syndrome in relation to a mutation in FOXE1 forkhead box E1 (thyroid transcription factor-2 (TTF-2)). FOXE1 functions as a thyroid transcription factor which likely plays a crucial role in thyroid morphogenesis. However, the exact role for FOXE1 in thyroid development is poorly understood. Here, its expression targets TSHR, TPO, TG, and THPO are shown to be important for thyroid gland function. Outcome effects: A homozygous missense mutation in FOXE1 causes a syndrome of thyroid dysgenesis, choanal atresia, cleft palate, and spiky hair also known as Bamforth-Lazarus syndrome. Phenotypic features include low set ears, extensive cleft palate, hypertelorism, spiky hair, and low posterior hairline. . Mutated gene: Mutated gene is shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 15665157 PMID: 19955175 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ac54acdd-320f-42cc-a2f3-1d4866e3610d FOXE1 Targets in Thyroid Dysgenesis (Hypothesis) uuid-ac54acdd-320f-42cc-a2f3-1d4866e3610d PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac54acdd-320f-42cc-a2f3-1d4866e3610d PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism refers to thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, while the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases, while 98% are of unknown cause. The pathway displays thyroid gland development and cleft palate syndrome in relation to a mutation in FOXE1 forkhead box E1 (thyroid transcription factor-2 (TTF-2)). FOXE1 functions as a thyroid transcription factor which likely plays a crucial role in thyroid morphogenesis. However, the exact role for FOXE1 in thyroid development is poorly understood. Here, its expression targets TSHR, TPO, TG, and THPO are shown to be important for thyroid gland function. Outcome effects: A homozygous missense mutation in FOXE1 causes a syndrome of thyroid dysgenesis, choanal atresia, cleft palate, and spiky hair also known as Bamforth-Lazarus syndrome. Phenotypic features include low set ears, extensive cleft palate, hypertelorism, spiky hair, and low posterior hairline. . Mutated gene: Mutated gene is shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15665157 PS:PMID 19955175 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell CellType: goblet cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac6a602f-5075-4d49-9753-20fd07638046 NodeType: Pathway Notes: Inflammatory mediators diffuse into the inner ear across the round window membrane, possibly causing damage to the cells of the inner ear and leading to various types of auditory dysfunction. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ear Organ_System: sensory system PMID: 19848242 PMID: 20531251 PMID: 21271590 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: middle ear mucosa urn:agi-pathway:uuid-ac6a602f-5075-4d49-9753-20fd07638046 Cytokines Trigger Otitis Media uuid-ac6a602f-5075-4d49-9753-20fd07638046 PS:CellType epithelial cell PS:CellType goblet cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac6a602f-5075-4d49-9753-20fd07638046 PS:NodeType Pathway PS:Notes Inflammatory mediators diffuse into the inner ear across the round window membrane, possibly causing damage to the cells of the inner ear and leading to various types of auditory dysfunction. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ear PS:Organ_System sensory system PS:PMID 19848242 PS:PMID 20531251 PS:PMID 21271590 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue middle ear mucosa PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Endocytosis is a process where cells ingest material including macromolecules, low-molecular weight molecules, and particles from outside the cell by enclosing it with a portion of their cell membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac8319ac-cbc5-429a-b919-d625ddb7bde5 NodeType: Pathway Notes: Headnote: Endocytosis is a process where cells ingest material including macromolecules, low-molecular weight molecules, and particles from outside the cell by enclosing it with a portion of their cell membrane and bringing it into the cell in a membrane-bound vesicle. Endocytosis is characterized as clathrin-dependent and clathrin-independent. Signaling description: Clathrin-dependent endocytosis (CDE) is the process when proteins located in the plasma membrane specifically interact with clathrin adaptor AP-1, -2, -3, and -4 localized in the membranes of clathrin-coated vesicles. This interaction promotes the movement of extracellular proteins towards the cytoplasm. Transferrin (TF) receptor (TFRC) and LDLR are classic examples of proteins transferred by means of CDE. Clathrin-independent endocytosis (CIE) is less studied. CIE involves CDC42 and ARF1 proteins which are responsible for the endocytosis of fluid-phase markers, glycosyl phosphatidylinositol (GPI)-anchored proteins, and bacterial toxins. CIE also recruits ARF6 protein to transfer the membrane proteins that carry no domains for binding to clathrin adapter proteins. During endocytosis, after relocating into primary clathrin-dependent or clathrin-independent vesicles, the molecules are transferred into early endosomes. Early endosomes are characterized by the presence of RAB5A and EEA1 proteins, along with PIK3CG and its product PtdIns3P. ESCRT complex is also located in early endosomes and binds monoubiquitylated proteins of the cytoplasm. Other important players of the endocytosis machinery are small GTPase proteins of the RAB family. These GTPases can exist in a GDP-bound """"""""off"""""""" state or a GTP-bound """"""""on"""""""" state. When GTP-bound, RAB proteins are capable of activating various proteins that control vesicle trafficking. Proteins in early endosomes are either directed to lysosomes for further degradation or to late endosomes and trans-Golgi network (TGN) or returned to the plasma membrane. In order to recycle endosomes back to the plasma membrane, ARF6 must activate PLD1 and 1-phosphatidylinositol-4-phosphate 5-kinase. ARF6 also activates RAB11FIP3 that in turn promotes endosomal recycling. Molecules transferred by clathrin-coated vesicles are recycled back to the plasma membrane by means of a fast mechanism that requires RAB4A and RAB35 proteins. RAB10, RAB11A, RAB22A, and RAB35 proteins are associated with microtubule-dependent endosomal recycling. This process also requires EHD1 protein in complex with PDCD6IP and RAB11FIP2. Organ: generic Organ_System: generic PMID: 19696797 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-ac8319ac-cbc5-429a-b919-d625ddb7bde5 Endosomal Recycling uuid-ac8319ac-cbc5-429a-b919-d625ddb7bde5 PS:CellType generic PS:Description Endocytosis is a process where cells ingest material including macromolecules, low-molecular weight molecules, and particles from outside the cell by enclosing it with a portion of their cell membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ac8319ac-cbc5-429a-b919-d625ddb7bde5 PS:NodeType Pathway PS:Notes Headnote: Endocytosis is a process where cells ingest material including macromolecules, low-molecular weight molecules, and particles from outside the cell by enclosing it with a portion of their cell membrane and bringing it into the cell in a membrane-bound vesicle. Endocytosis is characterized as clathrin-dependent and clathrin-independent. Signaling description: Clathrin-dependent endocytosis (CDE) is the process when proteins located in the plasma membrane specifically interact with clathrin adaptor AP-1, -2, -3, and -4 localized in the membranes of clathrin-coated vesicles. This interaction promotes the movement of extracellular proteins towards the cytoplasm. Transferrin (TF) receptor (TFRC) and LDLR are classic examples of proteins transferred by means of CDE. Clathrin-independent endocytosis (CIE) is less studied. CIE involves CDC42 and ARF1 proteins which are responsible for the endocytosis of fluid-phase markers, glycosyl phosphatidylinositol (GPI)-anchored proteins, and bacterial toxins. CIE also recruits ARF6 protein to transfer the membrane proteins that carry no domains for binding to clathrin adapter proteins. During endocytosis, after relocating into primary clathrin-dependent or clathrin-independent vesicles, the molecules are transferred into early endosomes. Early endosomes are characterized by the presence of RAB5A and EEA1 proteins, along with PIK3CG and its product PtdIns3P. ESCRT complex is also located in early endosomes and binds monoubiquitylated proteins of the cytoplasm. Other important players of the endocytosis machinery are small GTPase proteins of the RAB family. These GTPases can exist in a GDP-bound """"""""off"""""""" state or a GTP-bound """"""""on"""""""" state. When GTP-bound, RAB proteins are capable of activating various proteins that control vesicle trafficking. Proteins in early endosomes are either directed to lysosomes for further degradation or to late endosomes and trans-Golgi network (TGN) or returned to the plasma membrane. In order to recycle endosomes back to the plasma membrane, ARF6 must activate PLD1 and 1-phosphatidylinositol-4-phosphate 5-kinase. ARF6 also activates RAB11FIP3 that in turn promotes endosomal recycling. Molecules transferred by clathrin-coated vesicles are recycled back to the plasma membrane by means of a fast mechanism that requires RAB4A and RAB35 proteins. RAB10, RAB11A, RAB22A, and RAB35 proteins are associated with microtubule-dependent endosomal recycling. This process also requires EHD1 protein in complex with PDCD6IP and RAB11FIP2. PS:Organ generic PS:Organ_System generic PS:PMID 19696797 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-acb3b527-3bab-40a5-834d-d820b0098310 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-acb3b527-3bab-40a5-834d-d820b0098310 Glutathione Metabolism uuid-acb3b527-3bab-40a5-834d-d820b0098310 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-acb3b527-3bab-40a5-834d-d820b0098310 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-acc47a16-bedd-486f-97f9-9ca2c13a61e3 NodeType: Pathway Notes: Headnote: The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. Signaling description: The activation of HRH3 decreases histamine production and release, thus promoting sleep. Conversely, the blockade of HRH3 promotes wakefulness. Therefore, HRH3 constitutes a brain target for the treatment of sleep-wake disorders. Organ: brain Organ_System: nervous system PMID: 18626069 PMID: 20851648 PMID: 20864502 PMID: 21318261 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-acc47a16-bedd-486f-97f9-9ca2c13a61e3 HRH3 in Negative Regulation of Histamine Production and Release in Sleep Regulation uuid-acc47a16-bedd-486f-97f9-9ca2c13a61e3 PS:CellType neuron PS:Description The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-acc47a16-bedd-486f-97f9-9ca2c13a61e3 PS:NodeType Pathway PS:Notes Headnote: The histamine H3 receptor (HRH3) functions as an auto-receptor and regulates the synthesis and release of histamine. Signaling description: The activation of HRH3 decreases histamine production and release, thus promoting sleep. Conversely, the blockade of HRH3 promotes wakefulness. Therefore, HRH3 constitutes a brain target for the treatment of sleep-wake disorders. PS:Organ brain PS:Organ_System nervous system PS:PMID 18626069 PS:PMID 20851648 PS:PMID 20864502 PS:PMID 21318261 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Psoriasis and psoriatic arthritis (PsA), often termed as 'psoriatic disease" are autoimmune diseases which share certain similar pathological events and clinical features. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad105b0c-9930-4f25-ace5-2306a8e2bceb NodeType: Pathway Notes: Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Psoriatic disease used to be regarded as a Th1-driven disease, and now there is substantial evidence in support for a regulatory role of Th17 cells in the pathogenesis of psoriasis and PsA. Signaling description: Cytokines play a critical role in the inflammatory and proliferative cascades of both skin and joint tissues. The IL-23/IL-17 axis plays a prominent role in adaptive immunity and forms a complex interplay with TNFalpha and NFkB, and its disruption by genetic variation can contribute to PsA pathogenesis. Several genetic loci involved in Th-17 signaling have reached genome-wide significance (i.e., IL-12B, IL-23R, TYK2, and NFKBIA) or are approaching genomewide significance (i.e., IL-23A) in PsA. IL-23 is a heterodimeric cytokine (composed of a p19 subunit and a p40 subunit), which binds IL-23R and IL-12Rbeta1; the latter being shared with IL-12. IL-23, functioning through its receptor and signaling pathway, induces the production of several proinflammatory cytokines (e.g., IL-17, TNFalpha, IL-21, and IL-22). Outcome effects: IL-23 promotes the expansion and survival of Th-17 cells.IL-23 induced Th17 cytokines (IL-17 and IL-22) can contribute to all four pathologic events in a psoriatic disease: the development of psoriatic plaque, pannus formation in the joint, joint erosion and new bone formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 18039949 PMID: 19182814 PMID: 25445403 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-ad105b0c-9930-4f25-ace5-2306a8e2bceb Th17-Cell and Th1 Immune Responsein Psoriatic Arthritis uuid-ad105b0c-9930-4f25-ace5-2306a8e2bceb PS:CellType T-cell PS:Description Psoriasis and psoriatic arthritis (PsA), often termed as 'psoriatic disease" are autoimmune diseases which share certain similar pathological events and clinical features. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad105b0c-9930-4f25-ace5-2306a8e2bceb PS:NodeType Pathway PS:Notes Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Psoriatic disease used to be regarded as a Th1-driven disease, and now there is substantial evidence in support for a regulatory role of Th17 cells in the pathogenesis of psoriasis and PsA. Signaling description: Cytokines play a critical role in the inflammatory and proliferative cascades of both skin and joint tissues. The IL-23/IL-17 axis plays a prominent role in adaptive immunity and forms a complex interplay with TNFalpha and NFkB, and its disruption by genetic variation can contribute to PsA pathogenesis. Several genetic loci involved in Th-17 signaling have reached genome-wide significance (i.e., IL-12B, IL-23R, TYK2, and NFKBIA) or are approaching genomewide significance (i.e., IL-23A) in PsA. IL-23 is a heterodimeric cytokine (composed of a p19 subunit and a p40 subunit), which binds IL-23R and IL-12Rbeta1; the latter being shared with IL-12. IL-23, functioning through its receptor and signaling pathway, induces the production of several proinflammatory cytokines (e.g., IL-17, TNFalpha, IL-21, and IL-22). Outcome effects: IL-23 promotes the expansion and survival of Th-17 cells.IL-23 induced Th17 cytokines (IL-17 and IL-22) can contribute to all four pathologic events in a psoriatic disease: the development of psoriatic plaque, pannus formation in the joint, joint erosion and new bone formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 18039949 PS:PMID 19182814 PS:PMID 25445403 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad34df1a-3cb0-4cdf-80c6-3b794f4f04ef NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ad34df1a-3cb0-4cdf-80c6-3b794f4f04ef Proteins with Altered Expression in Medulloblastoma uuid-ad34df1a-3cb0-4cdf-80c6-3b794f4f04ef PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad34df1a-3cb0-4cdf-80c6-3b794f4f04ef PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad449474-2d56-42ed-874a-47e05ae02300 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ad449474-2d56-42ed-874a-47e05ae02300 IL6R -> CEBP/ELK/SRF Signaling uuid-ad449474-2d56-42ed-874a-47e05ae02300 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad449474-2d56-42ed-874a-47e05ae02300 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad4ce5ee-10f9-4a45-833c-f6a3a7729fc5 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-ad4ce5ee-10f9-4a45-833c-f6a3a7729fc5 Elevated Receptors -> Expression Targets in Kidney uuid-ad4ce5ee-10f9-4a45-833c-f6a3a7729fc5 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad4ce5ee-10f9-4a45-833c-f6a3a7729fc5 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad5c466c-5c13-409f-9213-f1a02fc7a6d7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ad5c466c-5c13-409f-9213-f1a02fc7a6d7 CTGF -> FOXO3A Expression Target uuid-ad5c466c-5c13-409f-9213-f1a02fc7a6d7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad5c466c-5c13-409f-9213-f1a02fc7a6d7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad73fe20-58c8-4599-bbd6-6bc303749fb7 NodeType: Pathway Notes: As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Proliferation (Fig. 4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ad73fe20-58c8-4599-bbd6-6bc303749fb7 3_1_Beta-cell proliferation and compensation: proliferation uuid-ad73fe20-58c8-4599-bbd6-6bc303749fb7 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad73fe20-58c8-4599-bbd6-6bc303749fb7 PS:NodeType Pathway PS:Notes As beta-cell death progresses, the pancreas compensates for the loss of beta cells by increasing insulin production. The mass of beta cell decreases until the ability of the pancreas to compensate for their loss is exceeded: Pathway 3. Beta-cell proliferation and compensation: Proliferation (Fig. 4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad793241-7548-4a4f-9a82-1a68197ab169 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-ad793241-7548-4a4f-9a82-1a68197ab169 Heme Biosynthesis uuid-ad793241-7548-4a4f-9a82-1a68197ab169 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad793241-7548-4a4f-9a82-1a68197ab169 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad7d0787-6e68-4660-b4c9-9701ae669498 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-ad7d0787-6e68-4660-b4c9-9701ae669498 ACE2 genetic variants uuid-ad7d0787-6e68-4660-b4c9-9701ae669498 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ad7d0787-6e68-4660-b4c9-9701ae669498 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ade19d9e-f577-482b-82c2-8f79aa07ef0e NodeType: Pathway Notes: Headnote: The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation during the second month of gestation requires the action of several genes, of which one of the most important one is SRY, the sex-determining region of the Y chromosome. When SRY a gene is defective, the indifferent gonads fail to differentiate into testes in a genetically male fetus. Mutations of SRY account for many cases of Swyer syndrome or XY gonadal dysgenesis, a type of hypogonadism in a person who has male karyotype (46, XY). This person is externally female with streak gonads, and without treatment will not experience puberty. Signaling description: When complexed with the SF1 (NR5A1) protein, SRY acts as a transcription factor that can upregulate other transcription factors, most importantly SOX9, which then activates and forms a feedforward loop with FGF9. Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. Mutations in SOX9 lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal and cleft palate. Sertoli cell proliferation and differentiation is mainly activated by FGF9. SOX9 expression causes the development of primary sex cords, which later develop into seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now induced Leydig cells of the testis then start secreting testosterone while the Sertoli cells produce anti-Müllerian hormone (AMH) to inhibit the creation of a female reproductive system.Other transcription factors such as SP1, WT1, GATA4, FOG2 (ZFPM2), SIX1/4 play role in the control of the SRY expression. For example, mutation in WT1 results in reduced male gonad size. Deletion of the gene resulted in complete sex reversal. DAX1 (NR0B1) is an antagonist of male development. NR0B1 acts early in human testis determination, as its dysregulation via either a duplication of the Xp21 region encompassing the NR0B1 gene or a large deletion upstream of NR0B1 leads to 46XY male-to-female sex reversal.Other genes which take part in gonadal development and mutations in which lead to the male infertility include CBX2, SOX3, DHH, AMH, AMHR2, CYP17A1, CYP11A1, and STAR. Outcome effects: Without testes, no testosterone and anti-Müllerian hormone (AMH) is produced; the Wolffian ducts fail to develop; no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in normal female genitalia. Without AMH, the Müllerian ducts develop into internal female organs. Organ: paramesonephric duct Organ: testis Organ_System: reproductive system PMID: 17237341 PMID: 18989307 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ade19d9e-f577-482b-82c2-8f79aa07ef0e Testicular Dysgenesis Causes Male Infertility uuid-ade19d9e-f577-482b-82c2-8f79aa07ef0e PS:Description The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ade19d9e-f577-482b-82c2-8f79aa07ef0e PS:NodeType Pathway PS:Notes Headnote: The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation during the second month of gestation requires the action of several genes, of which one of the most important one is SRY, the sex-determining region of the Y chromosome. When SRY a gene is defective, the indifferent gonads fail to differentiate into testes in a genetically male fetus. Mutations of SRY account for many cases of Swyer syndrome or XY gonadal dysgenesis, a type of hypogonadism in a person who has male karyotype (46, XY). This person is externally female with streak gonads, and without treatment will not experience puberty. Signaling description: When complexed with the SF1 (NR5A1) protein, SRY acts as a transcription factor that can upregulate other transcription factors, most importantly SOX9, which then activates and forms a feedforward loop with FGF9. Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. Mutations in SOX9 lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal and cleft palate. Sertoli cell proliferation and differentiation is mainly activated by FGF9. SOX9 expression causes the development of primary sex cords, which later develop into seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now induced Leydig cells of the testis then start secreting testosterone while the Sertoli cells produce anti-Müllerian hormone (AMH) to inhibit the creation of a female reproductive system.Other transcription factors such as SP1, WT1, GATA4, FOG2 (ZFPM2), SIX1/4 play role in the control of the SRY expression. For example, mutation in WT1 results in reduced male gonad size. Deletion of the gene resulted in complete sex reversal. DAX1 (NR0B1) is an antagonist of male development. NR0B1 acts early in human testis determination, as its dysregulation via either a duplication of the Xp21 region encompassing the NR0B1 gene or a large deletion upstream of NR0B1 leads to 46XY male-to-female sex reversal.Other genes which take part in gonadal development and mutations in which lead to the male infertility include CBX2, SOX3, DHH, AMH, AMHR2, CYP17A1, CYP11A1, and STAR. Outcome effects: Without testes, no testosterone and anti-Müllerian hormone (AMH) is produced; the Wolffian ducts fail to develop; no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in normal female genitalia. Without AMH, the Müllerian ducts develop into internal female organs. PS:Organ paramesonephric duct PS:Organ testis PS:Organ_System reproductive system PS:PMID 17237341 PS:PMID 18989307 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-adfd5ef6-ded3-4849-8dc8-4f7acee5eb1b NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-adfd5ef6-ded3-4849-8dc8-4f7acee5eb1b CD86 -> ATF/CREB/CREBBP Expression Targets uuid-adfd5ef6-ded3-4849-8dc8-4f7acee5eb1b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-adfd5ef6-ded3-4849-8dc8-4f7acee5eb1b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae2be89e-e649-464c-97de-b636fc883911 NodeType: Pathway Notes: Headnote: The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. Signaling description: MMR recognizes a wide spectrum of mismatches in base-pairing nucleotides and removes a patch of DNA including the misincorporated nucleotide. New DNA is synthesized using the complementary strand as a template. The mismatch is initially bound by heterodimer MSH2/MSH6 for base-base mismatches and one- or two-base loops or MutS beta heterodimer (MSH2/MSH3) for loops of 2-14bp. The mismatch-bound MSH2/MSH6 heterodimer is converted to a sliding clamp capable of translocating along the DNA molecule in an ATP-dependent manner. The MSH2/MSH6/ATP/DNA complex is bound by a second heterodimer, MLH1/PMS2. This complex searches a strand discontinuity and is able to translocate in either direction. MSH2 also forms a heterodimer with MSH3. This MutS beta complex binds to insertion/deletion mispairs but displays little if any affinity for base-base mismatches. In strand resynthesis, the MSH2/MSH6 sliding clamp stimulates the activity of EXO1, starting from a nick situated 5' from the mispair and traveling towards the mispair. Outcome effects: Polymerases and their cofactors, PCNA and DNA replication factor C fill in the resulting single-stranded gap and LIG1 seals the remaining nick. Any defect in this system dramatically increases mutation rates. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-ae2be89e-e649-464c-97de-b636fc883911 Single-Strand Mismatch uuid-ae2be89e-e649-464c-97de-b636fc883911 PS:CellType generic PS:Description The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae2be89e-e649-464c-97de-b636fc883911 PS:NodeType Pathway PS:Notes Headnote: The mismatch repair (MMR) system is responsible for the post-replicative repair of mismatches and small single-stranded DNA loops. Signaling description: MMR recognizes a wide spectrum of mismatches in base-pairing nucleotides and removes a patch of DNA including the misincorporated nucleotide. New DNA is synthesized using the complementary strand as a template. The mismatch is initially bound by heterodimer MSH2/MSH6 for base-base mismatches and one- or two-base loops or MutS beta heterodimer (MSH2/MSH3) for loops of 2-14bp. The mismatch-bound MSH2/MSH6 heterodimer is converted to a sliding clamp capable of translocating along the DNA molecule in an ATP-dependent manner. The MSH2/MSH6/ATP/DNA complex is bound by a second heterodimer, MLH1/PMS2. This complex searches a strand discontinuity and is able to translocate in either direction. MSH2 also forms a heterodimer with MSH3. This MutS beta complex binds to insertion/deletion mispairs but displays little if any affinity for base-base mismatches. In strand resynthesis, the MSH2/MSH6 sliding clamp stimulates the activity of EXO1, starting from a nick situated 5' from the mispair and traveling towards the mispair. Outcome effects: Polymerases and their cofactors, PCNA and DNA replication factor C fill in the resulting single-stranded gap and LIG1 seals the remaining nick. Any defect in this system dramatically increases mutation rates. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae57d10f-e493-40a5-b611-b80139795f01 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-ae57d10f-e493-40a5-b611-b80139795f01 NTRK1/2/3 -> Acetylcholine Production uuid-ae57d10f-e493-40a5-b611-b80139795f01 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae57d10f-e493-40a5-b611-b80139795f01 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae58188d-5fb4-4abf-96c0-9ab1a25f08cd NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-ae58188d-5fb4-4abf-96c0-9ab1a25f08cd BDKRB1/2 -> Ion Channels uuid-ae58188d-5fb4-4abf-96c0-9ab1a25f08cd PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae58188d-5fb4-4abf-96c0-9ab1a25f08cd PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae5b49b6-4a46-470b-8660-f9e79000d019 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-ae5b49b6-4a46-470b-8660-f9e79000d019 C5AR1 -> Expression Targets in Lymphoid System and Blood uuid-ae5b49b6-4a46-470b-8660-f9e79000d019 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae5b49b6-4a46-470b-8660-f9e79000d019 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae713df3-3704-4ba6-b37b-0eda3805765d NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-ae713df3-3704-4ba6-b37b-0eda3805765d Dopamine Release in Nociception uuid-ae713df3-3704-4ba6-b37b-0eda3805765d PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ae713df3-3704-4ba6-b37b-0eda3805765d PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Myostatin (MSTN) is a member of the TGF-beta family that acts as a repressor of muscle differentiation and growth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aea0de6e-a3c1-428a-881e-d23ae29b8ca9 NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Myostatin (MSTN) is a member of the TGF-beta family that acts as a repressor of muscle differentiation and growth. MSTN is produced by muscle cells and once secreted binds to FST, FSTL3, and WFIKKN2 which are extracellular regulators of MSTN activity. MSTN acts on muscle cells through activin type II receptor (ACVR2A and ACVR2B). Upon ligand-receptor binding, ACVR1B and TGFBR1 coreceptors are recruited to initiate SMAD activation. Another mechanism of repressing myogenesis is MSTN-induced activation of MAPKs through MAP3K7/ mitogen-activated protein kinase kinase (MAPKK) and Ras/Raf/MEK cascades. Outcome effects: SMADs repress myogenic factors such as MYOD1, MYOG, and PAX3 and positively regulate protein degradation through FOXO3/TRIM63 and FBXO32. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-aea0de6e-a3c1-428a-881e-d23ae29b8ca9 Myostatin in Skeletal Muscles in Muscular Dystrophies uuid-aea0de6e-a3c1-428a-881e-d23ae29b8ca9 PS:CellType muscle cell PS:Description Myostatin (MSTN) is a member of the TGF-beta family that acts as a repressor of muscle differentiation and growth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aea0de6e-a3c1-428a-881e-d23ae29b8ca9 PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Myostatin (MSTN) is a member of the TGF-beta family that acts as a repressor of muscle differentiation and growth. MSTN is produced by muscle cells and once secreted binds to FST, FSTL3, and WFIKKN2 which are extracellular regulators of MSTN activity. MSTN acts on muscle cells through activin type II receptor (ACVR2A and ACVR2B). Upon ligand-receptor binding, ACVR1B and TGFBR1 coreceptors are recruited to initiate SMAD activation. Another mechanism of repressing myogenesis is MSTN-induced activation of MAPKs through MAP3K7/ mitogen-activated protein kinase kinase (MAPKK) and Ras/Raf/MEK cascades. Outcome effects: SMADs repress myogenic factors such as MYOD1, MYOG, and PAX3 and positively regulate protein degradation through FOXO3/TRIM63 and FBXO32. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Arterial Hypertension (AH) is a medical condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aebbfdb7-bbc9-4327-9b54-5a2eb34d06d9 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction, which is believed to be an early component of the arterial hypertensive process. Signaling description: Endothelin 1 (EDN1) is one of the most potent vasoconstrictors, which is secreted by endothelial cells and adrenal zona glomerulosa cells in response to specific stimuli such as hypoxia. However, factors that regulate the adrenal EDN1 production are yet to be identified. EDN1 acts as a local regulator of vascular tone and endothelial cell proliferation and acts as an independent stimulator of aldosterone secretion in adrenal zona glomerulosa. Abundant levels of EDN1 elevate the production of aldosterone and promote adrenal zona glomerulosa cell proliferation, which leads to arterial hypertension. EDN1 binds EDNRA/B on adrenal zona glomerulosa cells. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum (ER). PLCB1 mediates the cleavage of PIP2 to diacylglycerol and IP3. Further, IP3 binds ITPR1 on the ER, thus releasing Ca2+ and raising cytosolic Ca2+ concentrations. Diacylglycerol activates PKC, which phosphorylates PRKD1. Outcome effects: PRKD1 directly phosphorylates and activates CREB1, and PKC activates the MAPK pathway via PTK2B/SRC and is involved in adrenal zona glomerulosa cell proliferation and growth. GNA11 binds PIK3CA, via activated PDPK1 by PIP3, to induce the activation of AKT1. Next, AKT1 activates CREB1, which binds NR4A2, which in turn has a critical role in the stimulation of CYP11B2 gene expression. Aldosterone is synthesized by CYP11B2 and regulates salt and water homeostasis and blood pressure. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: adrenal gland Organ: zona glomerulosa Organ_System: endocrine system PMID: 17113976 PMID: 20848158 PMID: 21248162 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-aebbfdb7-bbc9-4327-9b54-5a2eb34d06d9 Endothelin Signaling in Arterial Hypertension uuid-aebbfdb7-bbc9-4327-9b54-5a2eb34d06d9 PS:CellType endothelial cell PS:Description Arterial Hypertension (AH) is a medical condition in which the blood pressure is chronically elevated. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aebbfdb7-bbc9-4327-9b54-5a2eb34d06d9 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction, which is believed to be an early component of the arterial hypertensive process. Signaling description: Endothelin 1 (EDN1) is one of the most potent vasoconstrictors, which is secreted by endothelial cells and adrenal zona glomerulosa cells in response to specific stimuli such as hypoxia. However, factors that regulate the adrenal EDN1 production are yet to be identified. EDN1 acts as a local regulator of vascular tone and endothelial cell proliferation and acts as an independent stimulator of aldosterone secretion in adrenal zona glomerulosa. Abundant levels of EDN1 elevate the production of aldosterone and promote adrenal zona glomerulosa cell proliferation, which leads to arterial hypertension. EDN1 binds EDNRA/B on adrenal zona glomerulosa cells. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLCB1 and phosphatidyl-inositol-calcium second messenger system resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum (ER). PLCB1 mediates the cleavage of PIP2 to diacylglycerol and IP3. Further, IP3 binds ITPR1 on the ER, thus releasing Ca2+ and raising cytosolic Ca2+ concentrations. Diacylglycerol activates PKC, which phosphorylates PRKD1. Outcome effects: PRKD1 directly phosphorylates and activates CREB1, and PKC activates the MAPK pathway via PTK2B/SRC and is involved in adrenal zona glomerulosa cell proliferation and growth. GNA11 binds PIK3CA, via activated PDPK1 by PIP3, to induce the activation of AKT1. Next, AKT1 activates CREB1, which binds NR4A2, which in turn has a critical role in the stimulation of CYP11B2 gene expression. Aldosterone is synthesized by CYP11B2 and regulates salt and water homeostasis and blood pressure. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ adrenal gland PS:Organ zona glomerulosa PS:Organ_System endocrine system PS:PMID 17113976 PS:PMID 20848158 PS:PMID 21248162 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: hepatocyte Description: Hyperammonemia Type II (ICD10 - E72.4) is an autosomal-recessive disease that caused by mutation in OTC gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aebe1539-4510-4bd3-ba55-d530d4f0f48c NodeType: Pathway Notes: Hyperammonemia Type II (ICD10 - E72.4) is an autosomal-recessive disease that caused by mutation in OTC gene. Organ: liver PMID: 11124797 PMID: 20301396 PMID: 24772957 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: generic urn:agi-pathway:uuid-aebe1539-4510-4bd3-ba55-d530d4f0f48c Hyperammonemia Type II uuid-aebe1539-4510-4bd3-ba55-d530d4f0f48c PS:CellType hepatocyte PS:Description Hyperammonemia Type II (ICD10 - E72.4) is an autosomal-recessive disease that caused by mutation in OTC gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aebe1539-4510-4bd3-ba55-d530d4f0f48c PS:NodeType Pathway PS:Notes Hyperammonemia Type II (ICD10 - E72.4) is an autosomal-recessive disease that caused by mutation in OTC gene. PS:Organ liver PS:PMID 11124797 PS:PMID 20301396 PS:PMID 24772957 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aede4e2a-b3d2-459a-8282-d75490db5427 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-aede4e2a-b3d2-459a-8282-d75490db5427 ANGPT2 -> AP-1/CREBBP/MYC Expression Targets uuid-aede4e2a-b3d2-459a-8282-d75490db5427 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-aede4e2a-b3d2-459a-8282-d75490db5427 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af0d3c11-cf26-4cba-8288-071109dee596 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-af0d3c11-cf26-4cba-8288-071109dee596 Anti-psoriatic drugs influence PPARG signaling uuid-af0d3c11-cf26-4cba-8288-071109dee596 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af0d3c11-cf26-4cba-8288-071109dee596 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af0f8f81-72fa-48b7-bf2a-4bc96b8beced NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-af0f8f81-72fa-48b7-bf2a-4bc96b8beced Notch->EMT uuid-af0f8f81-72fa-48b7-bf2a-4bc96b8beced PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af0f8f81-72fa-48b7-bf2a-4bc96b8beced PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af1d6824-7278-4586-8d55-63fb50501545 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-af1d6824-7278-4586-8d55-63fb50501545 Proteins Involved in Diabetes Mellitus Type 2 uuid-af1d6824-7278-4586-8d55-63fb50501545 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af1d6824-7278-4586-8d55-63fb50501545 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af22928f-3207-45df-b55a-fc6ccbd1e924 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-af22928f-3207-45df-b55a-fc6ccbd1e924 AngiopoietinR+>myofibroblasts (hypothesis) uuid-af22928f-3207-45df-b55a-fc6ccbd1e924 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af22928f-3207-45df-b55a-fc6ccbd1e924 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af252e5c-fdd2-4cd0-9c56-5e892fc03907 NodeType: Pathway Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-af252e5c-fdd2-4cd0-9c56-5e892fc03907 Proteins Involved in Breast Cancer Related to NOTCH Signaling Pathway uuid-af252e5c-fdd2-4cd0-9c56-5e892fc03907 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af252e5c-fdd2-4cd0-9c56-5e892fc03907 PS:NodeType Pathway PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af2b9827-1e69-45ee-8e18-fc244b5d686c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-af2b9827-1e69-45ee-8e18-fc244b5d686c pyruvate dehydrogenase complex template uuid-af2b9827-1e69-45ee-8e18-fc244b5d686c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af2b9827-1e69-45ee-8e18-fc244b5d686c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af31b04d-cf65-4cb5-b8ab-4c43f3ec8623 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-af31b04d-cf65-4cb5-b8ab-4c43f3ec8623 Biotin biosynthesis template uuid-af31b04d-cf65-4cb5-b8ab-4c43f3ec8623 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af31b04d-cf65-4cb5-b8ab-4c43f3ec8623 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron CellType: sensory hair cell Description: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af439c95-8626-4646-ba70-faeeb40288ef NodeType: Pathway Notes: Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Some of the proteins whose genes are mutated in Usher syndrome are involved in synaptic transduction between the inner ear hair cell and neuron. Mutated proteins: Mutated proteins are shown in white-out style. Organ: ear Organ_System: sensory system PMID: 16545802 PMID: 16987892 PMID: 20379205 PMID: 20624897 PMID: 22311968 PMID: 22363448 PMID: 23613530 PMID: 24022220 PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-af439c95-8626-4646-ba70-faeeb40288ef Proteins Mutated in Cochlear Hair Cell Synapse uuid-af439c95-8626-4646-ba70-faeeb40288ef PS:CellType neuron PS:CellType sensory hair cell PS:Description Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af439c95-8626-4646-ba70-faeeb40288ef PS:NodeType Pathway PS:Notes Headnote: Usher syndrome is a rare genetic disorder characterized by hearing loss and a gradual vision loss due to retinitis pigmentosa (progressive degeneration of photoreceptor cells in the retina). Some of the proteins whose genes are mutated in Usher syndrome are involved in synaptic transduction between the inner ear hair cell and neuron. Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ ear PS:Organ_System sensory system PS:PMID 16545802 PS:PMID 16987892 PS:PMID 20379205 PS:PMID 20624897 PS:PMID 22311968 PS:PMID 22363448 PS:PMID 23613530 PS:PMID 24022220 PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af5c9648-aba0-48fb-bdc4-c1b418a42e60 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-af5c9648-aba0-48fb-bdc4-c1b418a42e60 PPARG negative regulators and targets uuid-af5c9648-aba0-48fb-bdc4-c1b418a42e60 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af5c9648-aba0-48fb-bdc4-c1b418a42e60 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af650163-2ac3-47a1-b653-20cecbe2d7f9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-af650163-2ac3-47a1-b653-20cecbe2d7f9 LPA Expression Targets uuid-af650163-2ac3-47a1-b653-20cecbe2d7f9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af650163-2ac3-47a1-b653-20cecbe2d7f9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af6fd535-c535-469a-9dc1-0869e4851b2f NodeType: Pathway Organ: stomach Organ_System: digestive system PMID: 11373617 PMID: 14755326 PMID: 15123077 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-af6fd535-c535-469a-9dc1-0869e4851b2f Stomach Mucosal Layer Disruption uuid-af6fd535-c535-469a-9dc1-0869e4851b2f PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af6fd535-c535-469a-9dc1-0869e4851b2f PS:NodeType Pathway PS:Organ stomach PS:Organ_System digestive system PS:PMID 11373617 PS:PMID 14755326 PS:PMID 15123077 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af79dd19-0866-4a6a-abb9-40e161570a69 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-af79dd19-0866-4a6a-abb9-40e161570a69 HCAR1/HCAR2 -> MAPK Signaling uuid-af79dd19-0866-4a6a-abb9-40e161570a69 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af79dd19-0866-4a6a-abb9-40e161570a69 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Telomeres become shorter with aging of the cell because of the specialties of DNA replication. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af7e1658-9dfa-40aa-9cd5-8099a288b1a4 NodeType: Pathway Notes: Headnote: Telomeres are repetitive nucleotide sequences located at the end of chromosomes. Telomeres become shorter with aging of the cell because of the specialties in DNA replication at chromosomal ends during the each replication cycle. Signaling description: Telomerase complex is the main mechanism of telomeres length restoration and capable to add TTAGGG repeats to the 3' end of chromosomes. hTERT (the part of telomerase complex) is generally repressed in normal non- pluripotent cells. Shelterin complex and telomere capping protects telomeres against double-strand break (DSB) repair by homologous recombination (HR) and non-homologous end joining (NHEJ). When telomeres ends become too short and loss their capping they are processed by enzymes of DNA repair mechanism. With continued cell divisions telomere loss became accumulating and not recovering due to the limited capacity of "recovering mechanisms". At this point, defective telomeres will trigger DNA damage signals such as TP53. The telomere binding protein TRF2 binds to ATM kinase and can inhibit its function and DNA repair. Outcome effects: Activated by dysfunctional telomeres TP53 leads to upregulation of functional DNA damage responses. Shorter telomeres during cell division cause genome instability via chromosome fusions, chromosome breaks, etc. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: generic PMID: 18391173 PMID: 23478256 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-af7e1658-9dfa-40aa-9cd5-8099a288b1a4 Telomer Attrition Triggers Genomic Instability uuid-af7e1658-9dfa-40aa-9cd5-8099a288b1a4 PS:CellType generic PS:Description Telomeres become shorter with aging of the cell because of the specialties of DNA replication. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-af7e1658-9dfa-40aa-9cd5-8099a288b1a4 PS:NodeType Pathway PS:Notes Headnote: Telomeres are repetitive nucleotide sequences located at the end of chromosomes. Telomeres become shorter with aging of the cell because of the specialties in DNA replication at chromosomal ends during the each replication cycle. Signaling description: Telomerase complex is the main mechanism of telomeres length restoration and capable to add TTAGGG repeats to the 3' end of chromosomes. hTERT (the part of telomerase complex) is generally repressed in normal non- pluripotent cells. Shelterin complex and telomere capping protects telomeres against double-strand break (DSB) repair by homologous recombination (HR) and non-homologous end joining (NHEJ). When telomeres ends become too short and loss their capping they are processed by enzymes of DNA repair mechanism. With continued cell divisions telomere loss became accumulating and not recovering due to the limited capacity of "recovering mechanisms". At this point, defective telomeres will trigger DNA damage signals such as TP53. The telomere binding protein TRF2 binds to ATM kinase and can inhibit its function and DNA repair. Outcome effects: Activated by dysfunctional telomeres TP53 leads to upregulation of functional DNA damage responses. Shorter telomeres during cell division cause genome instability via chromosome fusions, chromosome breaks, etc. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PMID 18391173 PS:PMID 23478256 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afa46537-57bb-4af0-a1dc-5daf0d01b5c0 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-afa46537-57bb-4af0-a1dc-5daf0d01b5c0 PGE1 Expression Targets uuid-afa46537-57bb-4af0-a1dc-5daf0d01b5c0 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afa46537-57bb-4af0-a1dc-5daf0d01b5c0 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afafbb93-372d-482b-8e31-e7303af04814 NodeType: Pathway urn:agi-pathway:uuid-afafbb93-372d-482b-8e31-e7303af04814 Integrins in Focal Junction Assembly uuid-afafbb93-372d-482b-8e31-e7303af04814 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afafbb93-372d-482b-8e31-e7303af04814 PS:NodeType Pathway PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afb9f42c-d22a-44d4-85ed-02e402d402ca NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-afb9f42c-d22a-44d4-85ed-02e402d402ca AMH/AMHR2 Expression Targets uuid-afb9f42c-d22a-44d4-85ed-02e402d402ca PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afb9f42c-d22a-44d4-85ed-02e402d402ca PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afdd58f9-9881-4388-8219-165a545a0e88 NodeType: Pathway Organ: breast Organ: ovary PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-afdd58f9-9881-4388-8219-165a545a0e88 Genes with Mutations Associated with Hereditary Breast and/or Ovarian Cancer Syndrome uuid-afdd58f9-9881-4388-8219-165a545a0e88 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-afdd58f9-9881-4388-8219-165a545a0e88 PS:NodeType Pathway PS:Organ breast PS:Organ ovary PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b001be62-938f-489f-bf56-7b4dd7f78a7c NodeType: Pathway Notes: Headnote: The antiphospholipid syndrome (APS), is characterized by recurrent thrombosis (arterial or venous, or both) and/or morbidity during pregnancy (recurrent miscarriages / stillbirths) associated with high levels of anti-phospholipid antibodies (aPL). Signaling description: aPL antibodies bind to beta-2GPI (APOH) which in turn binds to endothelial cell membrane receptors (TLR4 and ANXA2) and induces phosphorylation of p38 MAPK (MAPK14) and NFkB activation leading to a proinflammatory and prothrombotic effect (expression of VCAM1, ICAM1, SELE, F3, IL-1A, IL-6 and IL-8). Organ: blood vessel Organ_System: cardiovascular system PMID: 17894016 PMID: 20822807 PMID: 21556027 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b001be62-938f-489f-bf56-7b4dd7f78a7c Antiphospholipid Antibodies in Endothelial Cell uuid-b001be62-938f-489f-bf56-7b4dd7f78a7c PS:CellType endothelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b001be62-938f-489f-bf56-7b4dd7f78a7c PS:NodeType Pathway PS:Notes Headnote: The antiphospholipid syndrome (APS), is characterized by recurrent thrombosis (arterial or venous, or both) and/or morbidity during pregnancy (recurrent miscarriages / stillbirths) associated with high levels of anti-phospholipid antibodies (aPL). Signaling description: aPL antibodies bind to beta-2GPI (APOH) which in turn binds to endothelial cell membrane receptors (TLR4 and ANXA2) and induces phosphorylation of p38 MAPK (MAPK14) and NFkB activation leading to a proinflammatory and prothrombotic effect (expression of VCAM1, ICAM1, SELE, F3, IL-1A, IL-6 and IL-8). PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 17894016 PS:PMID 20822807 PS:PMID 21556027 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: generic Description: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b03f5f92-0c7c-4dbb-95c3-50c0e30c5571 NodeType: Pathway Notes: Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. It plays a crucial role in carbohydrate, fat, and protein metabolism in insulin-dependent tissues. Insulin action is similar in both hepatocytes and myocytes. The hormone provides glucose conversion to glycogen and triggers protein synthesis. Insulin influence on protein synthesis is realized in its regulation of translation. Signaling description: The hormone promotes translation by activating EIF4E and RPS6 in addition to inhibiting EIF2S1. The main signaling occurs through AKT1. Insulin (INS) binds to its receptor, INSR and the signal through PIK3R1 is transduced to IRS which activates PI3K. PI3K-generated PIP3 then activates AKT1. Activated by PIP3, PDPK1 induces the same reaction. AKT1 inhibits proteins which lead to the suppression of the translation responsive elements. AKT1 phosphorylates GSK3B, rendering it inactive. In other cases, GSK3B phosphorylates the protein complex of eukaryotic translation initiation factors (eIF) that negatively regulate the initiation of protein translation. Involved in signaling, MTOR via AKT1 promotes translation by phosphorylation and activation of RPS6KB1 which affects RPS6 and inhibition of EIF4EBP1 which is EIF4E suppressor. EIF4E and RPS6 are key regulators of protein synthesis. Through SHC1/SOS1/RAF1/MAPK3, INS phosphorylates MYC which binds to the promoter region of EIF4E. Organ: generic Organ_System: generic PMID: 10227847 PMID: 11780752 PMID: 18537611 PMID: 21498522 PMID: 9932214 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-b03f5f92-0c7c-4dbb-95c3-50c0e30c5571 Insulin Influence on Protein Synthesis uuid-b03f5f92-0c7c-4dbb-95c3-50c0e30c5571 PS:CellType generic PS:Description Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b03f5f92-0c7c-4dbb-95c3-50c0e30c5571 PS:NodeType Pathway PS:Notes Headnote: Insulin is a peptide hormone produced by pancreatic beta-cells located in the islets of Langerhans. It plays a crucial role in carbohydrate, fat, and protein metabolism in insulin-dependent tissues. Insulin action is similar in both hepatocytes and myocytes. The hormone provides glucose conversion to glycogen and triggers protein synthesis. Insulin influence on protein synthesis is realized in its regulation of translation. Signaling description: The hormone promotes translation by activating EIF4E and RPS6 in addition to inhibiting EIF2S1. The main signaling occurs through AKT1. Insulin (INS) binds to its receptor, INSR and the signal through PIK3R1 is transduced to IRS which activates PI3K. PI3K-generated PIP3 then activates AKT1. Activated by PIP3, PDPK1 induces the same reaction. AKT1 inhibits proteins which lead to the suppression of the translation responsive elements. AKT1 phosphorylates GSK3B, rendering it inactive. In other cases, GSK3B phosphorylates the protein complex of eukaryotic translation initiation factors (eIF) that negatively regulate the initiation of protein translation. Involved in signaling, MTOR via AKT1 promotes translation by phosphorylation and activation of RPS6KB1 which affects RPS6 and inhibition of EIF4EBP1 which is EIF4E suppressor. EIF4E and RPS6 are key regulators of protein synthesis. Through SHC1/SOS1/RAF1/MAPK3, INS phosphorylates MYC which binds to the promoter region of EIF4E. PS:Organ generic PS:Organ_System generic PS:PMID 10227847 PS:PMID 11780752 PS:PMID 18537611 PS:PMID 21498522 PS:PMID 9932214 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b04bc3b4-63b2-4daa-968b-9cbef6703dd1 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b04bc3b4-63b2-4daa-968b-9cbef6703dd1 Overview. Diseases of the blood (chapter 3) uuid-b04bc3b4-63b2-4daa-968b-9cbef6703dd1 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b04bc3b4-63b2-4daa-968b-9cbef6703dd1 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0626e12-e73f-4da2-86fe-ab2f94b953d6 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b0626e12-e73f-4da2-86fe-ab2f94b953d6 Fatty acid elongation (animal cytoplasm) template uuid-b0626e12-e73f-4da2-86fe-ab2f94b953d6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0626e12-e73f-4da2-86fe-ab2f94b953d6 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b08c6af3-dd7f-432e-a38b-ed40f36ff9f0 NodeType: Pathway Notes: TGFB signaling is the primary stimulator of terminal chondrocyte differentiation. Mutations in genes that encode proteins involved with the TGFB-related cascades have strong associations with OA development in some populations. Overexpression of MMP13, COL10A1, BGLAP, SPP1, and SPARC by chondrocytes in patients with OA provokes endochondral ossification and disease progression. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: bone Organ_System: skeletal system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b08c6af3-dd7f-432e-a38b-ed40f36ff9f0 3_TGFB signaling provokes endochondral ossification with osteophyte formation uuid-b08c6af3-dd7f-432e-a38b-ed40f36ff9f0 PS:CellType chondrocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b08c6af3-dd7f-432e-a38b-ed40f36ff9f0 PS:NodeType Pathway PS:Notes TGFB signaling is the primary stimulator of terminal chondrocyte differentiation. Mutations in genes that encode proteins involved with the TGFB-related cascades have strong associations with OA development in some populations. Overexpression of MMP13, COL10A1, BGLAP, SPP1, and SPARC by chondrocytes in patients with OA provokes endochondral ossification and disease progression. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ bone PS:Organ_System skeletal system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: 10-15% of cancers use alternative lengthening of telomeres pathway to elongate telomere DNA instead of TERT re-activation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b097da41-f8e3-48e4-8348-d960981efafe NodeType: Pathway Notes: Headnote: Telomeres regulate cellular lifespan by maintaining genomic through the protection of chromosomal termini. The maintenance of telomere length is essential for neoplastic cells after they acquire mutations that disrupt cell cycle control regulation and, thus, increase cellular proliferation. Telomere length maintenance is achieved by cancerous cells through the expression of the telomerase enzyme or via alternative lengthening of telomeres (ALT), which is a telomerase-independent mechanism. Signaling description: The precise mechanism of ALT is poorly understood. One of the hypothesis is the following. ALT relies on TERT (Telomerase Reverse Transcriptase) expression inhibition, and E2F1 and TCEAL7 probably have a role in TERT inactivation. ALT requires permissive mutations that involve p53, ATRX, DAXX and H3F3A. The ATRX-DAXX complex is required for chromatin deposition in histone H3.3, a histone variant associated with transcriptionally active open chromatin, transcription factor binding sites and telomeres. Mutations in H3F3A, encoding H3.3, may affect telomere dynamics by altering histone incorporation throughout the genome with subsequent changes in chromatin remodeling and gene expression. Loss of ATRX or DAXX would limit H3.3 incorporation into telomeric chromatin, which in turn disrupts telomeric heterochromatin and facilitates telomere recombination. Impaired p53 may be also associated with ALT activation. Outcome effects: ALT promotes maintenance of telomere length in a TERT-independent manner. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Enabling of Replicative Immortality" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20351727 PMID: 20542034 PMID: 20937668 PMID: 23219603 PMID: 23429284 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-b097da41-f8e3-48e4-8348-d960981efafe Alternative Lengthening of Telomeres in Cancer uuid-b097da41-f8e3-48e4-8348-d960981efafe PS:CellType cancer cell PS:CellType cancer stem cell PS:Description 10-15% of cancers use alternative lengthening of telomeres pathway to elongate telomere DNA instead of TERT re-activation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b097da41-f8e3-48e4-8348-d960981efafe PS:NodeType Pathway PS:Notes Headnote: Telomeres regulate cellular lifespan by maintaining genomic through the protection of chromosomal termini. The maintenance of telomere length is essential for neoplastic cells after they acquire mutations that disrupt cell cycle control regulation and, thus, increase cellular proliferation. Telomere length maintenance is achieved by cancerous cells through the expression of the telomerase enzyme or via alternative lengthening of telomeres (ALT), which is a telomerase-independent mechanism. Signaling description: The precise mechanism of ALT is poorly understood. One of the hypothesis is the following. ALT relies on TERT (Telomerase Reverse Transcriptase) expression inhibition, and E2F1 and TCEAL7 probably have a role in TERT inactivation. ALT requires permissive mutations that involve p53, ATRX, DAXX and H3F3A. The ATRX-DAXX complex is required for chromatin deposition in histone H3.3, a histone variant associated with transcriptionally active open chromatin, transcription factor binding sites and telomeres. Mutations in H3F3A, encoding H3.3, may affect telomere dynamics by altering histone incorporation throughout the genome with subsequent changes in chromatin remodeling and gene expression. Loss of ATRX or DAXX would limit H3.3 incorporation into telomeric chromatin, which in turn disrupts telomeric heterochromatin and facilitates telomere recombination. Impaired p53 may be also associated with ALT activation. Outcome effects: ALT promotes maintenance of telomere length in a TERT-independent manner. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Enabling of Replicative Immortality" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20351727 PS:PMID 20542034 PS:PMID 20937668 PS:PMID 23219603 PS:PMID 23429284 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b09900a4-045b-4e93-9008-cf82636e0ab1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-b09900a4-045b-4e93-9008-cf82636e0ab1 MLX Role in Glycolysis in Muscles uuid-b09900a4-045b-4e93-9008-cf82636e0ab1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b09900a4-045b-4e93-9008-cf82636e0ab1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Following contact with the endothelial cells of blood vessels, mature neutrophils change their shape and become capable of penetrating blood vessels towards the focus of inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0b406e8-9c00-4933-bfea-75e0112a076e NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Following contact with the endothelial cells of blood vessels, mature neutrophils change their shape and become capable of penetrating blood vessels towards the focus of inflammation. The activation of neutrophils through adherence to endothelial cells is dependent on integrins and selectins that are expressed on the surface of neutrophils and endothelial cells. L-selectin (SELL) is expressed in neutrophils and associates with P-selectin (SELP) expressed on the surface of endothelial cells, therefore providing rolling of neutrophils on the surface of blood vessels. There are other ligands for SELL that facilitate weak neutrophil binding. SELPLG is the ligand for E-selectin (SELE) on the surface of neutrophils. It is important for neutrophil rolling and for integrin-dependent activation of the adhesion of neutrophils on blood vessel cells. Following the binding of SELPLG to SELE, SYK is activated through LYN/TYROBP, which results in the activation of ITGAL/ITGB2 complex by MAPK1. In addition, ITGAL, ITGB2, and ITGB1/ITGA9 receptors on the neutrophil surface facilitate high levels of adhesion between neutrophils and endothelial cells, mainly through the association with ICAM1. In addition, chemoattractants for neutrophils, such as IL8, can increase integrin-dependent adhesion of neutrophils by stimulating the synthesis of integrins or by changing the cell shape through direct reorganization of the actin cytoskeleton. IL8-triggered binding of TLN1 can induce ITGB3 integrin clustering. Signaling description: The activation of integrins on the neutrophil surface not only leads to adhesion to endothelial cells, but also activates signaling pathways in the neutrophil itself. The main result is the alteration of the cytoskeleton, which causes the movement of secretory vesicles of neutrophils toward the external membrane and enrichment of the membrane with specific proteins that initiate transmigration of neutrophils through the blood vessel. Secretory vesicles, a subtype of neutrophilic granules, form in the late stages of neutrophil maturation and include proteins such as CR1, FCGR2A, MME, and FPR1. The modulation of the actin cytoskeleton and migration/degranulation of neutrophils is carried out by several methods and the pathway illustrates only some of the possible signaling cascades. Furthermore, integrins trigger intracellular signaling cascades that lead to ROS production through PI3K/RAC1-related signaling. Integrins also stimulate the synthesis of proinflammatory cytokines. The stage of neutrophil movement through the vascular basement membrane is facilitated by the release of MMP9 from tertiary granules. Tertiary granules contain metalloproteases required for the degradation of the extracellular matrix and transmigration of neutrophils. The binding of IL8 to CXCR2 causes the release of MMP9 from the tertiary granules. The degranulation of tertiary granules may be a result of the synthesis of arachidonic acid derivatives, which hypothetically can be stimulated by the activation of intracellular integrin-dependent signaling pathways. The mechanisms of the transmigration of neutrophils through the blood vessel wall are not well established. Organ: generic Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: endothelium Tissue: generic urn:agi-pathway:uuid-b0b406e8-9c00-4933-bfea-75e0112a076e Neutrophil Activation via Adherence on Endothelial Cells uuid-b0b406e8-9c00-4933-bfea-75e0112a076e PS:CellType neutrophil PS:Description Following contact with the endothelial cells of blood vessels, mature neutrophils change their shape and become capable of penetrating blood vessels towards the focus of inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0b406e8-9c00-4933-bfea-75e0112a076e PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Following contact with the endothelial cells of blood vessels, mature neutrophils change their shape and become capable of penetrating blood vessels towards the focus of inflammation. The activation of neutrophils through adherence to endothelial cells is dependent on integrins and selectins that are expressed on the surface of neutrophils and endothelial cells. L-selectin (SELL) is expressed in neutrophils and associates with P-selectin (SELP) expressed on the surface of endothelial cells, therefore providing rolling of neutrophils on the surface of blood vessels. There are other ligands for SELL that facilitate weak neutrophil binding. SELPLG is the ligand for E-selectin (SELE) on the surface of neutrophils. It is important for neutrophil rolling and for integrin-dependent activation of the adhesion of neutrophils on blood vessel cells. Following the binding of SELPLG to SELE, SYK is activated through LYN/TYROBP, which results in the activation of ITGAL/ITGB2 complex by MAPK1. In addition, ITGAL, ITGB2, and ITGB1/ITGA9 receptors on the neutrophil surface facilitate high levels of adhesion between neutrophils and endothelial cells, mainly through the association with ICAM1. In addition, chemoattractants for neutrophils, such as IL8, can increase integrin-dependent adhesion of neutrophils by stimulating the synthesis of integrins or by changing the cell shape through direct reorganization of the actin cytoskeleton. IL8-triggered binding of TLN1 can induce ITGB3 integrin clustering. Signaling description: The activation of integrins on the neutrophil surface not only leads to adhesion to endothelial cells, but also activates signaling pathways in the neutrophil itself. The main result is the alteration of the cytoskeleton, which causes the movement of secretory vesicles of neutrophils toward the external membrane and enrichment of the membrane with specific proteins that initiate transmigration of neutrophils through the blood vessel. Secretory vesicles, a subtype of neutrophilic granules, form in the late stages of neutrophil maturation and include proteins such as CR1, FCGR2A, MME, and FPR1. The modulation of the actin cytoskeleton and migration/degranulation of neutrophils is carried out by several methods and the pathway illustrates only some of the possible signaling cascades. Furthermore, integrins trigger intracellular signaling cascades that lead to ROS production through PI3K/RAC1-related signaling. Integrins also stimulate the synthesis of proinflammatory cytokines. The stage of neutrophil movement through the vascular basement membrane is facilitated by the release of MMP9 from tertiary granules. Tertiary granules contain metalloproteases required for the degradation of the extracellular matrix and transmigration of neutrophils. The binding of IL8 to CXCR2 causes the release of MMP9 from the tertiary granules. The degranulation of tertiary granules may be a result of the synthesis of arachidonic acid derivatives, which hypothetically can be stimulated by the activation of intracellular integrin-dependent signaling pathways. The mechanisms of the transmigration of neutrophils through the blood vessel wall are not well established. PS:Organ generic PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue endothelium PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0bc9109-d3a3-4e5f-94bf-b412f807fe6f NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-b0bc9109-d3a3-4e5f-94bf-b412f807fe6f Globoside-Type Glycosphingolipid Biosynthesis uuid-b0bc9109-d3a3-4e5f-94bf-b412f807fe6f PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0bc9109-d3a3-4e5f-94bf-b412f807fe6f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Dendritic cells (DCs) play a central role in systemic lupus erythematosus (SLE) development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0cfef12-c823-4602-810b-0a3cfc73b2b2 NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Dendritic cells (DCs) play a central role in systemic lupus erythematosus (SLE) development. Signaling description: Autoantibodies and apoptotic cell products activate the synthesis of type I interferon and cytokines in plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs). IFN alpha (IFNA1) activates mDCs, which express co-stimulatory molecules and trigger the differentiation of autoreactive CD4 and CD8 T cells, thereby maintaining chronic inflammation. Polymorphisms in DNASE1, PARP1, CAMP, and TREX1 genes, which can cause diminished activity of these enzymes, are associated with SLE. DNASE1, PARP1, CAMP, and TREX1 are important proteins for utilizing products of apoptosis. In addition, cellular debris such as fragments of DNA, RNA, or HMGB1 activates Toll-like receptor (TLR) signaling on the cell membrane and inside the cell. TLR signaling leads to the high level of expression of type I interferon and cytokines by a yet to be identified mechanism. A possible signaling route involves the MYD88 and TICAM1-related NF-kB, AP-1 (Jun/Fos), IRF5, and IRF7 activation. DCs have an active inflammasome for the secretion of IL1B, IL18, IL33 and IL1A which support chronic immunological reactions. The details of inflammasome activation are unclear with calcium-related inflammasome complex activation being a possible scenario. Additionally, mutated FCGR2A can cause alterations in endocytosis and the presentation of autoantigens, which then triggers T-cell differentiation. Outcome effects: The high level of type I interferon recursively activates mDCs. This occurs through the interaction between IFNA1 and IFNAR2 or IFNAR1. The exact mechanism of IFNAR1 signaling in SLE is poorly understood, however signal transduction through JAK1 and TYK2, which phosphorylate IFNAR1 leading to the recruitment and phosphorylation of the signal transducers and activators of transcription (STAT1 and STAT2) is likely. Polymorphisms in TYK2 are highly associated with SLE. STAT heterodimers associate with IRF9. This complex translocates to the nucleus to induce IFN-stimulated genes from IFN-stimulated response elements (ISREs). Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes with mutations linked to SLE are shown in white-out style. Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b0cfef12-c823-4602-810b-0a3cfc73b2b2 Dendritic Cell Activation in Systemic Lupus Erythematosis uuid-b0cfef12-c823-4602-810b-0a3cfc73b2b2 PS:CellType dendritic cell PS:Description Dendritic cells (DCs) play a central role in systemic lupus erythematosus (SLE) development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0cfef12-c823-4602-810b-0a3cfc73b2b2 PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Dendritic cells (DCs) play a central role in systemic lupus erythematosus (SLE) development. Signaling description: Autoantibodies and apoptotic cell products activate the synthesis of type I interferon and cytokines in plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs). IFN alpha (IFNA1) activates mDCs, which express co-stimulatory molecules and trigger the differentiation of autoreactive CD4 and CD8 T cells, thereby maintaining chronic inflammation. Polymorphisms in DNASE1, PARP1, CAMP, and TREX1 genes, which can cause diminished activity of these enzymes, are associated with SLE. DNASE1, PARP1, CAMP, and TREX1 are important proteins for utilizing products of apoptosis. In addition, cellular debris such as fragments of DNA, RNA, or HMGB1 activates Toll-like receptor (TLR) signaling on the cell membrane and inside the cell. TLR signaling leads to the high level of expression of type I interferon and cytokines by a yet to be identified mechanism. A possible signaling route involves the MYD88 and TICAM1-related NF-kB, AP-1 (Jun/Fos), IRF5, and IRF7 activation. DCs have an active inflammasome for the secretion of IL1B, IL18, IL33 and IL1A which support chronic immunological reactions. The details of inflammasome activation are unclear with calcium-related inflammasome complex activation being a possible scenario. Additionally, mutated FCGR2A can cause alterations in endocytosis and the presentation of autoantigens, which then triggers T-cell differentiation. Outcome effects: The high level of type I interferon recursively activates mDCs. This occurs through the interaction between IFNA1 and IFNAR2 or IFNAR1. The exact mechanism of IFNAR1 signaling in SLE is poorly understood, however signal transduction through JAK1 and TYK2, which phosphorylate IFNAR1 leading to the recruitment and phosphorylation of the signal transducers and activators of transcription (STAT1 and STAT2) is likely. Polymorphisms in TYK2 are highly associated with SLE. STAT heterodimers associate with IRF9. This complex translocates to the nucleus to induce IFN-stimulated genes from IFN-stimulated response elements (ISREs). Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes with mutations linked to SLE are shown in white-out style. PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Leydig cell CellType: adrenal cortex cell CellType: granulosa cell Description: Steroids are converted from cholesterol into other steroids in adrenal cortex and gonads. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0d03236-ba9a-4f33-af05-d0841bb41673 NodeType: Pathway Notes: Headnote: Steroidogenesis is the biological process in which steroids are generated from cholesterol and changed into other steroids. The major classes of steroid hormones are the progestogens, corticosteroids (corticoids), androgens, and estrogens. Progestogens are the precursors of all other human steroids, and all human tissues which produce steroids must first convert cholesterol to pregnenolone. This conversion is the rate-limiting step of steroid synthesis. Corticosteroids (glucocorticoids and mineralocorticoids) are produced in the adrenal cortex. Estrogen and progesterone are made primarily in the ovary and the placenta during pregnancy, and testosterone in the testes and to a much lesser degree in adrenal cortex. Testosterone is also converted to estrogen in both females and males. Signaling description: In the adrenal cortex, granulosa cell of the ovary and Leydig cells of the testis, ACTH acts on melanocortin 2 receptors (MC2R). Binding of ACTH to MC2R mediates ADCY/cAMP/PKA signaling which causes a rapid increase in cholesterol biosynthesis. Cholesterol is the precursor for mineralocorticoids (mainly aldosterone) and glucocorticoids (mainly cortisol). Cholesterol is transported from cellular stores to the outer mitochondrial membrane, where steroidogenic acute regulatory (STAR) protein facilitates the movement of cholesterol into the inner mitochondrial membrane. STAR mediated transport of cholesterol is the limiting step of the production of corticoids. In zona glomerulosa of adrenal cortex, CYP11A1 converts cholesterol to pregnenolone, and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is hydrolyzed to desoxycorticosterone by CYP21A2. CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. In zona fasciculate of adrenal cortex, CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, and HSD3B2 catalyzes 17-hydroxypregnenolone to 17-hydroxyprogesterone which is converted by CYP21A2 to 11-deoxycortisol. CYP11B1 hydroxylates 11-deoxycortisol to cortisol. In zona reticularis of adrenal cortex, CYP17A1 converts 17-hydroxypregnenolone to dehydroepiandrosterone, HSD3B2 catalyzes dehydroepiandrosterone to androstenedione and HSD17B3 converts androstenedione to testosterone. HSD3B2 and HSD17B3 also act in the testis. In granulosa cell of the ovary, CYP19A1 converts testosterone to estrogens. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Steroids are converted to other steroids from cholesterol in adrenal cortex and the gonads. Animal data: not shown Description of Highlighted proteins: not shown Description of Mutated genes: not shown References: 1) 16426683 2) 25460300 3) 24793988 4) 27252161 Organ: adrenal gland Organ: ovary Organ: testis Organ_System: endocrine system Organ_System: reproductive system PMID: 16426683 PMID: 24793988 PMID: 25460300 PMID: 27252161 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-b0d03236-ba9a-4f33-af05-d0841bb41673 Steroid Hormones Steroidogenesis uuid-b0d03236-ba9a-4f33-af05-d0841bb41673 PS:CellType Leydig cell PS:CellType adrenal cortex cell PS:CellType granulosa cell PS:Description Steroids are converted from cholesterol into other steroids in adrenal cortex and gonads. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0d03236-ba9a-4f33-af05-d0841bb41673 PS:NodeType Pathway PS:Notes Headnote: Steroidogenesis is the biological process in which steroids are generated from cholesterol and changed into other steroids. The major classes of steroid hormones are the progestogens, corticosteroids (corticoids), androgens, and estrogens. Progestogens are the precursors of all other human steroids, and all human tissues which produce steroids must first convert cholesterol to pregnenolone. This conversion is the rate-limiting step of steroid synthesis. Corticosteroids (glucocorticoids and mineralocorticoids) are produced in the adrenal cortex. Estrogen and progesterone are made primarily in the ovary and the placenta during pregnancy, and testosterone in the testes and to a much lesser degree in adrenal cortex. Testosterone is also converted to estrogen in both females and males. Signaling description: In the adrenal cortex, granulosa cell of the ovary and Leydig cells of the testis, ACTH acts on melanocortin 2 receptors (MC2R). Binding of ACTH to MC2R mediates ADCY/cAMP/PKA signaling which causes a rapid increase in cholesterol biosynthesis. Cholesterol is the precursor for mineralocorticoids (mainly aldosterone) and glucocorticoids (mainly cortisol). Cholesterol is transported from cellular stores to the outer mitochondrial membrane, where steroidogenic acute regulatory (STAR) protein facilitates the movement of cholesterol into the inner mitochondrial membrane. STAR mediated transport of cholesterol is the limiting step of the production of corticoids. In zona glomerulosa of adrenal cortex, CYP11A1 converts cholesterol to pregnenolone, and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is hydrolyzed to desoxycorticosterone by CYP21A2. CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. In zona fasciculate of adrenal cortex, CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, and HSD3B2 catalyzes 17-hydroxypregnenolone to 17-hydroxyprogesterone which is converted by CYP21A2 to 11-deoxycortisol. CYP11B1 hydroxylates 11-deoxycortisol to cortisol. In zona reticularis of adrenal cortex, CYP17A1 converts 17-hydroxypregnenolone to dehydroepiandrosterone, HSD3B2 catalyzes dehydroepiandrosterone to androstenedione and HSD17B3 converts androstenedione to testosterone. HSD3B2 and HSD17B3 also act in the testis. In granulosa cell of the ovary, CYP19A1 converts testosterone to estrogens. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Steroids are converted to other steroids from cholesterol in adrenal cortex and the gonads. Animal data: not shown Description of Highlighted proteins: not shown Description of Mutated genes: not shown References: 1) 16426683 2) 25460300 3) 24793988 4) 27252161 PS:Organ adrenal gland PS:Organ ovary PS:Organ testis PS:Organ_System endocrine system PS:Organ_System reproductive system PS:PMID 16426683 PS:PMID 24793988 PS:PMID 25460300 PS:PMID 27252161 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0fd62f2-29d3-4db4-b344-afaa6048c4d8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-b0fd62f2-29d3-4db4-b344-afaa6048c4d8 Sphingosine, Ceramide metabolism uuid-b0fd62f2-29d3-4db4-b344-afaa6048c4d8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b0fd62f2-29d3-4db4-b344-afaa6048c4d8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1053d4a-6590-4ef5-b0a9-5bb05c72ed1d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b1053d4a-6590-4ef5-b0a9-5bb05c72ed1d PDGFD -> STAT Expression Targets uuid-b1053d4a-6590-4ef5-b0a9-5bb05c72ed1d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1053d4a-6590-4ef5-b0a9-5bb05c72ed1d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1069744-253a-40ec-bb8d-8a913d6bce89 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-b1069744-253a-40ec-bb8d-8a913d6bce89 OSBP Depended MAPK1/3 Activation uuid-b1069744-253a-40ec-bb8d-8a913d6bce89 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1069744-253a-40ec-bb8d-8a913d6bce89 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b125154a-695e-4a20-856b-22d7bfe9932a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-b125154a-695e-4a20-856b-22d7bfe9932a ORF3b, ORF7b interactions uuid-b125154a-695e-4a20-856b-22d7bfe9932a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b125154a-695e-4a20-856b-22d7bfe9932a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Diabetic nephropathy (DN) is one of the most significant diabetic complications. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b12c3b91-667b-4e1a-93c0-2670c1ee7dcc NodeType: Pathway Notes: Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Chronic hyperglycemia induces dysfunction in various cell types in the kidney including endothelial cells. Endothelial dysfunction has been implicated as a major mechanism for renal chronic microvascular complications in diabetic patients. Signaling description: Glomerular endothelial cells are highly specialized cells with regions of attenuated cytoplasm punctuated by numerous circular transcellular pores called fenestrae. High glucose promotes TGFB1 transcription in the kidney and activates TGFBR2 which interacts with SMAD 2/3/4 to form a heterodimeric complex which translocates into the nucleus and regulates target genes such as endothelin (EDN1). In addition, activated TGFBR2 mediates mitogen-activated protein kinases (MAPKs). Outcome effects: The overproduction of EDN1 causes a reduction of glomerular filtration. Podocytes and proximal tubular epithelial cells are likely the major sources for VEGFA. Further, VEGFA activates vascular endothelial growth factor receptors which mediate MAPK and JAK (Janus kinase) cascades. These kinases participate in endothelial cell proliferation. Progressive endothelial cell proliferation results in decreased glomerular filtration rate and ultimately renal failure. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 19017763 PMID: 20224802 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b12c3b91-667b-4e1a-93c0-2670c1ee7dcc Endothelial Cell Dysfunction in Progressive Diabetic Nephropathy uuid-b12c3b91-667b-4e1a-93c0-2670c1ee7dcc PS:CellType endothelial cell PS:Description Diabetic nephropathy (DN) is one of the most significant diabetic complications. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b12c3b91-667b-4e1a-93c0-2670c1ee7dcc PS:NodeType Pathway PS:Notes Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Chronic hyperglycemia induces dysfunction in various cell types in the kidney including endothelial cells. Endothelial dysfunction has been implicated as a major mechanism for renal chronic microvascular complications in diabetic patients. Signaling description: Glomerular endothelial cells are highly specialized cells with regions of attenuated cytoplasm punctuated by numerous circular transcellular pores called fenestrae. High glucose promotes TGFB1 transcription in the kidney and activates TGFBR2 which interacts with SMAD 2/3/4 to form a heterodimeric complex which translocates into the nucleus and regulates target genes such as endothelin (EDN1). In addition, activated TGFBR2 mediates mitogen-activated protein kinases (MAPKs). Outcome effects: The overproduction of EDN1 causes a reduction of glomerular filtration. Podocytes and proximal tubular epithelial cells are likely the major sources for VEGFA. Further, VEGFA activates vascular endothelial growth factor receptors which mediate MAPK and JAK (Janus kinase) cascades. These kinases participate in endothelial cell proliferation. Progressive endothelial cell proliferation results in decreased glomerular filtration rate and ultimately renal failure. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 19017763 PS:PMID 20224802 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1359d52-a71e-4813-93ed-f08a3bf2ec7f NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-b1359d52-a71e-4813-93ed-f08a3bf2ec7f Mannose Metabolism uuid-b1359d52-a71e-4813-93ed-f08a3bf2ec7f PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1359d52-a71e-4813-93ed-f08a3bf2ec7f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b141df11-2bfd-42ff-a14c-04b244cd5aeb NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-b141df11-2bfd-42ff-a14c-04b244cd5aeb PTGER2/3 -> Vascular Motility uuid-b141df11-2bfd-42ff-a14c-04b244cd5aeb PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b141df11-2bfd-42ff-a14c-04b244cd5aeb PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b18db0a9-ad51-4da4-9e08-824e16bfaf32 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-b18db0a9-ad51-4da4-9e08-824e16bfaf32 GPCRs -> Expression Targets in Brain uuid-b18db0a9-ad51-4da4-9e08-824e16bfaf32 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b18db0a9-ad51-4da4-9e08-824e16bfaf32 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b194209f-ea5f-4c8b-9d75-2f4f57d23e57 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-b194209f-ea5f-4c8b-9d75-2f4f57d23e57 Proteins Involved in Glioblastoma uuid-b194209f-ea5f-4c8b-9d75-2f4f57d23e57 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b194209f-ea5f-4c8b-9d75-2f4f57d23e57 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b19709b8-a245-4f03-8054-d28aaed48d65 NodeType: Pathway Organ: generic Organ_System: generic PMID: 11929866 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-b19709b8-a245-4f03-8054-d28aaed48d65 MERTK Signaling uuid-b19709b8-a245-4f03-8054-d28aaed48d65 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b19709b8-a245-4f03-8054-d28aaed48d65 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 11929866 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1b94e8f-3f9c-48ff-b20e-e696e05168d7 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the smooth muscle mass within the airway wall is increased in asthma via hypertrophy and/or hyperplasia, with the intrinsic contractile properties of individual muscle cells being unchanged. ASM cells express both FceRII/CD23 and FceRI, and IgE can modulate the contractile and synthetic function of the human ASM cells. IgE was recently shown to induce ASM cell proliferation via MAPK, Akt, and STAT3 signaling pathways. Outcome effects: IgE stimulation of ASM induced the release of Th2 and proinflammatory mediators IL4, -5, -13, TNF, IL6, CCL11/eotaxin-1, and TSLP, and enhanced intracellular Ca2+ mobilization. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 24499258 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b1b94e8f-3f9c-48ff-b20e-e696e05168d7 IgE Induces Airway Smooth Muscle Cell Proliferation uuid-b1b94e8f-3f9c-48ff-b20e-e696e05168d7 PS:CellType vascular smooth muscle cell PS:Description In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1b94e8f-3f9c-48ff-b20e-e696e05168d7 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the smooth muscle mass within the airway wall is increased in asthma via hypertrophy and/or hyperplasia, with the intrinsic contractile properties of individual muscle cells being unchanged. ASM cells express both FceRII/CD23 and FceRI, and IgE can modulate the contractile and synthetic function of the human ASM cells. IgE was recently shown to induce ASM cell proliferation via MAPK, Akt, and STAT3 signaling pathways. Outcome effects: IgE stimulation of ASM induced the release of Th2 and proinflammatory mediators IL4, -5, -13, TNF, IL6, CCL11/eotaxin-1, and TSLP, and enhanced intracellular Ca2+ mobilization. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 24499258 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: In diabetes mellitus type 1, impaired peripheral tolerance to autoantigens can occur due to the disruption of signal transduction in regulatory T-lymphocytes (Treg). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1cb57cf-6c6c-427a-9290-d0e7d5952e21 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: In diabetes mellitus type 1, impaired peripheral tolerance to autoantigens including insulin, glutamate decarboxylase 2, and protein tyrosine phosphatase can occur due to the disruption of signal transduction in regulatory T-lymphocytes (Treg), which normally suppress autoaggressive T-cells during maturation. The process occurs in the thymus where MHC class II protein complex (MHCII) with autoantigens on the surface of dendritic cells binds to T-cell receptor (TCR) of Treg cells. In healthy individuals, the signaling triggers FOXP3 activation in Treg cells. FOXP3 is a transcription factor for immunosuppressive cytokines such as interleukin 10 (IL10) and transforming growth factor beta (TGFB). Outcome effects: The mechanism of FOXP3 in Treg cells is the following: the signal from TCR is transduced to ZAP70 and then to LAT. In turn, LAT activates PLCG1 and GRB2. PLCG1 participates in diacylglycerol and inositol trisphosphate (IP3) generation. IP3 then provokes calcium efflux from endoplasmic reticulum which results in NF-AT activation through calcineurin. Diacylglycerol activates NF-kB through PRKCQ, while LAT induces JUN/FOS through GRB2/SOS1/Ras/RAF1/MAPK and activates NF-AT. Further, NF-AT and NF-kB bind to the promoter region of FOXP3 and initiate its transcription. Treg cells require antigen presentation by MHCII molecules, presence of co-stimulatory molecules, stimulation of high-affinity interleukin 2 (IL2) receptor by exogenous IL2, and cell-to-cell contact for maturation. The stimulation of IL2 receptor activates JAK1 and JAK3 which phosphorylate STAT5A which is then STAT5A translocated into the nucleus where it upregulates the synthesis of intracellular FOXP3. Mutations in HLA-DQA1, HLA-DQB1, HLA-DRB3, HLA-DRB4, and FOXP3 have a strong association with diabetes mellitus type 1. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: generic Organ_System: endocrine system PMID: 17709886 PMID: 20016504 PMID: 22567309 PMID: 22737152 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: generic urn:agi-pathway:uuid-b1cb57cf-6c6c-427a-9290-d0e7d5952e21 Peripheral Tolerance to Autoantigens Recession in Diabetes Mellitus Type 1 uuid-b1cb57cf-6c6c-427a-9290-d0e7d5952e21 PS:CellType generic PS:Description In diabetes mellitus type 1, impaired peripheral tolerance to autoantigens can occur due to the disruption of signal transduction in regulatory T-lymphocytes (Treg). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1cb57cf-6c6c-427a-9290-d0e7d5952e21 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: In diabetes mellitus type 1, impaired peripheral tolerance to autoantigens including insulin, glutamate decarboxylase 2, and protein tyrosine phosphatase can occur due to the disruption of signal transduction in regulatory T-lymphocytes (Treg), which normally suppress autoaggressive T-cells during maturation. The process occurs in the thymus where MHC class II protein complex (MHCII) with autoantigens on the surface of dendritic cells binds to T-cell receptor (TCR) of Treg cells. In healthy individuals, the signaling triggers FOXP3 activation in Treg cells. FOXP3 is a transcription factor for immunosuppressive cytokines such as interleukin 10 (IL10) and transforming growth factor beta (TGFB). Outcome effects: The mechanism of FOXP3 in Treg cells is the following: the signal from TCR is transduced to ZAP70 and then to LAT. In turn, LAT activates PLCG1 and GRB2. PLCG1 participates in diacylglycerol and inositol trisphosphate (IP3) generation. IP3 then provokes calcium efflux from endoplasmic reticulum which results in NF-AT activation through calcineurin. Diacylglycerol activates NF-kB through PRKCQ, while LAT induces JUN/FOS through GRB2/SOS1/Ras/RAF1/MAPK and activates NF-AT. Further, NF-AT and NF-kB bind to the promoter region of FOXP3 and initiate its transcription. Treg cells require antigen presentation by MHCII molecules, presence of co-stimulatory molecules, stimulation of high-affinity interleukin 2 (IL2) receptor by exogenous IL2, and cell-to-cell contact for maturation. The stimulation of IL2 receptor activates JAK1 and JAK3 which phosphorylate STAT5A which is then STAT5A translocated into the nucleus where it upregulates the synthesis of intracellular FOXP3. Mutations in HLA-DQA1, HLA-DQB1, HLA-DRB3, HLA-DRB4, and FOXP3 have a strong association with diabetes mellitus type 1. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ generic PS:Organ_System endocrine system PS:PMID 17709886 PS:PMID 20016504 PS:PMID 22567309 PS:PMID 22737152 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1ec0882-c2f2-4e63-842b-445af83832e4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-b1ec0882-c2f2-4e63-842b-445af83832e4 OPRD/OPRM -> Ion Channels uuid-b1ec0882-c2f2-4e63-842b-445af83832e4 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b1ec0882-c2f2-4e63-842b-445af83832e4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2217ce2-def3-468c-bba6-4def3ba522be NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-b2217ce2-def3-468c-bba6-4def3ba522be Genes with Mutations Associated with Glomerulonephritis uuid-b2217ce2-def3-468c-bba6-4def3ba522be PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2217ce2-def3-468c-bba6-4def3ba522be PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b222f84a-2075-4723-a83a-1f364b44ff39 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b222f84a-2075-4723-a83a-1f364b44ff39 ureide degradation template uuid-b222f84a-2075-4723-a83a-1f364b44ff39 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b222f84a-2075-4723-a83a-1f364b44ff39 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b233769a-e625-4ae1-b849-00d4037e3e36 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b233769a-e625-4ae1-b849-00d4037e3e36 IL9 Expression Targets uuid-b233769a-e625-4ae1-b849-00d4037e3e36 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b233769a-e625-4ae1-b849-00d4037e3e36 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: hepatocyte Description: Uric acid is generated as a part of the normal turnover of nucleic acids or produced by de novo synthesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b24c386f-8ee6-411f-a151-7abe724462f9 NodeType: Pathway Notes: Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. The disruption of renal uric acid excretion is the prevalent cause of gout. Signaling description: Uric acid is generated as a part of normal turnover of nucleic acids or is produced de novo. The first step of de novo synthesis is phosphoribosyl-PP production via the addition of an additional phosphate group (from ATP) to modified sugar ribose-5-phosphate (ribose-5-P). This step is performed by the enzyme PRPS1. Subsequently, several reactions result in inosine monophosphate (IMP) formation which can then be transformed to guanosine monophosphate (GMP). Further, purines (IMP and GMP) are metabolized to nucleosides (inosine and guanosine) and then to nucleotides (hypoxanthine and guanine) by NT5C2 and PNP, respectively. Normally, purine bases derived from nucleic acids are re-used. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT1) salvages hypoxanthine to IMP and guanine to GMP. In a similar salvage pathway, adenosine phosphoribosyltransferase (APRT) converts adenine to adenosine monophosphate (AMP). Xanthene dehydrogenase (XDH) is the enzyme that catalyzes the terminal steps in urate production, specifically the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Outcome effects: Increased fructose uptake can cause elevated uric acid synthesis as a result of ATP degradation. Specifically, increased net ATP degradation leads to the accumulation of adenosine diphosphate (ADP) and AMP which can be rapidly degraded to uric acid. Also, HPRT1 deficiency and phosphoribosyl pyrophosphate synthetase 1 (PRPS1) superactivity can be the cause of secondary gout. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: liver Organ_System: digestive system PMID: 19808794 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-b24c386f-8ee6-411f-a151-7abe724462f9 Uric Acid Synthesis in Gout uuid-b24c386f-8ee6-411f-a151-7abe724462f9 PS:CellType hepatocyte PS:Description Uric acid is generated as a part of the normal turnover of nucleic acids or produced by de novo synthesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b24c386f-8ee6-411f-a151-7abe724462f9 PS:NodeType Pathway PS:Notes Headnote: Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) monohydrate crystals in the joint with clinical manifestations which include acute gouty arthritis, chronic gouty arthropathy, tophi and renal functional impairment. The disruption of renal uric acid excretion is the prevalent cause of gout. Signaling description: Uric acid is generated as a part of normal turnover of nucleic acids or is produced de novo. The first step of de novo synthesis is phosphoribosyl-PP production via the addition of an additional phosphate group (from ATP) to modified sugar ribose-5-phosphate (ribose-5-P). This step is performed by the enzyme PRPS1. Subsequently, several reactions result in inosine monophosphate (IMP) formation which can then be transformed to guanosine monophosphate (GMP). Further, purines (IMP and GMP) are metabolized to nucleosides (inosine and guanosine) and then to nucleotides (hypoxanthine and guanine) by NT5C2 and PNP, respectively. Normally, purine bases derived from nucleic acids are re-used. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT1) salvages hypoxanthine to IMP and guanine to GMP. In a similar salvage pathway, adenosine phosphoribosyltransferase (APRT) converts adenine to adenosine monophosphate (AMP). Xanthene dehydrogenase (XDH) is the enzyme that catalyzes the terminal steps in urate production, specifically the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Outcome effects: Increased fructose uptake can cause elevated uric acid synthesis as a result of ATP degradation. Specifically, increased net ATP degradation leads to the accumulation of adenosine diphosphate (ADP) and AMP which can be rapidly degraded to uric acid. Also, HPRT1 deficiency and phosphoribosyl pyrophosphate synthetase 1 (PRPS1) superactivity can be the cause of secondary gout. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 19808794 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b24dd906-d1dd-4299-8a7b-a8c0e511ea71 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b24dd906-d1dd-4299-8a7b-a8c0e511ea71 Polyol metabolism template uuid-b24dd906-d1dd-4299-8a7b-a8c0e511ea71 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b24dd906-d1dd-4299-8a7b-a8c0e511ea71 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2536875-475c-462a-abc2-c30b08c4b83e NodeType: Pathway Notes: Headnote: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. The apoptosis of chondrocytes, the only cells present in cartilage, occurs in OA and is induced by TNF which is synthesized during mechanical stress. Signaling description: TNF promotes cell death by two mechanisms including direct induction of apoptosis and indirect priming of cells for apoptosis by FASLG presentation. Direct induction includes the activation of caspase cascade. TNF, through TNFRSF1A, leads to the recruitment of TRADD-FADD complex and CASP8, which in turn cleaves BID and then, its active part is translocated into mitochondria where the protein triggers CYCS release through BAX activation. This process is sustained by inhibiting BCL2 with TRAF2/MAP3K5/MAPK8 and MAPK14. In addition, TNF triggers FASLG presentation through NF-kB involvement. Outcome effects: CYCS affects CASP9 and the latter activates CASP3 leading to apoptosis. Furthermore, FASLG presentation through NF-kB also primes chondrocyte for apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 12082286 PMID: 22172041 PMID: 22179031 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b2536875-475c-462a-abc2-c30b08c4b83e Apoptosis of Chondrocyte uuid-b2536875-475c-462a-abc2-c30b08c4b83e PS:CellType chondrocyte PS:Description Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2536875-475c-462a-abc2-c30b08c4b83e PS:NodeType Pathway PS:Notes Headnote: Osteoarthritis (OA) is a degenerative disease of the joints and is characterized by the degradation of the hyaline articular cartilage and remodeling of the subchondral bone. The apoptosis of chondrocytes, the only cells present in cartilage, occurs in OA and is induced by TNF which is synthesized during mechanical stress. Signaling description: TNF promotes cell death by two mechanisms including direct induction of apoptosis and indirect priming of cells for apoptosis by FASLG presentation. Direct induction includes the activation of caspase cascade. TNF, through TNFRSF1A, leads to the recruitment of TRADD-FADD complex and CASP8, which in turn cleaves BID and then, its active part is translocated into mitochondria where the protein triggers CYCS release through BAX activation. This process is sustained by inhibiting BCL2 with TRAF2/MAP3K5/MAPK8 and MAPK14. In addition, TNF triggers FASLG presentation through NF-kB involvement. Outcome effects: CYCS affects CASP9 and the latter activates CASP3 leading to apoptosis. Furthermore, FASLG presentation through NF-kB also primes chondrocyte for apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 12082286 PS:PMID 22172041 PS:PMID 22179031 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Direct DNA repair are single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b254a2c4-8a89-4ace-9610-d9e25b8e85d5 NodeType: Pathway Notes: Headnote: Direct DNA repair includes single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. Signaling description: In humans, the main type of direct DNA damage reversal systems repair alkylating damage by alkyltransferases and dioxygenases. Alkylation damage may be the result of environmental exposure of DNA to compounds like nitrosoguanidine or methyl mesylate, which cause a variety of O-alkylated and N-alkylated adducts. Biologically important lesions formed in double-stranded DNA (dsDNA) are 6-methoxyguanine, 3-methylcytosine, and 1-methyladenine. Although alkylated bases can be removed by multistep excision repair processes, several lesions are also subject to effective and highly specific direct repair mechanisms. Outcome effects: Dioxygenases ALKBH2 and ALKBH3 preferentially repair 1-methyladenine and 3-methylcytosine lesions by oxidative demethylation. ALKBH3 prefers single-stranded DNA (ssDNA) or RNA substrates while ALKBH2 preferentially acts on dsDNA. MGMT directly dealkylates mutagenic 6-methoxyguanine lesions within DNA. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-b254a2c4-8a89-4ace-9610-d9e25b8e85d5 Direct DNA Repair uuid-b254a2c4-8a89-4ace-9610-d9e25b8e85d5 PS:CellType generic PS:Description Direct DNA repair are single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b254a2c4-8a89-4ace-9610-d9e25b8e85d5 PS:NodeType Pathway PS:Notes Headnote: Direct DNA repair includes single-enzyme mechanisms that can repair lesions without the incision of DNA sugar-phosphate backbone or base excision. Signaling description: In humans, the main type of direct DNA damage reversal systems repair alkylating damage by alkyltransferases and dioxygenases. Alkylation damage may be the result of environmental exposure of DNA to compounds like nitrosoguanidine or methyl mesylate, which cause a variety of O-alkylated and N-alkylated adducts. Biologically important lesions formed in double-stranded DNA (dsDNA) are 6-methoxyguanine, 3-methylcytosine, and 1-methyladenine. Although alkylated bases can be removed by multistep excision repair processes, several lesions are also subject to effective and highly specific direct repair mechanisms. Outcome effects: Dioxygenases ALKBH2 and ALKBH3 preferentially repair 1-methyladenine and 3-methylcytosine lesions by oxidative demethylation. ALKBH3 prefers single-stranded DNA (ssDNA) or RNA substrates while ALKBH2 preferentially acts on dsDNA. MGMT directly dealkylates mutagenic 6-methoxyguanine lesions within DNA. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b261e950-f3c3-4968-8ece-97c26d003c27 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b261e950-f3c3-4968-8ece-97c26d003c27 Suberin biosynthesis template uuid-b261e950-f3c3-4968-8ece-97c26d003c27 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b261e950-f3c3-4968-8ece-97c26d003c27 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b26e32be-1dae-4b78-9d1e-3e7447c99847 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-b26e32be-1dae-4b78-9d1e-3e7447c99847 Proteins Involved in Glomerulonephritis uuid-b26e32be-1dae-4b78-9d1e-3e7447c99847 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b26e32be-1dae-4b78-9d1e-3e7447c99847 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: cancer sem cell CellType: pericyte CellType: vascular smooth muscle cell Description: PDGFB/PDGFRB and HBEGF/EGFR/ERBB2 signaling plays a major role in regulation of VSMCs/pericytes proliferation and migration Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27302c5-4afd-4402-a8f1-debd3492c941 NodeType: Pathway Notes: Headnote: Vascular smooth muscle cells (VSMCs) and pericytes belong to the same cell lineage and both cell types are responsible for the contraction of vessels. VSMCs are found in arteries, whereas pericytes are associated with small vessels (arterioles, capillaries, and venules). Endothelial cells and pericytes constantly communicate via reciprocal exchange of growth factors. VSMCs, pericytes and ECs are required for angiogenesis and vasculogenesis and tumor neovascularization. Signaling description: PDGFB/PDGFRB and HBEGF/EGFR/ERBB2 signaling are central in the regulation of VSMCs/pericyte proliferation and migration. They activate downstream signaling cascades, including PI3K-RAC1, PLCG, SRC pathways and others. IGF1, FGF2, SPP1 may also have an additional role in these processes. VEGFA negatively regulate VSMCs/pericyte proliferation and migration. Outcome effects: The activation of MAPK/JUN/FOS leads to VSMCs/pericyte proliferation. The activation of actin-myosin system is necessary for the induction of migration. Animal data: The majority of the data on VSMC and pericyte signaling have been obtained through the analysis of genetic mouse models. Organ: blood vessel Organ_System: cardiovascular system PMID: 12958167 PMID: 18997771 PMID: 21839917 PMID: 24657887 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-b27302c5-4afd-4402-a8f1-debd3492c941 Vascular Smooth Muscle Cell/Pericyte Migration and Proliferation uuid-b27302c5-4afd-4402-a8f1-debd3492c941 PS:CellType cancer cell PS:CellType cancer sem cell PS:CellType pericyte PS:CellType vascular smooth muscle cell PS:Description PDGFB/PDGFRB and HBEGF/EGFR/ERBB2 signaling plays a major role in regulation of VSMCs/pericytes proliferation and migration PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27302c5-4afd-4402-a8f1-debd3492c941 PS:NodeType Pathway PS:Notes Headnote: Vascular smooth muscle cells (VSMCs) and pericytes belong to the same cell lineage and both cell types are responsible for the contraction of vessels. VSMCs are found in arteries, whereas pericytes are associated with small vessels (arterioles, capillaries, and venules). Endothelial cells and pericytes constantly communicate via reciprocal exchange of growth factors. VSMCs, pericytes and ECs are required for angiogenesis and vasculogenesis and tumor neovascularization. Signaling description: PDGFB/PDGFRB and HBEGF/EGFR/ERBB2 signaling are central in the regulation of VSMCs/pericyte proliferation and migration. They activate downstream signaling cascades, including PI3K-RAC1, PLCG, SRC pathways and others. IGF1, FGF2, SPP1 may also have an additional role in these processes. VEGFA negatively regulate VSMCs/pericyte proliferation and migration. Outcome effects: The activation of MAPK/JUN/FOS leads to VSMCs/pericyte proliferation. The activation of actin-myosin system is necessary for the induction of migration. Animal data: The majority of the data on VSMC and pericyte signaling have been obtained through the analysis of genetic mouse models. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 12958167 PS:PMID 18997771 PS:PMID 21839917 PS:PMID 24657887 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Wolfram Syndrome induce s diabetes mellitus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27cc5e8-4730-4be4-8d59-c4f11a034dd4 NodeType: Pathway Notes: Headnote: Wolfram syndrome, also refered to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare genetic disorder which is characterized by a range of symptoms including diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome is also associated with an increased incidence of psychiatric disorders and a significantly shortened life span, averaging only 30 years. Wolfram syndrome is caused by mutations in the WFS1 and CISD2 genes. Signaling description: WFS1 is related to endoplasmic reticulum (ER) dysfunction in beta cells and the progression of type 2 diabetes. WFS1-deficient beta cells from individuals with Wolfram syndrome show increased levels of ER stress molecules and decreased insulin content. In Wolfram subject samples, XBP1, ATF4, nuclear ATF6 alpha, EIF2AK3, and HSPA5 were increased. Outcome effects: ER stress did not reduce insulin secretion by inducing cell death, but rather by affecting insulin secretion. In mice, mutated CISD2 causes ER stress and the unfolded protein response. In addition, loss of CISD2 causes a depletion of ER Ca2 stores, a dramatic increase in mitochondrial Ca2 load, increased reactive oxygen and nitrogen species, an increase in the glutathione disulfide/ glutathione and NAD /NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 21602428 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-b27cc5e8-4730-4be4-8d59-c4f11a034dd4 Wolfram Syndrome Progression (Hypothesis) uuid-b27cc5e8-4730-4be4-8d59-c4f11a034dd4 PS:CellType insulin-secreting cell PS:Description Wolfram Syndrome induce s diabetes mellitus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27cc5e8-4730-4be4-8d59-c4f11a034dd4 PS:NodeType Pathway PS:Notes Headnote: Wolfram syndrome, also refered to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare genetic disorder which is characterized by a range of symptoms including diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome is also associated with an increased incidence of psychiatric disorders and a significantly shortened life span, averaging only 30 years. Wolfram syndrome is caused by mutations in the WFS1 and CISD2 genes. Signaling description: WFS1 is related to endoplasmic reticulum (ER) dysfunction in beta cells and the progression of type 2 diabetes. WFS1-deficient beta cells from individuals with Wolfram syndrome show increased levels of ER stress molecules and decreased insulin content. In Wolfram subject samples, XBP1, ATF4, nuclear ATF6 alpha, EIF2AK3, and HSPA5 were increased. Outcome effects: ER stress did not reduce insulin secretion by inducing cell death, but rather by affecting insulin secretion. In mice, mutated CISD2 causes ER stress and the unfolded protein response. In addition, loss of CISD2 causes a depletion of ER Ca2 stores, a dramatic increase in mitochondrial Ca2 load, increased reactive oxygen and nitrogen species, an increase in the glutathione disulfide/ glutathione and NAD /NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 21602428 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27fe3a7-93d8-42f1-a403-36746b1cb352 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b27fe3a7-93d8-42f1-a403-36746b1cb352 Acrylonitrile degradation template uuid-b27fe3a7-93d8-42f1-a403-36746b1cb352 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b27fe3a7-93d8-42f1-a403-36746b1cb352 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b29c9af0-671a-42aa-9a92-dc1e34ab13fd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b29c9af0-671a-42aa-9a92-dc1e34ab13fd FGF10 -> STAT Expression Targets uuid-b29c9af0-671a-42aa-9a92-dc1e34ab13fd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b29c9af0-671a-42aa-9a92-dc1e34ab13fd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2ae1ca8-1399-42d6-ba05-2bab4a45b8eb NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b2ae1ca8-1399-42d6-ba05-2bab4a45b8eb AVP/Gq -> MEF/MYOD/NFATC/MYOG Expression Targets uuid-b2ae1ca8-1399-42d6-ba05-2bab4a45b8eb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2ae1ca8-1399-42d6-ba05-2bab4a45b8eb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2db1bac-49ca-4a5b-9cea-1b9cb55308d7 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-b2db1bac-49ca-4a5b-9cea-1b9cb55308d7 H2BK120 Ubiquitination uuid-b2db1bac-49ca-4a5b-9cea-1b9cb55308d7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2db1bac-49ca-4a5b-9cea-1b9cb55308d7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2f3a12b-48bf-41f9-bb56-525160973393 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b2f3a12b-48bf-41f9-bb56-525160973393 Sterol biosynthesis template uuid-b2f3a12b-48bf-41f9-bb56-525160973393 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2f3a12b-48bf-41f9-bb56-525160973393 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2f8f13c-f955-4932-87fc-5b87da6669ab NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b2f8f13c-f955-4932-87fc-5b87da6669ab Stilbenoid biosinthesis template uuid-b2f8f13c-f955-4932-87fc-5b87da6669ab PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2f8f13c-f955-4932-87fc-5b87da6669ab PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2fec12d-b503-4e59-bce5-2d6e44d5825a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-b2fec12d-b503-4e59-bce5-2d6e44d5825a EMT inhibition by SMAD6,7 uuid-b2fec12d-b503-4e59-bce5-2d6e44d5825a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b2fec12d-b503-4e59-bce5-2d6e44d5825a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b31b41b7-f18b-4605-bb42-73a677a80ea5 NodeType: Pathway Organ: testis Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b31b41b7-f18b-4605-bb42-73a677a80ea5 Proteins Involved in Azoospermia uuid-b31b41b7-f18b-4605-bb42-73a677a80ea5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b31b41b7-f18b-4605-bb42-73a677a80ea5 PS:NodeType Pathway PS:Organ testis PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b322b74b-22e8-440b-8e0c-71e50b5f9a9f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b322b74b-22e8-440b-8e0c-71e50b5f9a9f Juvenile hormone biosynthesis template uuid-b322b74b-22e8-440b-8e0c-71e50b5f9a9f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b322b74b-22e8-440b-8e0c-71e50b5f9a9f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b324081c-10fa-45ae-8dd5-e7e6e13f8ff5 NodeType: Pathway Notes: In early diabetes, progressive beta-cell dysfunction and apoptosis induced by the action of autoantibodies and of cytotoxic T-cell attack cause metabolic abnormalities including the disruption of insulin secretion and glucose metabolism. During the activation of the cell-mediated immune response, islet beta cells stop producing insulin and undergo apoptosis and pancreatic tissue becomes inflamed. Continued inflammation triggers further beta-cell dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b324081c-10fa-45ae-8dd5-e7e6e13f8ff5 3_Islet beta-cell destruction in T1D uuid-b324081c-10fa-45ae-8dd5-e7e6e13f8ff5 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b324081c-10fa-45ae-8dd5-e7e6e13f8ff5 PS:NodeType Pathway PS:Notes In early diabetes, progressive beta-cell dysfunction and apoptosis induced by the action of autoantibodies and of cytotoxic T-cell attack cause metabolic abnormalities including the disruption of insulin secretion and glucose metabolism. During the activation of the cell-mediated immune response, islet beta cells stop producing insulin and undergo apoptosis and pancreatic tissue becomes inflamed. Continued inflammation triggers further beta-cell dysfunction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3470290-ec6f-485c-a00b-d7c0a6b7e5d2 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: Retina Organ_System: sensory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-b3470290-ec6f-485c-a00b-d7c0a6b7e5d2 Elevated Receptors -> Expression Targets in Retina uuid-b3470290-ec6f-485c-a00b-d7c0a6b7e5d2 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3470290-ec6f-485c-a00b-d7c0a6b7e5d2 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ Retina PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: insulin-secreting cell Description: Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3499ed5-88c8-4b5a-9e31-d1cafa1faf82 NodeType: Pathway Notes: Headnote: Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas. PanNETs have increased in incidence in recent years. These tumors are usually asymptomatic and may be associated with metastasis. PanNETs may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Signaling description: Most frequently PanNETs are related to mutations in DAXX, ATRX, and MEN1 genes and the overexpression of IGF1R, ERBB2, and SRC. MEN1 is a component of a histone methyltransferase complex and also activates many transcription factors involved in cell proliferation, differentiation, and cell cycle. TGFBR2 binds to DAXX which activates MAP3K5 and JNK cascade (MAPK8, MAPK9, and MAPK10) resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. DAXX interacts with ATRX which binds to RAD51m which is involved in DNA repair, while ATRX participates in chromatin remodeling. Clinically, mutations in MEN1 and DAXX/ATRX genes are associated with a better prognosis. Ligand-bound ERBB2 and IGF1R activate PIK3CA through SRC and IRS1 proteins. Further, activated PIK3CA activates AKT1 via PIP3 and PDPK1, and then activated AKT1 phosphorylates and activates MTOR. In addition, growth factor receptors activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: Overall, these alterations cause the constitutive activation of AKT1 cascades and mitogen-activated protein kinases (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation and migration of epithelial pancreatic cells, block of chromatin remodeling, and DNA repair. Specifically, MTOR is a central regulator of cellular metabolism, growth and survival in response to hormones and growth factors. BRAF activates MAPK1/3 signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system Organ_System: endocrine system PMID: 21252315 PMID: 23135763 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-b3499ed5-88c8-4b5a-9e31-d1cafa1faf82 Pancreatic Neuroendocrine Tumors uuid-b3499ed5-88c8-4b5a-9e31-d1cafa1faf82 PS:CellType cancer cell PS:CellType insulin-secreting cell PS:Description Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3499ed5-88c8-4b5a-9e31-d1cafa1faf82 PS:NodeType Pathway PS:Notes Headnote: Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas. PanNETs have increased in incidence in recent years. These tumors are usually asymptomatic and may be associated with metastasis. PanNETs may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Signaling description: Most frequently PanNETs are related to mutations in DAXX, ATRX, and MEN1 genes and the overexpression of IGF1R, ERBB2, and SRC. MEN1 is a component of a histone methyltransferase complex and also activates many transcription factors involved in cell proliferation, differentiation, and cell cycle. TGFBR2 binds to DAXX which activates MAP3K5 and JNK cascade (MAPK8, MAPK9, and MAPK10) resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. DAXX interacts with ATRX which binds to RAD51m which is involved in DNA repair, while ATRX participates in chromatin remodeling. Clinically, mutations in MEN1 and DAXX/ATRX genes are associated with a better prognosis. Ligand-bound ERBB2 and IGF1R activate PIK3CA through SRC and IRS1 proteins. Further, activated PIK3CA activates AKT1 via PIP3 and PDPK1, and then activated AKT1 phosphorylates and activates MTOR. In addition, growth factor receptors activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: Overall, these alterations cause the constitutive activation of AKT1 cascades and mitogen-activated protein kinases (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation and migration of epithelial pancreatic cells, block of chromatin remodeling, and DNA repair. Specifically, MTOR is a central regulator of cellular metabolism, growth and survival in response to hormones and growth factors. BRAF activates MAPK1/3 signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:Organ_System endocrine system PS:PMID 21252315 PS:PMID 23135763 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: podocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b36b826d-0a16-4673-9055-0207b4b5f2b3 NodeType: Pathway Notes: Mesangial cells are located in the intercapillary space and regulate glomerular filtration rate. Overexpressed PDGFB, PDGFD, TGFB1, FGF2, and EGF can stimulate mesangial cells to become matrix-producing cells with the concomitant loss of their main function. Mesangial cell proliferation and their dysfunction resulting from glomerulonephritis contribute to extracellular matrix degradation and remodeling and ultimately to glomerular fibrosis. Mesangial expansion and the degree of fibrosis present correlate inversely with glomerular filtration rate. It is a critical step in the progression to end-stage renal disease. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: kidney Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epithelium urn:agi-pathway:uuid-b36b826d-0a16-4673-9055-0207b4b5f2b3 3_Mesangial cell dysfunction in glomerulonephritis uuid-b36b826d-0a16-4673-9055-0207b4b5f2b3 PS:CellType podocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b36b826d-0a16-4673-9055-0207b4b5f2b3 PS:NodeType Pathway PS:Notes Mesangial cells are located in the intercapillary space and regulate glomerular filtration rate. Overexpressed PDGFB, PDGFD, TGFB1, FGF2, and EGF can stimulate mesangial cells to become matrix-producing cells with the concomitant loss of their main function. Mesangial cell proliferation and their dysfunction resulting from glomerulonephritis contribute to extracellular matrix degradation and remodeling and ultimately to glomerular fibrosis. Mesangial expansion and the degree of fibrosis present correlate inversely with glomerular filtration rate. It is a critical step in the progression to end-stage renal disease. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage Description: The mannose receptor (MRC1) is a recognition receptor for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3787035-3efe-480c-88bb-0f9e85f415fb NodeType: Pathway Notes: Headnote: The mannose receptor (MRC1) is a recognition receptor for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. It is present on the surface of macrophages and dendritic cells. Signaling description: MRC1 recognizes and binds to carbohydrates on the surface of pathogens and its activation triggers endocytosis and phagocytosis of the microbe. MRC1 belongs to the multilectin receptor protein group and like TLRs provides a link between innate and adaptive immunity. Organ: generic Organ_System: generic PMID: 19162368 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-b3787035-3efe-480c-88bb-0f9e85f415fb Mannose Receptor Signaling uuid-b3787035-3efe-480c-88bb-0f9e85f415fb PS:CellType dendritic cell PS:CellType macrophage PS:Description The mannose receptor (MRC1) is a recognition receptor for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3787035-3efe-480c-88bb-0f9e85f415fb PS:NodeType Pathway PS:Notes Headnote: The mannose receptor (MRC1) is a recognition receptor for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. It is present on the surface of macrophages and dendritic cells. Signaling description: MRC1 recognizes and binds to carbohydrates on the surface of pathogens and its activation triggers endocytosis and phagocytosis of the microbe. MRC1 belongs to the multilectin receptor protein group and like TLRs provides a link between innate and adaptive immunity. PS:Organ generic PS:Organ_System generic PS:PMID 19162368 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: gonadotroph CellType: lactotroph Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b389f822-a680-4b27-ac57-795db5955db4 NodeType: Pathway Notes: Headnote: Hyperprolactinaemia refers to abnormally high levels of prolactin in the blood. Inhibition of prolactin (PRL) production and release through activation of DRD2 receptor signaling by dopamine is a well-known mechanism for the development of hyperprolactinaemia. Pharmacological inhibitors of DRD2 were shown to induce hyperprolactinemia. Signaling description: Several drugs may determine a significant increase in PRL serum concentration. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. The second- and third generation of antipsychotics have a weaker affinity for DRD2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. Other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ: pituitary gland Organ_System: endocrine system PMID: 18404390 PMID: 18473017 PMID: 20521318 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b389f822-a680-4b27-ac57-795db5955db4 DRD2 Pharmacological Inhibition in Hyperprolactinemia uuid-b389f822-a680-4b27-ac57-795db5955db4 PS:CellType gonadotroph PS:CellType lactotroph PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b389f822-a680-4b27-ac57-795db5955db4 PS:NodeType Pathway PS:Notes Headnote: Hyperprolactinaemia refers to abnormally high levels of prolactin in the blood. Inhibition of prolactin (PRL) production and release through activation of DRD2 receptor signaling by dopamine is a well-known mechanism for the development of hyperprolactinaemia. Pharmacological inhibitors of DRD2 were shown to induce hyperprolactinemia. Signaling description: Several drugs may determine a significant increase in PRL serum concentration. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. The second- and third generation of antipsychotics have a weaker affinity for DRD2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. Other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 18404390 PS:PMID 18473017 PS:PMID 20521318 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: plasma cell Description: NF-kB classical pathway activation in multiple myeloma (MM) cells results from the signaling by TNFSF13 and TNFSF13B ligands that stimulate TNFRSF13B and TNFRSF17 receptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3acd365-8b57-4619-a7d7-7efe710f3e33 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: NF-kB classical pathway activation in multiple myeloma (MM) cells results from signaling via TNFSF13 and TNFSF13B ligands that stimulate TNFRSF13B and TNFRSF17 receptors. Following stimulation by TRAF5, TRAF2, RIPK1, and MAP3K7, IKBK family proteins are activated and in turn phosphorylate the inhibitory subunit of NFKBIA leading to its proteasomal degradation. NFKBIA is a negative regulator of NF-kB1/RELA. Outcome effects: Following NFKBIA removal, the NF-kB1/RELA complex activates the transcription of several downstream target genes (cytokines, adhesion molecules, and cell cycle regulators) resulting in block of apoptosis, tumor cell proliferation, vascularization (angiogenesis), and neoplasm metastasis. The classical NF-kB pathway is negatively regulated by NFKBIA, TNIP1, and CYLD. Lastly, mutations in NF-kB1, TNFRSF13B, and CYLD genes were shown to be important in MM pathogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: skeletal system PMID: 20430962 PMID: 20890394 PMID: 22440007 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-b3acd365-8b57-4619-a7d7-7efe710f3e33 TNFR/NF-kB Classical Pathway in Multiple Myeloma Plasma Cells uuid-b3acd365-8b57-4619-a7d7-7efe710f3e33 PS:CellType cancer cell PS:CellType plasma cell PS:Description NF-kB classical pathway activation in multiple myeloma (MM) cells results from the signaling by TNFSF13 and TNFSF13B ligands that stimulate TNFRSF13B and TNFRSF17 receptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3acd365-8b57-4619-a7d7-7efe710f3e33 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: NF-kB classical pathway activation in multiple myeloma (MM) cells results from signaling via TNFSF13 and TNFSF13B ligands that stimulate TNFRSF13B and TNFRSF17 receptors. Following stimulation by TRAF5, TRAF2, RIPK1, and MAP3K7, IKBK family proteins are activated and in turn phosphorylate the inhibitory subunit of NFKBIA leading to its proteasomal degradation. NFKBIA is a negative regulator of NF-kB1/RELA. Outcome effects: Following NFKBIA removal, the NF-kB1/RELA complex activates the transcription of several downstream target genes (cytokines, adhesion molecules, and cell cycle regulators) resulting in block of apoptosis, tumor cell proliferation, vascularization (angiogenesis), and neoplasm metastasis. The classical NF-kB pathway is negatively regulated by NFKBIA, TNIP1, and CYLD. Lastly, mutations in NF-kB1, TNFRSF13B, and CYLD genes were shown to be important in MM pathogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System skeletal system PS:PMID 20430962 PS:PMID 20890394 PS:PMID 22440007 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3b4a8c9-d79e-4ba0-a8cf-f30980cbb83b NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the intrinsic contractile properties of asthmatic ASM are indeed different from normal. Contraction of smooth muscle, which causes airway narrowing, can be physiologically induced by the release of acetylcholine from efferent parasympathetic nerves or histamine and cysteinyl leukotrienes from mast cells and basophils. The major signaling pathway involved in ASM contraction is a Ca2+ related pathway. Interaction of contractile agonists with their G protein-coupled receptors (GPCR) leads to the activation of PLCb/ Ca2 /calmodulin/ MLCK pathway. Outcome effects: MLCK phosphorylates myosin light chain (MLC), leading to ASM contraction, which is terminated by MLC phosphatase (MLCP). In addition to IP3, Ca2+ release is also stimulated by agonist-induced activation of CD38. Ca2+ can flow across the plasma membrane through ion channels. MLCK expression was increased in all patients with asthma and COPD compared to controls in a subset of studies. The expression of the ATP2A2 isoform mRNA in human ASM was reduced in patients with moderately severe asthma. The reduction of ATP2A2 expression resulted in phenotypic shifting to an asthmatic ASM type with increased motility, secretion, and slow Ca2+ recovery. Overexpression of ORMDL3 was found to be associated with reduced ATP2A2 activity. NOX4 expression, an important source of ROS, was also increased in asthmatic ASM. ORMDL3 is an asthma candidate gene. SNPs in the region which contains the ORMDL3 gene on chromosome 17q21 were related to childhood asthma risk. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 16333374 PMID: 23577039 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b3b4a8c9-d79e-4ba0-a8cf-f30980cbb83b Airway Smooth Muscle Cell Contraction uuid-b3b4a8c9-d79e-4ba0-a8cf-f30980cbb83b PS:CellType vascular smooth muscle cell PS:Description In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b3b4a8c9-d79e-4ba0-a8cf-f30980cbb83b PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the intrinsic contractile properties of asthmatic ASM are indeed different from normal. Contraction of smooth muscle, which causes airway narrowing, can be physiologically induced by the release of acetylcholine from efferent parasympathetic nerves or histamine and cysteinyl leukotrienes from mast cells and basophils. The major signaling pathway involved in ASM contraction is a Ca2+ related pathway. Interaction of contractile agonists with their G protein-coupled receptors (GPCR) leads to the activation of PLCb/ Ca2 /calmodulin/ MLCK pathway. Outcome effects: MLCK phosphorylates myosin light chain (MLC), leading to ASM contraction, which is terminated by MLC phosphatase (MLCP). In addition to IP3, Ca2+ release is also stimulated by agonist-induced activation of CD38. Ca2+ can flow across the plasma membrane through ion channels. MLCK expression was increased in all patients with asthma and COPD compared to controls in a subset of studies. The expression of the ATP2A2 isoform mRNA in human ASM was reduced in patients with moderately severe asthma. The reduction of ATP2A2 expression resulted in phenotypic shifting to an asthmatic ASM type with increased motility, secretion, and slow Ca2+ recovery. Overexpression of ORMDL3 was found to be associated with reduced ATP2A2 activity. NOX4 expression, an important source of ROS, was also increased in asthmatic ASM. ORMDL3 is an asthma candidate gene. SNPs in the region which contains the ORMDL3 gene on chromosome 17q21 were related to childhood asthma risk. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16333374 PS:PMID 23577039 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b41139aa-e679-4deb-ac2c-2176f7765d4e NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-b41139aa-e679-4deb-ac2c-2176f7765d4e NCAM1 -> Expression Targets in Nerve Tissue uuid-b41139aa-e679-4deb-ac2c-2176f7765d4e PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b41139aa-e679-4deb-ac2c-2176f7765d4e PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: Purkinje cell CellType: astrocyte CellType: neuron Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4388f90-1882-45c9-add2-484f17e29d55 NodeType: Pathway Notes: Known mutations associated with FHM are the basis of glutamate and K+ accumulation in the synapse. Excess glutamate leads to the release of increased levels of K+ in the synaptic cleft. Excess K+ results in postsynaptic membrane depolarization, which plays an important role in the progression of cortical depression (spreading depolarization, cortical spreading depression, CSD). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: brain Organ_System: nervous system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b4388f90-1882-45c9-add2-484f17e29d55 2_Glutamate overload caused by mutations uuid-b4388f90-1882-45c9-add2-484f17e29d55 PS:CellType Purkinje cell PS:CellType astrocyte PS:CellType neuron PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4388f90-1882-45c9-add2-484f17e29d55 PS:NodeType Pathway PS:Notes Known mutations associated with FHM are the basis of glutamate and K+ accumulation in the synapse. Excess glutamate leads to the release of increased levels of K+ in the synaptic cleft. Excess K+ results in postsynaptic membrane depolarization, which plays an important role in the progression of cortical depression (spreading depolarization, cortical spreading depression, CSD). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ brain PS:Organ_System nervous system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Nitric oxide (NO) can become toxic to beta cells if present at high levels due to the formation of reactive oxygen species (ROS) and protein nitrosylation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b43d51d5-f9af-4c32-9c36-65429d7fc47e NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: Pro-inflammatory cytokines induce the overexpression of NOS2 in beta cells leading to the overproduction of NO, which decreases mitochondrial respiration, via aconitase inhibition, and prevents accumulation of ATP. In high quantities, NO can nitrosylate specific cysteine residues of various proteins (S-nitrosylation). In most cases S-nitrosylation leads to rapid degradation of the nitrosylated proteins. NO also decreases the expression levels of transcription factors responsible for beta cell differentiation and function including PDX1 and ISL1. Cytokines related to NO increase downregulate the ER Ca2 pump ATP2A2. Decreased ATP2A2 expression leads to ER Ca2 depletion and severe ER stress which results in beta cell apoptosis. Human islets have been shown to be less sensitive to NO-induced damage compared to rodent cells. The resistance of human islets towards NO is speculated to be caused by higher levels of HSPA1A in human beta cells compared to rodent. Outcome effects: Nitric oxide (NO) can become toxic to beta cells if present at high levels due to the formation of reactive oxygen species (ROS) and protein nitrosylation which causes mitochondrial damage, endoplasmic reticulum (ER) stress, and apoptosis. References: 1). Vincenz L, et al. (2011) Cytokine-Induced - Cell Stress and Death in Type 1 Diabetes Mellitus. In: Type 1 Diabetes - Complications, Pathogenesis, and Alternative Treatments, edited by Chih-Pin Liu, ISBN 978-953-307-756-7. InTech, 2011, 214-222. Organ: pancreas Organ_System: endocrine system PMID: 19470609 PMID: 24559923 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b43d51d5-f9af-4c32-9c36-65429d7fc47e Nitric Oxide Effects on beta-Cell uuid-b43d51d5-f9af-4c32-9c36-65429d7fc47e PS:CellType insulin-secreting cell PS:Description Nitric oxide (NO) can become toxic to beta cells if present at high levels due to the formation of reactive oxygen species (ROS) and protein nitrosylation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b43d51d5-f9af-4c32-9c36-65429d7fc47e PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Signaling description: Pro-inflammatory cytokines induce the overexpression of NOS2 in beta cells leading to the overproduction of NO, which decreases mitochondrial respiration, via aconitase inhibition, and prevents accumulation of ATP. In high quantities, NO can nitrosylate specific cysteine residues of various proteins (S-nitrosylation). In most cases S-nitrosylation leads to rapid degradation of the nitrosylated proteins. NO also decreases the expression levels of transcription factors responsible for beta cell differentiation and function including PDX1 and ISL1. Cytokines related to NO increase downregulate the ER Ca2 pump ATP2A2. Decreased ATP2A2 expression leads to ER Ca2 depletion and severe ER stress which results in beta cell apoptosis. Human islets have been shown to be less sensitive to NO-induced damage compared to rodent cells. The resistance of human islets towards NO is speculated to be caused by higher levels of HSPA1A in human beta cells compared to rodent. Outcome effects: Nitric oxide (NO) can become toxic to beta cells if present at high levels due to the formation of reactive oxygen species (ROS) and protein nitrosylation which causes mitochondrial damage, endoplasmic reticulum (ER) stress, and apoptosis. References: 1). Vincenz L, et al. (2011) Cytokine-Induced - Cell Stress and Death in Type 1 Diabetes Mellitus. In: Type 1 Diabetes - Complications, Pathogenesis, and Alternative Treatments, edited by Chih-Pin Liu, ISBN 978-953-307-756-7. InTech, 2011, 214-222. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 19470609 PS:PMID 24559923 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4566a2d-1b41-4131-8d4d-513d18792a4e NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b4566a2d-1b41-4131-8d4d-513d18792a4e ANGPT2 -> STAT Expression Targets uuid-b4566a2d-1b41-4131-8d4d-513d18792a4e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4566a2d-1b41-4131-8d4d-513d18792a4e PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b47a27b1-0cc3-4c3f-b6f3-e324122d40b7 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b47a27b1-0cc3-4c3f-b6f3-e324122d40b7 Proteins with Altered Expression in Glaucoma uuid-b47a27b1-0cc3-4c3f-b6f3-e324122d40b7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b47a27b1-0cc3-4c3f-b6f3-e324122d40b7 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b47ff6db-eb6c-4292-b7fa-10e562d40544 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b47ff6db-eb6c-4292-b7fa-10e562d40544 Inositol phosphate metabolism template uuid-b47ff6db-eb6c-4292-b7fa-10e562d40544 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b47ff6db-eb6c-4292-b7fa-10e562d40544 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b48bb80d-a2ec-4ee9-ab08-a3e19cbcdf1a NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-b48bb80d-a2ec-4ee9-ab08-a3e19cbcdf1a Proteins with Altered Expression in Amyotrophic Lateral Sclerosis uuid-b48bb80d-a2ec-4ee9-ab08-a3e19cbcdf1a PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b48bb80d-a2ec-4ee9-ab08-a3e19cbcdf1a PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Link PS:NodeType PS:Organ_System PS:PMID PS:Pathway_Author PS:Source CellType: dendritic cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4b866b9-e117-4bad-9b68-6229f5c34b10 NodeType: Pathway Organ_System: hematological system PMID: 17643932 PMID: 19703986 PMID: 20652065 PMID: 21060334 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Cell Process urn:agi-pathway:uuid-b4b866b9-e117-4bad-9b68-6229f5c34b10 AGER-TLR Signaling in Viral Stress Response uuid-b4b866b9-e117-4bad-9b68-6229f5c34b10 PS:CellType dendritic cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4b866b9-e117-4bad-9b68-6229f5c34b10 PS:NodeType Pathway PS:Organ_System hematological system PS:PMID 17643932 PS:PMID 19703986 PS:PMID 20652065 PS:PMID 21060334 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Cell Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4db2084-5754-4df7-abc6-e0658bf70890 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-b4db2084-5754-4df7-abc6-e0658bf70890 NGFR -> NF-kB Signaling uuid-b4db2084-5754-4df7-abc6-e0658bf70890 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4db2084-5754-4df7-abc6-e0658bf70890 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: astrocyte CellType: neuron Description: Glutamate is the main excitatory neurotransmitter in the CNS. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4fb8674-62b1-4715-a38c-4d5ec36ce4a0 NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Glutamate is the main excitatory neurotransmitter in the CNS. Under normal physiological conditions, glutamate is released from presynaptic terminals via Ca2+- dependent exocytosis and activates receptors expressed on postsynaptic motor neurons including AMPA receptor, N-methyl-D-aspartate (NMDA) selective glutamate receptor, and voltage-gated Ca2 channels. This leads to Ca2+ influx into the cell. Typically, the GluR2 (GRIA2) subunit regulates and restricts Ca2+ permeability in AMPA receptors. Since this subunit is deficient in motor neurons, the motor neuronal AMPA receptor is unusually Ca2+ permeable and therefore vulnerable to excessive glutamate stimulation. The action of glutamate in the cleft is terminated by its rapid reuptake via glutamate transporter proteins. SLC1A3 and SLC1A2 are expressed on glial cells, with astrocytes and SLC1A2 being primarily responsible for the most part of glutamate reuptake. SLC1A1 is located mainly on the presynaptic motor neurons. Glutamate excitotoxicity is a neuronal injury, which results from excessive glutamate-induced stimulation of postsynaptic glutamate receptors. It is largely caused by the impairment of glutamate reuptake. In most cases (~65/%) of sporadic ALS, there is a profound reduction in the expression and activity of SLC1A2 both in the cortex and spinal cord. One suggestion is that the loss of SLC1A2 arises from splicing errors in SLC1A2 mRNA. CASP3 is overexpressed in ALS astrocytes and cleaves SLC1A2. In addition, HNRNPK is required for SLC1A2 transcriptional activation and its reduced expression is found in ALS. Increased reactive oxygen species (ROS) in ALS inhibit the function of SLC1A2 and SLC1A3. A high level of lipid peroxidation product 4-hydroxynonenal has been found in the spinal cords of ALS patients and this has been linked to the inhibition of SLC1A2. Furthermore, D-amino acid oxidase (DAO) is responsible for the oxidative deamination of D-serine, an activator and co-agonist of NMDA receptor. Mutations in DAO may potentially contribute to excitotoxic motor neuron injury. Outcome effects: Excitotoxicity leads to increased intracellular Ca2+, which in turn leads to increased nitric oxide (NO) formation. Peroxynitrite, which is generated by the reaction of superoxide radical and NO, can subsequently lead to oxidative damage. Ca2+-dependent Ca2+ release from endoplasmic reticulum by RYR3 may accelerate intracellular Ca2+ overload. Normally, mitochondrial Ca2+ uptake responds dynamically and sensitively to changes in cytosolic Ca2+ levels and plays a crucial role in sequestering the large Ca2+ loads. The excessive influx of Ca2+ into mitochondria may result in mitochondrial dysfunction. In ALS, mitochondria may be a critical intracellular target of injury after intense Ca2+ channel stimulation and may trigger apoptosis. Mutated genes: Mutated genes are shown in white-out style. References: 1). Le Verche V, et al.(2011) Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise? Journal of Receptor, Ligand and Channel Research.4:1-22. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 19413484 PMID: 22051914 PMID: 22482452 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-b4fb8674-62b1-4715-a38c-4d5ec36ce4a0 Glutamate Mediated Excitotoxicity in Amyotrophic Lateral Sclerosis uuid-b4fb8674-62b1-4715-a38c-4d5ec36ce4a0 PS:CellType astrocyte PS:CellType neuron PS:Description Glutamate is the main excitatory neurotransmitter in the CNS. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b4fb8674-62b1-4715-a38c-4d5ec36ce4a0 PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Glutamate is the main excitatory neurotransmitter in the CNS. Under normal physiological conditions, glutamate is released from presynaptic terminals via Ca2+- dependent exocytosis and activates receptors expressed on postsynaptic motor neurons including AMPA receptor, N-methyl-D-aspartate (NMDA) selective glutamate receptor, and voltage-gated Ca2 channels. This leads to Ca2+ influx into the cell. Typically, the GluR2 (GRIA2) subunit regulates and restricts Ca2+ permeability in AMPA receptors. Since this subunit is deficient in motor neurons, the motor neuronal AMPA receptor is unusually Ca2+ permeable and therefore vulnerable to excessive glutamate stimulation. The action of glutamate in the cleft is terminated by its rapid reuptake via glutamate transporter proteins. SLC1A3 and SLC1A2 are expressed on glial cells, with astrocytes and SLC1A2 being primarily responsible for the most part of glutamate reuptake. SLC1A1 is located mainly on the presynaptic motor neurons. Glutamate excitotoxicity is a neuronal injury, which results from excessive glutamate-induced stimulation of postsynaptic glutamate receptors. It is largely caused by the impairment of glutamate reuptake. In most cases (~65/%) of sporadic ALS, there is a profound reduction in the expression and activity of SLC1A2 both in the cortex and spinal cord. One suggestion is that the loss of SLC1A2 arises from splicing errors in SLC1A2 mRNA. CASP3 is overexpressed in ALS astrocytes and cleaves SLC1A2. In addition, HNRNPK is required for SLC1A2 transcriptional activation and its reduced expression is found in ALS. Increased reactive oxygen species (ROS) in ALS inhibit the function of SLC1A2 and SLC1A3. A high level of lipid peroxidation product 4-hydroxynonenal has been found in the spinal cords of ALS patients and this has been linked to the inhibition of SLC1A2. Furthermore, D-amino acid oxidase (DAO) is responsible for the oxidative deamination of D-serine, an activator and co-agonist of NMDA receptor. Mutations in DAO may potentially contribute to excitotoxic motor neuron injury. Outcome effects: Excitotoxicity leads to increased intracellular Ca2+, which in turn leads to increased nitric oxide (NO) formation. Peroxynitrite, which is generated by the reaction of superoxide radical and NO, can subsequently lead to oxidative damage. Ca2+-dependent Ca2+ release from endoplasmic reticulum by RYR3 may accelerate intracellular Ca2+ overload. Normally, mitochondrial Ca2+ uptake responds dynamically and sensitively to changes in cytosolic Ca2+ levels and plays a crucial role in sequestering the large Ca2+ loads. The excessive influx of Ca2+ into mitochondria may result in mitochondrial dysfunction. In ALS, mitochondria may be a critical intracellular target of injury after intense Ca2+ channel stimulation and may trigger apoptosis. Mutated genes: Mutated genes are shown in white-out style. References: 1). Le Verche V, et al.(2011) Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise? Journal of Receptor, Ligand and Channel Research.4:1-22. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 19413484 PS:PMID 22051914 PS:PMID 22482452 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte CellType: fibroblast Description: Angiotensin II plays a key role in cardiac remodeling and functions as a growth factor influencing cell proliferation and growth, cell differentiation, and tissue fibrosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b511e7f5-9f6b-4c70-981d-f8d1c42479b6 NodeType: Pathway Notes: Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: Angiotensin II (AGT) plays a key role in cardiac remodeling and functions as a growth factor influencing cell proliferation and growth, cell differentiation, and tissue fibrosis. AGT acts through the AGTR1 receptor. The primary transduction pathway of AGTR1 is the coupling to the G-protein GNA11 and GNAQ with activation of phospholipase C (PLCB1) cascade resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum and activation of PRKCD/PRKCE. AGTR1 also activates MAPK3/MAPK1 pathway directly through PKC, through the transactivation of EGFR, or through the ARRB1/ARRB2 with MAP kinases. Outcome effects: The signaling pathways induce a variety of proteins and activate transcriptional regulators involved in cardiomyocyte proliferation, growth, and differentiation. AGTR1 also signals directly through AKT1, and activated AKT1 promotes MTOR and matrix metalloproteinases (MMPs) involved in vasculature remodeling, tissue repair, fibrosis, and extracellular matrix degradation. Highlighted proteins: Mutated gene is shown in white-out style. Organ: heart Organ_System: cardiovascular system PMID: 20590619 PMID: 21829898 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-b511e7f5-9f6b-4c70-981d-f8d1c42479b6 Myocardial Remodeling uuid-b511e7f5-9f6b-4c70-981d-f8d1c42479b6 PS:CellType cardiac myocyte PS:CellType fibroblast PS:Description Angiotensin II plays a key role in cardiac remodeling and functions as a growth factor influencing cell proliferation and growth, cell differentiation, and tissue fibrosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b511e7f5-9f6b-4c70-981d-f8d1c42479b6 PS:NodeType Pathway PS:Notes Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: Angiotensin II (AGT) plays a key role in cardiac remodeling and functions as a growth factor influencing cell proliferation and growth, cell differentiation, and tissue fibrosis. AGT acts through the AGTR1 receptor. The primary transduction pathway of AGTR1 is the coupling to the G-protein GNA11 and GNAQ with activation of phospholipase C (PLCB1) cascade resulting in the release of Ca2+ into the cytoplasm from the endoplasmic reticulum and activation of PRKCD/PRKCE. AGTR1 also activates MAPK3/MAPK1 pathway directly through PKC, through the transactivation of EGFR, or through the ARRB1/ARRB2 with MAP kinases. Outcome effects: The signaling pathways induce a variety of proteins and activate transcriptional regulators involved in cardiomyocyte proliferation, growth, and differentiation. AGTR1 also signals directly through AKT1, and activated AKT1 promotes MTOR and matrix metalloproteinases (MMPs) involved in vasculature remodeling, tissue repair, fibrosis, and extracellular matrix degradation. Highlighted proteins: Mutated gene is shown in white-out style. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 20590619 PS:PMID 21829898 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5153b72-4552-4335-9611-b55efb3cc272 NodeType: Pathway Organ_System: hematological system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-b5153b72-4552-4335-9611-b55efb3cc272 Proteins Involved in HPV Infection uuid-b5153b72-4552-4335-9611-b55efb3cc272 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5153b72-4552-4335-9611-b55efb3cc272 PS:NodeType Pathway PS:Organ_System hematological system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Apoptosis is constantly downregulated in melanoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b515ede1-c1f2-4add-98aa-078439c50b56 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Signaling description: Apoptosis is constantly downregulated in melanoma. BCL2, MCL1, BCL2L1, BCL2L11, and BIRC7 are overexpressed, while the expression of BAX and APAF1 is downregulated. This activation/inhibition results from constant KIT/PI3K and RAS/MAPK activation due to KIT, BRAF, NRAS, and PTEN mutations. TP53 and MDM2 are found to be mutated in 10-15% of melanoma cases. MITF regulates the transcription of BCL2, BIRC7, and HIF1A and may have an antiapoptotic effect. Outcome effects: The molecular mechanisms underlying the block of apoptosis in melanoma include down-regulation of apoptotic factors and activation of anti-apoptotic factors e.g. MCL1, BIRC7, as well as TP53, MDM2 and others. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes mutated in melanoma are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 18927540 PMID: 19571822 PMID: 22046555 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b515ede1-c1f2-4add-98aa-078439c50b56 Apoptosis Block in Melanoma Cell uuid-b515ede1-c1f2-4add-98aa-078439c50b56 PS:CellType cancer cell PS:CellType melanocyte PS:Description Apoptosis is constantly downregulated in melanoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b515ede1-c1f2-4add-98aa-078439c50b56 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Signaling description: Apoptosis is constantly downregulated in melanoma. BCL2, MCL1, BCL2L1, BCL2L11, and BIRC7 are overexpressed, while the expression of BAX and APAF1 is downregulated. This activation/inhibition results from constant KIT/PI3K and RAS/MAPK activation due to KIT, BRAF, NRAS, and PTEN mutations. TP53 and MDM2 are found to be mutated in 10-15% of melanoma cases. MITF regulates the transcription of BCL2, BIRC7, and HIF1A and may have an antiapoptotic effect. Outcome effects: The molecular mechanisms underlying the block of apoptosis in melanoma include down-regulation of apoptotic factors and activation of anti-apoptotic factors e.g. MCL1, BIRC7, as well as TP53, MDM2 and others. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Genes mutated in melanoma are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18927540 PS:PMID 19571822 PS:PMID 22046555 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5397b1f-2fe6-4747-9212-013fda9d5ecf NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-b5397b1f-2fe6-4747-9212-013fda9d5ecf CD22 -> NF-kB Expression Targets uuid-b5397b1f-2fe6-4747-9212-013fda9d5ecf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5397b1f-2fe6-4747-9212-013fda9d5ecf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5485fa9-86e6-4207-8745-70415e9262e9 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-b5485fa9-86e6-4207-8745-70415e9262e9 Proteins Involved in Raynaud Disease uuid-b5485fa9-86e6-4207-8745-70415e9262e9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5485fa9-86e6-4207-8745-70415e9262e9 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b555de47-81d3-44c6-aa7e-86b40fb19d07 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b555de47-81d3-44c6-aa7e-86b40fb19d07 Lipid A biosynthesis in cold template uuid-b555de47-81d3-44c6-aa7e-86b40fb19d07 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b555de47-81d3-44c6-aa7e-86b40fb19d07 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b586beb2-7dcd-4a9d-b842-29887bd4ddb9 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-b586beb2-7dcd-4a9d-b842-29887bd4ddb9 CHRM1/2/3/5 -> Ion Channels uuid-b586beb2-7dcd-4a9d-b842-29887bd4ddb9 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b586beb2-7dcd-4a9d-b842-29887bd4ddb9 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5895533-112f-4a83-b3e4-036510e32c80 NodeType: Pathway Organ: breast Organ_System: integumentary system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-b5895533-112f-4a83-b3e4-036510e32c80 Proteins Involved in Breast Cancer Related to ERBB2/VEGFR/Akt Signaling Pathway uuid-b5895533-112f-4a83-b3e4-036510e32c80 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5895533-112f-4a83-b3e4-036510e32c80 PS:NodeType Pathway PS:Organ breast PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b598d098-619d-4861-96d2-21c4a43731c6 NodeType: Pathway Organ: prostate Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b598d098-619d-4861-96d2-21c4a43731c6 Proteins Involved in Prostate Cancer uuid-b598d098-619d-4861-96d2-21c4a43731c6 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b598d098-619d-4861-96d2-21c4a43731c6 PS:NodeType Pathway PS:Organ prostate PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: TERT interplay with WNT signaling facilitate cancer progression by inducing epithelial-mesenchymal transition and stem cell phenotype. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5c06c77-f739-426b-8f6a-675ab5cc7078 NodeType: Pathway Notes: Headnote: The interaction of TERT with WNT signaling facilitates cancer progression by promoting the epithelial-mesenchymal transition and inducing the stem cell phenotype. Signaling description: In the canonical WNT signaling, WNT binds FZD and LRP5/6, which activates DVL. In turn, DVL inhibits the GSK3B, AXIN1 and APC containing complex, allowing CTNNB1 to be able to enter the nucleus and activate WNT target genes. A direct interplay between TERT and WNT pathway was shown recently with a positive feedback loop between TERT and CTNNB1. TERT forms a complex with the WNT-pathway transcription factor SMARCA4 and enhances the transcription of WNT target genes. CTNNB1 could directly bind the promoter of TERT and upregulate it. Moreover, MYC and KLF4, which are WNT/CTNNB1 target genes, regulate the transcription of TERT. Outcome effects: At the end, the interplay between TERT- CTNNB1 facilitates cancer progression by promoting the epithelial-mesenchymal transition and inducing the stem cell phenotype. Animal data: Some of the data were obtained from experiments on animals. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Organ: oncogenic Organ_System: oncogenic PMID: 23932019 PMID: 23993966 PMID: 24599132 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-b5c06c77-f739-426b-8f6a-675ab5cc7078 TERT/WNT Activation in Cancer uuid-b5c06c77-f739-426b-8f6a-675ab5cc7078 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description TERT interplay with WNT signaling facilitate cancer progression by inducing epithelial-mesenchymal transition and stem cell phenotype. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5c06c77-f739-426b-8f6a-675ab5cc7078 PS:NodeType Pathway PS:Notes Headnote: The interaction of TERT with WNT signaling facilitates cancer progression by promoting the epithelial-mesenchymal transition and inducing the stem cell phenotype. Signaling description: In the canonical WNT signaling, WNT binds FZD and LRP5/6, which activates DVL. In turn, DVL inhibits the GSK3B, AXIN1 and APC containing complex, allowing CTNNB1 to be able to enter the nucleus and activate WNT target genes. A direct interplay between TERT and WNT pathway was shown recently with a positive feedback loop between TERT and CTNNB1. TERT forms a complex with the WNT-pathway transcription factor SMARCA4 and enhances the transcription of WNT target genes. CTNNB1 could directly bind the promoter of TERT and upregulate it. Moreover, MYC and KLF4, which are WNT/CTNNB1 target genes, regulate the transcription of TERT. Outcome effects: At the end, the interplay between TERT- CTNNB1 facilitates cancer progression by promoting the epithelial-mesenchymal transition and inducing the stem cell phenotype. Animal data: Some of the data were obtained from experiments on animals. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 23932019 PS:PMID 23993966 PS:PMID 24599132 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5c1c0f8-03a5-44bd-a487-0c31bd0440cd NodeType: Pathway Notes: In the acute stage of HIV infection, the rapid replication of HIV in its target cells leads to the irreversible depletion of short-lived mucosal CD4+ memory T cells that have a half-life of less than a day. Then the virus reproduces in the next population of cells with a half-life of 1–4 weeks. The acute stage of HIV infection lasts no more than several weeks before the peak of viremia declines. Infected cells die by apoptosis induced through a combination of stress imposed by viral replication and immune system activation. HIVs are also able to delay apoptosis and the elimination of infected cells by CD8+ T cells to prolong the release of viral particles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b5c1c0f8-03a5-44bd-a487-0c31bd0440cd 2_HIV - induced depletion of CD4+ T-cells uuid-b5c1c0f8-03a5-44bd-a487-0c31bd0440cd PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5c1c0f8-03a5-44bd-a487-0c31bd0440cd PS:NodeType Pathway PS:Notes In the acute stage of HIV infection, the rapid replication of HIV in its target cells leads to the irreversible depletion of short-lived mucosal CD4+ memory T cells that have a half-life of less than a day. Then the virus reproduces in the next population of cells with a half-life of 1–4 weeks. The acute stage of HIV infection lasts no more than several weeks before the peak of viremia declines. Infected cells die by apoptosis induced through a combination of stress imposed by viral replication and immune system activation. HIVs are also able to delay apoptosis and the elimination of infected cells by CD8+ T cells to prolong the release of viral particles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/FBXO7 complex regulates mitotic spindle assembly and apoptosis. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5d38fbe-0945-4546-af77-4cd452c03caa NodeType: Pathway Notes: Headnote: the SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction.The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXO7 complex, FBXO7 (PKPS) acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of canonical SCF/FBXO7-ligase related signaling leads to regulation of mitotic spindle assembly and apoptosis. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SCF/FBXO7 targets and degrades the DLGAP5, a protein that involved in mitotic spindle assembly. Degradation of TRAF2 and BIRC2 leads to the inhibition of NFKB1 anti-apoptotic activity. Animal data: Role of SCF/FBXO7 in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 22212761 PMID: 24107298 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-b5d38fbe-0945-4546-af77-4cd452c03caa SCF/FBXO7 Complex uuid-b5d38fbe-0945-4546-af77-4cd452c03caa PS:CellType generic PS:Description SCF/FBXO7 complex regulates mitotic spindle assembly and apoptosis. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5d38fbe-0945-4546-af77-4cd452c03caa PS:NodeType Pathway PS:Notes Headnote: the SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction.The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXO7 complex, FBXO7 (PKPS) acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of canonical SCF/FBXO7-ligase related signaling leads to regulation of mitotic spindle assembly and apoptosis. The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SCF/FBXO7 targets and degrades the DLGAP5, a protein that involved in mitotic spindle assembly. Degradation of TRAF2 and BIRC2 leads to the inhibition of NFKB1 anti-apoptotic activity. Animal data: Role of SCF/FBXO7 in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22212761 PS:PMID 24107298 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: podocyte Description: Diabetic nephropathy (DN) is the most common cause of diabetic complications. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5f9de46-ffde-42cb-87c1-1d81fc71f190 NodeType: Pathway Notes: Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Podocyte injury contributes to basement membrane thickening and albuminuria as observed in early stages of DN as well as glomerular sclerosis and proteinuria in progressive stages of DN. Signaling description: Podocytes are specialized cells in the Bowman's capsule in the kidney which surround the capillaries of the glomeruli. Podocytes play a key role in glomerular structural integrity and glomerular filtration barrier. Podocytes express angiotensin II receptors (AGTR1). Over-activation of AGTR1 leads to the activation of HIF1A which inhibits the NPHS1 gene expression which codes for nephrin. Nephrin functions in the glomerular filtration barrier in the kidney and forms the slit diaphragm of glomerular podocytes. The loss of the slit diaphragm and failure of the podocyte structure leads to proteinuria. Glucose induces the formation of diacylglycerol that activates PRKCB. Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER, via PI3K and PRKCB, activate AKT1 which is involved in the inhibition of nephrin expression due to IKBK pathway. High glucose levels promote the transcription of TNF in the kidney. Activated TNFRSF1A up-regulates mitogen-activated protein kinases (MAPKs). Outcome effects: MAPKs are involved in the activation of caspases, as well as the regulation of podocin (NPHS2) and collagen expression. Further, caspases mediate podocyte apoptosis, whereas, podocin regulates glomerular permeability and collagen (I, III, IV, VI types) is involved in the extracellular matrix polymerization leading to the basement membrane thickening and glomerular sclerosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 12651605 PMID: 18726161 PMID: 20224802 PMID: 20716934 PMID: 21261520 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-b5f9de46-ffde-42cb-87c1-1d81fc71f190 Podocyte Dysfunction in Diabetic Nephropathy uuid-b5f9de46-ffde-42cb-87c1-1d81fc71f190 PS:CellType podocyte PS:Description Diabetic nephropathy (DN) is the most common cause of diabetic complications. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b5f9de46-ffde-42cb-87c1-1d81fc71f190 PS:NodeType Pathway PS:Notes Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Podocyte injury contributes to basement membrane thickening and albuminuria as observed in early stages of DN as well as glomerular sclerosis and proteinuria in progressive stages of DN. Signaling description: Podocytes are specialized cells in the Bowman's capsule in the kidney which surround the capillaries of the glomeruli. Podocytes play a key role in glomerular structural integrity and glomerular filtration barrier. Podocytes express angiotensin II receptors (AGTR1). Over-activation of AGTR1 leads to the activation of HIF1A which inhibits the NPHS1 gene expression which codes for nephrin. Nephrin functions in the glomerular filtration barrier in the kidney and forms the slit diaphragm of glomerular podocytes. The loss of the slit diaphragm and failure of the podocyte structure leads to proteinuria. Glucose induces the formation of diacylglycerol that activates PRKCB. Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER, via PI3K and PRKCB, activate AKT1 which is involved in the inhibition of nephrin expression due to IKBK pathway. High glucose levels promote the transcription of TNF in the kidney. Activated TNFRSF1A up-regulates mitogen-activated protein kinases (MAPKs). Outcome effects: MAPKs are involved in the activation of caspases, as well as the regulation of podocin (NPHS2) and collagen expression. Further, caspases mediate podocyte apoptosis, whereas, podocin regulates glomerular permeability and collagen (I, III, IV, VI types) is involved in the extracellular matrix polymerization leading to the basement membrane thickening and glomerular sclerosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 12651605 PS:PMID 18726161 PS:PMID 20224802 PS:PMID 20716934 PS:PMID 21261520 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: L-cell CellType: neuron Description: Products of L-cells (GCG, PYY, serotonin) regulate gastrointestinal functions, metabolism and satiety. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6038f4e-f59f-467f-afea-2f5ee6ad81f9 NodeType: Pathway Notes: Headnote: L-cells produce multifunctional regulators of gastrointestinal functions, metabolism and eating behavior. Signaling description: Glucagon-like peptide 1, glucagon-like peptide 2 and oxyntomodulin are released from L-cells following the processing of GCG. The PYY processes to peptide YY(3-36). Products of processing of GCG interact with LP1R and GLP2 in mucosal endings of vagal afferent neurons. The peptide YY(3-36) interacts with NPY2R. These receptors via G -proteins initiate 2 pathways: activation of cyclic nucleotide-gated channel by cAMP and PLC/ITPR1 signaling. In both cases a Ca2+ overload occurs leading to cGMP synthesis and K+ channel activation. Serotonin secreted by L-cells interacts with HTR3A which participates in the regulation of the K+ efflux. Transmission of the nerve impulse via the vagal nerve leads to pancreatic juice secretion, intestinal absorption, and the inhibition of gastric motility. Non-vagal actions of the peptides released by L-cells are due to transfer of the peptides through the blood stream. These peptides are positive regulators of the satiety. Glucagon-like peptide 1 and peptide YY(3-36) induce the release of insulin (INS). L-cells' peptides regulate the activation of Paneth cells. In addition, glucagon-like peptide-1 inhibits lymphocyte migration. Outcome effects: Peptides released by L-cells and serotonin regulate gastrointestinal functions via the vagal nerve. Presence of the peptides in plasma leads to the sense of satiety and insulin release. Organ: colon Organ: intestine Organ: nerve Organ: small intestine Organ_System: digestive system Organ_System: nervous system PMID: 22148102 PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: blood Tissue: nerve tissue urn:agi-pathway:uuid-b6038f4e-f59f-467f-afea-2f5ee6ad81f9 GCG and PPY Regulate Metabolism and Satiety uuid-b6038f4e-f59f-467f-afea-2f5ee6ad81f9 PS:CellType L-cell PS:CellType neuron PS:Description Products of L-cells (GCG, PYY, serotonin) regulate gastrointestinal functions, metabolism and satiety. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6038f4e-f59f-467f-afea-2f5ee6ad81f9 PS:NodeType Pathway PS:Notes Headnote: L-cells produce multifunctional regulators of gastrointestinal functions, metabolism and eating behavior. Signaling description: Glucagon-like peptide 1, glucagon-like peptide 2 and oxyntomodulin are released from L-cells following the processing of GCG. The PYY processes to peptide YY(3-36). Products of processing of GCG interact with LP1R and GLP2 in mucosal endings of vagal afferent neurons. The peptide YY(3-36) interacts with NPY2R. These receptors via G -proteins initiate 2 pathways: activation of cyclic nucleotide-gated channel by cAMP and PLC/ITPR1 signaling. In both cases a Ca2+ overload occurs leading to cGMP synthesis and K+ channel activation. Serotonin secreted by L-cells interacts with HTR3A which participates in the regulation of the K+ efflux. Transmission of the nerve impulse via the vagal nerve leads to pancreatic juice secretion, intestinal absorption, and the inhibition of gastric motility. Non-vagal actions of the peptides released by L-cells are due to transfer of the peptides through the blood stream. These peptides are positive regulators of the satiety. Glucagon-like peptide 1 and peptide YY(3-36) induce the release of insulin (INS). L-cells' peptides regulate the activation of Paneth cells. In addition, glucagon-like peptide-1 inhibits lymphocyte migration. Outcome effects: Peptides released by L-cells and serotonin regulate gastrointestinal functions via the vagal nerve. Presence of the peptides in plasma leads to the sense of satiety and insulin release. PS:Organ colon PS:Organ intestine PS:Organ nerve PS:Organ small intestine PS:Organ_System digestive system PS:Organ_System nervous system PS:PMID 22148102 PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue blood PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b62663ef-00e0-4a8c-a846-b8bfecd7da98 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b62663ef-00e0-4a8c-a846-b8bfecd7da98 FGF23 -> NCOR2 Expression Targets uuid-b62663ef-00e0-4a8c-a846-b8bfecd7da98 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b62663ef-00e0-4a8c-a846-b8bfecd7da98 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b63a5e6e-b960-4178-aa31-a77c13d25986 NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis.IL6 plays a dual role in inflammation: it can repress inflammation through the inhibition of TNFA and some pro-inflammatory cytokines and enhance inflammation through the up-regulation of acute phase proteins. IL6 binding to IL6R activates signaling through JAK/STAT cascade. resulting in the overexpression of STAT-regulated genes, including genes coding for acute phase proteins. JAK phosphorylates SHP2 protein (PTPN11) that activates Ras/Raf/MEK/MAPK1, VAV1/RAC1, and PI3K/AKT1 signaling pathways. Outcome effects: The increased activity of PI3K/Akt/NF-kB pathway represses apoptosis and promotes cell survival. Activation of the JAK/STAT cascade results in the overexpression of STAT-regulated genes, including genes coding for acute phase proteins. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-b63a5e6e-b960-4178-aa31-a77c13d25986 IL6 Promotes Inflammation in Muscular Dystrophies uuid-b63a5e6e-b960-4178-aa31-a77c13d25986 PS:CellType muscle cell PS:Description Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b63a5e6e-b960-4178-aa31-a77c13d25986 PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis.IL6 plays a dual role in inflammation: it can repress inflammation through the inhibition of TNFA and some pro-inflammatory cytokines and enhance inflammation through the up-regulation of acute phase proteins. IL6 binding to IL6R activates signaling through JAK/STAT cascade. resulting in the overexpression of STAT-regulated genes, including genes coding for acute phase proteins. JAK phosphorylates SHP2 protein (PTPN11) that activates Ras/Raf/MEK/MAPK1, VAV1/RAC1, and PI3K/AKT1 signaling pathways. Outcome effects: The increased activity of PI3K/Akt/NF-kB pathway represses apoptosis and promotes cell survival. Activation of the JAK/STAT cascade results in the overexpression of STAT-regulated genes, including genes coding for acute phase proteins. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b63b964e-1b9a-446e-a11e-da8a8e89ea91 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-b63b964e-1b9a-446e-a11e-da8a8e89ea91 EGFR+>cell migration uuid-b63b964e-1b9a-446e-a11e-da8a8e89ea91 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b63b964e-1b9a-446e-a11e-da8a8e89ea91 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Apoptosis resistance is one of the hallmarks of cancer enabling cancer cell not to die but to reach immortalization Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b65877e1-25d1-4ab9-90d6-4510aa08f5bf NodeType: Pathway Notes: Headnote: Mechanisms of apoptosis impairment include down-regulation of pro-apoptotic and upregulation of anti-apoptotic BCL2 family proteins, increased expression of apoptosis inhibitors, disruption of death receptor signaling and impaired function of caspases. Signaling description: The overexpression of pro-apoptotitc proteins BCL2, BCL2L1, MCL1, BCL2L2, BCL2A1, BCL2L10 and under-expression/inactivation mutations of anti-apoptotic proteins BID, BCL2L11, BBC3, PMAIP1, BAD, BMF, HRK, BAX, BAK1 lead to the impairment of apoptosis. The inactivation of some tumor suppressors (TP53, TP73, WWOX, FOXO3 and others) regulating the expression of BCL2 family proteins is also involved in the suppression of apoptosis. Inhibitors of apoptosis -BIRC2 and 3 - may be activated due to mutations. Other factors participating hyper-expression of IAPs include activation by HIF1A, STAT3, NFKB1, CTNNB1, ARHGEF3 and loss of suppression from TP53, XAF1 and DIABLO. Further, death receptor signaling may be impaired in cancers due to multiple mechanisms. FAS, TNFRSF10A/B, TRADD may be inactivated by mutations or NGFR and FADD may be downregulated. The disruption of caspase cascade may be due to either inactivating mutations (shown for CASP1/4/5/6/8/10) or inactivation by the inhibitors of apoptosis (BIRCs, XIAP, CFLAR). Impairment of CASP3/9 activation may also be due to inactivating mutations in NTN1 and DCC which directly regulates these caspases. Outcome effects: As a result, caspases evade activation and apoptosis is blocked. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Description of viral proteins: HPV16-E6 shown in grey is viral protein. Organ: oncogenic Organ_System: oncogenic PMID: 18931692 PMID: 21453675 PMID: 21943236 PMID: 23637280 PMID: 25013758 PMID: 25328816 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-b65877e1-25d1-4ab9-90d6-4510aa08f5bf Apoptosis Evasion in Cancer: Overview uuid-b65877e1-25d1-4ab9-90d6-4510aa08f5bf PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Apoptosis resistance is one of the hallmarks of cancer enabling cancer cell not to die but to reach immortalization PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b65877e1-25d1-4ab9-90d6-4510aa08f5bf PS:NodeType Pathway PS:Notes Headnote: Mechanisms of apoptosis impairment include down-regulation of pro-apoptotic and upregulation of anti-apoptotic BCL2 family proteins, increased expression of apoptosis inhibitors, disruption of death receptor signaling and impaired function of caspases. Signaling description: The overexpression of pro-apoptotitc proteins BCL2, BCL2L1, MCL1, BCL2L2, BCL2A1, BCL2L10 and under-expression/inactivation mutations of anti-apoptotic proteins BID, BCL2L11, BBC3, PMAIP1, BAD, BMF, HRK, BAX, BAK1 lead to the impairment of apoptosis. The inactivation of some tumor suppressors (TP53, TP73, WWOX, FOXO3 and others) regulating the expression of BCL2 family proteins is also involved in the suppression of apoptosis. Inhibitors of apoptosis -BIRC2 and 3 - may be activated due to mutations. Other factors participating hyper-expression of IAPs include activation by HIF1A, STAT3, NFKB1, CTNNB1, ARHGEF3 and loss of suppression from TP53, XAF1 and DIABLO. Further, death receptor signaling may be impaired in cancers due to multiple mechanisms. FAS, TNFRSF10A/B, TRADD may be inactivated by mutations or NGFR and FADD may be downregulated. The disruption of caspase cascade may be due to either inactivating mutations (shown for CASP1/4/5/6/8/10) or inactivation by the inhibitors of apoptosis (BIRCs, XIAP, CFLAR). Impairment of CASP3/9 activation may also be due to inactivating mutations in NTN1 and DCC which directly regulates these caspases. Outcome effects: As a result, caspases evade activation and apoptosis is blocked. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Description of viral proteins: HPV16-E6 shown in grey is viral protein. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18931692 PS:PMID 21453675 PS:PMID 21943236 PS:PMID 23637280 PS:PMID 25013758 PS:PMID 25328816 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b65f0a6b-94cf-4b57-a3e7-522851578f39 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b65f0a6b-94cf-4b57-a3e7-522851578f39 HBEGF -> HIF1A Expression Targets uuid-b65f0a6b-94cf-4b57-a3e7-522851578f39 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b65f0a6b-94cf-4b57-a3e7-522851578f39 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: T cells that are activated through interactions between T-cell receptor (TCR) and CD40 interact with B-lymphocytes which leads to B-cell proliferation and differentiation into plasma cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6738759-a9cb-4038-84ab-3f3964da6ee1 NodeType: Pathway Notes: Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. The presence of circulating, potentially functional, autoAbs argues in favor of a pathogenic role of B-cells in SSc. Signaling description: T-cells activated through interactions between T-cell receptor (TCR) and CD40, interact with B-lymphocytes which leads to B-cell proliferation and differentiation into plasma cells. The plasma cells produce autoantibodies (autoAbs) which have a role in SSc development. The protein encoded by IL13RA1 is a subunit of the IL13 receptor. This subunit forms a receptor complex with IL4R, a subunit shared by IL13 and IL4 receptors, which serves as the primary IL13-binding subunit of IL13 receptor and may also be a component of IL4 receptors. IL13 and IL4 stimulate B-cell differentiation with consequent production of autoAbs and isotype switching, in particular during the allergic response (IgM to IgE). Outcome effects: The plasma cells produce both stimulatory autoAbs including anti-PDGFR Abs that activate PDGF receptors on fibroblasts and inhibitory autoAbs as well as anti-matrix metalloproteinase (MMP) Abs which reduce the inhibition of collagen deposition normally exerted by MMPs. In addition, B-cells and other cell types secrete interleukin-6 (IL6) which stimulates fibroblasts to produce collagen. Serum levels of IL6, an important pro-inflammatory cytokine, have been shown to correlate with skin fibrosis. CD19 expression is also increased in B-cells in systemic scleroderma patients. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 16936269 PMID: 19707370 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-b6738759-a9cb-4038-84ab-3f3964da6ee1 B-Cells Function in Systemic Scleroderma uuid-b6738759-a9cb-4038-84ab-3f3964da6ee1 PS:CellType B-cell PS:Description T cells that are activated through interactions between T-cell receptor (TCR) and CD40 interact with B-lymphocytes which leads to B-cell proliferation and differentiation into plasma cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6738759-a9cb-4038-84ab-3f3964da6ee1 PS:NodeType Pathway PS:Notes Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. The presence of circulating, potentially functional, autoAbs argues in favor of a pathogenic role of B-cells in SSc. Signaling description: T-cells activated through interactions between T-cell receptor (TCR) and CD40, interact with B-lymphocytes which leads to B-cell proliferation and differentiation into plasma cells. The plasma cells produce autoantibodies (autoAbs) which have a role in SSc development. The protein encoded by IL13RA1 is a subunit of the IL13 receptor. This subunit forms a receptor complex with IL4R, a subunit shared by IL13 and IL4 receptors, which serves as the primary IL13-binding subunit of IL13 receptor and may also be a component of IL4 receptors. IL13 and IL4 stimulate B-cell differentiation with consequent production of autoAbs and isotype switching, in particular during the allergic response (IgM to IgE). Outcome effects: The plasma cells produce both stimulatory autoAbs including anti-PDGFR Abs that activate PDGF receptors on fibroblasts and inhibitory autoAbs as well as anti-matrix metalloproteinase (MMP) Abs which reduce the inhibition of collagen deposition normally exerted by MMPs. In addition, B-cells and other cell types secrete interleukin-6 (IL6) which stimulates fibroblasts to produce collagen. Serum levels of IL6, an important pro-inflammatory cytokine, have been shown to correlate with skin fibrosis. CD19 expression is also increased in B-cells in systemic scleroderma patients. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 16936269 PS:PMID 19707370 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6752351-c9e9-4356-854b-afdacef32d3b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-b6752351-c9e9-4356-854b-afdacef32d3b PTPRJ -> CTNND Signaling uuid-b6752351-c9e9-4356-854b-afdacef32d3b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6752351-c9e9-4356-854b-afdacef32d3b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b67671d7-fc0b-44a8-bbd0-3c985a763c6d NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-b67671d7-fc0b-44a8-bbd0-3c985a763c6d OPRK -> Pain Perception uuid-b67671d7-fc0b-44a8-bbd0-3c985a763c6d PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b67671d7-fc0b-44a8-bbd0-3c985a763c6d PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b67c92b0-2deb-43b9-bc3f-03687f17eef8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-b67c92b0-2deb-43b9-bc3f-03687f17eef8 Granulocytes recruitment in the COVID19 uuid-b67c92b0-2deb-43b9-bc3f-03687f17eef8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b67c92b0-2deb-43b9-bc3f-03687f17eef8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6a40777-1e2c-477d-8f2e-ad7a4b6a55de NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b6a40777-1e2c-477d-8f2e-ad7a4b6a55de Galactose metabolism template uuid-b6a40777-1e2c-477d-8f2e-ad7a4b6a55de PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6a40777-1e2c-477d-8f2e-ad7a4b6a55de PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6a93900-b28c-43db-9823-86b6d63ad747 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-b6a93900-b28c-43db-9823-86b6d63ad747 IL6ST -> STAT5B Signaling uuid-b6a93900-b28c-43db-9823-86b6d63ad747 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6a93900-b28c-43db-9823-86b6d63ad747 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6ac4780-9da5-44aa-9d0c-dea3f0900d3a NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b6ac4780-9da5-44aa-9d0c-dea3f0900d3a CNTF Expression Targets uuid-b6ac4780-9da5-44aa-9d0c-dea3f0900d3a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6ac4780-9da5-44aa-9d0c-dea3f0900d3a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6af6bad-44d9-47d4-a957-3de1c7d4f78a NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b6af6bad-44d9-47d4-a957-3de1c7d4f78a Proline metabolism template uuid-b6af6bad-44d9-47d4-a957-3de1c7d4f78a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6af6bad-44d9-47d4-a957-3de1c7d4f78a PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dopaminergic neuron CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6bb8681-69b6-476e-82fe-ce2c2b5d4966 NodeType: Pathway Notes: Dopamine is secreted by dopaminergic neurons and is synthesized there from tyramine, tryptophan, tyrosine and ascorbic acid. Organ: brain Organ_System: nervous system PMID: 21939738 PMID: 23683503 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-b6bb8681-69b6-476e-82fe-ce2c2b5d4966 Dopamine Synthesis and Release uuid-b6bb8681-69b6-476e-82fe-ce2c2b5d4966 PS:CellType dopaminergic neuron PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6bb8681-69b6-476e-82fe-ce2c2b5d4966 PS:NodeType Pathway PS:Notes Dopamine is secreted by dopaminergic neurons and is synthesized there from tyramine, tryptophan, tyrosine and ascorbic acid. PS:Organ brain PS:Organ_System nervous system PS:PMID 21939738 PS:PMID 23683503 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6d2e7c3-df25-40f7-8b6e-4edc018b5acb NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-b6d2e7c3-df25-40f7-8b6e-4edc018b5acb CD81 -> AP-1 Expression Targets uuid-b6d2e7c3-df25-40f7-8b6e-4edc018b5acb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6d2e7c3-df25-40f7-8b6e-4edc018b5acb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Natural glucocorticoids, such as cortisol in humans, are cholesterol-derived hormones secreted by the adrenal glands under stress or inflammation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6fb5579-18e3-49e9-a8f9-e590ad9c0e6a NodeType: Pathway Notes: Headnote: Natural glucocorticoids, such as cortisol in humans, are cholesterol-derived hormones secreted by the adrenal glands under stress or inflammation. The availability of natural cortisol in tissues is regulated by locally expressed 11b-hydroxysteroid dehydrogenase (HSD11B1). Signaling description: Both natural and synthetic glucocorticoids transduce their actions by binding to glucocorticoid receptor NR3C1. In the absence of glucocorticoids, NR3C1 resides in the cytoplasm in its inactive form bound to chaperone proteins such as HSP90AA1, HSPA1A, FKBP4, and PTGES3. Following binding to a glucocorticoid molecule, NR3C1 detaches from this multi-protein complex and translocates into the nucleus. The effects of steroids and their receptor complexes can be classified as genomic and non-genomic. In the genomic scenario, cortisol/NR3C1 homodimerizes in the nucleus and exerts its transcriptional activation or repression by direct binding to NR3C1 elements found in the promoters of glucocorticoid target genes. TSC22D3, SGK1, SLPI, ZFP36, and DUSP1 are examples of genes upregulated by activated NR3C1. DUSP1, TSC22D3, SLPI, and ANXA1 function as pivotal anti-inflammatory factors. The mechanism of TSC22D3 action as an anti-inflammatory factor is unclear; however it inhibits the expression of toll-like receptor 2 (TLR2) and reduces the production of proinflammatory mediators. SLPI was originally discovered as a secreted product of epithelial cells that cleaves serine proteases such as elastase (ELANE). SLPI and GRN appear to be a pair of host-derived anti-inflammatory mediators that serve to prevent excess innate immune responses. The binding of GRN by SLPI prevents its conversion into epithelins. Epithelins promote and GRN downregulates inflammatory reactions. SLPI and GRN block TNF-triggered neutrophil activation. SLPI also suppresses the macrophage response to LPS. In addition, ZFP36 binds to AU-rich elements of target mRNAs such as cytokines and growth factors, and then induces mRNA rapid degradation. ZFP36 inhibits TNF production from macrophages by destabilizing its mRNA. Other reported mRNA targets of ZFP36 include CSF2, IL3, IL2, IL6, and PTGS2. DUSP1, a member of the dual-specificity phosphatase family, acts to dephosphorylate and deactivate MAPKs resulting in the inhibition of inflammatory cell activation. The glucocorticoid-antagonizing proinflammatory MIF modulates glucocorticoid sensitivity via inhibition of glucocorticoid-induced DUSP1. NR3C1 also modulates gene transrepression by binding to the target gene containing binding sites for glucocorticoid-responsive elements (GREs) as well as other transcription factors. Thus, NR3C1 can regulate the contribution of other transcription factors to gene expression. The suppression of inflammation via cortisol may occur by NR3C1-mediated transrepression of proinflammatory transcription factor effects such as JUN/FOS, NF-kB, STAT3, and IRF3. The glucocorticoid/NR3C1 complex is able to powerfully inhibit gene transcription entrained by these proteins. Moreover, the glucocorticoid/NR3C1 complex physically interacts with NF-kB in the cytoplasm to block its nuclear complex to prevent gene transcription. The glucocorticoid/NR3C1complex also represses transcriptional activation mediated by JUN/FOS, through a direct interaction between NR3C1 and c-Jun/c-Fos. Outcome effects: Protein-protein interactions between glucocorticoid/NR3C1 complex and NF-kB and JUN/FOS result in the repression of the production of proinflammatory cytokines including IL2, IL6, IL8, CSF2 as well as PTGS2. NR3C1 isoforms are expressed in nearly all tissue types. Cortisol exerts a classic anti-inflammatory role by inhibiting NF-kB and JUN/FOS expression targets by acting on nearly all cell types of the immune system. Moreover, glucocorticoids suppress dendritic cell maturation. In the macrophage, glucocorticoids inhibit TGFB1 signaling by directly targeting the transcriptional activation function of SMAD3 in Organ: generic Organ_System: endocrine system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-b6fb5579-18e3-49e9-a8f9-e590ad9c0e6a Cortisol in Resolving Inflammation uuid-b6fb5579-18e3-49e9-a8f9-e590ad9c0e6a PS:CellType generic PS:Description Natural glucocorticoids, such as cortisol in humans, are cholesterol-derived hormones secreted by the adrenal glands under stress or inflammation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6fb5579-18e3-49e9-a8f9-e590ad9c0e6a PS:NodeType Pathway PS:Notes Headnote: Natural glucocorticoids, such as cortisol in humans, are cholesterol-derived hormones secreted by the adrenal glands under stress or inflammation. The availability of natural cortisol in tissues is regulated by locally expressed 11b-hydroxysteroid dehydrogenase (HSD11B1). Signaling description: Both natural and synthetic glucocorticoids transduce their actions by binding to glucocorticoid receptor NR3C1. In the absence of glucocorticoids, NR3C1 resides in the cytoplasm in its inactive form bound to chaperone proteins such as HSP90AA1, HSPA1A, FKBP4, and PTGES3. Following binding to a glucocorticoid molecule, NR3C1 detaches from this multi-protein complex and translocates into the nucleus. The effects of steroids and their receptor complexes can be classified as genomic and non-genomic. In the genomic scenario, cortisol/NR3C1 homodimerizes in the nucleus and exerts its transcriptional activation or repression by direct binding to NR3C1 elements found in the promoters of glucocorticoid target genes. TSC22D3, SGK1, SLPI, ZFP36, and DUSP1 are examples of genes upregulated by activated NR3C1. DUSP1, TSC22D3, SLPI, and ANXA1 function as pivotal anti-inflammatory factors. The mechanism of TSC22D3 action as an anti-inflammatory factor is unclear; however it inhibits the expression of toll-like receptor 2 (TLR2) and reduces the production of proinflammatory mediators. SLPI was originally discovered as a secreted product of epithelial cells that cleaves serine proteases such as elastase (ELANE). SLPI and GRN appear to be a pair of host-derived anti-inflammatory mediators that serve to prevent excess innate immune responses. The binding of GRN by SLPI prevents its conversion into epithelins. Epithelins promote and GRN downregulates inflammatory reactions. SLPI and GRN block TNF-triggered neutrophil activation. SLPI also suppresses the macrophage response to LPS. In addition, ZFP36 binds to AU-rich elements of target mRNAs such as cytokines and growth factors, and then induces mRNA rapid degradation. ZFP36 inhibits TNF production from macrophages by destabilizing its mRNA. Other reported mRNA targets of ZFP36 include CSF2, IL3, IL2, IL6, and PTGS2. DUSP1, a member of the dual-specificity phosphatase family, acts to dephosphorylate and deactivate MAPKs resulting in the inhibition of inflammatory cell activation. The glucocorticoid-antagonizing proinflammatory MIF modulates glucocorticoid sensitivity via inhibition of glucocorticoid-induced DUSP1. NR3C1 also modulates gene transrepression by binding to the target gene containing binding sites for glucocorticoid-responsive elements (GREs) as well as other transcription factors. Thus, NR3C1 can regulate the contribution of other transcription factors to gene expression. The suppression of inflammation via cortisol may occur by NR3C1-mediated transrepression of proinflammatory transcription factor effects such as JUN/FOS, NF-kB, STAT3, and IRF3. The glucocorticoid/NR3C1 complex is able to powerfully inhibit gene transcription entrained by these proteins. Moreover, the glucocorticoid/NR3C1 complex physically interacts with NF-kB in the cytoplasm to block its nuclear complex to prevent gene transcription. The glucocorticoid/NR3C1complex also represses transcriptional activation mediated by JUN/FOS, through a direct interaction between NR3C1 and c-Jun/c-Fos. Outcome effects: Protein-protein interactions between glucocorticoid/NR3C1 complex and NF-kB and JUN/FOS result in the repression of the production of proinflammatory cytokines including IL2, IL6, IL8, CSF2 as well as PTGS2. NR3C1 isoforms are expressed in nearly all tissue types. Cortisol exerts a classic anti-inflammatory role by inhibiting NF-kB and JUN/FOS expression targets by acting on nearly all cell types of the immune system. Moreover, glucocorticoids suppress dendritic cell maturation. In the macrophage, glucocorticoids inhibit TGFB1 signaling by directly targeting the transcriptional activation function of SMAD3 in PS:Organ generic PS:Organ_System endocrine system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: leukocyte Description: Advanced glycation end-products make impact into diabitic and age-related erectile dysfunction development due to impairment of penile endotheliocytes function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6fdd2db-8d31-40b6-88ad-b31e626946a7 NodeType: Pathway Notes: Headnote: Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). AGEs have multiple effects in cavernous tissue. Signaling description: AGEs upregulate the expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an important source of vascular oxidative stress and decrease expression of enzymes involved in antioxidant systems such as Mn-superoxide dismutase (SOD2). AGEs may also diminish eNOS (NOS3) activity. Furthermore, AGEs are able to antagonize erectile function by upregulating the expression of the vasoconstrictor endothelin-1 (EDN1) in endothelial cells. AGEs induce TGFB1 and collagens expressions leading to decreased elasticity of vascular bed and dysfunction of cavernous tissue. AGEs are chemotactic for monocytes, which allows its migration through the endothelial monolayer, and subsequent secretion of IGF1, PDGFB and other factors promoting increased blood vessels rigidity. AGEs attenuate composition and trapping of low-density lipoprotein (LDL) leading to the accumulation of perivascular amorphous hyalinized material that characterizes diabetic vascular disease.Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Compound with elevated level is highlighted in red and compound with reduced level is highlighted in blue. Organ: penis Organ_System: reproductive system PMID: 16892168 PMID: 21054801 PMID: 23822116 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b6fdd2db-8d31-40b6-88ad-b31e626946a7 Advanced Glycation End Products in Diabetes or Age Related Erectile Dysfunction uuid-b6fdd2db-8d31-40b6-88ad-b31e626946a7 PS:CellType leukocyte PS:Description Advanced glycation end-products make impact into diabitic and age-related erectile dysfunction development due to impairment of penile endotheliocytes function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b6fdd2db-8d31-40b6-88ad-b31e626946a7 PS:NodeType Pathway PS:Notes Headnote: Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). AGEs have multiple effects in cavernous tissue. Signaling description: AGEs upregulate the expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an important source of vascular oxidative stress and decrease expression of enzymes involved in antioxidant systems such as Mn-superoxide dismutase (SOD2). AGEs may also diminish eNOS (NOS3) activity. Furthermore, AGEs are able to antagonize erectile function by upregulating the expression of the vasoconstrictor endothelin-1 (EDN1) in endothelial cells. AGEs induce TGFB1 and collagens expressions leading to decreased elasticity of vascular bed and dysfunction of cavernous tissue. AGEs are chemotactic for monocytes, which allows its migration through the endothelial monolayer, and subsequent secretion of IGF1, PDGFB and other factors promoting increased blood vessels rigidity. AGEs attenuate composition and trapping of low-density lipoprotein (LDL) leading to the accumulation of perivascular amorphous hyalinized material that characterizes diabetic vascular disease.Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Compound with elevated level is highlighted in red and compound with reduced level is highlighted in blue. PS:Organ penis PS:Organ_System reproductive system PS:PMID 16892168 PS:PMID 21054801 PS:PMID 23822116 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7292379-b38a-44c0-aeaf-275476694df3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b7292379-b38a-44c0-aeaf-275476694df3 Furaneol biosynthesis template uuid-b7292379-b38a-44c0-aeaf-275476694df3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7292379-b38a-44c0-aeaf-275476694df3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b729ba00-8485-47e4-b48e-554966b3015f NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: adrenal gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-b729ba00-8485-47e4-b48e-554966b3015f Elevated Receptors -> Expression Targets in Adrenal Gland uuid-b729ba00-8485-47e4-b48e-554966b3015f PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b729ba00-8485-47e4-b48e-554966b3015f PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ adrenal gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Mucinous ovarian carcinomas (MOC) share some similarities with Serous ovarian carcinomas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7432394-0e55-42fe-a6ed-312c6d6819f7 NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Mucinous ovarian carcinomas (MOC) share some similarities with serous ovarian carcinomas. MOC develop slowly and unexpectedly transform from benign precursors. Signaling description: MOC is characterized primarily by mutations in the KRAS gene, and mutations in BRAF and PTEN genes may also rarely occur. In addition, the overexpression of EGFRs (EGFR and ERBB2) is also associated with MOC. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA via SRC. PIK3CA then activates V- AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling, and mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. Namely, AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, and MTOR is a central regulator of cellular metabolism, growth, and survival, which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates to the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs regulates Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 18317228 PMID: 19221485 PMID: 21347793 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-b7432394-0e55-42fe-a6ed-312c6d6819f7 Mucinous Ovarian Carcinoma uuid-b7432394-0e55-42fe-a6ed-312c6d6819f7 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Mucinous ovarian carcinomas (MOC) share some similarities with Serous ovarian carcinomas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7432394-0e55-42fe-a6ed-312c6d6819f7 PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Mucinous ovarian carcinomas (MOC) share some similarities with serous ovarian carcinomas. MOC develop slowly and unexpectedly transform from benign precursors. Signaling description: MOC is characterized primarily by mutations in the KRAS gene, and mutations in BRAF and PTEN genes may also rarely occur. In addition, the overexpression of EGFRs (EGFR and ERBB2) is also associated with MOC. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA via SRC. PIK3CA then activates V- AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling, and mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. Namely, AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, and MTOR is a central regulator of cellular metabolism, growth, and survival, which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates to the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs regulates Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF which activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18317228 PS:PMID 19221485 PS:PMID 21347793 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Upon UVR-induced, damage keratinocytes upregulate their expression of the pro-opiomelanocortin (POMC) gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b76cd536-3182-4ce4-a694-3733dbb1fc03 NodeType: Pathway Notes: Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: Chronic UV exposure causes damage to DNA, and activation of the ATM and ATR kinases. Upon activation, ATM and ATR phosphorylate Chk2 and Chk1, respectively which in turn catalyze the phosphorylation and accumulation of p53. As a transcription factor, p53 binds directly to the POMC gene promoter in keratinocytes and induces POMC, MMP2 and CASP transcription. Ultraviolet (UV) radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor, MC1R resulting in the expression of MITF which are highly correlated with melanocyte development and melanomagenesis. Upon UVR-induced, damage keratinocytes upregulate their expression of the pro-opiomelanocortin (POMC) gene. Outcome effects: POMC encodes a pro-peptide that is cleaved to generate alpha -MSH, ACTH and ß-endorphin. Together, these peptides have pleiotropic effects on endocrine and neuroendocrine signaling, and the immune system, in addition to the alpha -MSH function in melanogenesis. Highlighted proteins: POMC with increased expression in photoaging is highlighted in red. Organ_System: integumentary system PMID: 12231193 PMID: 22033528 PMID: 23539007 PMID: 7576239 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-b76cd536-3182-4ce4-a694-3733dbb1fc03 POMC Activation in Keratinocytes uuid-b76cd536-3182-4ce4-a694-3733dbb1fc03 PS:CellType keratinocyte PS:Description Upon UVR-induced, damage keratinocytes upregulate their expression of the pro-opiomelanocortin (POMC) gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b76cd536-3182-4ce4-a694-3733dbb1fc03 PS:NodeType Pathway PS:Notes Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture and depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Signaling description: Chronic UV exposure causes damage to DNA, and activation of the ATM and ATR kinases. Upon activation, ATM and ATR phosphorylate Chk2 and Chk1, respectively which in turn catalyze the phosphorylation and accumulation of p53. As a transcription factor, p53 binds directly to the POMC gene promoter in keratinocytes and induces POMC, MMP2 and CASP transcription. Ultraviolet (UV) radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor, MC1R resulting in the expression of MITF which are highly correlated with melanocyte development and melanomagenesis. Upon UVR-induced, damage keratinocytes upregulate their expression of the pro-opiomelanocortin (POMC) gene. Outcome effects: POMC encodes a pro-peptide that is cleaved to generate alpha -MSH, ACTH and ß-endorphin. Together, these peptides have pleiotropic effects on endocrine and neuroendocrine signaling, and the immune system, in addition to the alpha -MSH function in melanogenesis. Highlighted proteins: POMC with increased expression in photoaging is highlighted in red. PS:Organ_System integumentary system PS:PMID 12231193 PS:PMID 22033528 PS:PMID 23539007 PS:PMID 7576239 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b78fc8ad-8aa6-4795-9c27-9b0bd66b397c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b78fc8ad-8aa6-4795-9c27-9b0bd66b397c O-Glycan biosynthesis template uuid-b78fc8ad-8aa6-4795-9c27-9b0bd66b397c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b78fc8ad-8aa6-4795-9c27-9b0bd66b397c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7ccb14b-85e4-42af-8f1a-63de98a28799 NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b7ccb14b-85e4-42af-8f1a-63de98a28799 Proteins Involved in Endometriosis uuid-b7ccb14b-85e4-42af-8f1a-63de98a28799 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7ccb14b-85e4-42af-8f1a-63de98a28799 PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: Mast cells are dissipated in connective tissue and stored in spleen and bone marrow. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7e9e463-566d-417d-bb82-c72ea5fafad9 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in spleen and bone marrow and contain large amounts of cytoplasmic granules, including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. Signaling description: Mast cells are activated by several factors including cold, injury, and radiation. IgE-dependent activation of mast cells is typical for an allergic reaction. In this case, degranulation occurs quickly and mediators are released into the extracellular space producing an immediate effect. The content of granules within mast cells, which includes histamine, heparin, proteases, and cytokines, is pre-synthesized during maturation and proliferation of mast cells. IgE-dependent activation of mast cells involves the binding of IgE to several FCERI receptors.Each FCERI receptor consists of 4 subunits: alpha-particle which is responsible for IgE binding, intracellular beta-subunit, and two intracellular gamma subunits. For IgE-dependent activation, an antigen must bind at least two IgE molecules at the surface of a mast cell. Antigen binding to IgE results in the crosslinking of two FCERI, which leads to the phosphorylation of LYN. A multi-molecular complex, which includes GRAP2, LCP2, PLCG1, and VAV1, form on LAT. Outcome effects: FCERI aggregation induces PI3K, MAPK1, MAPK8, NF-kB, PLC, and PKC activation. The activation of RAC1, CDC42, and Ras leads to MAPK activation. These pathways result in degranulation, release of leukotrienes, and cytokine synthesis. An increase in calcium (Ca2+) also leads to the synthesis of arachidonic acid and lysophospholipid that support the fusion of mast cell granules with the membrane and release of their contents. In mast cells, STIM1 interacts with ORAI1 membrane protein which opens Ca2+ release-activated Ca2+ (CRAC) channels allowing the increase in intracellular Ca2+. Adaptor complexes such as BCL10-MALT1 permit FCERI-dependent IL6 and TNF release without degranulation. In addition, KITLG is a key protein that stimulates degranulation and synthesis of proinflammatory cytokines in mast cells. The intersection of signaling pathways initiated by KIT receptor (SHC1) and FCERI receptors (GRB2) leads to degranulation. KITLG is a factor of directed movement of mast cells. Upon activation, mast cells secrete numerous vasoactive and proinflammatory mediators. The key pre-stored mast cell mediators are biogenic amines (histamine and serotonin), chemokines (IL8, CCL2, CCL7, CCL5, CCL11, and CCL13), enzymes (chymase, kinogenases, phospholipases, and tryptase), peptides (ANG, CRH, EDN1, bradykinin, LEP, and SST), and proteoglycans (chondroitin sulfate, heparin, and hyaluronic acid). As a class, mast cells are heterogeneous and a single mast cell does not make all of these substances. Histamine and heparin dilate post-capillary venules and increase blood vessel permeability. This leads to local swelling, warmth, redness, and the attraction of other inflammatory cells to the source of inflammation. Mediators that are pre-stored in mast cells also lead to itching or pain. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-b7e9e463-566d-417d-bb82-c72ea5fafad9 Mast-Cell Activation via IgE Signaling uuid-b7e9e463-566d-417d-bb82-c72ea5fafad9 PS:CellType mast cell PS:Description Mast cells are dissipated in connective tissue and stored in spleen and bone marrow. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b7e9e463-566d-417d-bb82-c72ea5fafad9 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in spleen and bone marrow and contain large amounts of cytoplasmic granules, including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. Signaling description: Mast cells are activated by several factors including cold, injury, and radiation. IgE-dependent activation of mast cells is typical for an allergic reaction. In this case, degranulation occurs quickly and mediators are released into the extracellular space producing an immediate effect. The content of granules within mast cells, which includes histamine, heparin, proteases, and cytokines, is pre-synthesized during maturation and proliferation of mast cells. IgE-dependent activation of mast cells involves the binding of IgE to several FCERI receptors.Each FCERI receptor consists of 4 subunits: alpha-particle which is responsible for IgE binding, intracellular beta-subunit, and two intracellular gamma subunits. For IgE-dependent activation, an antigen must bind at least two IgE molecules at the surface of a mast cell. Antigen binding to IgE results in the crosslinking of two FCERI, which leads to the phosphorylation of LYN. A multi-molecular complex, which includes GRAP2, LCP2, PLCG1, and VAV1, form on LAT. Outcome effects: FCERI aggregation induces PI3K, MAPK1, MAPK8, NF-kB, PLC, and PKC activation. The activation of RAC1, CDC42, and Ras leads to MAPK activation. These pathways result in degranulation, release of leukotrienes, and cytokine synthesis. An increase in calcium (Ca2+) also leads to the synthesis of arachidonic acid and lysophospholipid that support the fusion of mast cell granules with the membrane and release of their contents. In mast cells, STIM1 interacts with ORAI1 membrane protein which opens Ca2+ release-activated Ca2+ (CRAC) channels allowing the increase in intracellular Ca2+. Adaptor complexes such as BCL10-MALT1 permit FCERI-dependent IL6 and TNF release without degranulation. In addition, KITLG is a key protein that stimulates degranulation and synthesis of proinflammatory cytokines in mast cells. The intersection of signaling pathways initiated by KIT receptor (SHC1) and FCERI receptors (GRB2) leads to degranulation. KITLG is a factor of directed movement of mast cells. Upon activation, mast cells secrete numerous vasoactive and proinflammatory mediators. The key pre-stored mast cell mediators are biogenic amines (histamine and serotonin), chemokines (IL8, CCL2, CCL7, CCL5, CCL11, and CCL13), enzymes (chymase, kinogenases, phospholipases, and tryptase), peptides (ANG, CRH, EDN1, bradykinin, LEP, and SST), and proteoglycans (chondroitin sulfate, heparin, and hyaluronic acid). As a class, mast cells are heterogeneous and a single mast cell does not make all of these substances. Histamine and heparin dilate post-capillary venules and increase blood vessel permeability. This leads to local swelling, warmth, redness, and the attraction of other inflammatory cells to the source of inflammation. Mediators that are pre-stored in mast cells also lead to itching or pain. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b817991e-75de-45a8-af93-76590ae28334 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b817991e-75de-45a8-af93-76590ae28334 Leu/Ile/Val biosynthesis template uuid-b817991e-75de-45a8-af93-76590ae28334 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b817991e-75de-45a8-af93-76590ae28334 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b81ddcf5-9fae-4d26-beba-abf9d30a0b45 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b81ddcf5-9fae-4d26-beba-abf9d30a0b45 ABA biosynthesis template uuid-b81ddcf5-9fae-4d26-beba-abf9d30a0b45 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b81ddcf5-9fae-4d26-beba-abf9d30a0b45 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pancreatic cancer is characterized by mutations in PTEN, KRAS, BRAF, and TP53 genes and overexpression of growth factors and their receptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b83655d7-3c43-418e-9c29-e257772f6482 NodeType: Pathway Notes: Headnote: Pancreatic cancer is malignant transformation of the pancreas, and is characterized by mutations in PTEN, KRAS, BRAF, and TP53 genes as well as overexpression of growth factors and their receptors including EGFRs, VEGFRs, MET, and IGF1R. Signaling description: The ERBB family of receptor tyrosine kinases consists of four related members including EGFR, ERBB2, ERBB3, and ERBB4. The family of vascular endothelial growth factor receptors consists of FLT1, KDR, and FLT4. Ligand-bound EGFRs, VEGFRs, MET, TGFBR1, and IGF1R activate PIK3CA via SRC and IRS1 proteins. PIK3CA, via PIP3 and PDPK1, activates AKT1. Activated AKT1 promotes several essential pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. Further, AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1). In addition, activated AKT1 inhibits FOXO1 and FOXO3. AKT1 also phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c (CYCS) from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. Finally, growth factor receptors regulate JAK1/2 (Janus kinases 1/2) which are involved in cell growth and activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: Overall, these alterations cause constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, proliferation, and migration of epithelial pancreatic cells. Specifically, MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. In the nucleus, activated beta-catenin interacts with TCF4 and LEF1 to induce the expression of downstream target genes which are involved in cell proliferation, differentiation, and migration. Further, BRAF activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 22806689 PMID: 23135763 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-b83655d7-3c43-418e-9c29-e257772f6482 Growth Factor Signaling in Pancreatic Neoplasms uuid-b83655d7-3c43-418e-9c29-e257772f6482 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pancreatic cancer is characterized by mutations in PTEN, KRAS, BRAF, and TP53 genes and overexpression of growth factors and their receptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b83655d7-3c43-418e-9c29-e257772f6482 PS:NodeType Pathway PS:Notes Headnote: Pancreatic cancer is malignant transformation of the pancreas, and is characterized by mutations in PTEN, KRAS, BRAF, and TP53 genes as well as overexpression of growth factors and their receptors including EGFRs, VEGFRs, MET, and IGF1R. Signaling description: The ERBB family of receptor tyrosine kinases consists of four related members including EGFR, ERBB2, ERBB3, and ERBB4. The family of vascular endothelial growth factor receptors consists of FLT1, KDR, and FLT4. Ligand-bound EGFRs, VEGFRs, MET, TGFBR1, and IGF1R activate PIK3CA via SRC and IRS1 proteins. PIK3CA, via PIP3 and PDPK1, activates AKT1. Activated AKT1 promotes several essential pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates the transcription of BCL2. Further, AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1). In addition, activated AKT1 inhibits FOXO1 and FOXO3. AKT1 also phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents formation of mitochondrial transition pore, release of cytochrome c (CYCS) from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. Finally, growth factor receptors regulate JAK1/2 (Janus kinases 1/2) which are involved in cell growth and activate KRAS and BRAF via SHC1/GRB2/SOS1. Outcome effects: Overall, these alterations cause constitutive activation of AKT1 cascades and mitogen-activated protein kinase (MAPK) signaling cascades which leads to block of apoptosis, loss of differentiation, proliferation, and migration of epithelial pancreatic cells. Specifically, MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. In the nucleus, activated beta-catenin interacts with TCF4 and LEF1 to induce the expression of downstream target genes which are involved in cell proliferation, differentiation, and migration. Further, BRAF activates ERK (MAPK1/3) signaling pathway inducing genes involved in cell proliferation, differentiation, migration, and vascularization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 22806689 PS:PMID 23135763 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8704b11-d74f-405d-adf1-490d64211fb6 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-b8704b11-d74f-405d-adf1-490d64211fb6 Possible Interplay between SOX11, CCND1 and EZH2 in Mantle Cell Lymphoma uuid-b8704b11-d74f-405d-adf1-490d64211fb6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8704b11-d74f-405d-adf1-490d64211fb6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b87fb1da-b46d-4795-89bd-70e2b4e6994a NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-b87fb1da-b46d-4795-89bd-70e2b4e6994a NMDA Receptors -> Ca2+/CREB Activation/PGE2 Synthesis uuid-b87fb1da-b46d-4795-89bd-70e2b4e6994a PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b87fb1da-b46d-4795-89bd-70e2b4e6994a PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8a0d326-05a4-4787-a25f-3227c2d715ea NodeType: Pathway Notes: G protein-coupled receptor T1R1/T1R3 is a direct sensor of amino acid availability. Taste receptors transfer the signal to mTORC1 which regulates protein synthesis and autophagy. Organ: pancreas Organ_System: endocrine system PMID: 22959271 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-b8a0d326-05a4-4787-a25f-3227c2d715ea mTOR Signaling Activation by Taste Sensor Receptors (Rodent Model) uuid-b8a0d326-05a4-4787-a25f-3227c2d715ea PS:CellType insulin-secreting cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8a0d326-05a4-4787-a25f-3227c2d715ea PS:NodeType Pathway PS:Notes G protein-coupled receptor T1R1/T1R3 is a direct sensor of amino acid availability. Taste receptors transfer the signal to mTORC1 which regulates protein synthesis and autophagy. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22959271 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8a5f09f-2b91-4467-aada-b704834785ae NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b8a5f09f-2b91-4467-aada-b704834785ae unstaurated fatty acid beta-oxidation template uuid-b8a5f09f-2b91-4467-aada-b704834785ae PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8a5f09f-2b91-4467-aada-b704834785ae PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8bd503a-be48-46ba-99d5-081a3d417b85 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b8bd503a-be48-46ba-99d5-081a3d417b85 Erythropoietin -> ELK/SRF Expression Targets uuid-b8bd503a-be48-46ba-99d5-081a3d417b85 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8bd503a-be48-46ba-99d5-081a3d417b85 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: hepatocyte Description: Non-Alcoholic Fatty Liver Disease (NAFLD) is a spectrum of liver diseases characterized by the presence of ectopic fat in the liver, which is irrelevant by alcohol consumption. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8c159ef-d142-41e3-923e-ca36c4230b57 NodeType: Pathway Notes: Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Liver is the major organ for the maintenance of energy homeostasis. A common associated clinical feature of patients with NAFLD is impaired lipid metabolism associated with insulin resistance.I Signaling description: Insulin resistance results in the inhibition of glycogenesis in the liver, which subsequently leads to the accumulation of fat. Normally, insulin (INS) stimulates glycogenesis. Activated INSR and IGF1R stimulate PDPK1 via IRS2, PIK3R1 and the formation of PIP3. PDPK1 activates AKT1, which phosphorylates GSK3B causing its proteolytic removal. Active GSK3B stimulates CEBPA and inhibits CREB1. CEBPA inactivates NR1H3 and CREB1 promotes SP1 and HIF1A. NR1H3, SP1, and HIF1A promote GCK, PCK2, PGM1, and PFKFB2 which are involved in glycogenesis. Outcome effects: High fatty acid conditions lead to the induction of PPARG, PPARGC1A, and CYP2E1. CYP2E1 is frequently induced in steatosis. Active CYP2E1 is involved in the production of reactive oxygen species (ROS) and plays an important role in oxidative stress. PPARGC1B activates SREBF1. SREBF1 and PPARG promote SCD, ACACA, ACSL1, DGAT1, GPAM, FADS2, ACLY, and FASN which are involved in fatty acid and triacylglycerol biosynthesis. The overproduction and deposit of lipids and triglycerides in hepatocytes are the main pathophysiological features of NAFLD. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: liver Organ_System: digestive system PMID: 23394097 PMID: 25045276 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-b8c159ef-d142-41e3-923e-ca36c4230b57 Lipid Metabolism Impairement in non-Alcoholic Fatty Liver Disease uuid-b8c159ef-d142-41e3-923e-ca36c4230b57 PS:CellType adipocyte PS:CellType hepatocyte PS:Description Non-Alcoholic Fatty Liver Disease (NAFLD) is a spectrum of liver diseases characterized by the presence of ectopic fat in the liver, which is irrelevant by alcohol consumption. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8c159ef-d142-41e3-923e-ca36c4230b57 PS:NodeType Pathway PS:Notes Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Liver is the major organ for the maintenance of energy homeostasis. A common associated clinical feature of patients with NAFLD is impaired lipid metabolism associated with insulin resistance.I Signaling description: Insulin resistance results in the inhibition of glycogenesis in the liver, which subsequently leads to the accumulation of fat. Normally, insulin (INS) stimulates glycogenesis. Activated INSR and IGF1R stimulate PDPK1 via IRS2, PIK3R1 and the formation of PIP3. PDPK1 activates AKT1, which phosphorylates GSK3B causing its proteolytic removal. Active GSK3B stimulates CEBPA and inhibits CREB1. CEBPA inactivates NR1H3 and CREB1 promotes SP1 and HIF1A. NR1H3, SP1, and HIF1A promote GCK, PCK2, PGM1, and PFKFB2 which are involved in glycogenesis. Outcome effects: High fatty acid conditions lead to the induction of PPARG, PPARGC1A, and CYP2E1. CYP2E1 is frequently induced in steatosis. Active CYP2E1 is involved in the production of reactive oxygen species (ROS) and plays an important role in oxidative stress. PPARGC1B activates SREBF1. SREBF1 and PPARG promote SCD, ACACA, ACSL1, DGAT1, GPAM, FADS2, ACLY, and FASN which are involved in fatty acid and triacylglycerol biosynthesis. The overproduction and deposit of lipids and triglycerides in hepatocytes are the main pathophysiological features of NAFLD. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ liver PS:Organ_System digestive system PS:PMID 23394097 PS:PMID 25045276 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8d24235-808b-4d2f-b6f9-de2f9600577d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-b8d24235-808b-4d2f-b6f9-de2f9600577d FGF8 -> STAT Expression Targets uuid-b8d24235-808b-4d2f-b6f9-de2f9600577d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8d24235-808b-4d2f-b6f9-de2f9600577d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8e883ef-907d-4c50-8e84-dc364d9c2040 NodeType: Pathway Notes: Resting memory CD4+ T cells and other cells with extended half-lives and cells resistant to viral-induced apoptosis maintain stores of provirus particles and host the production of virions episodically (blips) during the chronic phase of viral infection. Pathway 3. HIV latency and evasion of reservoir cell apoptosis in HIV chronic phase: Low level of viral production (Fig. 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-b8e883ef-907d-4c50-8e84-dc364d9c2040 3_1_HIV latency and low level of viral production uuid-b8e883ef-907d-4c50-8e84-dc364d9c2040 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b8e883ef-907d-4c50-8e84-dc364d9c2040 PS:NodeType Pathway PS:Notes Resting memory CD4+ T cells and other cells with extended half-lives and cells resistant to viral-induced apoptosis maintain stores of provirus particles and host the production of virions episodically (blips) during the chronic phase of viral infection. Pathway 3. HIV latency and evasion of reservoir cell apoptosis in HIV chronic phase: Low level of viral production (Fig. 3). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: CDKN2B-AS1 is a hotspot for disease-associated polymorphisms and has been consistently associated with cardiovascular disease, several cancers, diabetes, glaucoma, and other conditions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b906c7e6-9019-497e-b6a3-575760ccd8c0 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. CDKN2B-AS1 is a long, non-coding RNA encoded in chromosome 9p21 region. This locus is a hotspot for disease-associated polymorphisms and has been consistently associated with cardiovascular disease, several cancers, diabetes, glaucoma, and other conditions. Signaling description: The distinctive role of CDKN2B-AS1 in the pathogenesis of these conditions is yet to be determined. CDKN2B-AS1 binds PRC2 to induce methylation of histone H3 and results in silencing of the CDKN2A/B locus. CDKN2B-AS1 binds PRC1, which allows the recognition of histone H3 necessary for monoubiquitination at histone H2A and silencing maintenance. The expression of CDKN2B-AS1 may be regulated by Ras, STAT1, and ATM/E2F1. Outcome effects: CDKN2B-AS1 modulation impacts the repressing ability of PRC1/2 proteins, inducing or inhibiting expression of CDKN2A/B, and possibly other distant loci by histone modification. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 22428042 PMID: 23111177 PMID: 23306151 PMID: 23416462 PMID: 23963167 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-b906c7e6-9019-497e-b6a3-575760ccd8c0 CDKN2B-AS1 in Epigenetic Regulation of Glaucoma uuid-b906c7e6-9019-497e-b6a3-575760ccd8c0 PS:Description CDKN2B-AS1 is a hotspot for disease-associated polymorphisms and has been consistently associated with cardiovascular disease, several cancers, diabetes, glaucoma, and other conditions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b906c7e6-9019-497e-b6a3-575760ccd8c0 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. CDKN2B-AS1 is a long, non-coding RNA encoded in chromosome 9p21 region. This locus is a hotspot for disease-associated polymorphisms and has been consistently associated with cardiovascular disease, several cancers, diabetes, glaucoma, and other conditions. Signaling description: The distinctive role of CDKN2B-AS1 in the pathogenesis of these conditions is yet to be determined. CDKN2B-AS1 binds PRC2 to induce methylation of histone H3 and results in silencing of the CDKN2A/B locus. CDKN2B-AS1 binds PRC1, which allows the recognition of histone H3 necessary for monoubiquitination at histone H2A and silencing maintenance. The expression of CDKN2B-AS1 may be regulated by Ras, STAT1, and ATM/E2F1. Outcome effects: CDKN2B-AS1 modulation impacts the repressing ability of PRC1/2 proteins, inducing or inhibiting expression of CDKN2A/B, and possibly other distant loci by histone modification. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 22428042 PS:PMID 23111177 PS:PMID 23306151 PS:PMID 23416462 PS:PMID 23963167 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top mutated genes associated with facioscapulohumeral muscular dystrophy in the network constructed from biomedical literature (Resnet-2020). DUX4 has noticeably higher number of supporting references. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9097d58-c235-49e2-bb44-5f36769198fe NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-b9097d58-c235-49e2-bb44-5f36769198fe Muscular Facioscapulohumeral Dystrophy Mutated Genes uuid-b9097d58-c235-49e2-bb44-5f36769198fe PS:Description Top mutated genes associated with facioscapulohumeral muscular dystrophy in the network constructed from biomedical literature (Resnet-2020). DUX4 has noticeably higher number of supporting references. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9097d58-c235-49e2-bb44-5f36769198fe PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9165648-a91e-444a-95e4-34e3505cc94b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-b9165648-a91e-444a-95e4-34e3505cc94b Urea cycle and Arginine metabolism template uuid-b9165648-a91e-444a-95e4-34e3505cc94b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9165648-a91e-444a-95e4-34e3505cc94b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Orexin A/B (hypocretin, HCRT) is a neuropeptide responsible for regulation of sleep / arousal. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9265e33-b471-4b44-a022-d3d27f790c31 NodeType: Pathway Notes: Headnote: Orexin A/B (hypocretin, HCRT) is a neuropeptide responsible for regulation of sleep / arousal. Elevated activity in HCRT neurons has been hypothesized to underlie sleep and arousal dysregulation in primary insomnia. Elevated HCRT level in haemodialysis patients was associated with insomnia. Insomnia is a common side effect of MAOIs. Signaling description: Orexins have an excitatory activity in monoaminergic neurons. Noradrenergic cells of the locus coeruleus, dopaminergic cells of the ventral tegmental area, serotonergic cells of the dorsal raphe, histaminergic cells from tuberomammillary nucleus and cholinergic neurons of the basal forebrain have been shown to be activated by orexins and are implicated in regulation of arousal. Monoamine oxidase A (MAOA) is an enzyme that degrades norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine. Monoamine oxidase inhibitors (MAOIs) were the first type of developed antidepressant. Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs are not effective. Organ: brain Organ_System: nervous system PMID: 17910982 PMID: 18652859 PMID: 23034387 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-b9265e33-b471-4b44-a022-d3d27f790c31 Hypocretin Elevation and Monoamine Oxidase Decrease/Inhibition uuid-b9265e33-b471-4b44-a022-d3d27f790c31 PS:CellType neuron PS:Description Orexin A/B (hypocretin, HCRT) is a neuropeptide responsible for regulation of sleep / arousal. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9265e33-b471-4b44-a022-d3d27f790c31 PS:NodeType Pathway PS:Notes Headnote: Orexin A/B (hypocretin, HCRT) is a neuropeptide responsible for regulation of sleep / arousal. Elevated activity in HCRT neurons has been hypothesized to underlie sleep and arousal dysregulation in primary insomnia. Elevated HCRT level in haemodialysis patients was associated with insomnia. Insomnia is a common side effect of MAOIs. Signaling description: Orexins have an excitatory activity in monoaminergic neurons. Noradrenergic cells of the locus coeruleus, dopaminergic cells of the ventral tegmental area, serotonergic cells of the dorsal raphe, histaminergic cells from tuberomammillary nucleus and cholinergic neurons of the basal forebrain have been shown to be activated by orexins and are implicated in regulation of arousal. Monoamine oxidase A (MAOA) is an enzyme that degrades norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine. Monoamine oxidase inhibitors (MAOIs) were the first type of developed antidepressant. Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs are not effective. PS:Organ brain PS:Organ_System nervous system PS:PMID 17910982 PS:PMID 18652859 PS:PMID 23034387 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is the most common cancer in women. Most BC a B1532re luminal tumors that start in the inner (luminal) cells in the mammary ducts. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b940e1cc-6f74-46cd-9e14-5873d4a28d35 NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: Luminal breast tumors are subdivided into two different types called luminal A and luminal B cancers. Luminal A cancer has ER (estrogen receptor) and/or PR (progesterone receptor) positive, human epidermal growth factor receptor 2 (HER2/neu) negative status. Luminal B cancer has ER and/or PR, ERBB2 positive, HER2/neu positive status. Women with luminal B cancer are often diagnosed at a younger age than those with luminal A cancer and have poorer prognosis factors including high tumor grade, larger and more aggressive tumors, and lymph node metastasis. The crucial pathogenic processes involved in luminal BC are cell proliferation, block of apoptosis, cell invasion, chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. ESR1/ERBB-positive luminal BC demonstrates overexpression of ESR1 and growth factor receptors such as EGFRs (ERBB1/2), IGF1R, and VEGFRs (FLT1/VEGFR1, KDR/VEGFR2, and FLT4/VEGFR3). In addition, there may be mutations in PTEN (antagonist of PIK3CA and suppressor of AKT-mediated signaling pathways) and DNA repair genes such as BRCA1, BRCA2, PALB2, RAD51, NBN, BRIP1, PARP1, and MLH1. Almost half of all familial breast cancer cases have mutations in BRCA1 and BRCA2 genes. Outcome effects: The overexpression of membrane-bound ESR1, EGFRs, VEGFRs, and IGF1R causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. Nuclear ESR1 induces genes involved in cell proliferation and differentiation. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2 via NBN. Mutations in these genes lead to block of DNA repair and dysfunction in response to DNA damage. Luminal BC, particularly in post-menopausal women, is responsive to hormones. ESR1 antagonist (Fulvestrant) and selective ESR1 modulators (Tamoxifen and Toremifene) inhibit tumor growth and increase survival. MTOR inhibitors (Everolimus and Temsirolimus), inhibitor of SRC (Dasatinib), inhibitors of EGFRs (Iressa (Gefitinib), Trastuzumab, Lapatinib, and Cetuximab), inhibitor of VEGFA (Bevacizumab), inhibitors of KDR (Bevacizumab and Sutent (Sunitinib)) are used for the treatment of BC. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: breast Organ_System: integumentary system PMID: 18779615 PMID: 19574486 PMID: 19729680 PMID: 21556249 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-b940e1cc-6f74-46cd-9e14-5873d4a28d35 ESR1/ERBB Positive Luminal Breast Cancer uuid-b940e1cc-6f74-46cd-9e14-5873d4a28d35 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is the most common cancer in women. Most BC a B1532re luminal tumors that start in the inner (luminal) cells in the mammary ducts. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b940e1cc-6f74-46cd-9e14-5873d4a28d35 PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: Luminal breast tumors are subdivided into two different types called luminal A and luminal B cancers. Luminal A cancer has ER (estrogen receptor) and/or PR (progesterone receptor) positive, human epidermal growth factor receptor 2 (HER2/neu) negative status. Luminal B cancer has ER and/or PR, ERBB2 positive, HER2/neu positive status. Women with luminal B cancer are often diagnosed at a younger age than those with luminal A cancer and have poorer prognosis factors including high tumor grade, larger and more aggressive tumors, and lymph node metastasis. The crucial pathogenic processes involved in luminal BC are cell proliferation, block of apoptosis, cell invasion, chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. ESR1/ERBB-positive luminal BC demonstrates overexpression of ESR1 and growth factor receptors such as EGFRs (ERBB1/2), IGF1R, and VEGFRs (FLT1/VEGFR1, KDR/VEGFR2, and FLT4/VEGFR3). In addition, there may be mutations in PTEN (antagonist of PIK3CA and suppressor of AKT-mediated signaling pathways) and DNA repair genes such as BRCA1, BRCA2, PALB2, RAD51, NBN, BRIP1, PARP1, and MLH1. Almost half of all familial breast cancer cases have mutations in BRCA1 and BRCA2 genes. Outcome effects: The overexpression of membrane-bound ESR1, EGFRs, VEGFRs, and IGF1R causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that lead to block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. Nuclear ESR1 induces genes involved in cell proliferation and differentiation. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2 via NBN. Mutations in these genes lead to block of DNA repair and dysfunction in response to DNA damage. Luminal BC, particularly in post-menopausal women, is responsive to hormones. ESR1 antagonist (Fulvestrant) and selective ESR1 modulators (Tamoxifen and Toremifene) inhibit tumor growth and increase survival. MTOR inhibitors (Everolimus and Temsirolimus), inhibitor of SRC (Dasatinib), inhibitors of EGFRs (Iressa (Gefitinib), Trastuzumab, Lapatinib, and Cetuximab), inhibitor of VEGFA (Bevacizumab), inhibitors of KDR (Bevacizumab and Sutent (Sunitinib)) are used for the treatment of BC. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ breast PS:Organ_System integumentary system PS:PMID 18779615 PS:PMID 19574486 PS:PMID 19729680 PS:PMID 21556249 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The molecular mechanism of action of thyroid hormones may be genomic or non-genomic. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9460c55-a84d-415f-aaff-809df937d3fe NodeType: Pathway Notes: Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. Signaling description: The molecular mechanism of action of thyroid hormones can be genomic or non-genomic. The non-genomic actions of thyroid hormones may be initiated at the plasma membrane, in the cytoplasm or at intracellular organelles such as mitochondria, and do not primarily involve thyroid hormone nuclear receptors. There are several mechanisms of non-genomic actions of thyroid hormones. Through the vitronectin receptor (integrin), thyroid hormones stimulate MAP2K1 and MAP2K2 (ERK1/2), AKT1, and the release of calcium (Ca2 ) through phospholipase PTK2. Thyroxine (T4) is unable to activate PI3K. In the cytoplasm, plasma membrane ion pumps are critical to cell function. Ca2 -ATPase and Na /K -ATPase are known to be regulated by thyroid hormones by both genomic and non-genomic mechanisms. The non-genomic effects of thyroid hormones on Ca2 pump (Ca2 -ATPase) activity have been documented. Further, triiodothyronine (T3) can bind to THRB in the cytoplasm. Lastly, PIK3CA and HIF1A transcription may be activated. Outcome effects: Complex cellular events induced by the integrin cell surface receptor include angiogenesis (endothelial and vascular smooth muscle cells) and tumor cell proliferation. Hyper- and hypothyroidism are associated with increased and decreased human erythrocyte Ca2 -ATPase activity, respectively. Cytoplasmic THRB activation is not linked to cell proliferation but to the shuttling of THRA from cytoplasm to nucleus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: endocrine system Organ_System: generic PMID: 17983645 PMID: 20051527 PMID: 22945636 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: generic urn:agi-pathway:uuid-b9460c55-a84d-415f-aaff-809df937d3fe Thyroid Hormones Common non-Genomic Effects in Hyperthyroidism uuid-b9460c55-a84d-415f-aaff-809df937d3fe PS:CellType generic PS:Description The molecular mechanism of action of thyroid hormones may be genomic or non-genomic. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9460c55-a84d-415f-aaff-809df937d3fe PS:NodeType Pathway PS:Notes Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. Signaling description: The molecular mechanism of action of thyroid hormones can be genomic or non-genomic. The non-genomic actions of thyroid hormones may be initiated at the plasma membrane, in the cytoplasm or at intracellular organelles such as mitochondria, and do not primarily involve thyroid hormone nuclear receptors. There are several mechanisms of non-genomic actions of thyroid hormones. Through the vitronectin receptor (integrin), thyroid hormones stimulate MAP2K1 and MAP2K2 (ERK1/2), AKT1, and the release of calcium (Ca2 ) through phospholipase PTK2. Thyroxine (T4) is unable to activate PI3K. In the cytoplasm, plasma membrane ion pumps are critical to cell function. Ca2 -ATPase and Na /K -ATPase are known to be regulated by thyroid hormones by both genomic and non-genomic mechanisms. The non-genomic effects of thyroid hormones on Ca2 pump (Ca2 -ATPase) activity have been documented. Further, triiodothyronine (T3) can bind to THRB in the cytoplasm. Lastly, PIK3CA and HIF1A transcription may be activated. Outcome effects: Complex cellular events induced by the integrin cell surface receptor include angiogenesis (endothelial and vascular smooth muscle cells) and tumor cell proliferation. Hyper- and hypothyroidism are associated with increased and decreased human erythrocyte Ca2 -ATPase activity, respectively. Cytoplasmic THRB activation is not linked to cell proliferation but to the shuttling of THRA from cytoplasm to nucleus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System endocrine system PS:Organ_System generic PS:PMID 17983645 PS:PMID 20051527 PS:PMID 22945636 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author CellType: cancer cell Description: Connexins, or gap-junctional proteins, play a significant role in communication, transport, and signaling between epithelial cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b950265b-fabc-4a06-a062-3985b25f64b6 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Connexins, or gap-junctional proteins, play a significant role in communication, transport, and signaling between epithelial cells. Connexin 32 (CX32, also known as GJB1) has been shown to be a tumor suppressor in several tissues such as liver and lung. It has been demonstrated that the expression and subsequent functioning of GJA1 (connexin 43, CX43) and GJB1 are down regulated in prostate cancer specimens compared to that in normal prostate. Forced expression of GJA1 and GJB1 in the androgen-responsive prostate cancer cell lines decreases the rate of growth and initiates differentiation. Outcome effects: There is also evidence that androgens control the expression of GJB1 by increasing its level and inducing gap junction formation. In the absence of androgens, GJB1 is degraded via an endoplasmic reticulum-associated degradation mechanism. In addition to androgens, transcription factor HNF1A is another positive regulator of GJB1 containing a site for this transcription factor in the GJB1 promoter region. Organ: prostate Organ_System: urinary tract PMID: 17520286 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin urn:agi-pathway:uuid-b950265b-fabc-4a06-a062-3985b25f64b6 Androgen Receptor/GJB1 Signaling uuid-b950265b-fabc-4a06-a062-3985b25f64b6 PS:CellType cancer cell PS:Description Connexins, or gap-junctional proteins, play a significant role in communication, transport, and signaling between epithelial cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b950265b-fabc-4a06-a062-3985b25f64b6 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Connexins, or gap-junctional proteins, play a significant role in communication, transport, and signaling between epithelial cells. Connexin 32 (CX32, also known as GJB1) has been shown to be a tumor suppressor in several tissues such as liver and lung. It has been demonstrated that the expression and subsequent functioning of GJA1 (connexin 43, CX43) and GJB1 are down regulated in prostate cancer specimens compared to that in normal prostate. Forced expression of GJA1 and GJB1 in the androgen-responsive prostate cancer cell lines decreases the rate of growth and initiates differentiation. Outcome effects: There is also evidence that androgens control the expression of GJB1 by increasing its level and inducing gap junction formation. In the absence of androgens, GJB1 is degraded via an endoplasmic reticulum-associated degradation mechanism. In addition to androgens, transcription factor HNF1A is another positive regulator of GJB1 containing a site for this transcription factor in the GJB1 promoter region. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 17520286 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9712812-d5e0-48cc-87ed-0dcddb7c06ad NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-b9712812-d5e0-48cc-87ed-0dcddb7c06ad IL2R -> STAT Signaling uuid-b9712812-d5e0-48cc-87ed-0dcddb7c06ad PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9712812-d5e0-48cc-87ed-0dcddb7c06ad PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: insulin-secreting cell Description: Maturity onset diabetes of young (MODY) is a monogenic and autosomal dominant form of diabetes mellitus with the onset of the disease often before 25 years of age. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9734d79-b7e8-4daa-a2e8-ba073376a369 NodeType: Pathway Notes: Headnote: Maturity onset diabetes of young (MODY) is a monogenic autosomal dominant form of diabetes mellitus with the onset of the disease usualy before 25 years of age. The disease is due to a dysfunction of the pancreatic beta-cells characterized by non-ketotic diabetes and the absence of pancreatic auto-antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus. The disease is rare and accounts for only 1-2% of all diabetes. Signaling description: There are 11 types of monogenic MODY. Specifically, MODY 1 is associated with a HNF4A mutation, whereas MODY 2 is associated with a GCK mutation and accounts for 30-50% of MODY cases. Further, MODY 3 is associated by a HNF1A mutation and also accounts for 30-50% of MODY cases. MODY 4 is associated with a PDX1 mutation, and MODY 5 is associated with a HNF1B mutation; while, MODY 6 is associated with a NEUROD1 mutation. Then, MODY 7 is associated with a KLF11 mutation and MODY 8 is associated with a bile salt dependent lipase (CEL) mutation (not shown). MODY 9 is associated with PAX4 mutation and MODY 10 is associated with INS mutation. Lastly, MODY 11 is associated with a mutation in the B-lymphocyte specific tyrosine kinase (BLK) (not shown). Outcome effects: Most of the described genes with mutations related to MODY encode transcription factors responsible for the development of pancreatic endocrine cells. GCK is an enzyme that phosphorylates glucose to glucose-6-phosphate as the rate-limiting step in glucose metabolism. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. References: 1). Attiya K., Sahar F (2012) Maturity-onset Diabetes of the Young (MODY) Genes: Literature Review.Clinical Practice 1(1): 4-11. Organ: pancreas Organ_System: endocrine system PMID: 22654519 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-b9734d79-b7e8-4daa-a2e8-ba073376a369 Maturity Onset Diabetes of the Young (MODY) uuid-b9734d79-b7e8-4daa-a2e8-ba073376a369 PS:CellType insulin-secreting cell PS:Description Maturity onset diabetes of young (MODY) is a monogenic and autosomal dominant form of diabetes mellitus with the onset of the disease often before 25 years of age. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9734d79-b7e8-4daa-a2e8-ba073376a369 PS:NodeType Pathway PS:Notes Headnote: Maturity onset diabetes of young (MODY) is a monogenic autosomal dominant form of diabetes mellitus with the onset of the disease usualy before 25 years of age. The disease is due to a dysfunction of the pancreatic beta-cells characterized by non-ketotic diabetes and the absence of pancreatic auto-antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus. The disease is rare and accounts for only 1-2% of all diabetes. Signaling description: There are 11 types of monogenic MODY. Specifically, MODY 1 is associated with a HNF4A mutation, whereas MODY 2 is associated with a GCK mutation and accounts for 30-50% of MODY cases. Further, MODY 3 is associated by a HNF1A mutation and also accounts for 30-50% of MODY cases. MODY 4 is associated with a PDX1 mutation, and MODY 5 is associated with a HNF1B mutation; while, MODY 6 is associated with a NEUROD1 mutation. Then, MODY 7 is associated with a KLF11 mutation and MODY 8 is associated with a bile salt dependent lipase (CEL) mutation (not shown). MODY 9 is associated with PAX4 mutation and MODY 10 is associated with INS mutation. Lastly, MODY 11 is associated with a mutation in the B-lymphocyte specific tyrosine kinase (BLK) (not shown). Outcome effects: Most of the described genes with mutations related to MODY encode transcription factors responsible for the development of pancreatic endocrine cells. GCK is an enzyme that phosphorylates glucose to glucose-6-phosphate as the rate-limiting step in glucose metabolism. Highlighted proteins: Entities with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. References: 1). Attiya K., Sahar F (2012) Maturity-onset Diabetes of the Young (MODY) Genes: Literature Review.Clinical Practice 1(1): 4-11. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22654519 PS:PathwayType signaling PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte CellType: stem cell Description: In AGA hair quiescence (telogen phase) stage in its growth cycle is prolonged. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9c188da-0860-41f4-adc0-7a42236a60d9 NodeType: Pathway Notes: Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss and is due to the shortening or absence of the anagen phase of hair growth. Signaling description: The three stages of hair growth include: active growth (anagen phase), hair follicle degeneration (catagen phase), and quiescence (telogen phase). At certain point, telogen phase ends and new hair growth cycle begins due to the activity of stem and stem-like cells. In androgenetic alopecia (AGA) patients, the catagen phase is initiated prematurely while the telogen phase is lengthened. Hair follicle miniaturization occurs and hair type changes from a thick and pigmented shaft to thin vellus hair. In the following cycle, anagen phase onset is often absent. The transition from telogen phase to anagen phase occurs due to stem and stem-like cells including the pool of pluripotent cells in the outer root sheath (bulge region) and progenitor cells adjacent to dermal papilla (DP) or secondary germ. Secondary germ cells arise from the bulge at the end of catagen. The activation of anagen occurs in two stages. First, secondary germ cells are activated; then they stimulate activation of multipotent keratinocyte progenitor cells (bulge region), which in turn are the main source for hair follicle matrix cell mass that further form all cellular layers of hair. Defects in the conversion of hair follicle stem cells to progenitor cells play a role in the pathogenesis of AGA. In bald areas in patients with AGA, there is a loss of progenitor cells such as CD200hiItga6hi and CD34hi cells, but not stem cells. A decrease in progenitor cell population by DP, possibly due to a lack of replenishment from bulge cells, could potentially result in diminished numbers of bulb matrix cells in the DP of the hair follicle and as a result the new (lower) hair follicle that forms at anagen onset is smaller than its predecessor in AGA. Telogen is the resting phase for the cells and major signaling pathways within. WNT signaling pathway which leads to cell proliferation is inactive, as well as BMP signaling pathway that leads to cell differentiation. Quiescence is provided by reciprocal inhibiting feedback loops in these signaling pathways where WNT suppresses BMP and BMP suppresses WNT. BMP2 and BMP4 gene expression, as well as the expression of DKK1 and SFRP4 genes inhibit the expression of WNT family genes; and thus, limit hair follicle development to the stage of refractory telogen. In patients with AGA, cells of DP, in the presence of androgens, produce excessive amounts of factors that inhibit WNT, such as DKK1. BMP signaling pathway suppresses itself by triggering the expression of NOG. It has been shown that FGF18 expression in the skin is also required for maintaining refractory telogen stage. Outcome effects: Typically, telogen ends and anagen begins when the balance shifts towards WNT signaling pathway activity. First, stocks of cells in the DP that produce WNT inhibiting signals become exhausted at the end of telogen. Second, the external signal capable of amplifying WNT expression in secondary germ is required for the initiation of a new cycle. The molecular signal and the cells that initiate the anagen phase are currently unknown. It is possible that the cells of the sebaceous gland or fibroblasts surrounding the hair follicle may be the origin of the initial stimulating signal. For instance, adipocytes secrete PDGFA that can activate WNT10B gene expression through the action of CREB1 transcription factor. WNT10B has been shown to promote hair-shaft growth via WNT/CTNNB1 signaling (canonical WNT signaling) pathway, and maintains the anagen phase. SHH signals may also be involved in the induction of WNT signaling (and anagen) in neighboring telogen hair follicle cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 15617565 PMID: 21206086 PMID: 21392083 PMID: 21527712 PMID: 21884937 PMID: 22293183 PMID: 22297635 PMID: 8934941 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-b9c188da-0860-41f4-adc0-7a42236a60d9 Telogen Maintenance in Androgenic Alopecia uuid-b9c188da-0860-41f4-adc0-7a42236a60d9 PS:CellType keratinocyte PS:CellType stem cell PS:Description In AGA hair quiescence (telogen phase) stage in its growth cycle is prolonged. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9c188da-0860-41f4-adc0-7a42236a60d9 PS:NodeType Pathway PS:Notes Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss and is due to the shortening or absence of the anagen phase of hair growth. Signaling description: The three stages of hair growth include: active growth (anagen phase), hair follicle degeneration (catagen phase), and quiescence (telogen phase). At certain point, telogen phase ends and new hair growth cycle begins due to the activity of stem and stem-like cells. In androgenetic alopecia (AGA) patients, the catagen phase is initiated prematurely while the telogen phase is lengthened. Hair follicle miniaturization occurs and hair type changes from a thick and pigmented shaft to thin vellus hair. In the following cycle, anagen phase onset is often absent. The transition from telogen phase to anagen phase occurs due to stem and stem-like cells including the pool of pluripotent cells in the outer root sheath (bulge region) and progenitor cells adjacent to dermal papilla (DP) or secondary germ. Secondary germ cells arise from the bulge at the end of catagen. The activation of anagen occurs in two stages. First, secondary germ cells are activated; then they stimulate activation of multipotent keratinocyte progenitor cells (bulge region), which in turn are the main source for hair follicle matrix cell mass that further form all cellular layers of hair. Defects in the conversion of hair follicle stem cells to progenitor cells play a role in the pathogenesis of AGA. In bald areas in patients with AGA, there is a loss of progenitor cells such as CD200hiItga6hi and CD34hi cells, but not stem cells. A decrease in progenitor cell population by DP, possibly due to a lack of replenishment from bulge cells, could potentially result in diminished numbers of bulb matrix cells in the DP of the hair follicle and as a result the new (lower) hair follicle that forms at anagen onset is smaller than its predecessor in AGA. Telogen is the resting phase for the cells and major signaling pathways within. WNT signaling pathway which leads to cell proliferation is inactive, as well as BMP signaling pathway that leads to cell differentiation. Quiescence is provided by reciprocal inhibiting feedback loops in these signaling pathways where WNT suppresses BMP and BMP suppresses WNT. BMP2 and BMP4 gene expression, as well as the expression of DKK1 and SFRP4 genes inhibit the expression of WNT family genes; and thus, limit hair follicle development to the stage of refractory telogen. In patients with AGA, cells of DP, in the presence of androgens, produce excessive amounts of factors that inhibit WNT, such as DKK1. BMP signaling pathway suppresses itself by triggering the expression of NOG. It has been shown that FGF18 expression in the skin is also required for maintaining refractory telogen stage. Outcome effects: Typically, telogen ends and anagen begins when the balance shifts towards WNT signaling pathway activity. First, stocks of cells in the DP that produce WNT inhibiting signals become exhausted at the end of telogen. Second, the external signal capable of amplifying WNT expression in secondary germ is required for the initiation of a new cycle. The molecular signal and the cells that initiate the anagen phase are currently unknown. It is possible that the cells of the sebaceous gland or fibroblasts surrounding the hair follicle may be the origin of the initial stimulating signal. For instance, adipocytes secrete PDGFA that can activate WNT10B gene expression through the action of CREB1 transcription factor. WNT10B has been shown to promote hair-shaft growth via WNT/CTNNB1 signaling (canonical WNT signaling) pathway, and maintains the anagen phase. SHH signals may also be involved in the induction of WNT signaling (and anagen) in neighboring telogen hair follicle cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15617565 PS:PMID 21206086 PS:PMID 21392083 PS:PMID 21527712 PS:PMID 21884937 PS:PMID 22293183 PS:PMID 22297635 PS:PMID 8934941 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9eb0aad-84f9-45e2-8052-e488134ecd3f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-b9eb0aad-84f9-45e2-8052-e488134ecd3f corneal nerve regeneration uuid-b9eb0aad-84f9-45e2-8052-e488134ecd3f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-b9eb0aad-84f9-45e2-8052-e488134ecd3f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba0b5408-9dc7-45bc-89bf-d4dcf8566b2b NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-ba0b5408-9dc7-45bc-89bf-d4dcf8566b2b Elevated Receptors -> Expression Targets in Lung uuid-ba0b5408-9dc7-45bc-89bf-d4dcf8566b2b PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba0b5408-9dc7-45bc-89bf-d4dcf8566b2b PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba4d6b03-09a0-4b27-8ac5-d2e38d86ae03 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-ba4d6b03-09a0-4b27-8ac5-d2e38d86ae03 Serine and Glycine Metabolism uuid-ba4d6b03-09a0-4b27-8ac5-d2e38d86ae03 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba4d6b03-09a0-4b27-8ac5-d2e38d86ae03 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba6c2b96-93bd-4096-ac24-d1df727cf7cd NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ba6c2b96-93bd-4096-ac24-d1df727cf7cd Proteins with Altered Expression in Parkinson's Disease uuid-ba6c2b96-93bd-4096-ac24-d1df727cf7cd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba6c2b96-93bd-4096-ac24-d1df727cf7cd PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: Astrocytoma is a malignant brain tumor that originates in a certain type of glial cells known as astrocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba9b82e6-b66f-4faf-8bb1-54e4580d5667 NodeType: Pathway Notes: Headnote: Astrocytoma is a malignant brain tumor that originates from a specific type of neuroglial cells called astrocytes. This type of tumor does not typically spread outside the brain and spinal cord and usually does not affect other organs. Astrocytomas are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord. The World Health Organization (WHO) system assigns astrocytomas a grade from I to IV, with I being the least aggressive and IV being the most aggressive. Signaling description: Pilocytic astrocytoma (WHO I) is a slow-growing tumor where activating BRAF mutations or inactivating NF1 mutations may be found in a subset of patients. Low-grade (diffuse) astrocytoma (WHO II) is characterized by TP53 mutations and/or PDGFRA amplification and overexpression. IDH1 mutations may also be observed in low-grade astrocytomas. Anaplastic astrocytoma (WHO III) is characterized by additional gain of CDK4/6 amplification and overexpression, as well as RB1 mutations. Additional genetic events lead to the development of glioblastoma multiforme (GBM, WHO IV). Outcome effects: The final tumorigenic events caused by these genetic alterations are the activation of proliferation and inhibition of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12702575 PMID: 17974913 PMID: 19554337 PMID: 23439714 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ba9b82e6-b66f-4faf-8bb1-54e4580d5667 Astrocytoma uuid-ba9b82e6-b66f-4faf-8bb1-54e4580d5667 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description Astrocytoma is a malignant brain tumor that originates in a certain type of glial cells known as astrocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba9b82e6-b66f-4faf-8bb1-54e4580d5667 PS:NodeType Pathway PS:Notes Headnote: Astrocytoma is a malignant brain tumor that originates from a specific type of neuroglial cells called astrocytes. This type of tumor does not typically spread outside the brain and spinal cord and usually does not affect other organs. Astrocytomas are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord. The World Health Organization (WHO) system assigns astrocytomas a grade from I to IV, with I being the least aggressive and IV being the most aggressive. Signaling description: Pilocytic astrocytoma (WHO I) is a slow-growing tumor where activating BRAF mutations or inactivating NF1 mutations may be found in a subset of patients. Low-grade (diffuse) astrocytoma (WHO II) is characterized by TP53 mutations and/or PDGFRA amplification and overexpression. IDH1 mutations may also be observed in low-grade astrocytomas. Anaplastic astrocytoma (WHO III) is characterized by additional gain of CDK4/6 amplification and overexpression, as well as RB1 mutations. Additional genetic events lead to the development of glioblastoma multiforme (GBM, WHO IV). Outcome effects: The final tumorigenic events caused by these genetic alterations are the activation of proliferation and inhibition of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12702575 PS:PMID 17974913 PS:PMID 19554337 PS:PMID 23439714 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba9df89e-15c6-471e-b624-69603a7211e6 NodeType: Pathway Notes: Headnote: Premature ovarian failure, also known as premature ovarian insufficiency, primary ovarian insufficiency, premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. It is characterized by amenorrhea, hypergonadotropinism, and hypoestrogenism. Mutations in several oocyte-specific genes may cause primary ovarian insufficiency, among them newborn ovary homeobox (NOBOX), factor in the germline alpha (FIGLA), bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), zona pellucida glycoprotein 1 (ZP1). Signaling description: NOBOX is a homeobox gene that is critical for specifying an oocyte-restricted gene expression pattern including OCT4 (POU5F1), ZAR1, GDF9, BMP15, and H1FOO transcripts. FIGLA is involved in formation of the primordial follicle. It is also involved in coordinating expression of the zona pellucida (ZP) genes. Regulators of the development of primordial to primary follicles also include spermatogenesis- and oogenesis-specific basic HLH1 (SOHLH1) and 2 (SOHLH2) transcription factors and Lim homeobox protein 8 (LHX8). All of these are expressed in the late embryonic and newborn ovaries, and knockout models lack primordial follicles and are sterile. SOHLH1 and SOHLH2 appear to be master-master regulators of other master transcription factors. Zona pellucida sperm-binding protein 1 is a protein that cross-links ZP2 and ZP3. Aberrant ZP1 results in sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte. Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 16143663 PMID: 16690745 PMID: 17701902 PMID: 18499083 PMID: 20364094 PMID: 21856374 PMID: 21896560 PMID: 24670168 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ba9df89e-15c6-471e-b624-69603a7211e6 Oocyte-Specific Gene Mutations in Primary Ovarian Insufficiency uuid-ba9df89e-15c6-471e-b624-69603a7211e6 PS:CellType oocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ba9df89e-15c6-471e-b624-69603a7211e6 PS:NodeType Pathway PS:Notes Headnote: Premature ovarian failure, also known as premature ovarian insufficiency, primary ovarian insufficiency, premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. It is characterized by amenorrhea, hypergonadotropinism, and hypoestrogenism. Mutations in several oocyte-specific genes may cause primary ovarian insufficiency, among them newborn ovary homeobox (NOBOX), factor in the germline alpha (FIGLA), bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), zona pellucida glycoprotein 1 (ZP1). Signaling description: NOBOX is a homeobox gene that is critical for specifying an oocyte-restricted gene expression pattern including OCT4 (POU5F1), ZAR1, GDF9, BMP15, and H1FOO transcripts. FIGLA is involved in formation of the primordial follicle. It is also involved in coordinating expression of the zona pellucida (ZP) genes. Regulators of the development of primordial to primary follicles also include spermatogenesis- and oogenesis-specific basic HLH1 (SOHLH1) and 2 (SOHLH2) transcription factors and Lim homeobox protein 8 (LHX8). All of these are expressed in the late embryonic and newborn ovaries, and knockout models lack primordial follicles and are sterile. SOHLH1 and SOHLH2 appear to be master-master regulators of other master transcription factors. Zona pellucida sperm-binding protein 1 is a protein that cross-links ZP2 and ZP3. Aberrant ZP1 results in sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte. Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 16143663 PS:PMID 16690745 PS:PMID 17701902 PS:PMID 18499083 PS:PMID 20364094 PS:PMID 21856374 PS:PMID 21896560 PS:PMID 24670168 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baac9d2e-ee4b-4b65-b36b-6119fa9f8adb NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-baac9d2e-ee4b-4b65-b36b-6119fa9f8adb TNFRSF1A -> CREB/ELK-SRF Signaling uuid-baac9d2e-ee4b-4b65-b36b-6119fa9f8adb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baac9d2e-ee4b-4b65-b36b-6119fa9f8adb PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SIRT7 is located in nucleolus of cells and regulates genes transcription. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baad01ac-ab1d-4c6d-9030-74b85c0476f7 NodeType: Pathway Notes: Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT7 is located in nucleolus of cells and regulates genes transcription. Signaling description: SIRT7 is an NAD+-dependent protein deacetylase which regulates RNA polymerase I transcription and pre-rRNA processing. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism. SIRT7 also plays a key role in maintenance of the epigenome by deacetylation of histone 3 (H3K18). SIRT7 participation was shown in control of ribosome biogenesis, mitochondrial gene expression, and hepatic lipid metabolism. Outcome effects: NAD+ dependency of SIRT7 can provide the link between metabolic activity and gene transcription and genome stability during aging. Animal data: Loss of Sirt7 in mice causes genomic instability and accelerated aging and induces cardiac hypertrophy. Organ: generic Organ_System: generic PMID: 17079682 PMID: 25435428 PMID: 28426094 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-baad01ac-ab1d-4c6d-9030-74b85c0476f7 SIRT7 Signaling in Aging uuid-baad01ac-ab1d-4c6d-9030-74b85c0476f7 PS:CellType generic PS:Description SIRT7 is located in nucleolus of cells and regulates genes transcription. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baad01ac-ab1d-4c6d-9030-74b85c0476f7 PS:NodeType Pathway PS:Notes Headnote: Sirtuins are proteins with deacetylase and/or ADP-ribosyltransferase activities. SIRT7 is located in nucleolus of cells and regulates genes transcription. Signaling description: SIRT7 is an NAD+-dependent protein deacetylase which regulates RNA polymerase I transcription and pre-rRNA processing. NAD+ is a classic co-enzyme that is synthesized from three major precursors - tryptophan, nicotinic acid, and nicotinamide. The level of NAD+ changes during oxidative stress or inflammation and probably with aging. SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism. SIRT7 also plays a key role in maintenance of the epigenome by deacetylation of histone 3 (H3K18). SIRT7 participation was shown in control of ribosome biogenesis, mitochondrial gene expression, and hepatic lipid metabolism. Outcome effects: NAD+ dependency of SIRT7 can provide the link between metabolic activity and gene transcription and genome stability during aging. Animal data: Loss of Sirt7 in mice causes genomic instability and accelerated aging and induces cardiac hypertrophy. PS:Organ generic PS:Organ_System generic PS:PMID 17079682 PS:PMID 25435428 PS:PMID 28426094 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bac42083-fc11-40b0-9b2e-981bbf004c20 NodeType: Pathway Notes: While there is evidence that DNA damage eventually leads to mTORC1 inhibition through p53-dependent mechanisms, there are also evidences that mTORC1 is activated following DNA damage. mTORC1 regulates the DNA damage response through the upregulation of FANCD2 gene expression, a key protein involved in the repair of DNA double-strand breaks. Organ: generic Organ_System: generic PMID: 23633493 PMID: 25460505 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-bac42083-fc11-40b0-9b2e-981bbf004c20 DNA Persistent Repair Inhibits mTOR Signaling uuid-bac42083-fc11-40b0-9b2e-981bbf004c20 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bac42083-fc11-40b0-9b2e-981bbf004c20 PS:NodeType Pathway PS:Notes While there is evidence that DNA damage eventually leads to mTORC1 inhibition through p53-dependent mechanisms, there are also evidences that mTORC1 is activated following DNA damage. mTORC1 regulates the DNA damage response through the upregulation of FANCD2 gene expression, a key protein involved in the repair of DNA double-strand breaks. PS:Organ generic PS:Organ_System generic PS:PMID 23633493 PS:PMID 25460505 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: CRH secretion is regulated by catecholamines, serotonin and several others biologically active substances. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bae9e3a9-7998-48a2-a0a0-775982d05586 NodeType: Pathway Notes: Headnote: Corticotropin-releasing hormone (CRH) is produced by parvocellular neuroendocrine cells (neurons) of the hypothalamus and released into the primary capillary plexus of the hypothalamo-hypophyseal portal system, where it regulates the production of ACTH and MSHs. Signaling description: Pathways activating CRH release are stress dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons. Norepinephrine/epinephrine, ADCYAP1 (adenylate cyclase-activating polypeptide) and beta-endorphin bind with ADRA1B, ADCYAP1R1 and OPRD1 and cause PLCB1/DAG/PKC/MAPKs/CREB1 signaling activation. Serotonin and ADCYAP1 stimulates ADCY/cAMP/PKA/CREB1 signaling via HTR4 and ADCYAP1R1. CREB1 promotes CRH expression. Glutamate and GABA through GRIN1 and GABRA1 regulate intracellular levels of Ca2+ and Cl- ions required for neuron function. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: CRH secretion is regulated by catecholamines, serotonin and several other biologically active substances. Animal data: Some of the data was revealed from animal model experiments Organ: brain Organ: hypothalamus Organ_System: nervous system PMID: 12600714 PMID: 12852256 PMID: 25612538 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-bae9e3a9-7998-48a2-a0a0-775982d05586 CRH Secretion Regulation uuid-bae9e3a9-7998-48a2-a0a0-775982d05586 PS:CellType neuron PS:Description CRH secretion is regulated by catecholamines, serotonin and several others biologically active substances. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bae9e3a9-7998-48a2-a0a0-775982d05586 PS:NodeType Pathway PS:Notes Headnote: Corticotropin-releasing hormone (CRH) is produced by parvocellular neuroendocrine cells (neurons) of the hypothalamus and released into the primary capillary plexus of the hypothalamo-hypophyseal portal system, where it regulates the production of ACTH and MSHs. Signaling description: Pathways activating CRH release are stress dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons. Norepinephrine/epinephrine, ADCYAP1 (adenylate cyclase-activating polypeptide) and beta-endorphin bind with ADRA1B, ADCYAP1R1 and OPRD1 and cause PLCB1/DAG/PKC/MAPKs/CREB1 signaling activation. Serotonin and ADCYAP1 stimulates ADCY/cAMP/PKA/CREB1 signaling via HTR4 and ADCYAP1R1. CREB1 promotes CRH expression. Glutamate and GABA through GRIN1 and GABRA1 regulate intracellular levels of Ca2+ and Cl- ions required for neuron function. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: CRH secretion is regulated by catecholamines, serotonin and several other biologically active substances. Animal data: Some of the data was revealed from animal model experiments PS:Organ brain PS:Organ hypothalamus PS:Organ_System nervous system PS:PMID 12600714 PS:PMID 12852256 PS:PMID 25612538 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: During S phase, each chromosome is replicated to produce two identical chromosomes termed sister chromatids. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baf70f5a-3348-4c92-b84e-374581d8d8ed NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. During the S phase, each chromosome is replicated to produce two identical chromosomes termed sister chromatids. Signaling description: Sister chromatids are paired along their entire length by the interaction of structural cohesins and the establishment factors. Cohesin is loaded onto chromatin in telophase and early G1 phase. The cohesin complex holds replicated sister chromatids together according to its ring shape which encircles and thereby topologically traps DNA. With the aid of accessory factors, such as PCNA, the replication fork-associated acetyltransferase ESCO1 facilitates its activation and thus cohesion between sisters is established. In mammalian cells, PDS5 retains centromeric cohesion and WAPAL facilitates the removal of centromeric cohesin. BUB1, through SGOL1, protects centromeric cohesin from the prophase cohesin removal pathway in a PP2A-dependent manner. At the beginning of metaphase, microtubules exert a pulling force on the chromosomes towards the opposite ends of the cells, while the cohesion between the sister chromatids oppose this force. PLK1 and AURKB are required for the chromosome-arm cohesin removal during metaphase. Outcome effects: When anaphase is imminent, cohesion is cleaved by ESPL1 followed by its release from the inhibitory partner, PTTG1 and the separated chromatids are pulled to opposite sides of the cell by the spindle microtubules. The physical movement of the spindle poles themselves causes further separation of the chromatids. MAD2L1 is a key effector of the spindle assembly checkpoint through the inhibition of APC/C. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-baf70f5a-3348-4c92-b84e-374581d8d8ed Sister Chromatid Cohesion uuid-baf70f5a-3348-4c92-b84e-374581d8d8ed PS:CellType generic PS:Description During S phase, each chromosome is replicated to produce two identical chromosomes termed sister chromatids. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baf70f5a-3348-4c92-b84e-374581d8d8ed PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. During the S phase, each chromosome is replicated to produce two identical chromosomes termed sister chromatids. Signaling description: Sister chromatids are paired along their entire length by the interaction of structural cohesins and the establishment factors. Cohesin is loaded onto chromatin in telophase and early G1 phase. The cohesin complex holds replicated sister chromatids together according to its ring shape which encircles and thereby topologically traps DNA. With the aid of accessory factors, such as PCNA, the replication fork-associated acetyltransferase ESCO1 facilitates its activation and thus cohesion between sisters is established. In mammalian cells, PDS5 retains centromeric cohesion and WAPAL facilitates the removal of centromeric cohesin. BUB1, through SGOL1, protects centromeric cohesin from the prophase cohesin removal pathway in a PP2A-dependent manner. At the beginning of metaphase, microtubules exert a pulling force on the chromosomes towards the opposite ends of the cells, while the cohesion between the sister chromatids oppose this force. PLK1 and AURKB are required for the chromosome-arm cohesin removal during metaphase. Outcome effects: When anaphase is imminent, cohesion is cleaved by ESPL1 followed by its release from the inhibitory partner, PTTG1 and the separated chromatids are pulled to opposite sides of the cell by the spindle microtubules. The physical movement of the spindle poles themselves causes further separation of the chromatids. MAD2L1 is a key effector of the spindle assembly checkpoint through the inhibition of APC/C. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baf7427c-125c-494c-924a-e169c04a4928 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-baf7427c-125c-494c-924a-e169c04a4928 Nitrate assimilation template uuid-baf7427c-125c-494c-924a-e169c04a4928 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-baf7427c-125c-494c-924a-e169c04a4928 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: goblet cell CellType: mucous cell Description: One of the general symptoms of cystic fibrosis (CF) is the increased synthesis and accumulation of mucoproteins in the respiratory and gastrointestinal tracts of CF patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb04b313-2986-40a9-872b-45a8807b05e8 NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. One of the general symptoms CF is the increased synthesis and accumulation of mucoproteins in the respiratory and gastrointestinal tracts of CF patients. Lung disease is the major cause of mortality of CF. Signaling description: In the lung, mucous glycoproteins or mucins are produced by two different cell types including goblet cells of the epithelium and mucous cells of the submucosal gland. TGFA and IL6 are the key cytokines that induce mucin biosynthesis. The expression of these cytokines is significantly increased in patients with CF due to the activation of NF-kB in lung cells. The activation of NF-kB occurs as the result of oxidative stress mediated by chemotaxis of neutrophils and the response of Toll-like receptors (TLRs) to the propagation of pathogens in lung tissues. Helper T-cells increase the production of IL13 in the airway environment in patients with CF. IL13 is a Th2-type cytokine released by activated T-cells, mast cells, and basophils in patients with CF. Outcome effects: Cytokine receptor signaling pathways activate the main transcription factors for mucin genes including Jun/Fos, STAT3, STAT6, SP1, and NF-kB. TLRs that activate their signaling after contacting pathogens in the lung also stimulate mucin synthesis. cAMP promotes mucin synthesis as well, but the details of this mechanism are poorly studied. In addition, free radicals that are abundant in the lungs of patients with CF also activate mucin synthesis. Excessive amounts of mucins in the lung prevent phagocytes and dendritic cells from binding and removing pathogens and cellular debris which maintains infection and inflammation. Mutated proteins: Mutated gene is shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 11860173 PMID: 17716382 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bb04b313-2986-40a9-872b-45a8807b05e8 Mucin Production in Goblet Airway Epithelial Cells uuid-bb04b313-2986-40a9-872b-45a8807b05e8 PS:CellType goblet cell PS:CellType mucous cell PS:Description One of the general symptoms of cystic fibrosis (CF) is the increased synthesis and accumulation of mucoproteins in the respiratory and gastrointestinal tracts of CF patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb04b313-2986-40a9-872b-45a8807b05e8 PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. One of the general symptoms CF is the increased synthesis and accumulation of mucoproteins in the respiratory and gastrointestinal tracts of CF patients. Lung disease is the major cause of mortality of CF. Signaling description: In the lung, mucous glycoproteins or mucins are produced by two different cell types including goblet cells of the epithelium and mucous cells of the submucosal gland. TGFA and IL6 are the key cytokines that induce mucin biosynthesis. The expression of these cytokines is significantly increased in patients with CF due to the activation of NF-kB in lung cells. The activation of NF-kB occurs as the result of oxidative stress mediated by chemotaxis of neutrophils and the response of Toll-like receptors (TLRs) to the propagation of pathogens in lung tissues. Helper T-cells increase the production of IL13 in the airway environment in patients with CF. IL13 is a Th2-type cytokine released by activated T-cells, mast cells, and basophils in patients with CF. Outcome effects: Cytokine receptor signaling pathways activate the main transcription factors for mucin genes including Jun/Fos, STAT3, STAT6, SP1, and NF-kB. TLRs that activate their signaling after contacting pathogens in the lung also stimulate mucin synthesis. cAMP promotes mucin synthesis as well, but the details of this mechanism are poorly studied. In addition, free radicals that are abundant in the lungs of patients with CF also activate mucin synthesis. Excessive amounts of mucins in the lung prevent phagocytes and dendritic cells from binding and removing pathogens and cellular debris which maintains infection and inflammation. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 11860173 PS:PMID 17716382 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb0acfc4-5ecd-4f11-81cd-cd2cdf54a994 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-bb0acfc4-5ecd-4f11-81cd-cd2cdf54a994 FGF,PDGF-+>myofibroblasts uuid-bb0acfc4-5ecd-4f11-81cd-cd2cdf54a994 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb0acfc4-5ecd-4f11-81cd-cd2cdf54a994 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Th17 cells produce mainly IL17, some IL22 and IL21, small amounts of IFNg, and no IL4. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb0b271c-69e6-4a5d-b934-a7b63a91b54c NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Th17 cells produce mostly IL17, a certain amount of IL22 and IL21, small amounts of IFNg, and no IL4. In asthma, IL17 is detectable in inflamed lungs. The percentages of Th17-cells are higher in allergic asthmatics than those in healthy subjects and show a tendency to increase with the disease severity. Th17 are a subset of T-helper cells which primarily produce the two major members of the IL17 family, IL-17A and IL17F involved in the recruitment, activation and neutrophil migration. In addition, these cells also secrete IL21 and IL22. In humans, a combination of TGFB, IL1B and IL23 induces Th17 differentiation from naive T-cells. Interleukin receptor, T-cell receptor and co-activator receptor (such as CD28) pathways activate transcriptional factors NfkB, STAT3, RORalpha and RORgamma for specific Th17 - related cytokines expression. Outcome effects: H IL17F induces CCL20 in bronchial epithelial cells. Human Th17 cells predominantly express the CCR6 receptor for CCL20 which is able to attract Th17 cells to the site of airway inflammation. This mechanism establishes a positive feedback loop resulting in the recruitment of additional Th17 cells via the induction of IL17F. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 20565710 PMID: 24829928 PMID: 24914235 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bb0b271c-69e6-4a5d-b934-a7b63a91b54c Th17-Cell Differentiation in Asthma uuid-bb0b271c-69e6-4a5d-b934-a7b63a91b54c PS:CellType T-cell PS:Description Th17 cells produce mainly IL17, some IL22 and IL21, small amounts of IFNg, and no IL4. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb0b271c-69e6-4a5d-b934-a7b63a91b54c PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Th17 cells produce mostly IL17, a certain amount of IL22 and IL21, small amounts of IFNg, and no IL4. In asthma, IL17 is detectable in inflamed lungs. The percentages of Th17-cells are higher in allergic asthmatics than those in healthy subjects and show a tendency to increase with the disease severity. Th17 are a subset of T-helper cells which primarily produce the two major members of the IL17 family, IL-17A and IL17F involved in the recruitment, activation and neutrophil migration. In addition, these cells also secrete IL21 and IL22. In humans, a combination of TGFB, IL1B and IL23 induces Th17 differentiation from naive T-cells. Interleukin receptor, T-cell receptor and co-activator receptor (such as CD28) pathways activate transcriptional factors NfkB, STAT3, RORalpha and RORgamma for specific Th17 - related cytokines expression. Outcome effects: H IL17F induces CCL20 in bronchial epithelial cells. Human Th17 cells predominantly express the CCR6 receptor for CCL20 which is able to attract Th17 cells to the site of airway inflammation. This mechanism establishes a positive feedback loop resulting in the recruitment of additional Th17 cells via the induction of IL17F. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 20565710 PS:PMID 24829928 PS:PMID 24914235 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb194498-d4f3-4049-8fa8-d0016b00f1c9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-bb194498-d4f3-4049-8fa8-d0016b00f1c9 BDNF->nociceptors phenotypic switch uuid-bb194498-d4f3-4049-8fa8-d0016b00f1c9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb194498-d4f3-4049-8fa8-d0016b00f1c9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb236006-a83b-4b87-946e-5272be3fd03a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-bb236006-a83b-4b87-946e-5272be3fd03a SARS clinical pathway uuid-bb236006-a83b-4b87-946e-5272be3fd03a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb236006-a83b-4b87-946e-5272be3fd03a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: In eukaryotes, DNA replication only takes place during S phase of the cell cycle; however, the primary initiation of replication occurs in G1 phase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb2b1ec7-0189-4bbc-a911-ed187472009e NodeType: Pathway Notes: Headnote: In eukaryotes, DNA replication only takes place during S phase of the cell cycle; however, the primary initiation of replication occurs in G1 phase. The binding of the origin of replication recognition complex (ORC) to certain DNA loci called origins of replication is necessary for replication initiation. In the subsequent step of initiation, ORC becomes bound to prereplication complex (pre-RC) that may contain at least 14 distinct proteins conserved in all eukaryotes including CDT1, CDC6, and MCM complex. Signaling description: When the process of DNA synthesis is activated, initiator complexes promote unwinding of double-stranded DNA and formation of replicative fork. Each parent DNA strand may be the matrix for synthesis of a new complementary strand. When DNA strands are separated, DNA polymerase alpha (POLA1) recruits RNA oligonucleotides (primers) and initiates new DNA chain synthesis. During replication, two growing strands (leading and lagging) are formed by different mechanisms of DNA synthesis. For the leading strand formation, one RNA primer per one active origin of replication is used, whereas the lagging strand synthesis requires several RNA primers to produce separate serial fragments of complementary DNA (Okazaki fragments). DNA polymerase epsilon (POLE) drives polymerization of DNA in the leading strand while DNA polymerase delta (Pol delta) synthesizes the lagging strand. The activity of the polymerases requires the participation of a complex that consists of PCNA, replication factor A, and DNA replication factor C proteins. These proteins form torus-shaped mobile platform that keeps Pol delta anchored on the DNA strand during the polymerization process. Outcome effects: When DNA synthesis is complete, FEN1, DNA2, and DNA ligase are recruited to fill a single nick in the leading strand and multiple nicks in the lagging strand. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-bb2b1ec7-0189-4bbc-a911-ed187472009e DNA Replication in DNA Machinery uuid-bb2b1ec7-0189-4bbc-a911-ed187472009e PS:CellType generic PS:Description In eukaryotes, DNA replication only takes place during S phase of the cell cycle; however, the primary initiation of replication occurs in G1 phase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb2b1ec7-0189-4bbc-a911-ed187472009e PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, DNA replication only takes place during S phase of the cell cycle; however, the primary initiation of replication occurs in G1 phase. The binding of the origin of replication recognition complex (ORC) to certain DNA loci called origins of replication is necessary for replication initiation. In the subsequent step of initiation, ORC becomes bound to prereplication complex (pre-RC) that may contain at least 14 distinct proteins conserved in all eukaryotes including CDT1, CDC6, and MCM complex. Signaling description: When the process of DNA synthesis is activated, initiator complexes promote unwinding of double-stranded DNA and formation of replicative fork. Each parent DNA strand may be the matrix for synthesis of a new complementary strand. When DNA strands are separated, DNA polymerase alpha (POLA1) recruits RNA oligonucleotides (primers) and initiates new DNA chain synthesis. During replication, two growing strands (leading and lagging) are formed by different mechanisms of DNA synthesis. For the leading strand formation, one RNA primer per one active origin of replication is used, whereas the lagging strand synthesis requires several RNA primers to produce separate serial fragments of complementary DNA (Okazaki fragments). DNA polymerase epsilon (POLE) drives polymerization of DNA in the leading strand while DNA polymerase delta (Pol delta) synthesizes the lagging strand. The activity of the polymerases requires the participation of a complex that consists of PCNA, replication factor A, and DNA replication factor C proteins. These proteins form torus-shaped mobile platform that keeps Pol delta anchored on the DNA strand during the polymerization process. Outcome effects: When DNA synthesis is complete, FEN1, DNA2, and DNA ligase are recruited to fill a single nick in the leading strand and multiple nicks in the lagging strand. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glycoprotein, is abundant in protein plasma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb2f32d2-1f4e-471d-ae62-02fefbecb844 NodeType: Pathway Notes: Headnote: Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glycoprotein, is an abundant in protein plasma. Plasma proteins are essential for several normal physiological processes including coagulation, fibrinolysis, angiogenesis, tissue remodeling, transport of nutrients, and the detection and clearance of pathogens and dead cells. Signaling description: In healthy human adults, proteins such as HRG that maintain homeostasis of the vascular system are often present at relatively high concentrations (100-150ng/mL) in the plasma to provide immediate responses to foreign pathogens and vascular damage. It has been reported that HRG acts as a negative acute phase protein (APP) and circulating HRG levels are significantly lower during acute inflammation. HRG serves multiple functions including regulating blood clotting and fibrinolysis. Outcome effects: HRG strongly inhibits F12 autoactivation via increased Zn2+ levels in response to local platelet activation. Through plasminogen (PLG) binding, HRG inhibits fibrinolysis by reducing the amount of circulating PLG available for activation into plasmin. Second to SERPINC1, HRG is one of the most abundant heparin-binding proteins in human plasma. It has been shown to neutralize the anticoagulant activity of heparin by preventing the formation of heparin/SERPINC1 complexes. In the presence of heparin, HRG inhibits the activity of SERPIND1. In addition, HRG inhibits human T-lymphocyte activation and inhibits the expression of IL2R on activated T-cells, which causes the declined release of T-cell IFNG and altered T-cell-dependent inhibition of erythropoiesis. HRG is also involved in the detection and clearance of pathogens and dead cells and has been shown to facilitate the removal of late (permeabilized plasma membrane) apoptotic and necrotic cells. Under normal physiological conditions, the rapid removal of dead cells from the circulation and tissues by phagocytic cells plays a critical role in maintaining tissue turnover. IgG forms immune complexes with target antigen and facilitates the clearance and neutralization of microorganisms, foreign substances, or necrotic cells. HRG has been shown to interact with IgG and complement component C1q and regulate the formation of insoluble immune complexes. A complex consisting of both HRG and IgG is necessary to aid necrotic cell uptake by macrophages. HRG also regulates macrophage function by modulating Fc-gamma receptor (FcgammaR) expression. Furthermore, HRG has been shown to inhibit angiogenesis by modulating various signaling events that are important for endothelial cell survival, proliferation, and cell migration. For example, HRG is involved in inhibiting proliferation and inducing apoptosis in endothelial cells in vitro through the activation of CASP3. HRG may act as pro-angiogenic modulator through the inhibition of the anti-angiogenic effect of THBS1. It also blocks the anti-angiogenic activity of THBS2 by preventing it from binding to CD36 receptor expressed on endothelial cells. Lastly, HRG can exhibit pro- or anti-angiogenic effects by competing with FGF2, an angiogenesis activator, for binding heparan sulfate on endothelial cells, which has been shown to be necessary for activating FGFR. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-bb2f32d2-1f4e-471d-ae62-02fefbecb844 Histidine-Rich Glycoprotein (HRG) in Inflammation uuid-bb2f32d2-1f4e-471d-ae62-02fefbecb844 PS:Description Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glycoprotein, is abundant in protein plasma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb2f32d2-1f4e-471d-ae62-02fefbecb844 PS:NodeType Pathway PS:Notes Headnote: Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glycoprotein, is an abundant in protein plasma. Plasma proteins are essential for several normal physiological processes including coagulation, fibrinolysis, angiogenesis, tissue remodeling, transport of nutrients, and the detection and clearance of pathogens and dead cells. Signaling description: In healthy human adults, proteins such as HRG that maintain homeostasis of the vascular system are often present at relatively high concentrations (100-150ng/mL) in the plasma to provide immediate responses to foreign pathogens and vascular damage. It has been reported that HRG acts as a negative acute phase protein (APP) and circulating HRG levels are significantly lower during acute inflammation. HRG serves multiple functions including regulating blood clotting and fibrinolysis. Outcome effects: HRG strongly inhibits F12 autoactivation via increased Zn2+ levels in response to local platelet activation. Through plasminogen (PLG) binding, HRG inhibits fibrinolysis by reducing the amount of circulating PLG available for activation into plasmin. Second to SERPINC1, HRG is one of the most abundant heparin-binding proteins in human plasma. It has been shown to neutralize the anticoagulant activity of heparin by preventing the formation of heparin/SERPINC1 complexes. In the presence of heparin, HRG inhibits the activity of SERPIND1. In addition, HRG inhibits human T-lymphocyte activation and inhibits the expression of IL2R on activated T-cells, which causes the declined release of T-cell IFNG and altered T-cell-dependent inhibition of erythropoiesis. HRG is also involved in the detection and clearance of pathogens and dead cells and has been shown to facilitate the removal of late (permeabilized plasma membrane) apoptotic and necrotic cells. Under normal physiological conditions, the rapid removal of dead cells from the circulation and tissues by phagocytic cells plays a critical role in maintaining tissue turnover. IgG forms immune complexes with target antigen and facilitates the clearance and neutralization of microorganisms, foreign substances, or necrotic cells. HRG has been shown to interact with IgG and complement component C1q and regulate the formation of insoluble immune complexes. A complex consisting of both HRG and IgG is necessary to aid necrotic cell uptake by macrophages. HRG also regulates macrophage function by modulating Fc-gamma receptor (FcgammaR) expression. Furthermore, HRG has been shown to inhibit angiogenesis by modulating various signaling events that are important for endothelial cell survival, proliferation, and cell migration. For example, HRG is involved in inhibiting proliferation and inducing apoptosis in endothelial cells in vitro through the activation of CASP3. HRG may act as pro-angiogenic modulator through the inhibition of the anti-angiogenic effect of THBS1. It also blocks the anti-angiogenic activity of THBS2 by preventing it from binding to CD36 receptor expressed on endothelial cells. Lastly, HRG can exhibit pro- or anti-angiogenic effects by competing with FGF2, an angiogenesis activator, for binding heparan sulfate on endothelial cells, which has been shown to be necessary for activating FGFR. Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb50a472-3325-412c-8f7e-5439c0add505 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bb50a472-3325-412c-8f7e-5439c0add505 Phenylketonuria Clinical Trials uuid-bb50a472-3325-412c-8f7e-5439c0add505 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb50a472-3325-412c-8f7e-5439c0add505 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb57a151-1e12-4fdf-9ce2-d65cd7e004cb NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-bb57a151-1e12-4fdf-9ce2-d65cd7e004cb Genes with Mutations Associated with Sleep Disorder uuid-bb57a151-1e12-4fdf-9ce2-d65cd7e004cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb57a151-1e12-4fdf-9ce2-d65cd7e004cb PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: melanocyte Description: Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb74d419-31df-4d2f-a135-f65e65b6d408 NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss. Hydrogen peroxide has been shown to be a competitive inhibitor of tyrosinase, therefore it may affect melanin production. Numerous other proteins are also affected by oxidative stress, thus multiplying the effect. Outcome effects: In addition to the disruption of melanogenesis, the accumulation of ROS in melanocytes may lead to melanocyte destruction through apoptosis, as well as the accumulation of misfolded proteins resulting from the endoplasmic reticulum stress and the production of an "eat-me" signal. Highlighted proteins: Entities with decreased level or activity are highlighted in blue, and entities with decreased level or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 20958268 PMID: 23425123 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-bb74d419-31df-4d2f-a135-f65e65b6d408 Oxidative Stress in Vitiligo uuid-bb74d419-31df-4d2f-a135-f65e65b6d408 PS:CellType melanocyte PS:Description Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb74d419-31df-4d2f-a135-f65e65b6d408 PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss. Hydrogen peroxide has been shown to be a competitive inhibitor of tyrosinase, therefore it may affect melanin production. Numerous other proteins are also affected by oxidative stress, thus multiplying the effect. Outcome effects: In addition to the disruption of melanogenesis, the accumulation of ROS in melanocytes may lead to melanocyte destruction through apoptosis, as well as the accumulation of misfolded proteins resulting from the endoplasmic reticulum stress and the production of an "eat-me" signal. Highlighted proteins: Entities with decreased level or activity are highlighted in blue, and entities with decreased level or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 20958268 PS:PMID 23425123 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb864ea7-7156-449b-a588-bbeb3be5d824 NodeType: Pathway Notes: The TLR-mediated virus-sensing mechanisms inside the endosomes may not be sufficient for detecting the viruses within the host cell. Organ: heart Organ_System: cardiovascular system PMID: 16125763 PMID: 16625202 PMID: 16713980 PMID: 19451363 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-bb864ea7-7156-449b-a588-bbeb3be5d824 MAVS in Antiviral Innate Immune Response in Myocarditis uuid-bb864ea7-7156-449b-a588-bbeb3be5d824 PS:CellType cardiac myocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bb864ea7-7156-449b-a588-bbeb3be5d824 PS:NodeType Pathway PS:Notes The TLR-mediated virus-sensing mechanisms inside the endosomes may not be sufficient for detecting the viruses within the host cell. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 16125763 PS:PMID 16625202 PS:PMID 16713980 PS:PMID 19451363 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron CellType: sensory hair cell Description: A number of genes, encoding proteins implicated in synaptogenesis and synapse function may be mutated in congenital hearing loss: OTOF, GIPC3, SLC17A8, CACNA1D, MYO6. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbb3cbc3-5603-4c7e-be74-4f1159fe46bb NodeType: Pathway Notes: Headnote: A number of genes, encoding proteins implicated in synaptogenesis and synapse function may be mutated in congenital hearing loss: otoferlin (OTOF), GIPC PDZ domain containing family, member 3 (GIPC3), solute carrier family 17, vesicular glutamate transporter, member 8 (SLC17A8), calcium channel, voltage-dependent, L type, alpha 1D subunit (CACNA1D), MYO6 (myosin VI). Signaling description: OTOF has been proposed to be the calcium sensor in hair cell exocytosis, compensating for the classic synaptic fusion proteins synaptotagmin-1 (SYT1) and synaptotagmin-2 (SYT2). OTOF binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin-1 (STX1A) and SNAP25. Mutations in OTOF cause prelingual deafness DFNB9 and temperature-sensitive synaptic hearing impairment. Myosin VI (MYO6) was shown to be a novel OTOF-binding partner. Unlike in other synapses, hair cell ribbon synapses use CaV1.3 L-type Ca2+ channels (CACNA1D) for stimulus-secretion coupling. Recently, a loss of function mutation in the CACNA1D gene has been identified in families with congenital deafness and bradycardia, signifying the importance of CaV1.3 for hearing and atrial pacemaking. A mutation of the CABP2 gene has been demonstrated to cause a moderate sensorineural hearing impairment. CABP2 might play a role in regulating CACNA1D and inner hair cell synaptic transmission. The glutamatergic ribbon synapses of hair cells use the transporter SLC17A8 (VGLUT3) to load their synaptic vesicles with glutamate. This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. GIPC3 distribution in hair cells is reminiscent of vesicular staining and shows a similar localization as SLC17A8 and MYO6, proteins that regulate synaptic glutamate release and Ca2 + -dependent exocytosis at the hair cell ribbon synapse. GIPC3 may be part of a protein complex involved in vesicle trafficking that transports factors critical for signal aquisition and propagation in cochlear hair cells. Age-related hearing loss (ARHL), also known as presbycusis, is a multifactorial symmetric sensorineural loss that affects adults older than 50 years of age. The causes of presbycusis are likely a combination of environmental and genetic factors. A few loci have been identified as having a likely role in susceptibility to ARHL, and GRM7 is the only gene that has achieved genome-wide significance. A 500K-single nucleotide polymorphism genome-wide association study of a large European cohort of older adults resulted in the identification of one haplotype within GRM7 as harboring a significant risk allele for ARHL. L-glutamate is the major excitatory neurotransmitter in the central nervous system, and it activates both ionotropic and metabotropic glutamate receptors. GRM7 is localized at the pre-synaptic membrane and was shown to inhibit cyclic AMP cascade and synaptic gluatamate exocytisis providing a negative feedback. Lack of GRM7 function leads to neuronal damage due to glutamate exitotoxicity resulting in hearing loss.Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ear Organ_System: sensory system PMID: 17055430 PMID: 19047183 PMID: 19417007 PMID: 21326233 PMID: 23102807 PMID: 23628789 PMID: 24146964 PMID: 25140308 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-bbb3cbc3-5603-4c7e-be74-4f1159fe46bb Cochlear Hair Cell Synapse Proteins Mutations (Age-Related/Congenital) uuid-bbb3cbc3-5603-4c7e-be74-4f1159fe46bb PS:CellType neuron PS:CellType sensory hair cell PS:Description A number of genes, encoding proteins implicated in synaptogenesis and synapse function may be mutated in congenital hearing loss: OTOF, GIPC3, SLC17A8, CACNA1D, MYO6. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbb3cbc3-5603-4c7e-be74-4f1159fe46bb PS:NodeType Pathway PS:Notes Headnote: A number of genes, encoding proteins implicated in synaptogenesis and synapse function may be mutated in congenital hearing loss: otoferlin (OTOF), GIPC PDZ domain containing family, member 3 (GIPC3), solute carrier family 17, vesicular glutamate transporter, member 8 (SLC17A8), calcium channel, voltage-dependent, L type, alpha 1D subunit (CACNA1D), MYO6 (myosin VI). Signaling description: OTOF has been proposed to be the calcium sensor in hair cell exocytosis, compensating for the classic synaptic fusion proteins synaptotagmin-1 (SYT1) and synaptotagmin-2 (SYT2). OTOF binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin-1 (STX1A) and SNAP25. Mutations in OTOF cause prelingual deafness DFNB9 and temperature-sensitive synaptic hearing impairment. Myosin VI (MYO6) was shown to be a novel OTOF-binding partner. Unlike in other synapses, hair cell ribbon synapses use CaV1.3 L-type Ca2+ channels (CACNA1D) for stimulus-secretion coupling. Recently, a loss of function mutation in the CACNA1D gene has been identified in families with congenital deafness and bradycardia, signifying the importance of CaV1.3 for hearing and atrial pacemaking. A mutation of the CABP2 gene has been demonstrated to cause a moderate sensorineural hearing impairment. CABP2 might play a role in regulating CACNA1D and inner hair cell synaptic transmission. The glutamatergic ribbon synapses of hair cells use the transporter SLC17A8 (VGLUT3) to load their synaptic vesicles with glutamate. This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. GIPC3 distribution in hair cells is reminiscent of vesicular staining and shows a similar localization as SLC17A8 and MYO6, proteins that regulate synaptic glutamate release and Ca2 + -dependent exocytosis at the hair cell ribbon synapse. GIPC3 may be part of a protein complex involved in vesicle trafficking that transports factors critical for signal aquisition and propagation in cochlear hair cells. Age-related hearing loss (ARHL), also known as presbycusis, is a multifactorial symmetric sensorineural loss that affects adults older than 50 years of age. The causes of presbycusis are likely a combination of environmental and genetic factors. A few loci have been identified as having a likely role in susceptibility to ARHL, and GRM7 is the only gene that has achieved genome-wide significance. A 500K-single nucleotide polymorphism genome-wide association study of a large European cohort of older adults resulted in the identification of one haplotype within GRM7 as harboring a significant risk allele for ARHL. L-glutamate is the major excitatory neurotransmitter in the central nervous system, and it activates both ionotropic and metabotropic glutamate receptors. GRM7 is localized at the pre-synaptic membrane and was shown to inhibit cyclic AMP cascade and synaptic gluatamate exocytisis providing a negative feedback. Lack of GRM7 function leads to neuronal damage due to glutamate exitotoxicity resulting in hearing loss.Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ear PS:Organ_System sensory system PS:PMID 17055430 PS:PMID 19047183 PS:PMID 19417007 PS:PMID 21326233 PS:PMID 23102807 PS:PMID 23628789 PS:PMID 24146964 PS:PMID 25140308 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbbd692f-c270-41df-b1cd-65d6a79a44b4 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bbbd692f-c270-41df-b1cd-65d6a79a44b4 EREG -> CTNNB/CTNND Expression Target uuid-bbbd692f-c270-41df-b1cd-65d6a79a44b4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbbd692f-c270-41df-b1cd-65d6a79a44b4 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbc5ce23-cfc4-4a90-b737-5411cfc9425a NodeType: Pathway Notes: Headnote: Mammalian oocytes reach prophase of first meiosis around the time of birth, and remain at this stage for months or years, depending on the species. Only after puberty the fully grown oocytes will begin to resume meiosis which is stimulated by gonadotropin. Signaling description: High level of intra-oocyte cyclic adenosine 3',5'-monophosphate (cAMP) prevents oocyte meiosis resumption. The oocyte-specific G-protein-coupled receptor 3 (GPR3) is essential in maintaining meiotic arrest in mammalian oocytes. GPR3, activated either constitutively or by an unknown ligand from the follicle cells, activates GNAS, which stimulates ADCY to cause an elevation of cAMP. cAMP activates protein kinase A (PKA), which ultimately causes the cell cycle regulatory complex, CDK1/cyclin B (CYB), to be phosphorylated and thereby inactivated. PKA (directly or indirectly) phosphorylate the phosphatase CDC25b (CDC25b-P). PKA may also stimulate the activity of the WEE1/MYT1 kinase that phosphorylates CDK1 to keep it inactive and prevent meiotic resumption. The activity of the cAMP phosphodiesterase, PDE3A, is thought to be kept low in the immature oocyte. cGMP also has been found to play important roles in maintaining oocyte meiosis arrest. cGMP in the follicular somatic cells diffuses into the oocyte and causes an increase in oocyte cAMP, presumably by acting on PDE3A. Animal data: Disruption of GPR3 in the knockout mouse determines LH-independent resumption of meiosis resulting in early depletion of oocytes and thus premature ovarian aging. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ovary Organ_System: reproductive system PMID: 16322539 PMID: 18184921 PMID: 20453035 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-bbc5ce23-cfc4-4a90-b737-5411cfc9425a GPR3 in Oocyte Meiotic Arrest uuid-bbc5ce23-cfc4-4a90-b737-5411cfc9425a PS:CellType oocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbc5ce23-cfc4-4a90-b737-5411cfc9425a PS:NodeType Pathway PS:Notes Headnote: Mammalian oocytes reach prophase of first meiosis around the time of birth, and remain at this stage for months or years, depending on the species. Only after puberty the fully grown oocytes will begin to resume meiosis which is stimulated by gonadotropin. Signaling description: High level of intra-oocyte cyclic adenosine 3',5'-monophosphate (cAMP) prevents oocyte meiosis resumption. The oocyte-specific G-protein-coupled receptor 3 (GPR3) is essential in maintaining meiotic arrest in mammalian oocytes. GPR3, activated either constitutively or by an unknown ligand from the follicle cells, activates GNAS, which stimulates ADCY to cause an elevation of cAMP. cAMP activates protein kinase A (PKA), which ultimately causes the cell cycle regulatory complex, CDK1/cyclin B (CYB), to be phosphorylated and thereby inactivated. PKA (directly or indirectly) phosphorylate the phosphatase CDC25b (CDC25b-P). PKA may also stimulate the activity of the WEE1/MYT1 kinase that phosphorylates CDK1 to keep it inactive and prevent meiotic resumption. The activity of the cAMP phosphodiesterase, PDE3A, is thought to be kept low in the immature oocyte. cGMP also has been found to play important roles in maintaining oocyte meiosis arrest. cGMP in the follicular somatic cells diffuses into the oocyte and causes an increase in oocyte cAMP, presumably by acting on PDE3A. Animal data: Disruption of GPR3 in the knockout mouse determines LH-independent resumption of meiosis resulting in early depletion of oocytes and thus premature ovarian aging. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 16322539 PS:PMID 18184921 PS:PMID 20453035 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbd6f117-467d-4a0a-aa21-22e38aaeac85 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bbd6f117-467d-4a0a-aa21-22e38aaeac85 CCL7 Expression Targets uuid-bbd6f117-467d-4a0a-aa21-22e38aaeac85 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbd6f117-467d-4a0a-aa21-22e38aaeac85 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbd9f392-5ca9-4b2e-9cf9-3592e31fa783 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bbd9f392-5ca9-4b2e-9cf9-3592e31fa783 ADAM17 Expression Targets uuid-bbd9f392-5ca9-4b2e-9cf9-3592e31fa783 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbd9f392-5ca9-4b2e-9cf9-3592e31fa783 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbdc31bd-bbcb-4de8-92eb-7942335b0c03 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bbdc31bd-bbcb-4de8-92eb-7942335b0c03 EGF -> MEF/MYOD/NFATC Expression Targets uuid-bbdc31bd-bbcb-4de8-92eb-7942335b0c03 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbdc31bd-bbcb-4de8-92eb-7942335b0c03 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbf685e1-e637-47a9-9553-56577aefb424 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-bbf685e1-e637-47a9-9553-56577aefb424 Proteins Involved in Astrocytoma uuid-bbf685e1-e637-47a9-9553-56577aefb424 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bbf685e1-e637-47a9-9553-56577aefb424 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc2c665f-2532-407f-91ec-959361cac1a9 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bc2c665f-2532-407f-91ec-959361cac1a9 Achondroplasia Anatomy and Molecular Biomarkers uuid-bc2c665f-2532-407f-91ec-959361cac1a9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc2c665f-2532-407f-91ec-959361cac1a9 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc2e4cb2-7869-4493-a591-c06716e7f3fa NodeType: Pathway Notes: Headnote: Haploid gametes are produced by reductive nuclear division of a diploid germ cell in a specialized process known as meiosis. Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males. Retinoic acid (RA) induces expression of the critical pre-meiosis gene STRA8 in germ cells of the fetal ovary, pubertal testis and adult testis. Signaling description: The mesonephros attached to the testis expresses RA synthesizing enzymes RALDH2/3 (ALDH1A2/3) resulting in the production of high levels of RA. RA binds RAR/RXRs on both identified RAREs of the STRA8 promoter to induce transcription. In the testis, Sertoli and interstitial cells express the RA degrading enzyme CYP26B1, preventing RA from stimulating STRA8 transcription and subsequent meiosis in testicular germ cells. Additionally, FGF9 produced by the Sertoli cells acts directly on testicular germ cells to inhibit meiosis. NANOS2 functions to block meiosis via the suppression of STRA8. NANOS2 is specifically expressed only in the male germ cells after they have colonized the genital ridges, where they undergo cell-cycle arrest at G1/G0. Outcome effects: Normally germ cell meiosis in males starts at puberty. Retinoic aci/STRA8 signaling was shown to be important for female gonadal development. Inhibition of STRA8 during embryogenesis in males is regarded to be important to shift towards male gonadal program. Organ: ovary Organ: testis Organ_System: reproductive system PMID: 17715177 PMID: 18430166 PMID: 24576537 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-bc2e4cb2-7869-4493-a591-c06716e7f3fa Retinoic Acid Signaling Inhibition in Pre-Puberty Block of Meiosis uuid-bc2e4cb2-7869-4493-a591-c06716e7f3fa PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc2e4cb2-7869-4493-a591-c06716e7f3fa PS:NodeType Pathway PS:Notes Headnote: Haploid gametes are produced by reductive nuclear division of a diploid germ cell in a specialized process known as meiosis. Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males. Retinoic acid (RA) induces expression of the critical pre-meiosis gene STRA8 in germ cells of the fetal ovary, pubertal testis and adult testis. Signaling description: The mesonephros attached to the testis expresses RA synthesizing enzymes RALDH2/3 (ALDH1A2/3) resulting in the production of high levels of RA. RA binds RAR/RXRs on both identified RAREs of the STRA8 promoter to induce transcription. In the testis, Sertoli and interstitial cells express the RA degrading enzyme CYP26B1, preventing RA from stimulating STRA8 transcription and subsequent meiosis in testicular germ cells. Additionally, FGF9 produced by the Sertoli cells acts directly on testicular germ cells to inhibit meiosis. NANOS2 functions to block meiosis via the suppression of STRA8. NANOS2 is specifically expressed only in the male germ cells after they have colonized the genital ridges, where they undergo cell-cycle arrest at G1/G0. Outcome effects: Normally germ cell meiosis in males starts at puberty. Retinoic aci/STRA8 signaling was shown to be important for female gonadal development. Inhibition of STRA8 during embryogenesis in males is regarded to be important to shift towards male gonadal program. PS:Organ ovary PS:Organ testis PS:Organ_System reproductive system PS:PMID 17715177 PS:PMID 18430166 PS:PMID 24576537 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc40974e-3058-4243-a6f9-55f9334e07c3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-bc40974e-3058-4243-a6f9-55f9334e07c3 Glycolisys template uuid-bc40974e-3058-4243-a6f9-55f9334e07c3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc40974e-3058-4243-a6f9-55f9334e07c3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc45ca98-4b2e-48b7-a7a6-9b5cc02b16e4 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-bc45ca98-4b2e-48b7-a7a6-9b5cc02b16e4 Proteins Involved in Osteopetrosis uuid-bc45ca98-4b2e-48b7-a7a6-9b5cc02b16e4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc45ca98-4b2e-48b7-a7a6-9b5cc02b16e4 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc52fef0-217a-4e74-ae69-57e25bcd2927 NodeType: Pathway Notes: Approximately 4% of the cases of adult-onset primary open-angle glaucoma and 10%–33% of juvenile-onset cases are associated with myocilin (MYOC) mutations. The misfolded MYOC protein ultimately activates a mitochondria-independent apoptosis pathway, which causes cell death and the subsequent breakdown of the trabecular meshwork cell structure, obstruction of the aqueous humor outflow pathway, and consequent elevation of intraocular pressure. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ: trabecular meshwork Organ_System: sensory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-bc52fef0-217a-4e74-ae69-57e25bcd2927 2_MYOC-associated glaucoma uuid-bc52fef0-217a-4e74-ae69-57e25bcd2927 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc52fef0-217a-4e74-ae69-57e25bcd2927 PS:NodeType Pathway PS:Notes Approximately 4% of the cases of adult-onset primary open-angle glaucoma and 10%–33% of juvenile-onset cases are associated with myocilin (MYOC) mutations. The misfolded MYOC protein ultimately activates a mitochondria-independent apoptosis pathway, which causes cell death and the subsequent breakdown of the trabecular meshwork cell structure, obstruction of the aqueous humor outflow pathway, and consequent elevation of intraocular pressure. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ trabecular meshwork PS:Organ_System sensory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc55e69c-bc3c-48b8-b9fe-fd14435a1dfc NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-bc55e69c-bc3c-48b8-b9fe-fd14435a1dfc Proteins Involved in Photoaging uuid-bc55e69c-bc3c-48b8-b9fe-fd14435a1dfc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc55e69c-bc3c-48b8-b9fe-fd14435a1dfc PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Environmental factors, such as infection, certain drugs, stress or smoking, can play a significant role in Hashimoto's thyroiditis progression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc57d7b6-f6d1-4f5c-a9f4-61194552eb21 NodeType: Pathway Notes: Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. Environmental factors, such as infection, certain drugs, stress or smoking, can play a significant role in HT progression. The close relationship between HT and either excessive iodine levels or selenium deficiency has been demonstrated. High levels of certain chemical agents have also been implicated in the incidence of goiter and autoimmune thyroiditis. Moreover, the components of several viruses (hepatitis C, human parvovirus B19, coxsackie, and herpes viruses) were detected in the thyroid of HT patients. The possible involvement of the oxidative stress profile in HT pathogenesis was also reported. Signaling description: Several putative mechanisms for iodine involvement in thyroid autoimmunity have been proposed. Firstly, iodine exposure leads to a higher iodination of the major thyroid antigen, thyroglobulin (TG) and thus increases its immunogenicity and enhances the binding affinity of the T-cell receptor which may lead to the specific T-cell activation. Iodine excess has also been shown to promote follicular cell apoptosis by inducing an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the thyroid. Iodine exposure has been shown to increase the level of reactive oxygen species (ROS) in the thyrocyte during TPO oxidation of excessive amounts of iodine. Recent advances have shown that selenium (Se) is very important for thyroid function. There are at least 30 selenium dependent proteins, including the glutathione peroxidase enzyme. A Se deficiency may cause a decrease in the activity of glutathione peroxidase and consequently to an increase in ROS levels. Lastly, chronic IFNA1 and other cytokine treatment may also provoke HT. Outcome effects: ROS enhance the expression of the intracellular adhesion molecule-1 (ICAM-1) on the thyroid follicular cells which attract the immunocompetent cells into the thyroid gland and initiate an immune reaction. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: thyroid gland Organ_System: endocrine system PMID: 11335880 PMID: 12728462 PMID: 15762980 PMID: 19707359 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bc57d7b6-f6d1-4f5c-a9f4-61194552eb21 Hashimoto's Thyroiditis Triggers uuid-bc57d7b6-f6d1-4f5c-a9f4-61194552eb21 PS:CellType thyroid cell PS:Description Environmental factors, such as infection, certain drugs, stress or smoking, can play a significant role in Hashimoto's thyroiditis progression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bc57d7b6-f6d1-4f5c-a9f4-61194552eb21 PS:NodeType Pathway PS:Notes Headnote: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease in which the thyroid gland is progressively destroyed. HT is one of the most common causes of hypothyroidism affecting 2-10% of the population, with women being more susceptible. Environmental factors, such as infection, certain drugs, stress or smoking, can play a significant role in HT progression. The close relationship between HT and either excessive iodine levels or selenium deficiency has been demonstrated. High levels of certain chemical agents have also been implicated in the incidence of goiter and autoimmune thyroiditis. Moreover, the components of several viruses (hepatitis C, human parvovirus B19, coxsackie, and herpes viruses) were detected in the thyroid of HT patients. The possible involvement of the oxidative stress profile in HT pathogenesis was also reported. Signaling description: Several putative mechanisms for iodine involvement in thyroid autoimmunity have been proposed. Firstly, iodine exposure leads to a higher iodination of the major thyroid antigen, thyroglobulin (TG) and thus increases its immunogenicity and enhances the binding affinity of the T-cell receptor which may lead to the specific T-cell activation. Iodine excess has also been shown to promote follicular cell apoptosis by inducing an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the thyroid. Iodine exposure has been shown to increase the level of reactive oxygen species (ROS) in the thyrocyte during TPO oxidation of excessive amounts of iodine. Recent advances have shown that selenium (Se) is very important for thyroid function. There are at least 30 selenium dependent proteins, including the glutathione peroxidase enzyme. A Se deficiency may cause a decrease in the activity of glutathione peroxidase and consequently to an increase in ROS levels. Lastly, chronic IFNA1 and other cytokine treatment may also provoke HT. Outcome effects: ROS enhance the expression of the intracellular adhesion molecule-1 (ICAM-1) on the thyroid follicular cells which attract the immunocompetent cells into the thyroid gland and initiate an immune reaction. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 11335880 PS:PMID 12728462 PS:PMID 15762980 PS:PMID 19707359 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcad73da-9ad2-4f70-b688-a6b9857d05db NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-bcad73da-9ad2-4f70-b688-a6b9857d05db GABA(B)R -> Postsynaptic Inhibition uuid-bcad73da-9ad2-4f70-b688-a6b9857d05db PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcad73da-9ad2-4f70-b688-a6b9857d05db PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: gastric D cell Description: Activation of somatostatin expression and release from Delta cells (D-cell). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcb0dc52-21f1-4280-bd10-5492e7f83151 NodeType: Pathway Notes: Headnote: Somatostatin (SST) is expressed in Delta cells (D-cells) under VIP control. Release of SST by D-cells is under the control of nutrients (L-amino acids and lysophosphatidic acid) and acetylcholine which is coming from vagus nerve. Signaling description: VIP activates transcription of SST through cAMP/PKA/CREB1 signaling. L-amino acids and lysophosphatidic acid receptors activate PCLE1 through specific G-proteins. Gastrin receptor (CCKBR) interacts with GNAQ and activates PCLE1. Also, acetylcholine which is secreted from post-ganglionic fibers of vagus nerve interacts with cholinergic receptor (CHRM3) and activates PLCE1. PLC induces PKC activation and causes non-selective vesicle exocytosis and secretion of SST. Outcome effects: Activation of acid sensing ion channel (ASIC1) by H+ leads to Ca2+ influx of and changes the membrane polarization state. Secreted SST inhibits gastrins expression from G-cells of stomach providing internal regulation feedback. Organ: colon Organ: intestine Organ: small intestine Organ: stomach Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-bcb0dc52-21f1-4280-bd10-5492e7f83151 D-cell: Somatostatin Release uuid-bcb0dc52-21f1-4280-bd10-5492e7f83151 PS:CellType gastric D cell PS:Description Activation of somatostatin expression and release from Delta cells (D-cell). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcb0dc52-21f1-4280-bd10-5492e7f83151 PS:NodeType Pathway PS:Notes Headnote: Somatostatin (SST) is expressed in Delta cells (D-cells) under VIP control. Release of SST by D-cells is under the control of nutrients (L-amino acids and lysophosphatidic acid) and acetylcholine which is coming from vagus nerve. Signaling description: VIP activates transcription of SST through cAMP/PKA/CREB1 signaling. L-amino acids and lysophosphatidic acid receptors activate PCLE1 through specific G-proteins. Gastrin receptor (CCKBR) interacts with GNAQ and activates PCLE1. Also, acetylcholine which is secreted from post-ganglionic fibers of vagus nerve interacts with cholinergic receptor (CHRM3) and activates PLCE1. PLC induces PKC activation and causes non-selective vesicle exocytosis and secretion of SST. Outcome effects: Activation of acid sensing ion channel (ASIC1) by H+ leads to Ca2+ influx of and changes the membrane polarization state. Secreted SST inhibits gastrins expression from G-cells of stomach providing internal regulation feedback. PS:Organ colon PS:Organ intestine PS:Organ small intestine PS:Organ stomach PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcd67b95-fef8-42de-8a58-720c1985f62c NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: joint Organ_System: skeletal system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: Cartilage urn:agi-pathway:uuid-bcd67b95-fef8-42de-8a58-720c1985f62c Elevated Receptors -> Expression Targets in Joint uuid-bcd67b95-fef8-42de-8a58-720c1985f62c PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcd67b95-fef8-42de-8a58-720c1985f62c PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ joint PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue Cartilage PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcf2fd0a-6140-45f4-92fb-3cbbfd75a223 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-bcf2fd0a-6140-45f4-92fb-3cbbfd75a223 Phenylalanine and Tyrosine Metabolism uuid-bcf2fd0a-6140-45f4-92fb-3cbbfd75a223 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcf2fd0a-6140-45f4-92fb-3cbbfd75a223 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcf46951-c5ef-4fe6-9707-1d4ee9e54250 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bcf46951-c5ef-4fe6-9707-1d4ee9e54250 TGFA/AP-1/ATF Expression Targets uuid-bcf46951-c5ef-4fe6-9707-1d4ee9e54250 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bcf46951-c5ef-4fe6-9707-1d4ee9e54250 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd13512a-7d30-4a04-8201-bba4b108cb56 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bd13512a-7d30-4a04-8201-bba4b108cb56 Thrombopoietin -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-bd13512a-7d30-4a04-8201-bba4b108cb56 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd13512a-7d30-4a04-8201-bba4b108cb56 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: In patients with SLE, Th2-related cytokines are increased, whereas Th1-related cytokines are decreased. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd16dedb-5960-4821-8259-60dc145df675 NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. At the same time, the role of Th1 and Th2 cytokines in the pathogenesis of SLE is controversial. In patients with SLE, Th2-related cytokines are increased, while Th1 cytokines are decreased. Thus, SLE was initially considered to be a Th2 predominant disease. However, it appears that Th1 or Th2 dominance depends on the stage of the disease and involvement. One of the possible mechanisms is through the increase in calcium levels. This occurs due to the pathological activation of SYK signaling. Outcome effects: At the end of the SYK signaling cascade, the expression of IL4, IL5, IL9, IL13, and CD40LG is up-regulated. Finally, the Th2 response promotes the production of high amounts of antibodies by B-lymphocytes and induces the survival of eosinophils. Highlighted proteins: Entities with increased level or activity are highlighted in red. Proteins with decreased expression or activity are highlighted in blue. Organ_System: lymphatic system PMID: 19355907 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-bd16dedb-5960-4821-8259-60dc145df675 Th2-Cell Function in Systemic Lupus Erythematosus uuid-bd16dedb-5960-4821-8259-60dc145df675 PS:CellType T-cell PS:Description In patients with SLE, Th2-related cytokines are increased, whereas Th1-related cytokines are decreased. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd16dedb-5960-4821-8259-60dc145df675 PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. Aberrant T-cell activation due to abnormal antigen presenting cell (APC) function is one of the main molecular pathological mechanisms in systemic lupus erythematosus (SLE). Signaling description: T-cells have a central role in the pathogenesis of SLE. At the same time, the role of Th1 and Th2 cytokines in the pathogenesis of SLE is controversial. In patients with SLE, Th2-related cytokines are increased, while Th1 cytokines are decreased. Thus, SLE was initially considered to be a Th2 predominant disease. However, it appears that Th1 or Th2 dominance depends on the stage of the disease and involvement. One of the possible mechanisms is through the increase in calcium levels. This occurs due to the pathological activation of SYK signaling. Outcome effects: At the end of the SYK signaling cascade, the expression of IL4, IL5, IL9, IL13, and CD40LG is up-regulated. Finally, the Th2 response promotes the production of high amounts of antibodies by B-lymphocytes and induces the survival of eosinophils. Highlighted proteins: Entities with increased level or activity are highlighted in red. Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System lymphatic system PS:PMID 19355907 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd1cb90c-80b3-4a15-9108-2dadbc4156a0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-bd1cb90c-80b3-4a15-9108-2dadbc4156a0 Randle cycle in Muscles uuid-bd1cb90c-80b3-4a15-9108-2dadbc4156a0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd1cb90c-80b3-4a15-9108-2dadbc4156a0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd551665-6f7a-4cad-867f-5ff8841bd287 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-bd551665-6f7a-4cad-867f-5ff8841bd287 Sulfoquinovosyl diacylglycerol synthesis (thylakoid) template uuid-bd551665-6f7a-4cad-867f-5ff8841bd287 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd551665-6f7a-4cad-867f-5ff8841bd287 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author PS:Source CellType: cancer stem cell CellType: endothelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd698794-32ad-40f8-9d7d-ec8e8df1ce59 NodeType: Pathway Organ: Blood Vessels PMID: 14699013 PMID: 16406676 PMID: 22553494 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-bd698794-32ad-40f8-9d7d-ec8e8df1ce59 Angiostatic cornea signaling uuid-bd698794-32ad-40f8-9d7d-ec8e8df1ce59 PS:CellType cancer stem cell PS:CellType endothelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd698794-32ad-40f8-9d7d-ec8e8df1ce59 PS:NodeType Pathway PS:Organ Blood Vessels PS:PMID 14699013 PS:PMID 16406676 PS:PMID 22553494 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd6a21b0-8679-4c66-82ad-8962a9d593c9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bd6a21b0-8679-4c66-82ad-8962a9d593c9 Epinephrine/Gs Expression Targets uuid-bd6a21b0-8679-4c66-82ad-8962a9d593c9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd6a21b0-8679-4c66-82ad-8962a9d593c9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd7353ea-abe9-432b-8786-b7eb68347526 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-bd7353ea-abe9-432b-8786-b7eb68347526 IL17RD Depended MAPK1/3 Activation uuid-bd7353ea-abe9-432b-8786-b7eb68347526 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd7353ea-abe9-432b-8786-b7eb68347526 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Extracellular Matrix (ECM) Reformation in aging is a changing of quantitative and structural characteristics of proteins secreted from cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd92cb01-6c0d-47e9-a85a-b281e2faf676 NodeType: Pathway Notes: Headnote: Extracellular Matrix (ECM) Reformation in aging is a changing of quantitative and structural characteristics of proteins secreted from cells. Pathology of extracellular matrix reformation in aging is characterized with reduction in the collagenous content and progressive degradation of the elastic fibers in derma; forming of insoluble proteins and cross-links between damaged and modified proteins; increase of connective tissue stiffness. Cross-links accumulation is caused with high frequency in such long-lived proteins as collagen by oxidative reactions with carbohydrates which lead to the formation of advanced glycation end-products (AGEs). Also hyperglycemia influences the formation of AGEs. Signaling description: The glycation reaction between a carbohydrate (e.g. glucose) - and a protein amino group (e.g., a collagen lysine side-chain) forms unstable Schiff base. The unstable Schiff base becomes a stable intermediate keto amine (Amadori product). After several months or years chemical reactions finish with generation of metabolic by-products of glycolysis, which interact with ECM and form AGEs. Glucosepane (a lysinearginine crosslink) is the most abundant AGEs in collagen tissues. LOX is needed for regulation the formation of stable inter-molecular crosslinks within individual type-I collagen fibrils. AGEs can bind to different types of receptors on cell surfaces and altered their signaling. Outcome effects: How AGEs and collagen-related altered extracellular matrix mechanics exactly links with increases tissue stiffness in aging is poorly understood. AGEs leads to mechanical cell damage and the impairment of the interaction of collagen with other molecules such as LOX and cell integrins. Such AGEs as carboxyethyllysine (CEL), carboxymethyllysine (CML), glyoxal lysine dimers (GOLD), methylglyoxal lysine dimers (MOLD) and pentosidine are increased in tissue collagen with age. CEL and CML could also be generated during peroxidation of polyunsaturated fatty acids in phospholipids. Animal data: Experiments data obtained mostly on animal models. Highlighted proteins: Small molecules with red highlights have increased quantity in aged organisms. For references see "Proteins with Altered Expression in Cell Processes Associated with Aging" pathway. Organ: generic Organ_System: generic PMID: 18442328 PMID: 23333925 PMID: 25489547 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-bd92cb01-6c0d-47e9-a85a-b281e2faf676 Extracellular Matrix Reformation in Aging uuid-bd92cb01-6c0d-47e9-a85a-b281e2faf676 PS:CellType generic PS:Description Extracellular Matrix (ECM) Reformation in aging is a changing of quantitative and structural characteristics of proteins secreted from cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd92cb01-6c0d-47e9-a85a-b281e2faf676 PS:NodeType Pathway PS:Notes Headnote: Extracellular Matrix (ECM) Reformation in aging is a changing of quantitative and structural characteristics of proteins secreted from cells. Pathology of extracellular matrix reformation in aging is characterized with reduction in the collagenous content and progressive degradation of the elastic fibers in derma; forming of insoluble proteins and cross-links between damaged and modified proteins; increase of connective tissue stiffness. Cross-links accumulation is caused with high frequency in such long-lived proteins as collagen by oxidative reactions with carbohydrates which lead to the formation of advanced glycation end-products (AGEs). Also hyperglycemia influences the formation of AGEs. Signaling description: The glycation reaction between a carbohydrate (e.g. glucose) - and a protein amino group (e.g., a collagen lysine side-chain) forms unstable Schiff base. The unstable Schiff base becomes a stable intermediate keto amine (Amadori product). After several months or years chemical reactions finish with generation of metabolic by-products of glycolysis, which interact with ECM and form AGEs. Glucosepane (a lysinearginine crosslink) is the most abundant AGEs in collagen tissues. LOX is needed for regulation the formation of stable inter-molecular crosslinks within individual type-I collagen fibrils. AGEs can bind to different types of receptors on cell surfaces and altered their signaling. Outcome effects: How AGEs and collagen-related altered extracellular matrix mechanics exactly links with increases tissue stiffness in aging is poorly understood. AGEs leads to mechanical cell damage and the impairment of the interaction of collagen with other molecules such as LOX and cell integrins. Such AGEs as carboxyethyllysine (CEL), carboxymethyllysine (CML), glyoxal lysine dimers (GOLD), methylglyoxal lysine dimers (MOLD) and pentosidine are increased in tissue collagen with age. CEL and CML could also be generated during peroxidation of polyunsaturated fatty acids in phospholipids. Animal data: Experiments data obtained mostly on animal models. Highlighted proteins: Small molecules with red highlights have increased quantity in aged organisms. For references see "Proteins with Altered Expression in Cell Processes Associated with Aging" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 18442328 PS:PMID 23333925 PS:PMID 25489547 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Periostin may be a systemic biomarker of airway eosinophilia in asthmatic patients. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd95a55d-aed9-4dc3-93ca-c2b045cc4738 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Periostin may be a systemic biomarker of airway eosinophilia in asthmatic patients. Signaling description: Serum periostin levels are significantly increased in asthmatic patients exhibiting eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. Periostin is a secreted matricellular protein associated with fibrosis, and its expression is upregulated by recombinant IL13 in cultured bronchial epithelial cells. Outcome effects: In human asthmatic patients, periostin expression levels correlate with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 25981515 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-bd95a55d-aed9-4dc3-93ca-c2b045cc4738 Periostin (POSTN) Production by Airway Epithelium in Asthma uuid-bd95a55d-aed9-4dc3-93ca-c2b045cc4738 PS:CellType epithelial cell PS:Description Periostin may be a systemic biomarker of airway eosinophilia in asthmatic patients. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bd95a55d-aed9-4dc3-93ca-c2b045cc4738 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Periostin may be a systemic biomarker of airway eosinophilia in asthmatic patients. Signaling description: Serum periostin levels are significantly increased in asthmatic patients exhibiting eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. Periostin is a secreted matricellular protein associated with fibrosis, and its expression is upregulated by recombinant IL13 in cultured bronchial epithelial cells. Outcome effects: In human asthmatic patients, periostin expression levels correlate with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 25981515 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdb52adf-05df-42ac-b671-efde0d91bac1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-bdb52adf-05df-42ac-b671-efde0d91bac1 PI remodeling uuid-bdb52adf-05df-42ac-b671-efde0d91bac1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdb52adf-05df-42ac-b671-efde0d91bac1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdb571ef-65d5-4a27-b7bc-2ffa30d9b200 NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. The acute phase characterized by eczematous skin lesions, is facilitated by allergen/IgE-bound Langerhans cells and infiltrating skin-homing Th2 cells. Eczematous skin lesions develop as a result of complex immune and inflammatory responses driven by the release of proinflammatory cytokines and chemokines from various resident cell types. Signaling description: Following contact with an antigen e.g. Staphylococcus aureus, during the elicitation phase, cutaneous professional antigen presenting cells migrate to regional lymph nodes, where they present the processed peptides to naive T-cells. In the presence of IL4, naive T-lymphocytes differentiate toward the Th2 phenotype and induce class switching of B- lymphocytes to IgE production. Outcome effects: Circulating IgE binds to high affinity IgE receptors on tissue resident mast cells. Acute skin lesions of patients with AD have increased amounts of cells positive for IL4, IL5, and IL13 mRNA compared to normal or uninvolved skin. In contrast, there are few IFNG or IL12 mRNA expressing cells in acute skin lesions of patients with AD. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 21249468 PMID: 22561834 PMID: 22939651 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-bdb571ef-65d5-4a27-b7bc-2ffa30d9b200 Acute Phase in Atopic Dermatitis uuid-bdb571ef-65d5-4a27-b7bc-2ffa30d9b200 PS:CellType T-cell PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdb571ef-65d5-4a27-b7bc-2ffa30d9b200 PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to ongoing swelling and redness. The acute phase characterized by eczematous skin lesions, is facilitated by allergen/IgE-bound Langerhans cells and infiltrating skin-homing Th2 cells. Eczematous skin lesions develop as a result of complex immune and inflammatory responses driven by the release of proinflammatory cytokines and chemokines from various resident cell types. Signaling description: Following contact with an antigen e.g. Staphylococcus aureus, during the elicitation phase, cutaneous professional antigen presenting cells migrate to regional lymph nodes, where they present the processed peptides to naive T-cells. In the presence of IL4, naive T-lymphocytes differentiate toward the Th2 phenotype and induce class switching of B- lymphocytes to IgE production. Outcome effects: Circulating IgE binds to high affinity IgE receptors on tissue resident mast cells. Acute skin lesions of patients with AD have increased amounts of cells positive for IL4, IL5, and IL13 mRNA compared to normal or uninvolved skin. In contrast, there are few IFNG or IL12 mRNA expressing cells in acute skin lesions of patients with AD. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 21249468 PS:PMID 22561834 PS:PMID 22939651 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of Hedgehog signaling pathway contributes to uncontrolled cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdd1c90f-cacb-43e0-a965-7637a0bfcf6a NodeType: Pathway Notes: Headnote: The Hedgehog (Hh) pathway regulates cell proliferation, differentiation and the development of tissues in embryogenesis; it is mostly inhibited in adults but can become reactivated in cancer. Signaling description: In the absence of Hh ligand (SHH), Patched (PTCH) inhibits the activity of Smoothened (SMO), whose localization at the cell surface is essential to its function. Full-length GLI proteins are proteolytically cleaved to produce GLIR, derived mostly from GLI3, which represses Hh target genes. Binding of Hh to PTCH leads to its internalization and destabilization, so it no longer can carry the endogenous SMO agonist molecules outwards. The release of SMO inhibition leads to the production of GLIA, derived mostly from GLI2 ensuing the expression of the Hh target gene. Activating mutations in the SMO gene and overexpression of SHH and GLI1/2 lead to permanent Hh signaling stimulation in cancer cells. Outcome effects: Constant activation of Hh in cancer leads to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 19081070 PMID: 20696410 PMID: 21192841 PMID: 21789137 PMID: 24550577 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-bdd1c90f-cacb-43e0-a965-7637a0bfcf6a Hedgehog Signaling Activation by Blocking of Tumor Suppressors uuid-bdd1c90f-cacb-43e0-a965-7637a0bfcf6a PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of Hedgehog signaling pathway contributes to uncontrolled cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bdd1c90f-cacb-43e0-a965-7637a0bfcf6a PS:NodeType Pathway PS:Notes Headnote: The Hedgehog (Hh) pathway regulates cell proliferation, differentiation and the development of tissues in embryogenesis; it is mostly inhibited in adults but can become reactivated in cancer. Signaling description: In the absence of Hh ligand (SHH), Patched (PTCH) inhibits the activity of Smoothened (SMO), whose localization at the cell surface is essential to its function. Full-length GLI proteins are proteolytically cleaved to produce GLIR, derived mostly from GLI3, which represses Hh target genes. Binding of Hh to PTCH leads to its internalization and destabilization, so it no longer can carry the endogenous SMO agonist molecules outwards. The release of SMO inhibition leads to the production of GLIA, derived mostly from GLI2 ensuing the expression of the Hh target gene. Activating mutations in the SMO gene and overexpression of SHH and GLI1/2 lead to permanent Hh signaling stimulation in cancer cells. Outcome effects: Constant activation of Hh in cancer leads to uncontrolled cell proliferation. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 19081070 PS:PMID 20696410 PS:PMID 21192841 PS:PMID 21789137 PS:PMID 24550577 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bde8e268-8b44-4a73-bba1-765aca38eca9 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: musculoskeletal system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: muscle urn:agi-pathway:uuid-bde8e268-8b44-4a73-bba1-765aca38eca9 Elevated Receptors -> Expression Targets in Muscle uuid-bde8e268-8b44-4a73-bba1-765aca38eca9 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bde8e268-8b44-4a73-bba1-765aca38eca9 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System musculoskeletal system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue muscle PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be049a1c-51a5-48e6-b24e-77046f778ae8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-be049a1c-51a5-48e6-b24e-77046f778ae8 ACE+>inflammation uuid-be049a1c-51a5-48e6-b24e-77046f778ae8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be049a1c-51a5-48e6-b24e-77046f778ae8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be06e7f8-4f42-42e8-9a62-1e5f5c080cce NodeType: Pathway Notes: cAMP signaling regulates exocytosis in different secretory cells basically by activation PKA. Organ: brain Organ_System: nervous system PMID: 16183914 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-be06e7f8-4f42-42e8-9a62-1e5f5c080cce High Fat Diet Activates cAMP Related Exocytosis in Synapse and Endocrine Cell uuid-be06e7f8-4f42-42e8-9a62-1e5f5c080cce PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be06e7f8-4f42-42e8-9a62-1e5f5c080cce PS:NodeType Pathway PS:Notes cAMP signaling regulates exocytosis in different secretory cells basically by activation PKA. PS:Organ brain PS:Organ_System nervous system PS:PMID 16183914 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: sebocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be37b20e-fdbf-4dfa-9180-78eb02cb6f9f NodeType: Pathway Notes: Various factors stimulate sebocyte proliferation and provoke enlargement of the sebaceous gland. Among them are proinflammatory proteins, milk consumption, and hormones. Another inducer of this process is reactive oxygen species (ROS). P. acnes also contributes to this process by producing free fatty acids and activating the nuclear transcription factors PPARA and PPARG. The amplified proliferation of sebocytes causes growth of the sebaceous glands and is one of the main reasons for the formation of lesions in acne vulgaris. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-be37b20e-fdbf-4dfa-9180-78eb02cb6f9f 2_Hyperseborrhea in acne vulgaris uuid-be37b20e-fdbf-4dfa-9180-78eb02cb6f9f PS:CellType sebocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be37b20e-fdbf-4dfa-9180-78eb02cb6f9f PS:NodeType Pathway PS:Notes Various factors stimulate sebocyte proliferation and provoke enlargement of the sebaceous gland. Among them are proinflammatory proteins, milk consumption, and hormones. Another inducer of this process is reactive oxygen species (ROS). P. acnes also contributes to this process by producing free fatty acids and activating the nuclear transcription factors PPARA and PPARG. The amplified proliferation of sebocytes causes growth of the sebaceous glands and is one of the main reasons for the formation of lesions in acne vulgaris. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: TLR2-induced synovial fibroblast activation is commonly seen in rheumatoid arthritis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be39d325-ab38-4b14-997c-571395992bf4 NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: TLR2-induced synovial fibroblast activation is commonly seen in rheumatoid arthritis. IL1B, TNF, and lipopolysaccharide (LPS) induce increased expression of TLR2 on the synovial fibroblast surface in rheumatoid arthritis. Signal transduction occurs through TIRAP, MYD88, and TICAM proteins. MYD88 binds to IRAK4 and thereby facilitates IRAK4 phosphorylation of IRAK1 which triggers IRAK1 activation. IRAK1 and TICAM1 recruit TRAF6, which (through MAP3K7) leads to MAPK1 and MAPK8 activation, which in turn phosphorylate JUN and FOS transcription factors. NF-kB is involved in the signaling through the IKBKB inhibition. Outcome effects: The transcription factors JUN, FOS, and NF-kB promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), CXCL2, IL8, ICAM1 (recruitment of inflammatory cells in the synovium that leads to pannus formation), IL6 (osteoclast activation and bone resorption), and VEGFA (new vessel growth). Lastly, CXCL10, CCL5, CCL20, and IFNB1 are responsible for other immune reactions in RA. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 11759230 PMID: 15353290 PMID: 16824621 PMID: 17549500 PMID: 20739221 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-be39d325-ab38-4b14-997c-571395992bf4 TLR2 Induced Synovial Fibroblast Activation in Rheumatoid Arthritis uuid-be39d325-ab38-4b14-997c-571395992bf4 PS:CellType fibroblast PS:Description TLR2-induced synovial fibroblast activation is commonly seen in rheumatoid arthritis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be39d325-ab38-4b14-997c-571395992bf4 PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: TLR2-induced synovial fibroblast activation is commonly seen in rheumatoid arthritis. IL1B, TNF, and lipopolysaccharide (LPS) induce increased expression of TLR2 on the synovial fibroblast surface in rheumatoid arthritis. Signal transduction occurs through TIRAP, MYD88, and TICAM proteins. MYD88 binds to IRAK4 and thereby facilitates IRAK4 phosphorylation of IRAK1 which triggers IRAK1 activation. IRAK1 and TICAM1 recruit TRAF6, which (through MAP3K7) leads to MAPK1 and MAPK8 activation, which in turn phosphorylate JUN and FOS transcription factors. NF-kB is involved in the signaling through the IKBKB inhibition. Outcome effects: The transcription factors JUN, FOS, and NF-kB promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), CXCL2, IL8, ICAM1 (recruitment of inflammatory cells in the synovium that leads to pannus formation), IL6 (osteoclast activation and bone resorption), and VEGFA (new vessel growth). Lastly, CXCL10, CCL5, CCL20, and IFNB1 are responsible for other immune reactions in RA. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11759230 PS:PMID 15353290 PS:PMID 16824621 PS:PMID 17549500 PS:PMID 20739221 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Tissue bone tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be61e486-8641-4f9a-a474-d6cb59bb1900 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-be61e486-8641-4f9a-a474-d6cb59bb1900 ANS->Lacrimation overview uuid-be61e486-8641-4f9a-a474-d6cb59bb1900 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be61e486-8641-4f9a-a474-d6cb59bb1900 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be6259f1-0464-4f59-aa58-cfbda7233354 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-be6259f1-0464-4f59-aa58-cfbda7233354 NGF -> SMAD3/NF-kB Expression Targets uuid-be6259f1-0464-4f59-aa58-cfbda7233354 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be6259f1-0464-4f59-aa58-cfbda7233354 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Nephrolithiasis is a process of forming stones in kidneys. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be8699ab-1494-4e29-9d48-ae01bdc8b3d5 NodeType: Pathway Notes: Nephrolithiasis is a process of forming stones in kidneys. Acid-base homeostasis is critical for normal kidney physiology. Alkaline urine reduces solubility of calcium and phosphate products and promotes formation of kidney stones. Organ: kidney Organ_System: urinary tract PMID: 21170875 PMID: 26597304 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-be8699ab-1494-4e29-9d48-ae01bdc8b3d5 Alkalosis uuid-be8699ab-1494-4e29-9d48-ae01bdc8b3d5 PS:CellType epithelial cell PS:Description Nephrolithiasis is a process of forming stones in kidneys. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be8699ab-1494-4e29-9d48-ae01bdc8b3d5 PS:NodeType Pathway PS:Notes Nephrolithiasis is a process of forming stones in kidneys. Acid-base homeostasis is critical for normal kidney physiology. Alkaline urine reduces solubility of calcium and phosphate products and promotes formation of kidney stones. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 21170875 PS:PMID 26597304 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Apoptosis is the genetically programmed pathway of cell death. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be878e67-d551-45ea-a23d-6170599173a9 NodeType: Pathway Notes: Headnote: Apoptosis is the genetically regulated programmed cell death which occurs in mulaticellular organisms as part of their normal development and functioning. There are at least two broad pathways, extrinsic and intrinsic, leading to apoptosis. In both pathways, the signaling results in activation of caspases which act in a proteolytic cascade to dismantle and remove the dying cell. Signaling description: The extrinsic pathway begins outside the cell and is often related to the signaling of death receptors (DR). The members of the DR family that have been thoroughly studied are TNFRSF10A, TNFRSF10B, TNFRSF1A, TNFRSF25, FAS, EDAR, and NGFR. They are distinguished by a cytoplasmic region termed the death domain (DD). When these receptors are coupled with their corresponding ligands, a number of molecules are recruited to the DD and activate the downstream signaling cascade. FAS, TNFRSF10A, and TNFRSF10B interact with FADD which activates CASP8. CASP10 is activated by a similar mechanism. Active CASP8 then triggers downstream caspases such as CASP3 and CASP7. TNFRSF1A, TNFRSF25, EDAR, and NGFR recruit TRADD as a platform adaptor and, in turn, assemble alternative signaling complexes through secondary adaptors. The intrinsic apoptosis pathway begins when an injury occurs within the cell and is often referred to as the mitochondrial pathway of apoptosis. CASP8, activated through DR signaling, can cleave BID protein which is a member of BCL2 family proteins in the mitochondrial membrane. BCL2 family proteins have an essential role in the life-or-death choice in the cellular fate. The BCL2 family includes both anti- and proapoptotic members and the balance between their activities regulate the release of apoptosis-promoting compounds such as AIFM1, ENDOG, DIABLO, and cytochrome c (CYCS) from mitochondria. In addition to DRs, growth factors also influence mitochondrial apoptosis via PI3K and AKT1 pathways. AKT1 is important in BAD regulation, which is a proapoptotic member of the BCL2 family and is involved in mitochondrial apoptosis. Outcome effects: CYCS is released from mitochondria to bind APAF1. This interaction forms a heptamer protein complex called the apoptosome which can bind to seven molecules of CASP9. Active CASP9 can cleave and consequently activate CASP3. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-be878e67-d551-45ea-a23d-6170599173a9 Apoptosis uuid-be878e67-d551-45ea-a23d-6170599173a9 PS:CellType generic PS:Description Apoptosis is the genetically programmed pathway of cell death. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-be878e67-d551-45ea-a23d-6170599173a9 PS:NodeType Pathway PS:Notes Headnote: Apoptosis is the genetically regulated programmed cell death which occurs in mulaticellular organisms as part of their normal development and functioning. There are at least two broad pathways, extrinsic and intrinsic, leading to apoptosis. In both pathways, the signaling results in activation of caspases which act in a proteolytic cascade to dismantle and remove the dying cell. Signaling description: The extrinsic pathway begins outside the cell and is often related to the signaling of death receptors (DR). The members of the DR family that have been thoroughly studied are TNFRSF10A, TNFRSF10B, TNFRSF1A, TNFRSF25, FAS, EDAR, and NGFR. They are distinguished by a cytoplasmic region termed the death domain (DD). When these receptors are coupled with their corresponding ligands, a number of molecules are recruited to the DD and activate the downstream signaling cascade. FAS, TNFRSF10A, and TNFRSF10B interact with FADD which activates CASP8. CASP10 is activated by a similar mechanism. Active CASP8 then triggers downstream caspases such as CASP3 and CASP7. TNFRSF1A, TNFRSF25, EDAR, and NGFR recruit TRADD as a platform adaptor and, in turn, assemble alternative signaling complexes through secondary adaptors. The intrinsic apoptosis pathway begins when an injury occurs within the cell and is often referred to as the mitochondrial pathway of apoptosis. CASP8, activated through DR signaling, can cleave BID protein which is a member of BCL2 family proteins in the mitochondrial membrane. BCL2 family proteins have an essential role in the life-or-death choice in the cellular fate. The BCL2 family includes both anti- and proapoptotic members and the balance between their activities regulate the release of apoptosis-promoting compounds such as AIFM1, ENDOG, DIABLO, and cytochrome c (CYCS) from mitochondria. In addition to DRs, growth factors also influence mitochondrial apoptosis via PI3K and AKT1 pathways. AKT1 is important in BAD regulation, which is a proapoptotic member of the BCL2 family and is involved in mitochondrial apoptosis. Outcome effects: CYCS is released from mitochondria to bind APAF1. This interaction forms a heptamer protein complex called the apoptosome which can bind to seven molecules of CASP9. Active CASP9 can cleave and consequently activate CASP3. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bea907c1-0e6e-4a57-9edf-159211bc0f66 NodeType: Pathway Notes: Nephrolithiasis is a process of forming stones in kidneys. Organ: kidney Organ_System: urinary tract PMID: 19198886 PMID: 24376311 PMID: 25504362 PMID: 25905296 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-bea907c1-0e6e-4a57-9edf-159211bc0f66 Ions Reabsorption Dysregulation in Nephrolithiasis uuid-bea907c1-0e6e-4a57-9edf-159211bc0f66 PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bea907c1-0e6e-4a57-9edf-159211bc0f66 PS:NodeType Pathway PS:Notes Nephrolithiasis is a process of forming stones in kidneys. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 19198886 PS:PMID 24376311 PS:PMID 25504362 PS:PMID 25905296 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Effects of oxytocin on transcription activation and manifestation of symptoms of autistic disorder, the (Hypothesis). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-beb8af81-c3a5-491d-b1c6-6033e2c708f2 NodeType: Pathway Notes: Oxytocin is involved in transcriptional activation of genes involved in manifestation of autism symptoms (a (Hypothesis)). Organ: brain Organ_System: nervous system PMID: 22245314 PMID: 22986294 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-beb8af81-c3a5-491d-b1c6-6033e2c708f2 Oxytocin Signaling in Brain Nerve Cell (Hypothesis) uuid-beb8af81-c3a5-491d-b1c6-6033e2c708f2 PS:CellType neuron PS:Description Effects of oxytocin on transcription activation and manifestation of symptoms of autistic disorder, the (Hypothesis). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-beb8af81-c3a5-491d-b1c6-6033e2c708f2 PS:NodeType Pathway PS:Notes Oxytocin is involved in transcriptional activation of genes involved in manifestation of autism symptoms (a (Hypothesis)). PS:Organ brain PS:Organ_System nervous system PS:PMID 22245314 PS:PMID 22986294 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: High-grade serous ovarian carcinomas (HGSOC) are the most common and lethal form of Ovarian Cancers. HGSOC displays distinct genetic instability and mutations in TP53, BRCA1, and BRCA2 genes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-becb6548-f0ab-46b3-b591-6e66fed449c4 NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal form of epithelial ovarian cancer. HGSOC is a highly aggressive histotype of ovarian cancer that exhibits distinct genetic instability. Signaling description: HGSOC is characterized by mutations in TP53, BRCA1, and BRCA2 genes with no characteristic mutations in KRAS, BRAF, or PTEN genes. In addition, it has been shown that overexpression of EGFRs (EGFR and ERBB2), VEGFRs, LPARs, NTRK2, and NOTCH3 is associated with HGSOC. The ERBB family of receptor tyrosine kinases includes four related members isuch as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). The family of vascular endothelial growth factor receptors (VEGFRs) includes fms-related tyrosine kinase 1/vascular endothelial growth factor receptor 1 (FLT1/VEGFR1), kinase insert domain receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2), and fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR3). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs, VEGFRs and NTRK2 activate PIK3CA via SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. In addition, LPARs (lysophosphatidic acid receptor 2/3) regulate AKT1 activation. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Furthwer, activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs and VEGFRs regulate Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. In addition, EGFRs interact with SHC1/GRB2/SOS1 and activate BRAF, which then activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Further, NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. NOTCH3 receptors interact with surface-bound ligands JAG1, JAG2, DLL1, DLL3, and DLL4. Activated membrane-bound NOTCH3 receptor is cleaved by gamma-secretase complex. NOTCH intracellular domain (NICD) is transported into the nucleus and participates in the formation of the NICD- Organ: ovary Organ_System: reproductive system PMID: 18317228 PMID: 19221485 PMID: 19461510 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-becb6548-f0ab-46b3-b591-6e66fed449c4 High-Grade Serous Ovarian Carcinoma uuid-becb6548-f0ab-46b3-b591-6e66fed449c4 PS:CellType cancer cell PS:CellType epithelial cell PS:Description High-grade serous ovarian carcinomas (HGSOC) are the most common and lethal form of Ovarian Cancers. HGSOC displays distinct genetic instability and mutations in TP53, BRCA1, and BRCA2 genes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-becb6548-f0ab-46b3-b591-6e66fed449c4 PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal form of epithelial ovarian cancer. HGSOC is a highly aggressive histotype of ovarian cancer that exhibits distinct genetic instability. Signaling description: HGSOC is characterized by mutations in TP53, BRCA1, and BRCA2 genes with no characteristic mutations in KRAS, BRAF, or PTEN genes. In addition, it has been shown that overexpression of EGFRs (EGFR and ERBB2), VEGFRs, LPARs, NTRK2, and NOTCH3 is associated with HGSOC. The ERBB family of receptor tyrosine kinases includes four related members isuch as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). The family of vascular endothelial growth factor receptors (VEGFRs) includes fms-related tyrosine kinase 1/vascular endothelial growth factor receptor 1 (FLT1/VEGFR1), kinase insert domain receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2), and fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR3). These receptors couple extracellular growth factor ligands to intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs, VEGFRs and NTRK2 activate PIK3CA via SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. In addition, LPARs (lysophosphatidic acid receptor 2/3) regulate AKT1 activation. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival which responds to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 protein then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes involved in cell proliferation, differentiation, and migration. Furthwer, activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and the JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD leading to the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of the apoptotic caspase cascade. EGFRs and VEGFRs regulate Janus kinases 1/2 (JAK1/2) involved in the regulation of cell growth. In addition, EGFRs interact with SHC1/GRB2/SOS1 and activate BRAF, which then activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. Further, NOTCH signaling is a crucial regulator of multiple cellular processes including differentiation, proliferation, motility, and survival. NOTCH3 receptors interact with surface-bound ligands JAG1, JAG2, DLL1, DLL3, and DLL4. Activated membrane-bound NOTCH3 receptor is cleaved by gamma-secretase complex. NOTCH intracellular domain (NICD) is transported into the nucleus and participates in the formation of the NICD- PS:Organ ovary PS:Organ_System reproductive system PS:PMID 18317228 PS:PMID 19221485 PS:PMID 19461510 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bed1cebd-3509-40ce-b350-918a500b1aa7 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-bed1cebd-3509-40ce-b350-918a500b1aa7 Epinephrine/Norepinephrine Release in Nociception uuid-bed1cebd-3509-40ce-b350-918a500b1aa7 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bed1cebd-3509-40ce-b350-918a500b1aa7 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bee5fc64-de7b-45b7-827d-23a48ef970e6 NodeType: Pathway Notes: Cataract is a common complication in diabetes. High levels of glucose in patients with diabetes lead to cataract formation by an accumulation of sorbitol and fructose, which are both capable of modifying the structural proteins of the lenses. High glucose levels cause the accumulation of sorbitol and advanced glycation end products. They cause an increase of water influx, thereby provoking the formation of lens opacities. Glucose and osmolar stress decrease antioxidant defenses in the lens and therefore promote ROS damage of cellular proteins and an induction of Ca2 toxicity. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-bee5fc64-de7b-45b7-827d-23a48ef970e6 2_Diabetes-induced cataract uuid-bee5fc64-de7b-45b7-827d-23a48ef970e6 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bee5fc64-de7b-45b7-827d-23a48ef970e6 PS:NodeType Pathway PS:Notes Cataract is a common complication in diabetes. High levels of glucose in patients with diabetes lead to cataract formation by an accumulation of sorbitol and fructose, which are both capable of modifying the structural proteins of the lenses. High glucose levels cause the accumulation of sorbitol and advanced glycation end products. They cause an increase of water influx, thereby provoking the formation of lens opacities. Glucose and osmolar stress decrease antioxidant defenses in the lens and therefore promote ROS damage of cellular proteins and an induction of Ca2 toxicity. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-beed2bc7-561c-4f7a-88cd-3d3f4a6e9eb8 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-beed2bc7-561c-4f7a-88cd-3d3f4a6e9eb8 DDR1 -> NF-kB Signaling uuid-beed2bc7-561c-4f7a-88cd-3d3f4a6e9eb8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-beed2bc7-561c-4f7a-88cd-3d3f4a6e9eb8 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: The role of mutations in the MECP2 gene in the development of autism symptoms of Rett syndrome. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf0b65c6-b770-47d8-8da7-2749dff63a35 NodeType: Pathway Notes: MECP2 gene mutations are associated with the development of autism symptoms in patients with Rett syndrome. Organ_System: nervous system PMID: 26237041 PMID: 27071793 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-bf0b65c6-b770-47d8-8da7-2749dff63a35 Rett Syndrome uuid-bf0b65c6-b770-47d8-8da7-2749dff63a35 PS:Description The role of mutations in the MECP2 gene in the development of autism symptoms of Rett syndrome. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf0b65c6-b770-47d8-8da7-2749dff63a35 PS:NodeType Pathway PS:Notes MECP2 gene mutations are associated with the development of autism symptoms in patients with Rett syndrome. PS:Organ_System nervous system PS:PMID 26237041 PS:PMID 27071793 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Endometrial ovarian carcinoma (EOC) or endometrioid adenocarcinoma of the ovary are rare ovarian tumor accounting for less than 15 percent of ovarian carcinomas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf18412b-a966-4228-bdae-594bd9506604 NodeType: Pathway Notes: Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Endometrial ovarian carcinomas (EOC) or endometrioid adenocarcinomas of the ovary are rare ovarian tumors (less than 15% of ovarian carcinomas) with histological semblance to endometrial carcinomas of the uterus. Approximately, 5-10% of EOC cases are associated with endometriosis. A pathologist must differentiate EOCs from mucinous ovarian carcinomas and since squamous differentiation is very rare in mucinous tumors, this feature would favor an EOC. Signaling description: EOC is characterized by mutations in KRAS, BRAF, PTEN, and ARID1A genes. It has also been shown that the overexpression of EGFRs (EGFR and ERBB2), FBXO5, and LPARs are associated with EOC. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to the intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA through SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling, and thus, mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1) protein, which then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD, which leads to BCL2 and BCL2L1 activation and the suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and apoptotic caspase cascade activation. EGFRs regulates Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. LPARs (lysophosphatidic acid receptor 2/3) promote AKT1 the activation. Anaphase promoting complex (APC/C) is essentially required to exit from mitosis as it induces proteolysis of diverse cell cycle regulators. The activation of APC/C is mediated by CDC20, while FBXO5 is a negative regulator of CDC20. The overexpression of FBXO5 inhibits APC/C activation and induces cell proliferation. AT rich interactive domain 1A (ARID1A) is a component of the SWI/SNF chromatin remodeling complex, which also includes SMARCA4, ACTB, ACTL6A, ACTL6B, ARID1B, and SMARCD Organ: ovary Organ_System: reproductive system PMID: 17204312 PMID: 18317228 PMID: 19221485 PMID: 22987944 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-bf18412b-a966-4228-bdae-594bd9506604 Endometrioid Ovarian Carcinoma uuid-bf18412b-a966-4228-bdae-594bd9506604 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Endometrial ovarian carcinoma (EOC) or endometrioid adenocarcinoma of the ovary are rare ovarian tumor accounting for less than 15 percent of ovarian carcinomas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf18412b-a966-4228-bdae-594bd9506604 PS:NodeType Pathway PS:Notes Headnote: Ovarian cancer is the second most common malignancy among the gynecological cancers and the most common cause of cancer death, yet the etiology of ovarian malignant transformation remains poorly understood. Different types of ovarian cancer include serous, mucinous, endometrioid, clear cell, undifferentiated, and unclassifiable. Endometrial ovarian carcinomas (EOC) or endometrioid adenocarcinomas of the ovary are rare ovarian tumors (less than 15% of ovarian carcinomas) with histological semblance to endometrial carcinomas of the uterus. Approximately, 5-10% of EOC cases are associated with endometriosis. A pathologist must differentiate EOCs from mucinous ovarian carcinomas and since squamous differentiation is very rare in mucinous tumors, this feature would favor an EOC. Signaling description: EOC is characterized by mutations in KRAS, BRAF, PTEN, and ARID1A genes. It has also been shown that the overexpression of EGFRs (EGFR and ERBB2), FBXO5, and LPARs are associated with EOC. The ERBB family of receptor tyrosine kinases includes four related members such as epidermal growth factor receptor (EGFR/HER1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, HER2/neu), and v-erb-b2 erythroblastic leukemia viral oncogene homologs 3 and 4 (ERBB3/HER3 and ERBB4/HER4). These receptors couple extracellular growth factor ligands to the intracellular signaling pathways and, thus regulate cell processes including proliferation, differentiation, cell migration, and survival. The overexpression of these receptors causes the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades leading to block of apoptosis, loss of differentiation, hyperplastic growth, and migration of ovarian epithelial cells. Specifically, ligand-bound EGFRs activate PIK3CA through SRC. In turn, PIK3CA activates AKT1 via PIP3 and PDPK1. Normally, PTEN dephosphorylates PIP3 and suppresses AKT-mediated signaling, and thus, mutations in the PTEN gene lead to the constitutive activation of AKT1. Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) leading to the stabilization of cytosolic beta-catenin (CTNNB1) protein, which then translocates into the nucleus where it interacts with the T-cell factor 4 (TCF4) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and mediated JNK-cascade (MAPK8, MAPK9, and MAPK10). In addition, AKT1 phosphorylates and inhibits BAD, which leads to BCL2 and BCL2L1 activation and the suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and apoptotic caspase cascade activation. EGFRs regulates Janus kinases 1/2 (JAK1/2) involved in cell growth. EGFRs also interact with SHC1/GRB2/SOS1 and activate BRAF, which in turn activates ERK (MAPK1/3). This signaling pathway induces genes involved in cell proliferation. LPARs (lysophosphatidic acid receptor 2/3) promote AKT1 the activation. Anaphase promoting complex (APC/C) is essentially required to exit from mitosis as it induces proteolysis of diverse cell cycle regulators. The activation of APC/C is mediated by CDC20, while FBXO5 is a negative regulator of CDC20. The overexpression of FBXO5 inhibits APC/C activation and induces cell proliferation. AT rich interactive domain 1A (ARID1A) is a component of the SWI/SNF chromatin remodeling complex, which also includes SMARCA4, ACTB, ACTL6A, ACTL6B, ARID1B, and SMARCD PS:Organ ovary PS:Organ_System reproductive system PS:PMID 17204312 PS:PMID 18317228 PS:PMID 19221485 PS:PMID 22987944 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf272e07-56d5-4638-bb52-2d09646c2fe7 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-bf272e07-56d5-4638-bb52-2d09646c2fe7 CD8 -> STAT Expression Targets uuid-bf272e07-56d5-4638-bb52-2d09646c2fe7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf272e07-56d5-4638-bb52-2d09646c2fe7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf2b24e8-0b41-4ba2-9696-e53e6fa738e0 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-bf2b24e8-0b41-4ba2-9696-e53e6fa738e0 Carnitine shuttle of lipids into mitochondria template uuid-bf2b24e8-0b41-4ba2-9696-e53e6fa738e0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf2b24e8-0b41-4ba2-9696-e53e6fa738e0 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf381f60-e90a-4210-99f3-b6ec582c8ccf NodeType: Pathway Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-bf381f60-e90a-4210-99f3-b6ec582c8ccf Proteins Involved in Endometrial Cancer uuid-bf381f60-e90a-4210-99f3-b6ec582c8ccf PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf381f60-e90a-4210-99f3-b6ec582c8ccf PS:NodeType Pathway PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf451e0e-003a-4bde-b4ea-e1cf1e8536ee NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bf451e0e-003a-4bde-b4ea-e1cf1e8536ee TGFA -> STAT Expression Targets uuid-bf451e0e-003a-4bde-b4ea-e1cf1e8536ee PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf451e0e-003a-4bde-b4ea-e1cf1e8536ee PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf498a6c-0750-4184-bcc6-3266de21a540 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-bf498a6c-0750-4184-bcc6-3266de21a540 Proteins Involved in Friedreich Ataxia uuid-bf498a6c-0750-4184-bcc6-3266de21a540 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf498a6c-0750-4184-bcc6-3266de21a540 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf4d146d-848d-4ce5-845b-5b4456b07664 NodeType: Pathway Notes: Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. Signaling description: NK cell stimulatory receptors with ITSM motifs (CD244-related receptors) induce the phosphorylation of VAV1, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to additional VAV1 phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. The ITSM motifs of CD244-related receptors are phosphorylated by SH2D1A-associated protein and then recruit the adapters, FYN and LAT. Outcome effects: FYN and LAT activate two main NK cell-mediated responses including the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes lead to the death of target cells. Organ: generic Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-bf4d146d-848d-4ce5-845b-5b4456b07664 Natural Killer Cell Activation through ITSM-Containing Receptors uuid-bf4d146d-848d-4ce5-845b-5b4456b07664 PS:CellType natural killer cell PS:Description Natural killer (NK) cells can specifically destroy infected and transformed cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf4d146d-848d-4ce5-845b-5b4456b07664 PS:NodeType Pathway PS:Notes Headnote: Natural killer (NK) cells can specifically destroy infected and transformed cells. The activation of NK cells depends on stimulatory and inhibitory receptors whose type and copy number vary from cell to cell. Signaling description: NK cell stimulatory receptors with ITSM motifs (CD244-related receptors) induce the phosphorylation of VAV1, resulting in the actin-dependent clustering of activator receptors and their recruitment to lipid rafts. This leads to additional VAV1 phosphorylation, inducing a positive feedback loop which ultimately results in NK cell cytotoxicity. The ITSM motifs of CD244-related receptors are phosphorylated by SH2D1A-associated protein and then recruit the adapters, FYN and LAT. Outcome effects: FYN and LAT activate two main NK cell-mediated responses including the transcription of FAS receptor ligands and the formation of immunological synapses with granules of perforins (PRF1) and granzymes. FAS, PRF1, and granzymes lead to the death of target cells. PS:Organ generic PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf6725f1-7861-4b35-8b73-8846f402d9df NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bf6725f1-7861-4b35-8b73-8846f402d9df IGF1 -> STAT Expression Targets uuid-bf6725f1-7861-4b35-8b73-8846f402d9df PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf6725f1-7861-4b35-8b73-8846f402d9df PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf674c6c-8e41-48ef-be52-dcbc3a817eb1 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-bf674c6c-8e41-48ef-be52-dcbc3a817eb1 Familial Mediterranean Fever Clinical Trials uuid-bf674c6c-8e41-48ef-be52-dcbc3a817eb1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf674c6c-8e41-48ef-be52-dcbc3a817eb1 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf73d9e2-34fd-43b3-81d7-3d58e810ab4a NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-bf73d9e2-34fd-43b3-81d7-3d58e810ab4a Hereditary Breast and Ovarian Cancer Syndrome Mutated Genes uuid-bf73d9e2-34fd-43b3-81d7-3d58e810ab4a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf73d9e2-34fd-43b3-81d7-3d58e810ab4a PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf93b125-3f61-42f2-a542-cbfe673e2162 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-bf93b125-3f61-42f2-a542-cbfe673e2162 CXCL3 Expression Targets uuid-bf93b125-3f61-42f2-a542-cbfe673e2162 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf93b125-3f61-42f2-a542-cbfe673e2162 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf9bf2eb-9f80-4811-891f-99ca0e3b4454 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-bf9bf2eb-9f80-4811-891f-99ca0e3b4454 CD157/ITGB2 Signaling in Myeloid Cell uuid-bf9bf2eb-9f80-4811-891f-99ca0e3b4454 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bf9bf2eb-9f80-4811-891f-99ca0e3b4454 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Serotonin signaling is implicated in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bfcaf73f-0cff-461c-bd90-b34a8563ee81 NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: The aqueous humor (AH) of the eye is a transparent fluid consisting of water (98%), ions, amino acids, and biomolecules such as signaling molecules, growth factors, and extracellular matrix molecules. Serotonin signaling is implicated in the regulation of AH production by the ciliary body and intraocular pressure (IOP) regulation. The topical application of serotonin may both elevate and lower IOP. Outcome effects: HTR1A, HTR2A/2C, and HTR7 are expressed in the iris and ciliary body. HTR1A and HTR7 are linked to adenylate cyclase (ADCY) activity modulation. HTR1A activation inhibits cAMP production and decreases AH production, while HTR7 has the opposite effect. HTR2A/2C activation leads to IP3 production and an increase of AH production. HTR1B and HTR1D are localized at pre-synaptic membranes. Upon stimulation, they lead to the inhibition of serotonin release. The role of HTR1B/1D in IOP regulation has yet to be determined. The reuptake of serotonin is completed by SLC6A4. Selective serotonin reuptake inhibitors may provoke glaucoma. Organ: ciliary body Organ: eye Organ_System: sensory system PMID: 19052654 PMID: 19587851 PMID: 20426763 PMID: 22505971 PMID: 22699774 PMID: 24558600 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-bfcaf73f-0cff-461c-bd90-b34a8563ee81 Serotonin Signaling in the Ciliary Body uuid-bfcaf73f-0cff-461c-bd90-b34a8563ee81 PS:CellType neuron PS:Description Serotonin signaling is implicated in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bfcaf73f-0cff-461c-bd90-b34a8563ee81 PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: The aqueous humor (AH) of the eye is a transparent fluid consisting of water (98%), ions, amino acids, and biomolecules such as signaling molecules, growth factors, and extracellular matrix molecules. Serotonin signaling is implicated in the regulation of AH production by the ciliary body and intraocular pressure (IOP) regulation. The topical application of serotonin may both elevate and lower IOP. Outcome effects: HTR1A, HTR2A/2C, and HTR7 are expressed in the iris and ciliary body. HTR1A and HTR7 are linked to adenylate cyclase (ADCY) activity modulation. HTR1A activation inhibits cAMP production and decreases AH production, while HTR7 has the opposite effect. HTR2A/2C activation leads to IP3 production and an increase of AH production. HTR1B and HTR1D are localized at pre-synaptic membranes. Upon stimulation, they lead to the inhibition of serotonin release. The role of HTR1B/1D in IOP regulation has yet to be determined. The reuptake of serotonin is completed by SLC6A4. Selective serotonin reuptake inhibitors may provoke glaucoma. PS:Organ ciliary body PS:Organ eye PS:Organ_System sensory system PS:PMID 19052654 PS:PMID 19587851 PS:PMID 20426763 PS:PMID 22505971 PS:PMID 22699774 PS:PMID 24558600 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Long-chain nonesterified ("free") fatty acids (FFA) accumulate during starvation, anoxia, exhaustive exercise, and diabetes and able to modulate mitochondrial ROS generation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bfd8601e-f4a8-46e8-92e3-5b8f46c6ab20 NodeType: Pathway Notes: Headnote: Oxidative stress is a redox imbalance with an excess of oxidants or a defect in antioxidants (Sies, 1985). Oxidative stress in terms of "the mitochondrial oxidative stress theory of aging" is the reaction of reactive oxygen species (ROS), physiologically generated by mitochondrial electron transport chain, with cellular constituents and it initiates the changes associated with aging and determines the maximum longevity (Reinald Pamplona, 2008). Long-chain nonesterified ("free") fatty acids (FFA) accumulate during starvation, anoxia, exhaustive exercise, and diabetes and are able to modulate mitochondrial ROS generation. Polyunsaturated fatty acids (PUFA) are able to activate non-mitochondrial ROS production. Signaling description: FFA is accumulated due the activity of cytosolic phospholipase A2 and secretory phospholipase A2 which are able to modify membrane phospholipids. Despite the well-known effect of FFA on mitochondrial ROS production (both positive and negative), the underlying mechanism is poorly understood. Some of the hypotheses are described on the pathway. FFA is able to modulate non-mitochondrial ROS production by regulating the activity of plasma membrane NAD(P)H oxidase complex in neutrophils. PUFA are more potent inducers of ROS generation. Outcome effects: PUFA chains (two or more double bonds) are easily attacked by ROS than saturated (no double bonds) or monounsaturated (one double bond) side chains. Cellular membrane PUFAs peroxidation generates mixture of carbonyl compounds (RCS) with three to nine carbons in length. Carbonyl compounds react with proteins or other macromolecules and generate cross-linked unsoluble advanced lipoxidation end-products (ALEs). ALEs may cause structural changes on proteins, formation of protein-protein cross-links and aggregates, alteration of protein degradation and processing and others. Animal data: The majority of experimental data were obtained in animal models. Organ: generic Organ_System: generic PMID: 18482593 PMID: 18721793 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-bfd8601e-f4a8-46e8-92e3-5b8f46c6ab20 Fatty Acids Cause Oxidative Stress and Mitochondria Decline in Aging uuid-bfd8601e-f4a8-46e8-92e3-5b8f46c6ab20 PS:CellType generic PS:Description Long-chain nonesterified ("free") fatty acids (FFA) accumulate during starvation, anoxia, exhaustive exercise, and diabetes and able to modulate mitochondrial ROS generation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bfd8601e-f4a8-46e8-92e3-5b8f46c6ab20 PS:NodeType Pathway PS:Notes Headnote: Oxidative stress is a redox imbalance with an excess of oxidants or a defect in antioxidants (Sies, 1985). Oxidative stress in terms of "the mitochondrial oxidative stress theory of aging" is the reaction of reactive oxygen species (ROS), physiologically generated by mitochondrial electron transport chain, with cellular constituents and it initiates the changes associated with aging and determines the maximum longevity (Reinald Pamplona, 2008). Long-chain nonesterified ("free") fatty acids (FFA) accumulate during starvation, anoxia, exhaustive exercise, and diabetes and are able to modulate mitochondrial ROS generation. Polyunsaturated fatty acids (PUFA) are able to activate non-mitochondrial ROS production. Signaling description: FFA is accumulated due the activity of cytosolic phospholipase A2 and secretory phospholipase A2 which are able to modify membrane phospholipids. Despite the well-known effect of FFA on mitochondrial ROS production (both positive and negative), the underlying mechanism is poorly understood. Some of the hypotheses are described on the pathway. FFA is able to modulate non-mitochondrial ROS production by regulating the activity of plasma membrane NAD(P)H oxidase complex in neutrophils. PUFA are more potent inducers of ROS generation. Outcome effects: PUFA chains (two or more double bonds) are easily attacked by ROS than saturated (no double bonds) or monounsaturated (one double bond) side chains. Cellular membrane PUFAs peroxidation generates mixture of carbonyl compounds (RCS) with three to nine carbons in length. Carbonyl compounds react with proteins or other macromolecules and generate cross-linked unsoluble advanced lipoxidation end-products (ALEs). ALEs may cause structural changes on proteins, formation of protein-protein cross-links and aggregates, alteration of protein degradation and processing and others. Animal data: The majority of experimental data were obtained in animal models. PS:Organ generic PS:Organ_System generic PS:PMID 18482593 PS:PMID 18721793 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bffc0a0d-b3d7-4f5c-b11d-176246228a12 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-bffc0a0d-b3d7-4f5c-b11d-176246228a12 eIF5A hypusination template uuid-bffc0a0d-b3d7-4f5c-b11d-176246228a12 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-bffc0a0d-b3d7-4f5c-b11d-176246228a12 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c000e77f-ec96-41c0-82ef-3ae5d1a22773 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-c000e77f-ec96-41c0-82ef-3ae5d1a22773 VIPR1/VIPR2 -> Expression Targets in Lymphoid System and Blood uuid-c000e77f-ec96-41c0-82ef-3ae5d1a22773 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c000e77f-ec96-41c0-82ef-3ae5d1a22773 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/FBXW7 complex regulates G1/S and G2/M transition and cell proliferation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c01b418a-f4fe-45f4-af61-78659761e458 NodeType: Pathway Notes: Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXW7 complex, FBXW7 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/FBXW7 related signaling leads to regulation of cell cycle progression, and cell proliferation. The precise mechanism of the molecular signaling on this pathway is well known and is associated with negative regulation of AURKA, MYC, JUN, MYB, NFKB2, CSF3R, KLF5, MCL1, MTOR, NOTCH1, JUNB, CCNE1/2 and CDC6. Outcome effects: SCF/FBXW7 targets and degrades the CCNE1/2, CDC6, MTOR and AURKA needed for G1/S transition, S phase regulation and G2/M transition. Degradation of MYC, JUN, JUNB, MYB, NFKB2, CSF3R, KLF5, MCL1, MTOR and NOTCH1 leads to regulation of cell proliferation and tumor suppression. Animal data: Role of SCF/FBXW7 in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 22542766 PMID: 26528041 PMID: 26630263 PMID: 27156687 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-c01b418a-f4fe-45f4-af61-78659761e458 SCF/FBXW7 Complex uuid-c01b418a-f4fe-45f4-af61-78659761e458 PS:CellType generic PS:Description SCF/FBXW7 complex regulates G1/S and G2/M transition and cell proliferation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c01b418a-f4fe-45f4-af61-78659761e458 PS:NodeType Pathway PS:Notes Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds the F-box-protein. Each F-box protein binds to a specific subset of substrate proteins, promoting their degradation. In SCF/FBXW7 complex, FBXW7 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/FBXW7 related signaling leads to regulation of cell cycle progression, and cell proliferation. The precise mechanism of the molecular signaling on this pathway is well known and is associated with negative regulation of AURKA, MYC, JUN, MYB, NFKB2, CSF3R, KLF5, MCL1, MTOR, NOTCH1, JUNB, CCNE1/2 and CDC6. Outcome effects: SCF/FBXW7 targets and degrades the CCNE1/2, CDC6, MTOR and AURKA needed for G1/S transition, S phase regulation and G2/M transition. Degradation of MYC, JUN, JUNB, MYB, NFKB2, CSF3R, KLF5, MCL1, MTOR and NOTCH1 leads to regulation of cell proliferation and tumor suppression. Animal data: Role of SCF/FBXW7 in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22542766 PS:PMID 26528041 PS:PMID 26630263 PS:PMID 27156687 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c01fde19-2bc6-453d-be5a-697ec64eb04d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c01fde19-2bc6-453d-be5a-697ec64eb04d NSP9 inhibitors uuid-c01fde19-2bc6-453d-be5a-697ec64eb04d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c01fde19-2bc6-453d-be5a-697ec64eb04d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c02260a4-fa50-4d5d-9ad8-8b7eb8bd34cc NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c02260a4-fa50-4d5d-9ad8-8b7eb8bd34cc Methionine metabolism template uuid-c02260a4-fa50-4d5d-9ad8-8b7eb8bd34cc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c02260a4-fa50-4d5d-9ad8-8b7eb8bd34cc PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c023bc21-ca21-4007-9755-e7e657da9d51 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c023bc21-ca21-4007-9755-e7e657da9d51 NSP7 interactions uuid-c023bc21-ca21-4007-9755-e7e657da9d51 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c023bc21-ca21-4007-9755-e7e657da9d51 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c03e1f47-a41f-473b-9879-2bfbdb788558 NodeType: Pathway Notes: Headnote: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause the loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, even though the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases while 98% are of unknown cause. The loss-of-function autosomal dominant mutations of the paired box 8 (PAX8) gene are considered to primarily cause congenital hypothyroidism due to thyroid hypoplasia. PAX8 regulates the expression of genes encoding thyroglobulin (TG), thyroid peroxidase (TPO), and the sodium-iodide symporter (NIS) by binding to their promoter regions through its 128-amino acid paired domain. PAX8 is also expressed in the mesonephros and ureteric buds which may explain the increased incidence of genitourinary malformations in patients with congenital hypothyroidism. The role of PAX8 in thyroid development is poorly understood. The pathway displays thyroid gland development in relation to a mutation in PAX8. Outcome effects: PAX8 expression targets are shown to be important to thyroid gland function. The remaining proteins were added after the analysis of neighbors of PAX8 in Pathway Studio. Only those that are significant in the development of thyroid cells were included. Mutated genes: Mutated genes are shown in white-out style. Organ: thyroid gland Organ_System: endocrine system PMID: 15665157 PMID: 22898500 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-c03e1f47-a41f-473b-9879-2bfbdb788558 PAX8 Targets in Thyroid Dysgenesis (Hypothesis) uuid-c03e1f47-a41f-473b-9879-2bfbdb788558 PS:CellType thyroid cell PS:Description Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c03e1f47-a41f-473b-9879-2bfbdb788558 PS:NodeType Pathway PS:Notes Headnote: Congenital hypothyroidism is a condition of thyroid hormone deficiency present at birth. Approximately 1 out of 3000-4000 newborn infants has a severe deficiency of thyroid function. If left untreated, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily oral dosage of thyroxin. Most cases of congenital hypothyroidism are sporadic and an estimated 15 to 20 percent of cases are inherited. Signaling description: Gene mutations cause the loss of thyroid function in one of two ways: 1) mutations which disrupt the normal development of the thyroid gland before birth and 2) mutations which reduce the production of thyroid hormones, even though the thyroid gland is present. Mutations in PAX8, FOXE1, GLIS3, NKX2-1, and some mutations in thyroid-stimulating hormone receptor (TSHR) prevent or disrupt the normal development of the thyroid gland before birth. These account for only 2% of thyroid dysgenesis cases while 98% are of unknown cause. The loss-of-function autosomal dominant mutations of the paired box 8 (PAX8) gene are considered to primarily cause congenital hypothyroidism due to thyroid hypoplasia. PAX8 regulates the expression of genes encoding thyroglobulin (TG), thyroid peroxidase (TPO), and the sodium-iodide symporter (NIS) by binding to their promoter regions through its 128-amino acid paired domain. PAX8 is also expressed in the mesonephros and ureteric buds which may explain the increased incidence of genitourinary malformations in patients with congenital hypothyroidism. The role of PAX8 in thyroid development is poorly understood. The pathway displays thyroid gland development in relation to a mutation in PAX8. Outcome effects: PAX8 expression targets are shown to be important to thyroid gland function. The remaining proteins were added after the analysis of neighbors of PAX8 in Pathway Studio. Only those that are significant in the development of thyroid cells were included. Mutated genes: Mutated genes are shown in white-out style. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15665157 PS:PMID 22898500 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c06e83d8-a4af-46da-ab06-e70dcfef7d2f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c06e83d8-a4af-46da-ab06-e70dcfef7d2f Vitamin B12 biosynthesis template uuid-c06e83d8-a4af-46da-ab06-e70dcfef7d2f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c06e83d8-a4af-46da-ab06-e70dcfef7d2f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Endoplasmic reticulum (ER) stress caused by the presence of an excessive amount of unfolded or misfolded proteins may lead to a cascade of intracellular stress signaling events. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c085f2b9-8636-4a33-ba53-a3e7f3ea7eae NodeType: Pathway Notes: Headnote: Endoplasmic reticulum (ER) stress caused by the presence of an excessive amount of unfolded or misfolded proteins may lead to a cascade of intracellular stress signaling events known as unfolded protein response (UPR). Signaling description: During the UPR, protein translation is attenuated, ER-associated protein degradation (ERAD) is accelerated, and the production of molecular chaperones is increased. The presence of unfolded proteins in the ER lumen is sensed through the transmembrane signaling proteins EIF2AK3, ERN1, and ATF6. All three sensors are maintained in an inactive state through the interaction with the protein chaperone HSPA5. ERN1/XBP1 signaling activates the transcription of a subset of UPR genes encoding chaperones, catalysts of folding, and ERAD degradation machinery including EDEM1 and EDEM2. Outcome effects: If ER stress is not relieved, apoptosis is induced to protect from neoplasia. Apoptotic signals are produced at the ER by several mechanisms including EIF2AK3/EIF2S1-dependent induction of the proapoptotic transcription factor DDIT3, BAK1/BAX-regulated Ca2+ release from the ER, ERN1-mediated activation of MAP3K5/MAPK8, and the cleavage and activation of procaspase 12. Lastly, several drugs can directly block heat shock proteins (chaperones) in the ER, thus triggering UPR and subsequent apoptosis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-c085f2b9-8636-4a33-ba53-a3e7f3ea7eae ER Stress (Unfolded Protein Response) uuid-c085f2b9-8636-4a33-ba53-a3e7f3ea7eae PS:CellType generic PS:Description Endoplasmic reticulum (ER) stress caused by the presence of an excessive amount of unfolded or misfolded proteins may lead to a cascade of intracellular stress signaling events. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c085f2b9-8636-4a33-ba53-a3e7f3ea7eae PS:NodeType Pathway PS:Notes Headnote: Endoplasmic reticulum (ER) stress caused by the presence of an excessive amount of unfolded or misfolded proteins may lead to a cascade of intracellular stress signaling events known as unfolded protein response (UPR). Signaling description: During the UPR, protein translation is attenuated, ER-associated protein degradation (ERAD) is accelerated, and the production of molecular chaperones is increased. The presence of unfolded proteins in the ER lumen is sensed through the transmembrane signaling proteins EIF2AK3, ERN1, and ATF6. All three sensors are maintained in an inactive state through the interaction with the protein chaperone HSPA5. ERN1/XBP1 signaling activates the transcription of a subset of UPR genes encoding chaperones, catalysts of folding, and ERAD degradation machinery including EDEM1 and EDEM2. Outcome effects: If ER stress is not relieved, apoptosis is induced to protect from neoplasia. Apoptotic signals are produced at the ER by several mechanisms including EIF2AK3/EIF2S1-dependent induction of the proapoptotic transcription factor DDIT3, BAK1/BAX-regulated Ca2+ release from the ER, ERN1-mediated activation of MAP3K5/MAPK8, and the cleavage and activation of procaspase 12. Lastly, several drugs can directly block heat shock proteins (chaperones) in the ER, thus triggering UPR and subsequent apoptosis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c088228c-8685-43e8-96ae-c33bf1c65a1a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-c088228c-8685-43e8-96ae-c33bf1c65a1a limbal epithelial stem cells+>stroma uuid-c088228c-8685-43e8-96ae-c33bf1c65a1a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c088228c-8685-43e8-96ae-c33bf1c65a1a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c09cbdfd-5146-4d76-a1ca-caf9f12fa179 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-c09cbdfd-5146-4d76-a1ca-caf9f12fa179 Proteins with Altered Expression in Androgenetic Alopecia uuid-c09cbdfd-5146-4d76-a1ca-caf9f12fa179 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c09cbdfd-5146-4d76-a1ca-caf9f12fa179 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: insulin-secreting cell Description: Somatostatins block insulin secretion by alpha and beta cells in the pancreas. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0b5c45a-485c-4d67-b18b-fd58507f1cf1 NodeType: Pathway Notes: Headnote: Pancreatic alpha- and beta-cells of the are involved in the synthesis and secretion of insulin. Somatostatins negatively regulate insulin secretion. Signaling description: Alpha-cells produce GCG and glucagon-like peptide 1. The activation of SSTR2 (somatostatin receptor 2 (SSTR2)) expressed by alpha cells contributes to the blockade of the cAMP dependent signaling and to the inhibition of glucagon-like peptide 1 secretion. Beta-cells of pancreas synthesize insulin and release it under the influence of glucagon-like peptide 1. Beta-cells express somatostatin receptor 5 (SSTR5), whose activation contributes to the blockade of the cAMP dependent signaling pathway and inhibition of insulin secretion. Outcome effects: Somatostatins block insulin secretion in the alpha and beta cells of the pancreas. Organ: pancreas Organ_System: digestive system PMID: 11230804 PMID: 15927701 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-c0b5c45a-485c-4d67-b18b-fd58507f1cf1 Insulin Release Inhibition by Somatostatins uuid-c0b5c45a-485c-4d67-b18b-fd58507f1cf1 PS:CellType insulin-secreting cell PS:Description Somatostatins block insulin secretion by alpha and beta cells in the pancreas. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0b5c45a-485c-4d67-b18b-fd58507f1cf1 PS:NodeType Pathway PS:Notes Headnote: Pancreatic alpha- and beta-cells of the are involved in the synthesis and secretion of insulin. Somatostatins negatively regulate insulin secretion. Signaling description: Alpha-cells produce GCG and glucagon-like peptide 1. The activation of SSTR2 (somatostatin receptor 2 (SSTR2)) expressed by alpha cells contributes to the blockade of the cAMP dependent signaling and to the inhibition of glucagon-like peptide 1 secretion. Beta-cells of pancreas synthesize insulin and release it under the influence of glucagon-like peptide 1. Beta-cells express somatostatin receptor 5 (SSTR5), whose activation contributes to the blockade of the cAMP dependent signaling pathway and inhibition of insulin secretion. Outcome effects: Somatostatins block insulin secretion in the alpha and beta cells of the pancreas. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 11230804 PS:PMID 15927701 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue epithelium PS:Link PS:NodeType Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0ba4c39-422c-47cb-a30b-5d6a8557cf3e NodeType: Pathway urn:agi-pathway:uuid-c0ba4c39-422c-47cb-a30b-5d6a8557cf3e Mitochondrial DNA Replication and Transcription uuid-c0ba4c39-422c-47cb-a30b-5d6a8557cf3e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0ba4c39-422c-47cb-a30b-5d6a8557cf3e PS:NodeType Pathway PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0bd60d5-561d-4175-bd25-acac3f304b70 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: myocardium urn:agi-pathway:uuid-c0bd60d5-561d-4175-bd25-acac3f304b70 Elevated Receptors -> Expression Targets in Myocardium uuid-c0bd60d5-561d-4175-bd25-acac3f304b70 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c0bd60d5-561d-4175-bd25-acac3f304b70 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Nephropathy is the most common cause of progressive, chronic kidney disease and a major cause of mortality in patients with diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c10e3c4f-fb8f-4330-8058-dee068fb2d22 NodeType: Pathway Notes: Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. DN is characterized by renal remodeling which includes hypertrophy, increase in the thickness of glomerular basement membranes, extracellular matrix accumulation, and consequently progressive glomerulosclerosis. Signaling description: Endothelial dysfunction underlies the basic pathophysiology of microvascular complications of diabetes. Glomerular endothelial cells are highly specialized cells with regions of attenuated cytoplasm punctuated by numerous circular transcellular pores called fenestrae. Early clinical DN is characterized by elevated glomerular filtration associated with vasodilation. Glomerular hyperfiltration leads to the basement membrane thickening, which is the earliest change seen in diabetic nephropathy. Hyperglycemia is the major initiating factor in the pathogenesis of diabetic microvascular complications. Glucose induces the formation of diacylglycerol and activates PRKCA which stimulates NOX4 that is involved in reactive oxygen species (ROS) production. Advanced glycation end products (AGEs) activate the advanced glycosylation end product-specific receptor (AGER). In turn, AGER activates the mitogen-activated protein kinase (MAPK) pathway, and via PI3K activates the AKT1/NF-kB signaling pathway. Outcome effects: The activation of these pathways leads to endothelial cell proliferation and overexpression of NOS3, adhesion molecules, and interleukins such as IL6 and IL1A. NOS3 produces the main vasodilator, nitric oxide (NO) and adhesion molecules such as ICAM1, VCAM, and SELE which mediate the leukocyte-endothelial cell adhesion and interleukins involved in macrophage chemotaxis. Taken together, these events lead to the progressive abnormality of glomerular filtration and subsequent glomerular and interstitial tissue fibrosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 20224802 PMID: 20716934 PMID: 21261520 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-c10e3c4f-fb8f-4330-8058-dee068fb2d22 Endothelial Cell Dysfunction in Early Diabetic Nephropathy uuid-c10e3c4f-fb8f-4330-8058-dee068fb2d22 PS:CellType endothelial cell PS:Description Nephropathy is the most common cause of progressive, chronic kidney disease and a major cause of mortality in patients with diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c10e3c4f-fb8f-4330-8058-dee068fb2d22 PS:NodeType Pathway PS:Notes Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. DN is characterized by renal remodeling which includes hypertrophy, increase in the thickness of glomerular basement membranes, extracellular matrix accumulation, and consequently progressive glomerulosclerosis. Signaling description: Endothelial dysfunction underlies the basic pathophysiology of microvascular complications of diabetes. Glomerular endothelial cells are highly specialized cells with regions of attenuated cytoplasm punctuated by numerous circular transcellular pores called fenestrae. Early clinical DN is characterized by elevated glomerular filtration associated with vasodilation. Glomerular hyperfiltration leads to the basement membrane thickening, which is the earliest change seen in diabetic nephropathy. Hyperglycemia is the major initiating factor in the pathogenesis of diabetic microvascular complications. Glucose induces the formation of diacylglycerol and activates PRKCA which stimulates NOX4 that is involved in reactive oxygen species (ROS) production. Advanced glycation end products (AGEs) activate the advanced glycosylation end product-specific receptor (AGER). In turn, AGER activates the mitogen-activated protein kinase (MAPK) pathway, and via PI3K activates the AKT1/NF-kB signaling pathway. Outcome effects: The activation of these pathways leads to endothelial cell proliferation and overexpression of NOS3, adhesion molecules, and interleukins such as IL6 and IL1A. NOS3 produces the main vasodilator, nitric oxide (NO) and adhesion molecules such as ICAM1, VCAM, and SELE which mediate the leukocyte-endothelial cell adhesion and interleukins involved in macrophage chemotaxis. Taken together, these events lead to the progressive abnormality of glomerular filtration and subsequent glomerular and interstitial tissue fibrosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 20224802 PS:PMID 20716934 PS:PMID 21261520 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c15539f8-799a-45d1-96d7-b8bad7b839d4 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: brain Organ: hippocampus Organ_System: nervous system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c15539f8-799a-45d1-96d7-b8bad7b839d4 Elevated Receptors -> Expression Targets in Hippocampus uuid-c15539f8-799a-45d1-96d7-b8bad7b839d4 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c15539f8-799a-45d1-96d7-b8bad7b839d4 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ brain PS:Organ hippocampus PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c16f3637-55df-4fcb-815a-e3f8ecf899a8 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-c16f3637-55df-4fcb-815a-e3f8ecf899a8 Cervical Cancer Mutated Genes uuid-c16f3637-55df-4fcb-815a-e3f8ecf899a8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c16f3637-55df-4fcb-815a-e3f8ecf899a8 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: General of hypothetical mechanisms that lead to activation of nNOS in postsynaptic neurons by glutamate in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1bc498d-ef37-4b02-87de-272f42acf451 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. In FHM1, FHM2, and FHM3, the proposed increased amounts of glutamate in the synaptic cleft are caused by mutations in CACNA1A, ATP1A2, and SCN1A genes, respectively. Signaling description: Glutamate activates ionotropic receptors (NMDA) on postsynaptic neurons and metabotropic receptors (GRM5 or mGluR) on astrocyte membrane leading to the activation of pathways for arachidonic acid synthesis. In astrocytes, activated mGluR, acting through GNAQ, activates MAPK14 which in turn phosphorylates phospholipase A2. The product of the enzymatic activity of phospholipase A2 is arachidonic acid which is the precursor of prostaglandin H2 (PGH2), synthesized by prostaglandin synthase (PTGS1) in astrocytes. In neurons, PGH2 synthesis involves another mechanism. Activated ionotropic glutamate receptors provide intracellular calcium flux and activation of protein kinase C, gamma (PRKCG) and calmodulin. This in turn leads to the activation of phospholipase A2, group IVA (PLA2G4A) and the product of this phospholipase is also arachidonic acid. The synthesis of PGH2 from arachidonic acid is conducted by prostaglandin synthase (PTGS2) in neurons. Outcome effects: The following chemical reactions are identical in astrocytes and neurons. PGH2 is the substrate for prostaglandin E2 (PGE2) synthesis catalyzed by prostaglandin-E synthase enzyme (PTGES). PGH2 is considered to be a strong vasodilator due to its capability to activate endothelial NO synthase (NOS3). Thus, mutations in FHM1, FHM2, and FHM3 result in the continuous release of glutamate into the synaptic cleft and the activation of PGE2 synthesis in astrocytes and neurons. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 17691981 PMID: 19499287 PMID: 21458376 PMID: 23673269 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-c1bc498d-ef37-4b02-87de-272f42acf451 Prostaglandin E2 Synthesis Activation via Glutamate in Familial Hemiplegic Migraine uuid-c1bc498d-ef37-4b02-87de-272f42acf451 PS:CellType astrocyte PS:CellType neuron PS:Description General of hypothetical mechanisms that lead to activation of nNOS in postsynaptic neurons by glutamate in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1bc498d-ef37-4b02-87de-272f42acf451 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. In FHM1, FHM2, and FHM3, the proposed increased amounts of glutamate in the synaptic cleft are caused by mutations in CACNA1A, ATP1A2, and SCN1A genes, respectively. Signaling description: Glutamate activates ionotropic receptors (NMDA) on postsynaptic neurons and metabotropic receptors (GRM5 or mGluR) on astrocyte membrane leading to the activation of pathways for arachidonic acid synthesis. In astrocytes, activated mGluR, acting through GNAQ, activates MAPK14 which in turn phosphorylates phospholipase A2. The product of the enzymatic activity of phospholipase A2 is arachidonic acid which is the precursor of prostaglandin H2 (PGH2), synthesized by prostaglandin synthase (PTGS1) in astrocytes. In neurons, PGH2 synthesis involves another mechanism. Activated ionotropic glutamate receptors provide intracellular calcium flux and activation of protein kinase C, gamma (PRKCG) and calmodulin. This in turn leads to the activation of phospholipase A2, group IVA (PLA2G4A) and the product of this phospholipase is also arachidonic acid. The synthesis of PGH2 from arachidonic acid is conducted by prostaglandin synthase (PTGS2) in neurons. Outcome effects: The following chemical reactions are identical in astrocytes and neurons. PGH2 is the substrate for prostaglandin E2 (PGE2) synthesis catalyzed by prostaglandin-E synthase enzyme (PTGES). PGH2 is considered to be a strong vasodilator due to its capability to activate endothelial NO synthase (NOS3). Thus, mutations in FHM1, FHM2, and FHM3 result in the continuous release of glutamate into the synaptic cleft and the activation of PGE2 synthesis in astrocytes and neurons. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 17691981 PS:PMID 19499287 PS:PMID 21458376 PS:PMID 23673269 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1cb5065-7eb9-49d0-8974-c06be28aa25a NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-c1cb5065-7eb9-49d0-8974-c06be28aa25a TGFb+>STATs uuid-c1cb5065-7eb9-49d0-8974-c06be28aa25a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1cb5065-7eb9-49d0-8974-c06be28aa25a PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: fibroblast CellType: keratinocyte Description: Photoaging is caused by an imbalance in equilibrium between the accumulation and degradation of ECM components that provide structural and functional support to the skin tissue. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1f6e8bf-f1a7-457c-a2ad-791185555100 NodeType: Pathway Notes: Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Photoaging involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture. Histological and ultrastructural studies have revealed epidermal hyperplasia, damaged and disorganized collagen fibrils, and substantial accumulation of abnormal elastic material in dermal connective tissue. Signaling description: Ultraviolet (UV) irradiation activates cellular signaling transduction pathways which induce the production of matrix metalloproteinases (MMP-1, MMP-2 and MMP-9) responsible for the degradation or synthesis inhibition of collagenous extracellular matrix (COL1A1, COL1A2, COL3A1, COL7A1) in connective tissues. Collagen is the primary insoluble fibrous protein in the ECM and in connective tissue. Type I collagen is the most abundant subtype of collagen found within connective tissue of the skin, followed by small amounts of type III collagen. Degradation of collagen is normally regulated by MMPs and by the activity of their natural inhibitors. In the skin, epidermal keratinocytes and dermal fibroblasts mainly secrete MMP-1(interstitial collagenase or collagenase 1), a collagenase that degrades fibrillar collagens type I and III into specific fragments at a single site within the central triple helix. Other MMPs such as MMP-2 and MMP-9 (gelatinases), further hydrolyze these fragments, ultimately impairing the function of the collagen-rich dermis. The alterations made to the ECM by MMPs might contribute in skin wrinkling. Outcome effects: Photoaging is caused by an imbalance in equilibrium between the accumulation and degradation of ECM components that provide structural and functional support to the skin tissue. Cumulative exposure to the sun results in continuous degradation of ECM proteins such as collagen and elastin, and a decreased rate of renewal/synthesis of collagen. Highlighted proteins: MMP-1, MMP-2, and MMP-9 are highlighted in red, and COL1A1, COL1A2, COL3A1, and COL7A1 are highlighted in blue in order to emphasize the disruption of the protective skin barrier and degradation of ECM. Organ_System: integumentary system PMID: 16465304 PMID: 17968569 PMID: 25415508 PMID: 25495009 PMID: 25703056 PMID: 27271600 PMID: 27598131 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-c1f6e8bf-f1a7-457c-a2ad-791185555100 Extracellular Matrix Degradation in Skin Aging uuid-c1f6e8bf-f1a7-457c-a2ad-791185555100 PS:CellType fibroblast PS:CellType keratinocyte PS:Description Photoaging is caused by an imbalance in equilibrium between the accumulation and degradation of ECM components that provide structural and functional support to the skin tissue. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1f6e8bf-f1a7-457c-a2ad-791185555100 PS:NodeType Pathway PS:Notes Headnote: Photoaging refers to the cumulative specific alterations in the skin caused by chronic exposure to sunlight. The process depends on both environmental and intrinsic factors, with fair-skinned individuals showing more pronounced symptoms of photoaging than people with darker skin. Photoaging involves prominent cutaneous transformation that is clinically characterized by fine and coarse wrinkles, blotchy dyspigmentation, telangiectasia, sallowness, increased fragility, and rough skin texture. Histological and ultrastructural studies have revealed epidermal hyperplasia, damaged and disorganized collagen fibrils, and substantial accumulation of abnormal elastic material in dermal connective tissue. Signaling description: Ultraviolet (UV) irradiation activates cellular signaling transduction pathways which induce the production of matrix metalloproteinases (MMP-1, MMP-2 and MMP-9) responsible for the degradation or synthesis inhibition of collagenous extracellular matrix (COL1A1, COL1A2, COL3A1, COL7A1) in connective tissues. Collagen is the primary insoluble fibrous protein in the ECM and in connective tissue. Type I collagen is the most abundant subtype of collagen found within connective tissue of the skin, followed by small amounts of type III collagen. Degradation of collagen is normally regulated by MMPs and by the activity of their natural inhibitors. In the skin, epidermal keratinocytes and dermal fibroblasts mainly secrete MMP-1(interstitial collagenase or collagenase 1), a collagenase that degrades fibrillar collagens type I and III into specific fragments at a single site within the central triple helix. Other MMPs such as MMP-2 and MMP-9 (gelatinases), further hydrolyze these fragments, ultimately impairing the function of the collagen-rich dermis. The alterations made to the ECM by MMPs might contribute in skin wrinkling. Outcome effects: Photoaging is caused by an imbalance in equilibrium between the accumulation and degradation of ECM components that provide structural and functional support to the skin tissue. Cumulative exposure to the sun results in continuous degradation of ECM proteins such as collagen and elastin, and a decreased rate of renewal/synthesis of collagen. Highlighted proteins: MMP-1, MMP-2, and MMP-9 are highlighted in red, and COL1A1, COL1A2, COL3A1, and COL7A1 are highlighted in blue in order to emphasize the disruption of the protective skin barrier and degradation of ECM. PS:Organ_System integumentary system PS:PMID 16465304 PS:PMID 17968569 PS:PMID 25415508 PS:PMID 25495009 PS:PMID 25703056 PS:PMID 27271600 PS:PMID 27598131 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Hemidesmosomes are multi-protein adhesion complexes that promote the attachment of basal keratinocytes to the basement membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1fd5912-c3bb-44c0-973e-7ed3077c360b NodeType: Pathway Notes: Headnote: The hemidesmosomes are multi-protein adhesion complexes that provide the attachment of basal keratinocytes to the basement membrane, a meshwork of extracellular macromolecules separating the dermis from the epidermis. The hemidesmosomal protein complex is responsible for constant adhesion between the epidermis and the underlying dermis and provides resistance to mechanical stress. Signaling description: Hemidesmosomes contain ITGA6, ITGB4, COL17A1, and CD151 and the two plakin family members, PLEC and DST. It is the complex of ITGA6 and ITGB4 integrins that connects the cells to a major component of the basement membrane laminin-332. The cytoplasmic proteins PLEC and DST connect to the intermediate filaments, thereby creating a stable anchoring complex. CD151 is an early component of hemidesmosomal structures strongly associated with another laminin-binding integrin on keratinocytes, VLA-3 receptor (integrin). Although the VLA-3 receptor does not appear to participate directly in hemidesmosome assembly, it may serve as a nucleation site for the assembly of hemidesmosomes by ITGA6 and ITGB4. Outcome effects: ERBB2IP may have a general role in the establishment and maintenance of cell-cell and cell-basement membrane adhesions. In studies considering carcinoma cell invasion of keratinocyte migration, hemidesmosomes are broken down and their components are redistributed. The requirements for the regulation of each assembly and disassembly step are still unknown. Serine phosphorylation of the ITGB4 cytoplasmic domain by PKC is involved in the disassembly of hemidesmosomes in keratinocytes to initiate migration. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-c1fd5912-c3bb-44c0-973e-7ed3077c360b Hemidesmosome Assembly uuid-c1fd5912-c3bb-44c0-973e-7ed3077c360b PS:CellType generic PS:Description Hemidesmosomes are multi-protein adhesion complexes that promote the attachment of basal keratinocytes to the basement membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c1fd5912-c3bb-44c0-973e-7ed3077c360b PS:NodeType Pathway PS:Notes Headnote: The hemidesmosomes are multi-protein adhesion complexes that provide the attachment of basal keratinocytes to the basement membrane, a meshwork of extracellular macromolecules separating the dermis from the epidermis. The hemidesmosomal protein complex is responsible for constant adhesion between the epidermis and the underlying dermis and provides resistance to mechanical stress. Signaling description: Hemidesmosomes contain ITGA6, ITGB4, COL17A1, and CD151 and the two plakin family members, PLEC and DST. It is the complex of ITGA6 and ITGB4 integrins that connects the cells to a major component of the basement membrane laminin-332. The cytoplasmic proteins PLEC and DST connect to the intermediate filaments, thereby creating a stable anchoring complex. CD151 is an early component of hemidesmosomal structures strongly associated with another laminin-binding integrin on keratinocytes, VLA-3 receptor (integrin). Although the VLA-3 receptor does not appear to participate directly in hemidesmosome assembly, it may serve as a nucleation site for the assembly of hemidesmosomes by ITGA6 and ITGB4. Outcome effects: ERBB2IP may have a general role in the establishment and maintenance of cell-cell and cell-basement membrane adhesions. In studies considering carcinoma cell invasion of keratinocyte migration, hemidesmosomes are broken down and their components are redistributed. The requirements for the regulation of each assembly and disassembly step are still unknown. Serine phosphorylation of the ITGB4 cytoplasmic domain by PKC is involved in the disassembly of hemidesmosomes in keratinocytes to initiate migration. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c21d8244-84b2-45d6-9275-66d10d6a5e8a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-c21d8244-84b2-45d6-9275-66d10d6a5e8a HRAS-RAF-MAPK1/3 uuid-c21d8244-84b2-45d6-9275-66d10d6a5e8a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c21d8244-84b2-45d6-9275-66d10d6a5e8a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: The proneural subtype is of glioblastoma characterized by genetic alterations in PDGFRA, IDH1, PIK3CA, and PIK3R1 genes and a high expression of oligodendrocyte development genes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c255200c-a41c-415b-a8a3-f991108b1f74 NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The proneural subtype is characterized by genetic alterations in PDGFRA, IDH1, PIK3CA, and PIK3R1 genes, and a high expression of oligodendrocyte development genes including PDGFRA, NKX2-2, and OLIG2. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 20129251 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c255200c-a41c-415b-a8a3-f991108b1f74 Glioblastoma, Proneural Subtype uuid-c255200c-a41c-415b-a8a3-f991108b1f74 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description The proneural subtype is of glioblastoma characterized by genetic alterations in PDGFRA, IDH1, PIK3CA, and PIK3R1 genes and a high expression of oligodendrocyte development genes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c255200c-a41c-415b-a8a3-f991108b1f74 PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The proneural subtype is characterized by genetic alterations in PDGFRA, IDH1, PIK3CA, and PIK3R1 genes, and a high expression of oligodendrocyte development genes including PDGFRA, NKX2-2, and OLIG2. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 20129251 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c25845df-ce36-4bee-912e-afd3f4a34df6 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c25845df-ce36-4bee-912e-afd3f4a34df6 CD80 -> ATF/CREB/CREBBP Expression Targets uuid-c25845df-ce36-4bee-912e-afd3f4a34df6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c25845df-ce36-4bee-912e-afd3f4a34df6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c258812e-5720-43dd-ab31-5b90a1db677e NodeType: Pathway Notes: Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: MYCN amplification is found in about 22% of NB cases. Tumor suppressors including CHD5, MIR34A, and KIF1B may be affected due to a loss of the short arm of chromosome 1. TP53 or CDKN2A may be mutated in rare cases of NB and the amplification of MDM2, DDX1, and MYCL1 are found in small groups of NB. Activating germline mutations of ALK are responsible for the majority of hereditary NB cases. Moreover, ALK point mutations are often found in sporadic NB cases. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of NB. NB patients with PHOX2B mutations also may have familial disorders of the neural crest such as Hirschsprung disease and congenital central hypoventilation syndrome. Sonic hedgehog (SHH) signaling is one of the key pathways in NB development. PTCH1, SMO, GLI1, and GLI2 were found to be overexpressed while GLI3 was found to be underexpressed. In addition, neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. The family of neurotrophin receptors includes neurotrophic tyrosine kinase receptor type 1, 2, and 3 (NTRK1/2/3). The ligands of NTRK involved in NB pathogenesis include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 and 4 (NTF3/4). These ligand-receptor interactions induce the PI3K/AKT1 and Ras/MAPK signaling. In addition to NGFs, other growth factors are also significant in the development of the sympathoadrenal lineage cells and transformed neuroblasts such as EGF, VEGFA, and IGF1/2. Lastly, the expression of neurogenic transcription factors including PHOX2A, PHOX2B, ASCL1, and HAND2 is controlled by bone morphogenetic proteins (BMP2/4/7) and Notch signaling. Outcome effects: The growth factor signaling in NB promotes cell survival and proliferation. The genetic rearrangements found in NB also result in the inhibition of apoptosis and activation of proliferation. In addition, constant SHH activation drives cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ_System: nervous system PMID: 12438307 PMID: 12612655 PMID: 15288262 PMID: 19417027 PMID: 19622100 PMID: 21295685 PMID: 22430387 PMID: 22585002 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c258812e-5720-43dd-ab31-5b90a1db677e Neuroblastoma uuid-c258812e-5720-43dd-ab31-5b90a1db677e PS:CellType cancer cell PS:CellType neural stem cell PS:Description Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c258812e-5720-43dd-ab31-5b90a1db677e PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: MYCN amplification is found in about 22% of NB cases. Tumor suppressors including CHD5, MIR34A, and KIF1B may be affected due to a loss of the short arm of chromosome 1. TP53 or CDKN2A may be mutated in rare cases of NB and the amplification of MDM2, DDX1, and MYCL1 are found in small groups of NB. Activating germline mutations of ALK are responsible for the majority of hereditary NB cases. Moreover, ALK point mutations are often found in sporadic NB cases. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of NB. NB patients with PHOX2B mutations also may have familial disorders of the neural crest such as Hirschsprung disease and congenital central hypoventilation syndrome. Sonic hedgehog (SHH) signaling is one of the key pathways in NB development. PTCH1, SMO, GLI1, and GLI2 were found to be overexpressed while GLI3 was found to be underexpressed. In addition, neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. The family of neurotrophin receptors includes neurotrophic tyrosine kinase receptor type 1, 2, and 3 (NTRK1/2/3). The ligands of NTRK involved in NB pathogenesis include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 and 4 (NTF3/4). These ligand-receptor interactions induce the PI3K/AKT1 and Ras/MAPK signaling. In addition to NGFs, other growth factors are also significant in the development of the sympathoadrenal lineage cells and transformed neuroblasts such as EGF, VEGFA, and IGF1/2. Lastly, the expression of neurogenic transcription factors including PHOX2A, PHOX2B, ASCL1, and HAND2 is controlled by bone morphogenetic proteins (BMP2/4/7) and Notch signaling. Outcome effects: The growth factor signaling in NB promotes cell survival and proliferation. The genetic rearrangements found in NB also result in the inhibition of apoptosis and activation of proliferation. In addition, constant SHH activation drives cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System nervous system PS:PMID 12438307 PS:PMID 12612655 PS:PMID 15288262 PS:PMID 19417027 PS:PMID 19622100 PS:PMID 21295685 PS:PMID 22430387 PS:PMID 22585002 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c25e4aa0-4d9a-46a6-8454-69631771662e NodeType: Pathway Notes: Mucus overproduction is a central feature of bronchial asthma, contributing to mortality seen in the disease. Goblet cells are the primary mucus-producing cells. In asthma the airway surface liquid (ASL) thickness increases due to the overflow of water and the secretion of adds to excessive mucin, which accumulations in the lungs with asthma. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-c25e4aa0-4d9a-46a6-8454-69631771662e 3_1_Mucus accumulation in asthma uuid-c25e4aa0-4d9a-46a6-8454-69631771662e PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c25e4aa0-4d9a-46a6-8454-69631771662e PS:NodeType Pathway PS:Notes Mucus overproduction is a central feature of bronchial asthma, contributing to mortality seen in the disease. Goblet cells are the primary mucus-producing cells. In asthma the airway surface liquid (ASL) thickness increases due to the overflow of water and the secretion of adds to excessive mucin, which accumulations in the lungs with asthma. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2b0ce90-3038-4156-a453-983523410795 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c2b0ce90-3038-4156-a453-983523410795 Proteins Involved in Follicular Lymphoma uuid-c2b0ce90-3038-4156-a453-983523410795 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2b0ce90-3038-4156-a453-983523410795 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: chondrocyte Description: The growth factor, TGFB2, which normally strongly inhibits articular chondrocyte hypertrophy and maturation in children. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2bc3ab3-8661-4715-bf58-b4d49c1da6a0 NodeType: Pathway Notes: Headnote: Growth factor TGFB2, which normally strongly inhibits articular chondrocyte hypertrophy and maturation in children, plays an important role in the development of osteoarthritis (OA)-inducing cartilage degradation and osteophyte formation through the impaired inhibition of chondrocyte hypertrophy in older individuals. Signaling description: In healthy cartilage, the intracellular signaling initiated by TGFB2 is mediated through the TGFBR1 and TGFBR2 receptors. TGFB2 initially binds to TGFBR2, leading to the recruitment of TGFBR1 which phosphorylates SMAD2 or SMAD3. The phosphorylated SMAD2/3 thus dissociates from the receptor complex and forms a heteromeric complex with SMAD4. This heteromeric SMAD complex translocates into the nucleus where it accumulates and regulates the transcription of ACAN, COL2A1, TIMP1, and TIMP3 genes. In addition, activated TGFBR1 interacts with TAB1 and promotes ATF2 involvement in the signaling through the MAP3K7/MAP2K3/MAPK14 axis. At the same time, SMURF2 is elevated in OA and causes degradation of SMAD2 and TGFBR1. Outcome effects: ACAN and COL2A1 provide cartilage resistance to compression, while TIMP1 and TIMP3 inhibit metalloproteinases. The expression of ATF2 prevents chondrocyte hypertrophy. As a result of SMAD2 and TGFBR1 degradation, the pathways which promote the synthesis of extracellular matrix proteins and prevent chondrocyte hypertrophy are blocked. Therefore, the activation of signaling through ACVRL1 occurs which involves SMAD1, 5, and 9 and results in degradative enzyme (MMP13) synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ: bone Organ_System: skeletal system PMID: 21638205 PMID: 22178514 PMID: 22179031 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c2bc3ab3-8661-4715-bf58-b4d49c1da6a0 TGFB2 Signaling Impairement in Osteoarthritis uuid-c2bc3ab3-8661-4715-bf58-b4d49c1da6a0 PS:CellType chondrocyte PS:Description The growth factor, TGFB2, which normally strongly inhibits articular chondrocyte hypertrophy and maturation in children. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2bc3ab3-8661-4715-bf58-b4d49c1da6a0 PS:NodeType Pathway PS:Notes Headnote: Growth factor TGFB2, which normally strongly inhibits articular chondrocyte hypertrophy and maturation in children, plays an important role in the development of osteoarthritis (OA)-inducing cartilage degradation and osteophyte formation through the impaired inhibition of chondrocyte hypertrophy in older individuals. Signaling description: In healthy cartilage, the intracellular signaling initiated by TGFB2 is mediated through the TGFBR1 and TGFBR2 receptors. TGFB2 initially binds to TGFBR2, leading to the recruitment of TGFBR1 which phosphorylates SMAD2 or SMAD3. The phosphorylated SMAD2/3 thus dissociates from the receptor complex and forms a heteromeric complex with SMAD4. This heteromeric SMAD complex translocates into the nucleus where it accumulates and regulates the transcription of ACAN, COL2A1, TIMP1, and TIMP3 genes. In addition, activated TGFBR1 interacts with TAB1 and promotes ATF2 involvement in the signaling through the MAP3K7/MAP2K3/MAPK14 axis. At the same time, SMURF2 is elevated in OA and causes degradation of SMAD2 and TGFBR1. Outcome effects: ACAN and COL2A1 provide cartilage resistance to compression, while TIMP1 and TIMP3 inhibit metalloproteinases. The expression of ATF2 prevents chondrocyte hypertrophy. As a result of SMAD2 and TGFBR1 degradation, the pathways which promote the synthesis of extracellular matrix proteins and prevent chondrocyte hypertrophy are blocked. Therefore, the activation of signaling through ACVRL1 occurs which involves SMAD1, 5, and 9 and results in degradative enzyme (MMP13) synthesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ bone PS:Organ_System skeletal system PS:PMID 21638205 PS:PMID 22178514 PS:PMID 22179031 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2e3fa93-7ae3-4d4d-96d0-913f1c34a65d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c2e3fa93-7ae3-4d4d-96d0-913f1c34a65d BDNF Expression Targets uuid-c2e3fa93-7ae3-4d4d-96d0-913f1c34a65d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2e3fa93-7ae3-4d4d-96d0-913f1c34a65d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2fed0b6-65ea-460c-8357-b8287f5af4d3 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-c2fed0b6-65ea-460c-8357-b8287f5af4d3 CXCR4 -> ARRB1 Signaling uuid-c2fed0b6-65ea-460c-8357-b8287f5af4d3 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c2fed0b6-65ea-460c-8357-b8287f5af4d3 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c309709a-c2a2-4d62-88dc-ad2b497a203b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c309709a-c2a2-4d62-88dc-ad2b497a203b Tri-, Di-, mono- acylglycerol metabolism template uuid-c309709a-c2a2-4d62-88dc-ad2b497a203b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c309709a-c2a2-4d62-88dc-ad2b497a203b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Increase of expression of MIR155 compared to the norm was shown in multiple sclerosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c32178d6-2429-4cbb-8055-f6f8858929b8 NodeType: Pathway Notes: An increase of the level of MIR155 expression was observed in multiple sclerosis. Presumably, this MIR155 expression activation occurs due to the elevated content of the CD86 protein on the surface of antigen-presenting cells. Organ_System: lymphatic system PMID: 22466660 PMID: 24332164 PMID: 26349986 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-c32178d6-2429-4cbb-8055-f6f8858929b8 MIR155 Role in Th17-Cell in Multiple Sclerosis uuid-c32178d6-2429-4cbb-8055-f6f8858929b8 PS:CellType T-cell PS:Description Increase of expression of MIR155 compared to the norm was shown in multiple sclerosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c32178d6-2429-4cbb-8055-f6f8858929b8 PS:NodeType Pathway PS:Notes An increase of the level of MIR155 expression was observed in multiple sclerosis. Presumably, this MIR155 expression activation occurs due to the elevated content of the CD86 protein on the surface of antigen-presenting cells. PS:Organ_System lymphatic system PS:PMID 22466660 PS:PMID 24332164 PS:PMID 26349986 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3716a80-2c1f-4555-b3aa-ecaa8ea4debc NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c3716a80-2c1f-4555-b3aa-ecaa8ea4debc Cyanoamino acid biosynthesis template uuid-c3716a80-2c1f-4555-b3aa-ecaa8ea4debc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3716a80-2c1f-4555-b3aa-ecaa8ea4debc PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c393524d-36ba-45fa-8de5-47d865fc3a97 NodeType: Pathway Notes: Oxidized low-density lipoproteins (LDL), homocysteine and benzopyrene, a component of cigarette smoke, lead to the endoplasmic reticulum (ER) stress and activation of the apoptosis of retinal pigment epithelial (RPE) cells. Under ER and oxidative stress, retinal pigment epithelial (RPE) cells produce a high level of vascular epithelial growth factor A (VEGFA) and chemokines. VEGFA promotes neovascularization; interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) impact retinal inflammation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system Organelle: endoplasmic reticulum PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-c393524d-36ba-45fa-8de5-47d865fc3a97 3_Endoplasmic reticulum stress in age-related macular degeneration uuid-c393524d-36ba-45fa-8de5-47d865fc3a97 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c393524d-36ba-45fa-8de5-47d865fc3a97 PS:NodeType Pathway PS:Notes Oxidized low-density lipoproteins (LDL), homocysteine and benzopyrene, a component of cigarette smoke, lead to the endoplasmic reticulum (ER) stress and activation of the apoptosis of retinal pigment epithelial (RPE) cells. Under ER and oxidative stress, retinal pigment epithelial (RPE) cells produce a high level of vascular epithelial growth factor A (VEGFA) and chemokines. VEGFA promotes neovascularization; interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) impact retinal inflammation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:Organelle endoplasmic reticulum PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3a9d513-f1ae-469c-af05-dfcf5156e662 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c3a9d513-f1ae-469c-af05-dfcf5156e662 IL4 Expression Targets uuid-c3a9d513-f1ae-469c-af05-dfcf5156e662 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3a9d513-f1ae-469c-af05-dfcf5156e662 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3adb68e-eabc-4c70-b3c6-935f2a1315c6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c3adb68e-eabc-4c70-b3c6-935f2a1315c6 VEGFA -> NFATC Expression Targets uuid-c3adb68e-eabc-4c70-b3c6-935f2a1315c6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3adb68e-eabc-4c70-b3c6-935f2a1315c6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3d3446c-c4dd-4dc0-a57d-9ac856cd6104 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c3d3446c-c4dd-4dc0-a57d-9ac856cd6104 Glucoside biosynthesis template uuid-c3d3446c-c4dd-4dc0-a57d-9ac856cd6104 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3d3446c-c4dd-4dc0-a57d-9ac856cd6104 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3ff97b8-adb4-4b29-88ef-4c0abae791ef NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c3ff97b8-adb4-4b29-88ef-4c0abae791ef IL12B Expression Targets uuid-c3ff97b8-adb4-4b29-88ef-4c0abae791ef PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c3ff97b8-adb4-4b29-88ef-4c0abae791ef PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8 T cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4055723-56b6-409a-8173-b51338077c87 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: in patients with COPD, CD8 cytotoxic T-cells are the predominant T-cells in the airway and alveolar compartment. Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8 T-cells. CD8 cytotoxic T-cells are activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). DAMPs include HMGB1, BGN, heat shock proteins, hyaluronic acid, VCAN, and heparan sulfate. One of the most important PAMPs in COPD is bacterial LPS. Outcome effects: CD8 T-cells contribute to the cytotoxicity of lung tissue cells through the release of proteolytic enzymes perforin (PRF1) and granzyme B (GZMB). They also release IL6, IL1B, IL18, TNF, and IFNG leading to inflammation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 18410916 PMID: 21907865 PMID: 22070100 PMID: 23374856 PMID: 23956502 PMID: 23977698 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c4055723-56b6-409a-8173-b51338077c87 T-Cell Cytotoxic Activation uuid-c4055723-56b6-409a-8173-b51338077c87 PS:CellType T-cell PS:Description Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8 T cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4055723-56b6-409a-8173-b51338077c87 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: in patients with COPD, CD8 cytotoxic T-cells are the predominant T-cells in the airway and alveolar compartment. Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8 T-cells. CD8 cytotoxic T-cells are activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). DAMPs include HMGB1, BGN, heat shock proteins, hyaluronic acid, VCAN, and heparan sulfate. One of the most important PAMPs in COPD is bacterial LPS. Outcome effects: CD8 T-cells contribute to the cytotoxicity of lung tissue cells through the release of proteolytic enzymes perforin (PRF1) and granzyme B (GZMB). They also release IL6, IL1B, IL18, TNF, and IFNG leading to inflammation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18410916 PS:PMID 21907865 PS:PMID 22070100 PS:PMID 23374856 PS:PMID 23956502 PS:PMID 23977698 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40a72b6-648d-4006-9f2b-9d6c67a33f2a NodeType: Pathway Notes: Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The chromatin accessibility complex (CHRAC) is a imitation switch (ISWI)-containing chromatin remodeling complex. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. Outcome effects: The ISWI family of ATPases has a SANT domain adjacent to a SLIDE domain that forms a nucleosome recognition module that binds to an unmodified histone tail and helps mobilize nucleosomes in an ATP-dependent manner into a regularly-spaced nucleosomal array. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-c40a72b6-648d-4006-9f2b-9d6c67a33f2a CHRAC in Chromatin Remodeling uuid-c40a72b6-648d-4006-9f2b-9d6c67a33f2a PS:CellType generic PS:Description DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40a72b6-648d-4006-9f2b-9d6c67a33f2a PS:NodeType Pathway PS:Notes Headnote: DNA in eukaryotic cells is packaged into chromatin, a complex structure in which DNA is associated with histones and a multitude of other proteins. The chromatin accessibility complex (CHRAC) is a imitation switch (ISWI)-containing chromatin remodeling complex. Signaling description: A variety of mechanisms can be used to remodel chromatin; some act locally on a single nucleosome and others act more broadly. Chromatin remodeling can be accomplished by covalent modification of histones or by the action of ATP-dependent remodeling complexes. Outcome effects: The ISWI family of ATPases has a SANT domain adjacent to a SLIDE domain that forms a nucleosome recognition module that binds to an unmodified histone tail and helps mobilize nucleosomes in an ATP-dependent manner into a regularly-spaced nucleosomal array. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: Paneth cell Description: Paneth cells are granulated epithelial cells of small intestinal crypts which secrete antimicrobial peptides and proteins. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40a7c56-a971-4fd6-9dab-8ea5d0099ed0 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The chronic inflammatory response in the gastrointestinal tract in patients with Crohn's disease is thought to be caused by defects in the first defense mechanisms to commensal microflora in the gut. Paneth cells are granulated epithelial cells of small intestinal crypts which secrete antimicrobial peptides and proteins, including alpha-defensins, lysozyme, and secretory phospholipase A2, in response to bacterial products. Signaling description: NOD2 and TLR4 gene products are involved in pathogen pattern recognition in Paneth cells. Patients with Crohn's disease who have NOD2 abnormalities manifest more severe defects in alpha-defensin production than normally observed in Crohn's disease. The detailed molecular mechanisms of this effect remain unclear. The existing hypotheses on the NOD2-related regulation of MUC1 and defensins expression are shown on the pathway. TCF4 is a gene associated with Crohn's disease and Paneth cell antimicrobial function. The signaling of WNT-TCF4, TLR4, and phospholipase A2 in Paneth cells in patients with Crohn's disease requires further study. Outcome effects: Alterations in genes NOD2 and TLR4 are believed to be a cause of weak intestinal barrier and increased T-cell activation in Crohn's disease. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15618294 PMID: 19221600 PMID: 23295687 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-c40a7c56-a971-4fd6-9dab-8ea5d0099ed0 Paneth-Cell Function in Crohn's Disease uuid-c40a7c56-a971-4fd6-9dab-8ea5d0099ed0 PS:CellType Paneth cell PS:Description Paneth cells are granulated epithelial cells of small intestinal crypts which secrete antimicrobial peptides and proteins. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40a7c56-a971-4fd6-9dab-8ea5d0099ed0 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). The chronic inflammatory response in the gastrointestinal tract in patients with Crohn's disease is thought to be caused by defects in the first defense mechanisms to commensal microflora in the gut. Paneth cells are granulated epithelial cells of small intestinal crypts which secrete antimicrobial peptides and proteins, including alpha-defensins, lysozyme, and secretory phospholipase A2, in response to bacterial products. Signaling description: NOD2 and TLR4 gene products are involved in pathogen pattern recognition in Paneth cells. Patients with Crohn's disease who have NOD2 abnormalities manifest more severe defects in alpha-defensin production than normally observed in Crohn's disease. The detailed molecular mechanisms of this effect remain unclear. The existing hypotheses on the NOD2-related regulation of MUC1 and defensins expression are shown on the pathway. TCF4 is a gene associated with Crohn's disease and Paneth cell antimicrobial function. The signaling of WNT-TCF4, TLR4, and phospholipase A2 in Paneth cells in patients with Crohn's disease requires further study. Outcome effects: Alterations in genes NOD2 and TLR4 are believed to be a cause of weak intestinal barrier and increased T-cell activation in Crohn's disease. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15618294 PS:PMID 19221600 PS:PMID 23295687 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40e00c4-bf0b-4ed2-8897-36e016799ecb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-c40e00c4-bf0b-4ed2-8897-36e016799ecb Coagulation Factors->NFkB uuid-c40e00c4-bf0b-4ed2-8897-36e016799ecb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c40e00c4-bf0b-4ed2-8897-36e016799ecb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4272db9-87bc-45cf-aa35-eaae6dcb9dae NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c4272db9-87bc-45cf-aa35-eaae6dcb9dae CD80 -> NFATC Expression Targets uuid-c4272db9-87bc-45cf-aa35-eaae6dcb9dae PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4272db9-87bc-45cf-aa35-eaae6dcb9dae PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c44d8e58-acbb-456b-b057-ce8234b419f7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c44d8e58-acbb-456b-b057-ce8234b419f7 FGF2 -> RUNX Expression Targets uuid-c44d8e58-acbb-456b-b057-ce8234b419f7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c44d8e58-acbb-456b-b057-ce8234b419f7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c475e5be-0232-45a8-9456-0377f5efeaba NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c475e5be-0232-45a8-9456-0377f5efeaba Wiskott-Aldrich Syndrome Clinical Trials uuid-c475e5be-0232-45a8-9456-0377f5efeaba PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c475e5be-0232-45a8-9456-0377f5efeaba PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: hepatocyte Description: Non-Alcoholic Fatty Liver Disease (NAFLD) is a prevalent chronic liver disease that includes histologically and clinically different non-alcoholic diseases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c47b1dcd-02ef-4a1e-ab73-6a44aa0f32d5 NodeType: Pathway Notes: Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Signaling description: Insulin resistance results in the activation of gluconeogenesis in the liver, which subsequently leads to the accumulation of fat. Normally, insulin (INS) inhibits gluconeogenesis. Activated INSR and IGF1R stimulate PDPK1 via IRS2, PIK3R1, and the formation of PIP3. In turn, PDPK1 activates AKT1, which inhibits FOXO1. Outcome effects: FOXO1 promotes CEBPA resulting in the activation of G6PC, PCK1, LPIN1, RETN, and LEP which are involved in gluconeogenesis. Conversely, increased levels of fatty acids lead to the induction of PPARG which promotes CEBPA. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: liver Organ_System: digestive system PMID: 23394097 PMID: 25045276 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-c47b1dcd-02ef-4a1e-ab73-6a44aa0f32d5 Gluconeogenesis Impairment in non-Alcoholic Fatty Liver Disease uuid-c47b1dcd-02ef-4a1e-ab73-6a44aa0f32d5 PS:CellType adipocyte PS:CellType hepatocyte PS:Description Non-Alcoholic Fatty Liver Disease (NAFLD) is a prevalent chronic liver disease that includes histologically and clinically different non-alcoholic diseases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c47b1dcd-02ef-4a1e-ab73-6a44aa0f32d5 PS:NodeType Pathway PS:Notes Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. Signaling description: Insulin resistance results in the activation of gluconeogenesis in the liver, which subsequently leads to the accumulation of fat. Normally, insulin (INS) inhibits gluconeogenesis. Activated INSR and IGF1R stimulate PDPK1 via IRS2, PIK3R1, and the formation of PIP3. In turn, PDPK1 activates AKT1, which inhibits FOXO1. Outcome effects: FOXO1 promotes CEBPA resulting in the activation of G6PC, PCK1, LPIN1, RETN, and LEP which are involved in gluconeogenesis. Conversely, increased levels of fatty acids lead to the induction of PPARG which promotes CEBPA. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ liver PS:Organ_System digestive system PS:PMID 23394097 PS:PMID 25045276 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c485206e-5648-4587-8dc5-f2fbf6ec6b35 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-c485206e-5648-4587-8dc5-f2fbf6ec6b35 Genes with Mutations Associated with Hyper IgM Syndrome uuid-c485206e-5648-4587-8dc5-f2fbf6ec6b35 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c485206e-5648-4587-8dc5-f2fbf6ec6b35 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4a87f1a-f23f-47e4-bbf5-611ebf2d0b2f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-c4a87f1a-f23f-47e4-bbf5-611ebf2d0b2f EGFR/ERBB -> STAT Signaling uuid-c4a87f1a-f23f-47e4-bbf5-611ebf2d0b2f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4a87f1a-f23f-47e4-bbf5-611ebf2d0b2f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4c9f722-bf45-443f-bd4a-5d45982861f2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c4c9f722-bf45-443f-bd4a-5d45982861f2 Alpha-ketoglutarate dehydrogenase complex uuid-c4c9f722-bf45-443f-bd4a-5d45982861f2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4c9f722-bf45-443f-bd4a-5d45982861f2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4f9f49f-7504-4479-bca7-512ddb4773fa NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-c4f9f49f-7504-4479-bca7-512ddb4773fa Myeloblast -> Neutrophil Surface Expression Markers uuid-c4f9f49f-7504-4479-bca7-512ddb4773fa PS:CellType neutrophil PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4f9f49f-7504-4479-bca7-512ddb4773fa PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4fe4bbd-7396-4da4-aee5-5ca8d7b10953 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-c4fe4bbd-7396-4da4-aee5-5ca8d7b10953 ARRB2 and Frizzled Receptors Endocytosis uuid-c4fe4bbd-7396-4da4-aee5-5ca8d7b10953 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c4fe4bbd-7396-4da4-aee5-5ca8d7b10953 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5048007-3b06-4269-b422-31cbacb12752 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c5048007-3b06-4269-b422-31cbacb12752 NTRK2 -> Expression Targets in Brain uuid-c5048007-3b06-4269-b422-31cbacb12752 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5048007-3b06-4269-b422-31cbacb12752 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: In circumstances of infection or oxidative stress, oxidized phospholipids may be found in the blood. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c50c0bd8-8c3d-4acc-850b-cbdf6b8181ce NodeType: Pathway Notes: Headnote: In case of infection or oxidative stress, oxidized phospholipids may be found in the blood. It has long been established that oxidized low-density lipoprotein (oxLDL) induces platelet activation/adhesion and enhances platelet aggregation. Signaling description: Oxidized phospholipids serve as ligands for scavenger receptors and may play a role as pathological, exogenous ligands and activate platelet aggregation. Platelets constitutively express class B scavenger receptors such as CD36 and SCARB1. Class E scavenger receptor, OLR1 (also known as LOX-1) and class D scavenger receptor, CD68 appear on the cell membrane following platelet activation. Scavenger receptor CD36 is the major receptor on platelets that promotes platelet reactivity in response to a group of specific oxidized phospholipids. CD36 recognizes a number of distinct ligands including the family of oxidized choline glycerophospholipids (oxPCCD36), which bind to platelets via CD36 and activates it. CD36 is localized in caveolin-negative, cholesterol-enriched lipid rafts in platelet membranes. The signaling events induced by CD36 are poorly understood. CD36 possibly forms a multi-protein complex in rafts with Src-family kinases (FYN, LYN, and YES1), GP1B, CD9, and alpha 2b beta 3 integrin. LYN and CD36 do not interact directly, but do so through a raft-associated lipid mediator. CD36-anchored LYN may be negatively regulated by MATK in resting platelets. In platelet activation, CD36-anchored LYN is released from suppression through the rapid translocation and subsequent dephosphorylation of MATK. Both oxLDL and oxPCCD36 activate PRKCA and induce the phosphorylation of SYK and PLCG2. Outcome effects: The downstream targets of LYN and FYN include the VAV family of proteins. VAVs are rapidly phosphorylated in platelets in a CD36-dependent manner. The signaling pathways induced by oxLDL in platelets include the activation of RHOA/ROCK1. In platelets, MAPK14 is also downstream of CD36 signaling. CD36 may lead to the activation of alpha 2b beta 3 integrin complex. Hyperlipidemia in vivo and oxLDL in vitro activate MAPK8 and its upstream activator, MAP2K4 in platelets via CD36. The interaction of CD36 with alpha 2b beta 3 integrin bound to fibrinogen is thought to stabilize platelet aggregation. It is currently unknown whether MAPK14 and MAPK8 work synergistically or independently in the process of platelet activation by oxLDL. The precise function of MAPK8 in platelet biology also remains to be determined. In addition, human CD36-negative platelets exhibit a mild defect at the initial stages of adhesion to fibrillar collagen I. SCARB1 is the major receptor on platelets that recognizes oxHDL. HDL and HDL sub-fractions, HDL2 and HDL3 have no significant effect on the activation and aggregation responses of isolated platelets. However, HDL oxidized by various pathways strongly inhibits platelet activation and interferes with multiple physiologic agonists by inhibiting platelet alpha 2b beta 3 integrin complex activation. The inhibitory effect requires the binding of oxHDL to platelet SCARB1. The mechanism of SCARB1-mediated inhibition of platelet activation by oxHDL is currently under investigation. Organ: generic Organ_System: hematological system PMID: 16712941 PMID: 21292024 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-c50c0bd8-8c3d-4acc-850b-cbdf6b8181ce Scavenger Receptors in Platelet Activation uuid-c50c0bd8-8c3d-4acc-850b-cbdf6b8181ce PS:CellType blood platelet PS:Description In circumstances of infection or oxidative stress, oxidized phospholipids may be found in the blood. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c50c0bd8-8c3d-4acc-850b-cbdf6b8181ce PS:NodeType Pathway PS:Notes Headnote: In case of infection or oxidative stress, oxidized phospholipids may be found in the blood. It has long been established that oxidized low-density lipoprotein (oxLDL) induces platelet activation/adhesion and enhances platelet aggregation. Signaling description: Oxidized phospholipids serve as ligands for scavenger receptors and may play a role as pathological, exogenous ligands and activate platelet aggregation. Platelets constitutively express class B scavenger receptors such as CD36 and SCARB1. Class E scavenger receptor, OLR1 (also known as LOX-1) and class D scavenger receptor, CD68 appear on the cell membrane following platelet activation. Scavenger receptor CD36 is the major receptor on platelets that promotes platelet reactivity in response to a group of specific oxidized phospholipids. CD36 recognizes a number of distinct ligands including the family of oxidized choline glycerophospholipids (oxPCCD36), which bind to platelets via CD36 and activates it. CD36 is localized in caveolin-negative, cholesterol-enriched lipid rafts in platelet membranes. The signaling events induced by CD36 are poorly understood. CD36 possibly forms a multi-protein complex in rafts with Src-family kinases (FYN, LYN, and YES1), GP1B, CD9, and alpha 2b beta 3 integrin. LYN and CD36 do not interact directly, but do so through a raft-associated lipid mediator. CD36-anchored LYN may be negatively regulated by MATK in resting platelets. In platelet activation, CD36-anchored LYN is released from suppression through the rapid translocation and subsequent dephosphorylation of MATK. Both oxLDL and oxPCCD36 activate PRKCA and induce the phosphorylation of SYK and PLCG2. Outcome effects: The downstream targets of LYN and FYN include the VAV family of proteins. VAVs are rapidly phosphorylated in platelets in a CD36-dependent manner. The signaling pathways induced by oxLDL in platelets include the activation of RHOA/ROCK1. In platelets, MAPK14 is also downstream of CD36 signaling. CD36 may lead to the activation of alpha 2b beta 3 integrin complex. Hyperlipidemia in vivo and oxLDL in vitro activate MAPK8 and its upstream activator, MAP2K4 in platelets via CD36. The interaction of CD36 with alpha 2b beta 3 integrin bound to fibrinogen is thought to stabilize platelet aggregation. It is currently unknown whether MAPK14 and MAPK8 work synergistically or independently in the process of platelet activation by oxLDL. The precise function of MAPK8 in platelet biology also remains to be determined. In addition, human CD36-negative platelets exhibit a mild defect at the initial stages of adhesion to fibrillar collagen I. SCARB1 is the major receptor on platelets that recognizes oxHDL. HDL and HDL sub-fractions, HDL2 and HDL3 have no significant effect on the activation and aggregation responses of isolated platelets. However, HDL oxidized by various pathways strongly inhibits platelet activation and interferes with multiple physiologic agonists by inhibiting platelet alpha 2b beta 3 integrin complex activation. The inhibitory effect requires the binding of oxHDL to platelet SCARB1. The mechanism of SCARB1-mediated inhibition of platelet activation by oxHDL is currently under investigation. PS:Organ generic PS:Organ_System hematological system PS:PMID 16712941 PS:PMID 21292024 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c510b698-3095-40af-9494-09cb1655ba92 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c510b698-3095-40af-9494-09cb1655ba92 IFN signaling in alveolar cells uuid-c510b698-3095-40af-9494-09cb1655ba92 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c510b698-3095-40af-9494-09cb1655ba92 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: macrophage CellType: myeloid progenitor cell Description: Dectin-2 (CLEC6A), Mincle (CLEC4E) and BDCA2 (CLEC4C) are recognition receptors for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5212dac-4969-4f78-b6bb-867cadfa2521 NodeType: Pathway Notes: Headnote: Dectin-2 (CLEC6A), Mincle (CLEC4E) and BDCA2 (CLEC4C) are recognition receptors for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. Signaling description: The Dectin-2, Mincle and BDCA2 receptors are involved in fungal recognition and modulation of the innate immune response. As a result of binding to PAMPs from fungi, these proteins form a complex consisting of BLNK, BTK, and PLCG2, which induces calcium (Ca2+) mobilization and transduces signals through an Fc receptor gamma chain (FCER1G) and SYK-CARD9-NF-kB-dependent pathway. Outcome effects: The increase in Ca2+ appears to be involved in the inhibition of MYD88 adapter recruitment to TLR9 and in the reduction of the expression of IFNB1, TNF, and IL6. CLEC4C is a specific receptor for beta-glucans, which are polymers found in the cell walls of fungi such as the yeast Saccharomyces cerevisiae and Candida albicans. CLEC6A also recognizes, in a mannose-dependent manner, allergens from house dust and soluble elements from the eggs of Shistosoma mansoni altering adaptative immune responses. CLEC4E recognizes fungal alpha-mannose and the mycobacterial glycolipid, trehalose-6'6'-dimycolate (TDM), also known as cord factor of the immunostimulatory component of Mycobacterium tuberculosis. In addition, CLEC4E recognizes the endogenous damage-associated molecular patterns (DAMPs) on damaged cells. Organ: generic Organ_System: generic PMID: 15481152 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-c5212dac-4969-4f78-b6bb-867cadfa2521 Dectin-2 (CLEC6A)/Mincle (CLEC4E)/BDCA2 (CLEC4C) Signaling uuid-c5212dac-4969-4f78-b6bb-867cadfa2521 PS:CellType dendritic cell PS:CellType macrophage PS:CellType myeloid progenitor cell PS:Description Dectin-2 (CLEC6A), Mincle (CLEC4E) and BDCA2 (CLEC4C) are recognition receptors for pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5212dac-4969-4f78-b6bb-867cadfa2521 PS:NodeType Pathway PS:Notes Headnote: Dectin-2 (CLEC6A), Mincle (CLEC4E) and BDCA2 (CLEC4C) are recognition receptors for pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens. Signaling description: The Dectin-2, Mincle and BDCA2 receptors are involved in fungal recognition and modulation of the innate immune response. As a result of binding to PAMPs from fungi, these proteins form a complex consisting of BLNK, BTK, and PLCG2, which induces calcium (Ca2+) mobilization and transduces signals through an Fc receptor gamma chain (FCER1G) and SYK-CARD9-NF-kB-dependent pathway. Outcome effects: The increase in Ca2+ appears to be involved in the inhibition of MYD88 adapter recruitment to TLR9 and in the reduction of the expression of IFNB1, TNF, and IL6. CLEC4C is a specific receptor for beta-glucans, which are polymers found in the cell walls of fungi such as the yeast Saccharomyces cerevisiae and Candida albicans. CLEC6A also recognizes, in a mannose-dependent manner, allergens from house dust and soluble elements from the eggs of Shistosoma mansoni altering adaptative immune responses. CLEC4E recognizes fungal alpha-mannose and the mycobacterial glycolipid, trehalose-6'6'-dimycolate (TDM), also known as cord factor of the immunostimulatory component of Mycobacterium tuberculosis. In addition, CLEC4E recognizes the endogenous damage-associated molecular patterns (DAMPs) on damaged cells. PS:Organ generic PS:Organ_System generic PS:PMID 15481152 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (HTT) gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c537544b-b92e-41e9-98e9-1a999bfec3a2 NodeType: Pathway Notes: Headnote: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (HTT) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium spiny neurons (MCN). Glutamate (Glu) and dopamine (Dop) signaling pathways act synergistically to induce Ca2+ overload and apoptosis of MCN. Signaling description: Under normal physiological conditions Glu is released from presynaptic terminals via Ca2+- dependant exocytosis and activates NMDAR (N-Methyl D-Aspartate Receptor) expressed on postsynaptic motor neurons and voltage dependent Ca2+ channels. This leads to Ca2+ influx into the cell.Neuronal death may depend on excitotoxicity that results from increased glutamate (Glu) release from cortical neurons and increased activity of the glutamate receptor (NMDAR). Mutant huntingtin (mHTT) can enhance the NMDA receptor-mediated exitotoxicity interacting with PSD95 (DLG4) postsynaptic scaffold protein. mHTT also induces phosphorylation of the NR2B subunit contributing to overactivation of NMDAR. The number and subunit composition of NMDAR are not static, but in response to neuronal activity, this process is called NMDAR trafficking. NMDAR trafficking is impaired in HD by destabilization of the clathrin-mediated endocytotic complex that involves NMDAR, mHTT, and HIP-1.The stimulation of glutamate metabotropic receptor GRM5 by Glu activates the IP3 signaling pathway causes increased Ca2+ release from endoplasmic reticulum by ITPR1. mHTT binds to ITPR1 and renders the receptors more sensitive to IP3. Dop released from substantia nigra dopaminergic neurons stimulates D1- and D2- class receptors (DRD1/2), which are abundantly expressed in MSNs. DRD1 is coupled to GNAS/ADCY, cAMP production and PKA activation. PKA potentiates glutamate-induced Ca2+ signals by activating of ITPR1. DRD2 acts through PI3K/IP3 signaling leading to the same results. As a result, simultaneous activation of Glu and Dop receptors leads to cytosolic and mitochondrial Ca2+ overload in HD MSNs. Downregulation of pre-synaptic cannabinoid receptors type 1 (CNR1) and DRD2 which normally block Glu release make impact in HD development. Outcome effects: When mitochondrial Ca2+ storage capacity is exceeded, mitochondrial permeability transition pore (mPTP) opens, leading to release of cytochrome c (CYCS) into the cytosol and activation of caspases 9 and 3, which leads to progression of apoptosis. The mitochondrial Ca2+ handling is further destabilized by direct association of HTT with mitochondria. mHTT was shown to directly induce the opening of mPTP. Adenosine A2 receptors (A2AR) are abundant on the corticostriatal pre-synaptic terminals, where, when activated, they increase Glu release. Reduced BDNF production and release from the cortical afferents contribute to neuronal death. Striatal BDNF is produced in the cortex where its transcription is downregulated in the presence of mHTT. In addition, mHTT reduces BDNF vesicle transport. Both mechanisms result in loss of BDNF trophic support to striatal neurons.Decreased Glu uptake in glial cells by GLT-1 (SLC1A2) contributes to neuronal excitotoxicity.Quinolinate is an endogenous metabolite at the kynurenine pathway of glial cells acting as a selective agonist at the NMDA receptor, and produces membrane depolarization and Ca2+ influx into neuronal cells. Moreover, quinolinate induces ROS synthesis and increases oxidative stress. Quinolinate level is increased in HD due to high kynurenine 3-monooxygenase (KMO) activity induced by mHTT. Cholinergic system is dysfunctional in HD patients: expression of vesicular acetylcholine transporter (SLC18A3) and choline acetyltransferase (CHAT) are decreased in the striatum and cortex. Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Compounds with elevated level are highlighted in red and compound Organ: brain Organ_System: nervous system PMID: 16987871 PMID: 17184144 PMID: 17652581 PMID: 18781982 PMID: 20406248 PMID: 20664076 PMID: 20929960 PMID: 21163446 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c537544b-b92e-41e9-98e9-1a999bfec3a2 Glutamate Toxicity Effects on Striatum Medium Spiny Neurons in Huntington's Disease uuid-c537544b-b92e-41e9-98e9-1a999bfec3a2 PS:CellType neuron PS:Description Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (HTT) gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c537544b-b92e-41e9-98e9-1a999bfec3a2 PS:NodeType Pathway PS:Notes Headnote: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (HTT) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium spiny neurons (MCN). Glutamate (Glu) and dopamine (Dop) signaling pathways act synergistically to induce Ca2+ overload and apoptosis of MCN. Signaling description: Under normal physiological conditions Glu is released from presynaptic terminals via Ca2+- dependant exocytosis and activates NMDAR (N-Methyl D-Aspartate Receptor) expressed on postsynaptic motor neurons and voltage dependent Ca2+ channels. This leads to Ca2+ influx into the cell.Neuronal death may depend on excitotoxicity that results from increased glutamate (Glu) release from cortical neurons and increased activity of the glutamate receptor (NMDAR). Mutant huntingtin (mHTT) can enhance the NMDA receptor-mediated exitotoxicity interacting with PSD95 (DLG4) postsynaptic scaffold protein. mHTT also induces phosphorylation of the NR2B subunit contributing to overactivation of NMDAR. The number and subunit composition of NMDAR are not static, but in response to neuronal activity, this process is called NMDAR trafficking. NMDAR trafficking is impaired in HD by destabilization of the clathrin-mediated endocytotic complex that involves NMDAR, mHTT, and HIP-1.The stimulation of glutamate metabotropic receptor GRM5 by Glu activates the IP3 signaling pathway causes increased Ca2+ release from endoplasmic reticulum by ITPR1. mHTT binds to ITPR1 and renders the receptors more sensitive to IP3. Dop released from substantia nigra dopaminergic neurons stimulates D1- and D2- class receptors (DRD1/2), which are abundantly expressed in MSNs. DRD1 is coupled to GNAS/ADCY, cAMP production and PKA activation. PKA potentiates glutamate-induced Ca2+ signals by activating of ITPR1. DRD2 acts through PI3K/IP3 signaling leading to the same results. As a result, simultaneous activation of Glu and Dop receptors leads to cytosolic and mitochondrial Ca2+ overload in HD MSNs. Downregulation of pre-synaptic cannabinoid receptors type 1 (CNR1) and DRD2 which normally block Glu release make impact in HD development. Outcome effects: When mitochondrial Ca2+ storage capacity is exceeded, mitochondrial permeability transition pore (mPTP) opens, leading to release of cytochrome c (CYCS) into the cytosol and activation of caspases 9 and 3, which leads to progression of apoptosis. The mitochondrial Ca2+ handling is further destabilized by direct association of HTT with mitochondria. mHTT was shown to directly induce the opening of mPTP. Adenosine A2 receptors (A2AR) are abundant on the corticostriatal pre-synaptic terminals, where, when activated, they increase Glu release. Reduced BDNF production and release from the cortical afferents contribute to neuronal death. Striatal BDNF is produced in the cortex where its transcription is downregulated in the presence of mHTT. In addition, mHTT reduces BDNF vesicle transport. Both mechanisms result in loss of BDNF trophic support to striatal neurons.Decreased Glu uptake in glial cells by GLT-1 (SLC1A2) contributes to neuronal excitotoxicity.Quinolinate is an endogenous metabolite at the kynurenine pathway of glial cells acting as a selective agonist at the NMDA receptor, and produces membrane depolarization and Ca2+ influx into neuronal cells. Moreover, quinolinate induces ROS synthesis and increases oxidative stress. Quinolinate level is increased in HD due to high kynurenine 3-monooxygenase (KMO) activity induced by mHTT. Cholinergic system is dysfunctional in HD patients: expression of vesicular acetylcholine transporter (SLC18A3) and choline acetyltransferase (CHAT) are decreased in the striatum and cortex. Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Compounds with elevated level are highlighted in red and compound PS:Organ brain PS:Organ_System nervous system PS:PMID 16987871 PS:PMID 17184144 PS:PMID 17652581 PS:PMID 18781982 PS:PMID 20406248 PS:PMID 20664076 PS:PMID 20929960 PS:PMID 21163446 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte CellType: monocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c553a849-57f6-4165-b6e6-959a2f42b1b3 NodeType: Pathway Notes: The characteristic inflammatory reaction in acne vulgaris is caused by the bacterium P. acnes that activates Toll-like receptor (TLR2,4) signaling resulting in the synthesis of proinflammatory cytokines such as interleukin-1 beta (IL-1B) and tumor necrosis factor (TNF). Proinflammatory cytokines are highly expressed in acne lesions, and they stimulate the activation of mast cells, neutrophils, monocytes, and other cells of the immune system. The inflammatory reaction supported by immune cells causes redness and pain and the formation of purulence in acne lesion. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epidermis urn:agi-pathway:uuid-c553a849-57f6-4165-b6e6-959a2f42b1b3 1_Inflammation in keratinocytes in the pathology of acne uuid-c553a849-57f6-4165-b6e6-959a2f42b1b3 PS:CellType keratinocyte PS:CellType monocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c553a849-57f6-4165-b6e6-959a2f42b1b3 PS:NodeType Pathway PS:Notes The characteristic inflammatory reaction in acne vulgaris is caused by the bacterium P. acnes that activates Toll-like receptor (TLR2,4) signaling resulting in the synthesis of proinflammatory cytokines such as interleukin-1 beta (IL-1B) and tumor necrosis factor (TNF). Proinflammatory cytokines are highly expressed in acne lesions, and they stimulate the activation of mast cells, neutrophils, monocytes, and other cells of the immune system. The inflammatory reaction supported by immune cells causes redness and pain and the formation of purulence in acne lesion. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage CellType: neuron Description: The expression of the CD47 protein is down regulated in multiple sclerosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5a7bcb6-4781-498c-9701-58e4cf474cfb NodeType: Pathway Notes: The expression of the CD47 protein is down-regulated in multiple sclerosis. This leads to a weakening of CD47 - SIRPA ties and inhibits the PTPN6 - RHOA activation. Organ: brain Organ_System: nervous system PMID: 19952055 PMID: 22466660 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-c5a7bcb6-4781-498c-9701-58e4cf474cfb CD47 Repression by miRNAs uuid-c5a7bcb6-4781-498c-9701-58e4cf474cfb PS:CellType macrophage PS:CellType neuron PS:Description The expression of the CD47 protein is down regulated in multiple sclerosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5a7bcb6-4781-498c-9701-58e4cf474cfb PS:NodeType Pathway PS:Notes The expression of the CD47 protein is down-regulated in multiple sclerosis. This leads to a weakening of CD47 - SIRPA ties and inhibits the PTPN6 - RHOA activation. PS:Organ brain PS:Organ_System nervous system PS:PMID 19952055 PS:PMID 22466660 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: Breast cancer (BC) is the most common type of cancer among women. ERBB2, EGFR, and VEGFRs play a significant role in BC. The overexpression of these receptors causes the hyperplastic glandular growth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5b91e64-01de-4173-8604-aa73b69f31d9 NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: ERBB2, EGFR, and VEGFRs play a significant role in breast cancer (BC). The overexpression of these receptors causes the constitutive activation of AKT1 signaling which prevents apoptosis and differentiation of mammary epithelial cells in BC and leads to hyperplastic glandular growth. The ERBB family of receptor tyrosine kinases consists of four related members including epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ERBB2), and v-erb-b2 erythroblastic leukemia viral oncogene homolog 3/4 (ERBB3 and ERBB4). The family of vascular endothelial growth factor receptors (VEGFRs) consists of fms-related tyrosine kinase 1/vascular endothelial growth factor 1 (FLT1/VEGFR1), kinase insert domain receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2), and fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR3). Ligand-bound EGFRs and VEGFRs activate PIK3CA via insulin receptor substrate 1 (IRS1). PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with the T-cell factor 7 (TCF7) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. EGFRs and VEGFRs mediate Janus kinases 1/2 (JAK1/2), which are involved in cell growth and activate RAF1 via SHC1/GRB2/SOS1. RAF1 activates ERK (MAPK1/3) signaling pathway which induces genes involved in cell proliferation and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: breast Organ_System: integumentary system PMID: 17322919 PMID: 20462514 PMID: 21556249 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-c5b91e64-01de-4173-8604-aa73b69f31d9 ERBB/VEGFR/Akt Signaling in Breast Cancer uuid-c5b91e64-01de-4173-8604-aa73b69f31d9 PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description Breast cancer (BC) is the most common type of cancer among women. ERBB2, EGFR, and VEGFRs play a significant role in BC. The overexpression of these receptors causes the hyperplastic glandular growth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5b91e64-01de-4173-8604-aa73b69f31d9 PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer). Men may also develop BC but this accounts for less than 1% of all BCs. BC is a heterogeneous disease. Most BCs are luminal tumors that start in the inner (luminal) cells lining the mammary ducts. Signaling description: ERBB2, EGFR, and VEGFRs play a significant role in breast cancer (BC). The overexpression of these receptors causes the constitutive activation of AKT1 signaling which prevents apoptosis and differentiation of mammary epithelial cells in BC and leads to hyperplastic glandular growth. The ERBB family of receptor tyrosine kinases consists of four related members including epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ERBB2), and v-erb-b2 erythroblastic leukemia viral oncogene homolog 3/4 (ERBB3 and ERBB4). The family of vascular endothelial growth factor receptors (VEGFRs) consists of fms-related tyrosine kinase 1/vascular endothelial growth factor 1 (FLT1/VEGFR1), kinase insert domain receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2), and fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR3). Ligand-bound EGFRs and VEGFRs activate PIK3CA via insulin receptor substrate 1 (IRS1). PIK3CA via PIP3 and PDPK1 activates v-akt murine thymoma viral oncogene (AKT1). Outcome effects: Activated AKT1 promotes several antiapoptotic pathways. AKT1 phosphorylates and activates CREB1 and MTOR while inhibiting TP53. CREB1 regulates transcription of BCL2. MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits glycogen synthase kinase 3 beta (GSK3B) which leads to the stabilization of cytosolic beta-catenin (CTNNB1). CTNNB1 then translocates into the nucleus where it interacts with the T-cell factor 7 (TCF7) and lymphoid enhancing factor 1 (LEF1) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. Activated AKT1 inhibits forkhead box O1/O3 (FOXO1/FOXO3). In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. EGFRs and VEGFRs mediate Janus kinases 1/2 (JAK1/2), which are involved in cell growth and activate RAF1 via SHC1/GRB2/SOS1. RAF1 activates ERK (MAPK1/3) signaling pathway which induces genes involved in cell proliferation and migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ breast PS:Organ_System integumentary system PS:PMID 17322919 PS:PMID 20462514 PS:PMID 21556249 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5c53011-6986-45ec-86cd-c0f268b0a4f1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c5c53011-6986-45ec-86cd-c0f268b0a4f1 D-Alanine metabolism template uuid-c5c53011-6986-45ec-86cd-c0f268b0a4f1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5c53011-6986-45ec-86cd-c0f268b0a4f1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5ddb53d-d026-43dc-9e7d-34458f628072 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-c5ddb53d-d026-43dc-9e7d-34458f628072 NOTCH -> NF-kB Signaling uuid-c5ddb53d-d026-43dc-9e7d-34458f628072 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5ddb53d-d026-43dc-9e7d-34458f628072 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell Description: High titers of autoantibodies and abnormal B-cell activation and differentiation are shown in systemic lupus erythematosus (SLE). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5e3fdd7-de32-426c-a431-0a88efaf6e5e NodeType: Pathway Notes: Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. High titers of autoantibodies accompanied by abnormal B-cell activation and differentiation are shown in systemic lupus erythematosus (SLE). Signaling description: Autoantigens observed in SLE comprise nuclear antigens including dsDNA, the ribonucleoprotein (RNP) complex Ro, the RNA-binding protein La, RNPs, the RNA molecule/protein complex Sm, the C1 complement component subunit C1q, and phospholipids. High levels of CD40LG, IFNB1, and IFNA1 in SLE activate the differentiation of B-cells and production of autoantibodies. A high level of TNFSF13B may result in the rescue of self-reactive B-cells from elimination. The mechanism of this process likely includes activation of the non-classical NF-kB2 pathway by TNFSF13B via TNFRSF13C, which facilitates up-regulation of several antiapoptotic BCL2 family members, thus promoting cell survival. Further, polymorphisms in BANK1, LYN, BLK, and RASGRF1 are thought to alter B-cell activation and increase SLE risk by a yet to be identified mechanism. Overall, the exact process of B-cell activation in lupus is poorly understood. The pathway also reflects one of the possible signaling routes through the B-cell receptor (BCR) complex (IgM, CD79A and CD79B). B lymphocytes from patients with SLE display enhanced BCR-mediated fluxes of intracytoplasmic calcium. The FCGR2B receptor is expressed on B-cells and regulates B-cell survival and proliferation by down-modulating BCR signaling. Polymorphisms that alter the inhibitory function of FCGR2B in B-cells are associated with SLE. Outcome effects: The pathology of SLE involves alterations of B cell activation and survival through a number of signaling paths including the enhanced (BCR)-mediated signal transduction leading to increased intracytoplasmic calcium, as well as the activation of the non-classical NF-kB2 pathway by TNFSF13B via TNFRSF13C and others. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Genes with mutations linked to SLE are shown in white-out style. Organ_System: lymphatic system PMID: 11683571 PMID: 19411764 PMID: 19550330 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-c5e3fdd7-de32-426c-a431-0a88efaf6e5e B-Cell Activation in Systemic Lupus Erythematosus uuid-c5e3fdd7-de32-426c-a431-0a88efaf6e5e PS:CellType B-cell PS:Description High titers of autoantibodies and abnormal B-cell activation and differentiation are shown in systemic lupus erythematosus (SLE). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5e3fdd7-de32-426c-a431-0a88efaf6e5e PS:NodeType Pathway PS:Notes Headnote: Systemic lupus erythematosus (SLE) is an autoimmune disease that evolves due to a genetic predisposition and environmental or stochastic stimuli. The most common symptoms of SLE are skin lesions such as erythematous rash, as well as fever, joint and muscle pain, swollen lymph nodes, hair loss and fatigue. The disease is believed to be triggered by a combination of genetic, immune and environmental factors. High titers of autoantibodies accompanied by abnormal B-cell activation and differentiation are shown in systemic lupus erythematosus (SLE). Signaling description: Autoantigens observed in SLE comprise nuclear antigens including dsDNA, the ribonucleoprotein (RNP) complex Ro, the RNA-binding protein La, RNPs, the RNA molecule/protein complex Sm, the C1 complement component subunit C1q, and phospholipids. High levels of CD40LG, IFNB1, and IFNA1 in SLE activate the differentiation of B-cells and production of autoantibodies. A high level of TNFSF13B may result in the rescue of self-reactive B-cells from elimination. The mechanism of this process likely includes activation of the non-classical NF-kB2 pathway by TNFSF13B via TNFRSF13C, which facilitates up-regulation of several antiapoptotic BCL2 family members, thus promoting cell survival. Further, polymorphisms in BANK1, LYN, BLK, and RASGRF1 are thought to alter B-cell activation and increase SLE risk by a yet to be identified mechanism. Overall, the exact process of B-cell activation in lupus is poorly understood. The pathway also reflects one of the possible signaling routes through the B-cell receptor (BCR) complex (IgM, CD79A and CD79B). B lymphocytes from patients with SLE display enhanced BCR-mediated fluxes of intracytoplasmic calcium. The FCGR2B receptor is expressed on B-cells and regulates B-cell survival and proliferation by down-modulating BCR signaling. Polymorphisms that alter the inhibitory function of FCGR2B in B-cells are associated with SLE. Outcome effects: The pathology of SLE involves alterations of B cell activation and survival through a number of signaling paths including the enhanced (BCR)-mediated signal transduction leading to increased intracytoplasmic calcium, as well as the activation of the non-classical NF-kB2 pathway by TNFSF13B via TNFRSF13C and others. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Genes with mutations linked to SLE are shown in white-out style. PS:Organ_System lymphatic system PS:PMID 11683571 PS:PMID 19411764 PS:PMID 19550330 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5e5ab5e-0099-47c0-ae33-612a79d3201d NodeType: Pathway Notes: If uropathogens penetrate in the kidney, they attach to urothelium, move on it, and damage it. Different bacteria have their own mechanisms of adhesion, colonization, damage causation, and avoidance of normal protective factors. Despite this, kidney cells recognize pathogens by means of toll-like receptors and provide an immune response via the production of cytokines that recruit and activate immune cells. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: kidney Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epithelium urn:agi-pathway:uuid-c5e5ab5e-0099-47c0-ae33-612a79d3201d 1_The role of Toll-like receptors in pyelonephritis uuid-c5e5ab5e-0099-47c0-ae33-612a79d3201d PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5e5ab5e-0099-47c0-ae33-612a79d3201d PS:NodeType Pathway PS:Notes If uropathogens penetrate in the kidney, they attach to urothelium, move on it, and damage it. Different bacteria have their own mechanisms of adhesion, colonization, damage causation, and avoidance of normal protective factors. Despite this, kidney cells recognize pathogens by means of toll-like receptors and provide an immune response via the production of cytokines that recruit and activate immune cells. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5ea174d-dc18-4433-8c56-596918c62470 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c5ea174d-dc18-4433-8c56-596918c62470 ACE2->mTOR->defensins uuid-c5ea174d-dc18-4433-8c56-596918c62470 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c5ea174d-dc18-4433-8c56-596918c62470 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Phototransduction is the process of converting light into electrical neural signals which takes place in the outer segments of photoreceptors. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6163236-f4a6-4716-9029-4095dd7e2836 NodeType: Pathway Notes: Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: The vertebrate retina comprises two different types of photoreceptors including rods and cones. There is a general agreement that the basic molecular mechanism of excitation is similar in both classes of photoreceptors. Photoreceptor cells are unusual in that they depolarize in response to the absence of stimuli or scotopic conditions (darkness). The intracellular cGMP levels are critical for phototransduction. In the photoreceptor cells, cGMP is synthesized by membrane guanylate cyclases (GUCY2D and GUCY2F) and hydrolyzed by PDE6. In the dark, photoreceptor rhodopsin (RHO) dissociates from G-proteins, and G-protein alpha dissociates from PDE6. Thus, PDE6 is inactive and cGMP levels are elevated. This activates cyclic nucleotide gated channels (CNGA1 and CNGB1), which allows a steady inward Ca2+ and Na+ current (known as "dark current"). Outcome effects: The dark current keeps the cell depolarized and causes the vesicles containing glutamate to merge with the cell membrane, therefore releasing the neurotransmitter into the synaptic cleft, which transduces the signal to retinal bipolar cells. Highlighted proteins: Entities with decreased level are highlighted in blue. Organ: Retina Organ: eye Organ_System: sensory system PMID: 12596926 PMID: 22074925 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-c6163236-f4a6-4716-9029-4095dd7e2836 RHO Signaling (Dark) uuid-c6163236-f4a6-4716-9029-4095dd7e2836 PS:Description Phototransduction is the process of converting light into electrical neural signals which takes place in the outer segments of photoreceptors. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6163236-f4a6-4716-9029-4095dd7e2836 PS:NodeType Pathway PS:Notes Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: The vertebrate retina comprises two different types of photoreceptors including rods and cones. There is a general agreement that the basic molecular mechanism of excitation is similar in both classes of photoreceptors. Photoreceptor cells are unusual in that they depolarize in response to the absence of stimuli or scotopic conditions (darkness). The intracellular cGMP levels are critical for phototransduction. In the photoreceptor cells, cGMP is synthesized by membrane guanylate cyclases (GUCY2D and GUCY2F) and hydrolyzed by PDE6. In the dark, photoreceptor rhodopsin (RHO) dissociates from G-proteins, and G-protein alpha dissociates from PDE6. Thus, PDE6 is inactive and cGMP levels are elevated. This activates cyclic nucleotide gated channels (CNGA1 and CNGB1), which allows a steady inward Ca2+ and Na+ current (known as "dark current"). Outcome effects: The dark current keeps the cell depolarized and causes the vesicles containing glutamate to merge with the cell membrane, therefore releasing the neurotransmitter into the synaptic cleft, which transduces the signal to retinal bipolar cells. Highlighted proteins: Entities with decreased level are highlighted in blue. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 12596926 PS:PMID 22074925 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6174e06-eb3e-4778-b115-6854c7618a29 NodeType: Pathway Organ: generic Organ_System: generic PMID: 25015322 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-c6174e06-eb3e-4778-b115-6854c7618a29 Longevity Related Drugs uuid-c6174e06-eb3e-4778-b115-6854c7618a29 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6174e06-eb3e-4778-b115-6854c7618a29 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 25015322 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c617d47e-9768-4a6a-ad82-88f921f69a2e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c617d47e-9768-4a6a-ad82-88f921f69a2e NSP5 interactions uuid-c617d47e-9768-4a6a-ad82-88f921f69a2e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c617d47e-9768-4a6a-ad82-88f921f69a2e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Organ PS:PMID Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c623456d-90da-422f-9c75-5db501068416 NodeType: Pathway Organ: eye Organ: trabecular meshwork PMID: 17984096 PMID: 19188438 PMID: 20431268 PMID: 21709622 PMID: 22173078 PMID: 22216020 PMID: 23876925 urn:agi-pathway:uuid-c623456d-90da-422f-9c75-5db501068416 MYOC->Aqueous humor outflow in trabecular meshwork uuid-c623456d-90da-422f-9c75-5db501068416 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c623456d-90da-422f-9c75-5db501068416 PS:NodeType Pathway PS:Organ eye PS:Organ trabecular meshwork PS:PMID 17984096 PS:PMID 19188438 PS:PMID 20431268 PS:PMID 21709622 PS:PMID 22173078 PS:PMID 22216020 PS:PMID 23876925 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Cancer cells may avoid hypoxia-induced cell death Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c62735f5-632c-4f6b-8501-476dda4796db NodeType: Pathway Notes: Headnote: Hypoxia is typical for cancer due to the imbalance between oxygen supply and consumption, and also the formation of aberrant vessels with poor blood flow characteristic to tumors. Normally, hypoxia is linked to cell death. However, cancer cells can avoid hypoxia-induced cell death through a number of mechanisms. Signaling description: Hypoxia can induce apoptosis via HIF1A-dependent activation of TP53 with downstream signaling through BCL family proteins and the induction of the caspase cascade. HIF1A also regulates the expression of BNIP3L and BNIP3 which may initiate either apoptosis, as well as necrosis or autophagy. The exact mechanism by which cancer cells escape hypoxia-induced cell death is not quite clear. Several mechanisms have been described up to now. First, hyper-activated IGF1/IGFR1/PI3K/AKT1 signaling can inhibit apoptosis. In the same way, TWIST2 can inhibit apoptosis through PI3K/AKT1 activation. Also, CASP9 inhibition by BIRC3 was shown to have a role in evasion of hypoxia-induced apoptosis . Outcome effects: As a result, cancer cells may avoid hypoxia-induced cell death. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Organ: oncogenic Organ_System: oncogenic PMID: 11902584 PMID: 19479945 PMID: 22889244 PMID: 23946798 PMID: 26512660 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-c62735f5-632c-4f6b-8501-476dda4796db Hypoxia-Induced Cell Death Evasion in Cancer uuid-c62735f5-632c-4f6b-8501-476dda4796db PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Cancer cells may avoid hypoxia-induced cell death PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c62735f5-632c-4f6b-8501-476dda4796db PS:NodeType Pathway PS:Notes Headnote: Hypoxia is typical for cancer due to the imbalance between oxygen supply and consumption, and also the formation of aberrant vessels with poor blood flow characteristic to tumors. Normally, hypoxia is linked to cell death. However, cancer cells can avoid hypoxia-induced cell death through a number of mechanisms. Signaling description: Hypoxia can induce apoptosis via HIF1A-dependent activation of TP53 with downstream signaling through BCL family proteins and the induction of the caspase cascade. HIF1A also regulates the expression of BNIP3L and BNIP3 which may initiate either apoptosis, as well as necrosis or autophagy. The exact mechanism by which cancer cells escape hypoxia-induced cell death is not quite clear. Several mechanisms have been described up to now. First, hyper-activated IGF1/IGFR1/PI3K/AKT1 signaling can inhibit apoptosis. In the same way, TWIST2 can inhibit apoptosis through PI3K/AKT1 activation. Also, CASP9 inhibition by BIRC3 was shown to have a role in evasion of hypoxia-induced apoptosis . Outcome effects: As a result, cancer cells may avoid hypoxia-induced cell death. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 11902584 PS:PMID 19479945 PS:PMID 22889244 PS:PMID 23946798 PS:PMID 26512660 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c62d6915-afbb-4b1b-bd39-57420088e4cc NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-c62d6915-afbb-4b1b-bd39-57420088e4cc HTR5 -> TNF Production uuid-c62d6915-afbb-4b1b-bd39-57420088e4cc PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c62d6915-afbb-4b1b-bd39-57420088e4cc PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c637d4f9-9988-4eab-9d28-b7db73db0881 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-c637d4f9-9988-4eab-9d28-b7db73db0881 IL4R -> STAT Signaling uuid-c637d4f9-9988-4eab-9d28-b7db73db0881 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c637d4f9-9988-4eab-9d28-b7db73db0881 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: eosinophil Description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 - 6 percent of all white blood cells and circulate in blood for several hours. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c671255a-bb2d-4fff-b328-701b505e9eb7 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 to 6 percent of the entire population of white blood cells, and they circulate in blood for several hours. In lung, eosinophils appear only in case of disease (such as asthma) and survive for up to 12 days. The effector function of eosinophils is related to their cytotoxic properties. Allergic asthma is associated with eosinophilic inflammation in the airways. The proinflammatory mediators derived by eosinophils are the major contributors to inflammation in asthma, mucus hypersecretion, and fibrosis. Translocation of eosinophils from bone marrow to their site of action is caused by action of specific chemokines such as CCL24, CCL11. CCL24 and CCL26 mRNA and CCL24 protein were increased in airway epithelial brushings from patients with asthma and were the highest in cases of severe asthma. They bind to the receptor CCR3 which activates migration, degranulation, and synthesis of cytokines in eosinophils via G-protein-dependent mechanism. Degranulation and chemotaxis involve profound rearrangement of the actin cytoskeleton. Precise mechanism of signaling that leads to the remodeling of cytoskeleton in eosinophils is unknown. Key players in this process are small GTPase RhoA and its effector kinases, ROCK1 and ROCK2, which cause an increase in calcium levels under influence of CCR3 ligands. Ligand-bound CCR3 causes activation of MAPK1/MAPK3. Activation of MAPK1/ MAPK3 pathway mediates arachidonic acid release, contributing to the secretion of lipid mediators, leading to degranulation and inflammatory responses. LTB4, and PGD2 and neurokinins are additional chemoattractants and activators of eosinophils in inflammation. Other cytokines, chemokines, small molecules, and inflammatory mediators can also activate eosinophils, but in a much lesser extent. During inflammation, circulating granulocytes first interact with VCAM1, MADCAM1 on the inflamed vascular endothelium of blood vessels. Similarly to other granulocytes, eosinophils are activated by a signal from IgE. Eosinophils express FceRII (CD23), which is a calcium-dependent lectin receptor with less affinity to IgE, as compared to FceRI. Eosinophil expression of FceRI is minimal and does not activate eosinophils. Polymorphisms within FCER2, the gene encoding CD23, have been associated with atopy, increased risk of exacerbations in patients with asthma, and high serum IgE levels. Outcome effects: Upon activation, eosinophils release the content of their granules in the site of inflammation. Proteins PRG2, RNASE3, EPC, RNASE2 are specific for eosinophils. They are the enzymes directly implicated in the cell damage that possess cytotoxic activities. Upon activation, eosinophils can release free radicals. One of mechanisms for that is via the NADPH oxidase in the plasma membrane under the action of Rac1 and Rac2. EPX also participates in the production of free radicals. Eosinophils do not synthesize and release all of their mediators at once, and the process takes place in a selective manner. Mechanisms that regulate the selective synthesis of pro-inflammatory mediators require further research. Eosinophils are capable of both the release of histamine and its neutralization (enzymatically or through phagocytosis). That is to say, eosinophils can play either pro-allergic or defensive anti-allergic role. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 12688104 PMID: 22392053 PMID: 23015684 PMID: 23616768 PMID: 24247484 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-c671255a-bb2d-4fff-b328-701b505e9eb7 Eosinophil Activation and Degranulation in Asthma uuid-c671255a-bb2d-4fff-b328-701b505e9eb7 PS:CellType eosinophil PS:Description Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 - 6 percent of all white blood cells and circulate in blood for several hours. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c671255a-bb2d-4fff-b328-701b505e9eb7 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: Eosinophils are circulating granulocytes. In healthy humans, eosinophils comprise 1 to 6 percent of the entire population of white blood cells, and they circulate in blood for several hours. In lung, eosinophils appear only in case of disease (such as asthma) and survive for up to 12 days. The effector function of eosinophils is related to their cytotoxic properties. Allergic asthma is associated with eosinophilic inflammation in the airways. The proinflammatory mediators derived by eosinophils are the major contributors to inflammation in asthma, mucus hypersecretion, and fibrosis. Translocation of eosinophils from bone marrow to their site of action is caused by action of specific chemokines such as CCL24, CCL11. CCL24 and CCL26 mRNA and CCL24 protein were increased in airway epithelial brushings from patients with asthma and were the highest in cases of severe asthma. They bind to the receptor CCR3 which activates migration, degranulation, and synthesis of cytokines in eosinophils via G-protein-dependent mechanism. Degranulation and chemotaxis involve profound rearrangement of the actin cytoskeleton. Precise mechanism of signaling that leads to the remodeling of cytoskeleton in eosinophils is unknown. Key players in this process are small GTPase RhoA and its effector kinases, ROCK1 and ROCK2, which cause an increase in calcium levels under influence of CCR3 ligands. Ligand-bound CCR3 causes activation of MAPK1/MAPK3. Activation of MAPK1/ MAPK3 pathway mediates arachidonic acid release, contributing to the secretion of lipid mediators, leading to degranulation and inflammatory responses. LTB4, and PGD2 and neurokinins are additional chemoattractants and activators of eosinophils in inflammation. Other cytokines, chemokines, small molecules, and inflammatory mediators can also activate eosinophils, but in a much lesser extent. During inflammation, circulating granulocytes first interact with VCAM1, MADCAM1 on the inflamed vascular endothelium of blood vessels. Similarly to other granulocytes, eosinophils are activated by a signal from IgE. Eosinophils express FceRII (CD23), which is a calcium-dependent lectin receptor with less affinity to IgE, as compared to FceRI. Eosinophil expression of FceRI is minimal and does not activate eosinophils. Polymorphisms within FCER2, the gene encoding CD23, have been associated with atopy, increased risk of exacerbations in patients with asthma, and high serum IgE levels. Outcome effects: Upon activation, eosinophils release the content of their granules in the site of inflammation. Proteins PRG2, RNASE3, EPC, RNASE2 are specific for eosinophils. They are the enzymes directly implicated in the cell damage that possess cytotoxic activities. Upon activation, eosinophils can release free radicals. One of mechanisms for that is via the NADPH oxidase in the plasma membrane under the action of Rac1 and Rac2. EPX also participates in the production of free radicals. Eosinophils do not synthesize and release all of their mediators at once, and the process takes place in a selective manner. Mechanisms that regulate the selective synthesis of pro-inflammatory mediators require further research. Eosinophils are capable of both the release of histamine and its neutralization (enzymatically or through phagocytosis). That is to say, eosinophils can play either pro-allergic or defensive anti-allergic role. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 12688104 PS:PMID 22392053 PS:PMID 23015684 PS:PMID 23616768 PS:PMID 24247484 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c67c79fa-5757-4aaa-8879-ac34a823b2d2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c67c79fa-5757-4aaa-8879-ac34a823b2d2 IKBKB->NFKB Activation in Huntington Disease uuid-c67c79fa-5757-4aaa-8879-ac34a823b2d2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c67c79fa-5757-4aaa-8879-ac34a823b2d2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: SCF/SKP2 complex regulates G1/S transition, apoptosis and response to DNA damage. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c689a0f2-f685-4505-887e-28335810bc00 NodeType: Pathway Notes: Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific substrate proteins. In SCF/SKP2 complex, SKP2 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/SKP2 related signaling leads to regulation of cell cycle progression, apoptosis and DNA damage. The precise mechanism of molecular signaling depicted on this pathway is well known and is associated with CDKN1A, CDKN1B, CDKN1C, CCNE1, CCND1, FOXO1/3 and NBN protein recognition. Outcome effects: SCF/SKP2 targets and degrades the nuclear pools of CDKN1A, CDKN1B, CDKN1C and CDKN1D bound to cyclins/CDKs and causes G1/S transition. Degradation of FOXO1/3 and NBN by SCF/SKP2 leads to block of apoptosis. Disruption of this proteolytic system can lead to genomic instability and cancer. Animal data: Role of SCF/SKP2 in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 22542766 PMID: 26528041 PMID: 26630263 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-c689a0f2-f685-4505-887e-28335810bc00 SCF/SKP2 Complex uuid-c689a0f2-f685-4505-887e-28335810bc00 PS:CellType generic PS:Description SCF/SKP2 complex regulates G1/S transition, apoptosis and response to DNA damage. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c689a0f2-f685-4505-887e-28335810bc00 PS:NodeType Pathway PS:Notes Headnote: The SCF complex (SKP, Cullin, F-box containing complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in cell cycle and also marks various other cellular proteins for destruction. The SCF complex consists of four components: three constant subunits SKP1, RBX1 and CUL1, and a variable subunit, the F-box-protein. CUL1 (Cullin) is the core subunit on which the subunits RBX1 and SKP1 are assembled. RBX1 connects to E2 and SKP1 binds to the F-box-protein. Each F-box protein binds to a specific substrate proteins. In SCF/SKP2 complex, SKP2 acts as the substrate recognition F-box protein. Signaling description: Through a specific subset of substrate proteins, the core of SCF/SKP2 related signaling leads to regulation of cell cycle progression, apoptosis and DNA damage. The precise mechanism of molecular signaling depicted on this pathway is well known and is associated with CDKN1A, CDKN1B, CDKN1C, CCNE1, CCND1, FOXO1/3 and NBN protein recognition. Outcome effects: SCF/SKP2 targets and degrades the nuclear pools of CDKN1A, CDKN1B, CDKN1C and CDKN1D bound to cyclins/CDKs and causes G1/S transition. Degradation of FOXO1/3 and NBN by SCF/SKP2 leads to block of apoptosis. Disruption of this proteolytic system can lead to genomic instability and cancer. Animal data: Role of SCF/SKP2 in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 22542766 PS:PMID 26528041 PS:PMID 26630263 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6969aea-1b62-4e3e-a8f1-4862e7305dd7 NodeType: Pathway Notes: Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: The stimulation of nuclear receptor NR3C1 by glucocorticoids, particularly dexamethasone, activates the transcription of DKK1 and SOST, which are antagonists of the WNT signaling pathway. Thus, dexamethasone-induced toxic effects are generally mediated by the downregulation of WNT signaling pathway. Outcome effects: The inhibition of WNT pathway and subsequent activation of protein kinase GSK3B in various cell types results in the phosphorylation of insulin receptor substrates, IRS1 and IRS2; and also causes an interruption of the signaling pathway connecting insulin receptor (INSR) to glucose transporter (SLC2A4), which results in the cell becoming insensitive to insulin (INS). Organ: pancreas Organ_System: endocrine system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-c6969aea-1b62-4e3e-a8f1-4862e7305dd7 Dexamethasone Induced Diabetes uuid-c6969aea-1b62-4e3e-a8f1-4862e7305dd7 PS:CellType insulin-secreting cell PS:Description Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6969aea-1b62-4e3e-a8f1-4862e7305dd7 PS:NodeType Pathway PS:Notes Headnote: Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones and acts as an immunosuppressant and an anti-inflammatory agent. Signaling description: The stimulation of nuclear receptor NR3C1 by glucocorticoids, particularly dexamethasone, activates the transcription of DKK1 and SOST, which are antagonists of the WNT signaling pathway. Thus, dexamethasone-induced toxic effects are generally mediated by the downregulation of WNT signaling pathway. Outcome effects: The inhibition of WNT pathway and subsequent activation of protein kinase GSK3B in various cell types results in the phosphorylation of insulin receptor substrates, IRS1 and IRS2; and also causes an interruption of the signaling pathway connecting insulin receptor (INSR) to glucose transporter (SLC2A4), which results in the cell becoming insensitive to insulin (INS). PS:Organ pancreas PS:Organ_System endocrine system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6980c85-f401-4bed-b152-25410ae9927f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-c6980c85-f401-4bed-b152-25410ae9927f oxLDL->NFkB+AP1 uuid-c6980c85-f401-4bed-b152-25410ae9927f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6980c85-f401-4bed-b152-25410ae9927f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PMID Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c69f3879-7f12-4b3b-95b9-569c632f821c NodeType: Pathway PMID: 18313409 urn:agi-pathway:uuid-c69f3879-7f12-4b3b-95b9-569c632f821c TGFb+>STATs uuid-c69f3879-7f12-4b3b-95b9-569c632f821c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c69f3879-7f12-4b3b-95b9-569c632f821c PS:NodeType Pathway PS:PMID 18313409 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a054b2-44a2-4ea9-9792-ec4223e7fcea NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-c6a054b2-44a2-4ea9-9792-ec4223e7fcea Find me Signal: Apoptotic Cell Attracts Phagocyte uuid-c6a054b2-44a2-4ea9-9792-ec4223e7fcea PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a054b2-44a2-4ea9-9792-ec4223e7fcea PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a38a52-db00-4c50-956a-a29d4d5eb37f NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-c6a38a52-db00-4c50-956a-a29d4d5eb37f TGFBR+>Cell migration uuid-c6a38a52-db00-4c50-956a-a29d4d5eb37f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a38a52-db00-4c50-956a-a29d4d5eb37f PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a6737f-2c4e-489e-ae73-69bf153da6c0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-c6a6737f-2c4e-489e-ae73-69bf153da6c0 Thrombosis increases vascular permeability uuid-c6a6737f-2c4e-489e-ae73-69bf153da6c0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6a6737f-2c4e-489e-ae73-69bf153da6c0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b0fd78-6bfc-4300-842a-23ce36440303 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-c6b0fd78-6bfc-4300-842a-23ce36440303 USP22-Mediated Epigenetic and Non-Epigenetic Effects uuid-c6b0fd78-6bfc-4300-842a-23ce36440303 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b0fd78-6bfc-4300-842a-23ce36440303 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b214f9-d27e-4bb8-9c24-c93fa5165fce NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-c6b214f9-d27e-4bb8-9c24-c93fa5165fce Vitamin K Metabolism uuid-c6b214f9-d27e-4bb8-9c24-c93fa5165fce PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b214f9-d27e-4bb8-9c24-c93fa5165fce PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b534b4-106a-4d2a-ab2e-871dfac402d5 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-c6b534b4-106a-4d2a-ab2e-871dfac402d5 EphrinR -> STAT Signaling uuid-c6b534b4-106a-4d2a-ab2e-871dfac402d5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6b534b4-106a-4d2a-ab2e-871dfac402d5 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Melanoma is the most aggressive form of skin cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6cbe021-c7d0-473c-9421-fd293590cccc NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Signaling description: A family history of the disease is identified in 10% of all cases and associated with CDKN2A and CDK4 mutations. In addition, important genetic risk factors may be polymorphisms of the MC1R gene. Germline mutations of MC1R are found in 80% of individuals with red hair color, fair skin, and poor tanning. The highest risk of melanoma incidence is in populations with fair skin types with low melanin production. Melanin is an important chromophore in the skin and is able to absorb ultraviolet (UV) radiation and visible light; it is also able to scavenge molecular oxygen and hydroxyl radicals thereby protecting DNA from UV damage. UV induces malignant changes in the skin through direct DNA damage, impairing cutaneous immune response, inducing local growth factors, and giving rise to reactive oxygen species which cause DNA damage. UV radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor MC1R resulting in the expression of MITF, a master regulator of melanocyte function which also serves as an oncogene in melanoma cells. WNT3A/CTNNB1 signaling also induces MITF expression. MITF regulates the expression of genes such as TYR, TYRP1, DCT, MLANA, PMEL, RAB27A, and others and is responsible for melanin production and transportation to keratinocytes. In melanoma, the synthesis of melanin is continued but transportation of melanin to keratinocytes is disrupted due to the loss of normal melanocyte-keratinocyte junctions. Several hypotheses point to the pro-oncogenic effect of melanin in melanoma cells, but the exact mechanism is unknown. MITF plays both cancer-promoting and cancer-inhibiting roles in melanoma. MITF has the ability to upregulate transcription of melanoma-promoting genes (CCND1, BCL2, and MET) and also melanoma-repressing genes (CDKN2A, CDKN1A, and DIAPH1). Many melanocytic signaling pathways are initiated via activation of KIT receptor that triggers MAPK and PI3K pathway activation. KIT aberrations are found in 28-39% of melanoma cases. The mutagenic activation of the MAPK pathway is observed in up to 90% of melanoma cases and is most commonly achieved via mutations in NRAS or BRAF. In addition, PTEN is mutated in up to 10-30% of melanoma cases. 43-50% of melanoma cases have activated AKT3 due to mutation or gene amplification. CCND1, CDKN2B, TP53, and MDM2 may also be mutated. Furthermore, constant MAPK activation drives cell cycle progression and antiapoptotic signaling. BCL2, MCL1, BCL2L1, BCL2L11, and BIRC7 are found to be constantly activated. BAX and APAF1 are repressed. Metastatic progression is associated with the loss of E-cadherin (CDH1) and increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). The activation of NODAL plays a role in melanocyte dedifferentiation and is regulated by NOTCH4 signaling. POU5F1, driven by EPAS1, also plays a role in dedifferentiation. WNT5A is overexpressed in melanoma and downregulates CDH1; while, the metastasis suppressor KISS1 upregulates VIM and CD44 which is a tumor homing and metastasis antigen. Additionally, autocrine/paracrine signaling and intercellular interactions are important in melanoma progression, including IGF1/IGF1R, HGF/MET, VEGFA /FLT1, VEGFA/KDR, PGF/FLT1, PGF/KDR, EFNA1/EPHA2, EDN3/EDNRB, EGF/EGFR, FGF1/FGFR1, IL8/CXCR1/CXCR2, CXCL12/CXCR4, and PLAU/PLAUR interactions. Outcome effects: Following exposure to UV radiation multiple molecular alterations in signaling pathways lead to block of apoptosis, a Organ: skin Organ_System: integumentary system PMID: 12778131 PMID: 16822996 PMID: 18083379 PMID: 18927540 PMID: 19056669 PMID: 19571822 PMID: 19708915 PMID: 20067521 PMID: 20079807 PMID: 22046555 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c6cbe021-c7d0-473c-9421-fd293590cccc Melanoma uuid-c6cbe021-c7d0-473c-9421-fd293590cccc PS:CellType cancer cell PS:CellType melanocyte PS:Description Melanoma is the most aggressive form of skin cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6cbe021-c7d0-473c-9421-fd293590cccc PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Signaling description: A family history of the disease is identified in 10% of all cases and associated with CDKN2A and CDK4 mutations. In addition, important genetic risk factors may be polymorphisms of the MC1R gene. Germline mutations of MC1R are found in 80% of individuals with red hair color, fair skin, and poor tanning. The highest risk of melanoma incidence is in populations with fair skin types with low melanin production. Melanin is an important chromophore in the skin and is able to absorb ultraviolet (UV) radiation and visible light; it is also able to scavenge molecular oxygen and hydroxyl radicals thereby protecting DNA from UV damage. UV induces malignant changes in the skin through direct DNA damage, impairing cutaneous immune response, inducing local growth factors, and giving rise to reactive oxygen species which cause DNA damage. UV radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor MC1R resulting in the expression of MITF, a master regulator of melanocyte function which also serves as an oncogene in melanoma cells. WNT3A/CTNNB1 signaling also induces MITF expression. MITF regulates the expression of genes such as TYR, TYRP1, DCT, MLANA, PMEL, RAB27A, and others and is responsible for melanin production and transportation to keratinocytes. In melanoma, the synthesis of melanin is continued but transportation of melanin to keratinocytes is disrupted due to the loss of normal melanocyte-keratinocyte junctions. Several hypotheses point to the pro-oncogenic effect of melanin in melanoma cells, but the exact mechanism is unknown. MITF plays both cancer-promoting and cancer-inhibiting roles in melanoma. MITF has the ability to upregulate transcription of melanoma-promoting genes (CCND1, BCL2, and MET) and also melanoma-repressing genes (CDKN2A, CDKN1A, and DIAPH1). Many melanocytic signaling pathways are initiated via activation of KIT receptor that triggers MAPK and PI3K pathway activation. KIT aberrations are found in 28-39% of melanoma cases. The mutagenic activation of the MAPK pathway is observed in up to 90% of melanoma cases and is most commonly achieved via mutations in NRAS or BRAF. In addition, PTEN is mutated in up to 10-30% of melanoma cases. 43-50% of melanoma cases have activated AKT3 due to mutation or gene amplification. CCND1, CDKN2B, TP53, and MDM2 may also be mutated. Furthermore, constant MAPK activation drives cell cycle progression and antiapoptotic signaling. BCL2, MCL1, BCL2L1, BCL2L11, and BIRC7 are found to be constantly activated. BAX and APAF1 are repressed. Metastatic progression is associated with the loss of E-cadherin (CDH1) and increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). The activation of NODAL plays a role in melanocyte dedifferentiation and is regulated by NOTCH4 signaling. POU5F1, driven by EPAS1, also plays a role in dedifferentiation. WNT5A is overexpressed in melanoma and downregulates CDH1; while, the metastasis suppressor KISS1 upregulates VIM and CD44 which is a tumor homing and metastasis antigen. Additionally, autocrine/paracrine signaling and intercellular interactions are important in melanoma progression, including IGF1/IGF1R, HGF/MET, VEGFA /FLT1, VEGFA/KDR, PGF/FLT1, PGF/KDR, EFNA1/EPHA2, EDN3/EDNRB, EGF/EGFR, FGF1/FGFR1, IL8/CXCR1/CXCR2, CXCL12/CXCR4, and PLAU/PLAUR interactions. Outcome effects: Following exposure to UV radiation multiple molecular alterations in signaling pathways lead to block of apoptosis, a PS:Organ skin PS:Organ_System integumentary system PS:PMID 12778131 PS:PMID 16822996 PS:PMID 18083379 PS:PMID 18927540 PS:PMID 19056669 PS:PMID 19571822 PS:PMID 19708915 PS:PMID 20067521 PS:PMID 20079807 PS:PMID 22046555 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: osteoblast Description: In osteoblasts, WNT signaling influences the commitment of mesenchymal stem cells to osteoblasts, stimulation of osteoblast proliferation, and promotion of osteoblast and osteocyte survival. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6fb3814-2cf5-4c3d-a0f3-de40bc0684ca NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. More than 80% of MM patients develop bone disease with severe bone pain and pathologic fractures. Signaling description: The initiation of WNT signaling occurs following the binding of WNT to FZD and LRP6 receptors, which in turn activates downstream elements (DVL1 and FRAT1) leading to the accumulation of CTNNB1. CTNNB1 translocates to the nucleus where in conjunction with LEF, functions as a transcription activator of target genes such as TNFSF11 and TNFRSF11B. Normally, TNFSF11 promotes bone resorption while TNFRSF11B is involved in bone formation. WNT signaling leads to the increase of TNFRSF11B and the decrease of TNFSF11 production. There are several natural inhibitors of WNT including DKK1 and SFRP1. The disruption of this pathway by myeloma plasma cell-derived overexpressed DKK1 results in the suppression of osteoblast differentiation, enhanced osteoclast function, and bone destruction by the inhibition of the production of regulatory molecules such as TNFRSF11B which is normally produced by osteoblasts. Outcome effects: In osteoblasts, WNT signaling influences three major developmental functions: the commitment of mesenchymal stem cells to osteoblasts, stimulation of osteoblast proliferation, and promotion of osteoblast and osteocyte survival. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ_System: skeletal system PMID: 18294945 PMID: 21378363 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-c6fb3814-2cf5-4c3d-a0f3-de40bc0684ca WNT Inhibition by DKK1 in Osteoblast in Multiple Myelome uuid-c6fb3814-2cf5-4c3d-a0f3-de40bc0684ca PS:CellType cancer cell PS:CellType osteoblast PS:Description In osteoblasts, WNT signaling influences the commitment of mesenchymal stem cells to osteoblasts, stimulation of osteoblast proliferation, and promotion of osteoblast and osteocyte survival. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6fb3814-2cf5-4c3d-a0f3-de40bc0684ca PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. More than 80% of MM patients develop bone disease with severe bone pain and pathologic fractures. Signaling description: The initiation of WNT signaling occurs following the binding of WNT to FZD and LRP6 receptors, which in turn activates downstream elements (DVL1 and FRAT1) leading to the accumulation of CTNNB1. CTNNB1 translocates to the nucleus where in conjunction with LEF, functions as a transcription activator of target genes such as TNFSF11 and TNFRSF11B. Normally, TNFSF11 promotes bone resorption while TNFRSF11B is involved in bone formation. WNT signaling leads to the increase of TNFRSF11B and the decrease of TNFSF11 production. There are several natural inhibitors of WNT including DKK1 and SFRP1. The disruption of this pathway by myeloma plasma cell-derived overexpressed DKK1 results in the suppression of osteoblast differentiation, enhanced osteoclast function, and bone destruction by the inhibition of the production of regulatory molecules such as TNFRSF11B which is normally produced by osteoblasts. Outcome effects: In osteoblasts, WNT signaling influences three major developmental functions: the commitment of mesenchymal stem cells to osteoblasts, stimulation of osteoblast proliferation, and promotion of osteoblast and osteocyte survival. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ_System skeletal system PS:PMID 18294945 PS:PMID 21378363 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c72a5f45-9cd3-49ac-87ec-f84b8cd7102d NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-c72a5f45-9cd3-49ac-87ec-f84b8cd7102d Parasympathetic Pathway->Lacrimation uuid-c72a5f45-9cd3-49ac-87ec-f84b8cd7102d PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c72a5f45-9cd3-49ac-87ec-f84b8cd7102d PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Blau syndrome is a rare autosomal dominant disorder characterized by granulomatous polyarthritis, panuveitis, cranial neuropathies, and exanthema. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c741164a-5c16-4f88-9873-2a11395376c1 NodeType: Pathway Notes: Headnote: Blau syndrome is a rare autosomal dominant disorder characterized by granulomatous polyarthritis, panuveitis, cranial neuropathies, and exanthema. The signs and symptoms begin in childhood, usually before the age of 4. A form of skin inflammation called granulomatous dermatitis is typically the earliest sign of Blau syndrome. This skin condition causes a persistent rash that can be scaly or involve hard lumps which can be felt under the skin. The rash is usually found on the torso, arms, and legs. Arthritis is another common feature of Blau syndrome. In affected individuals, arthritis is characterized by the inflammation of the lining of the joints. This inflammation, known as synovitis, is associated with swelling and joint pain. Most people with Blau syndrome also develop uveitis, which is swelling and inflammation of the middle layer of the eye (uvea). Autoinflammatory Blau syndrome is associated with NOD2 gene mutations. Signaling description: NOD2 functions as an intracellular receptor for the muramyl dipeptide component of peptidoglycan. The pathogenic mechanism responsible for chronic inflammation that characterizes Blau syndrome may be related to the impaired production of both pro- and anti-inflammatory cytokines. The NOD2 pathway possibly interacts with either TLR2 or TLR4 pathway. NOD2 gene mutations which cause Blau syndrome result in an overactive NOD2 protein. All NOD2 mutations lie close to the ATP-binding site in the NACHT domain. It is believed that they may interfere directly with ATP hydrolysis or interfere indirectly with the conformational switch, suggesting that this would allow excessive signaling due to a reduced disassembly of NOD2 signaling complexes. Outcome effects: The excessive signaling results in constitutively increased NF-kB activation, leading to abnormal inflammatory reaction. However, it is not completely clear how overactivation of the NOD2 protein causes the specific pattern of inflammation affecting the joints, eyes, and skin characteristic of Blau syndrome. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ_System: hematological system PMID: 17223962 PMID: 20052476 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-c741164a-5c16-4f88-9873-2a11395376c1 Blau Syndrome uuid-c741164a-5c16-4f88-9873-2a11395376c1 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Blau syndrome is a rare autosomal dominant disorder characterized by granulomatous polyarthritis, panuveitis, cranial neuropathies, and exanthema. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c741164a-5c16-4f88-9873-2a11395376c1 PS:NodeType Pathway PS:Notes Headnote: Blau syndrome is a rare autosomal dominant disorder characterized by granulomatous polyarthritis, panuveitis, cranial neuropathies, and exanthema. The signs and symptoms begin in childhood, usually before the age of 4. A form of skin inflammation called granulomatous dermatitis is typically the earliest sign of Blau syndrome. This skin condition causes a persistent rash that can be scaly or involve hard lumps which can be felt under the skin. The rash is usually found on the torso, arms, and legs. Arthritis is another common feature of Blau syndrome. In affected individuals, arthritis is characterized by the inflammation of the lining of the joints. This inflammation, known as synovitis, is associated with swelling and joint pain. Most people with Blau syndrome also develop uveitis, which is swelling and inflammation of the middle layer of the eye (uvea). Autoinflammatory Blau syndrome is associated with NOD2 gene mutations. Signaling description: NOD2 functions as an intracellular receptor for the muramyl dipeptide component of peptidoglycan. The pathogenic mechanism responsible for chronic inflammation that characterizes Blau syndrome may be related to the impaired production of both pro- and anti-inflammatory cytokines. The NOD2 pathway possibly interacts with either TLR2 or TLR4 pathway. NOD2 gene mutations which cause Blau syndrome result in an overactive NOD2 protein. All NOD2 mutations lie close to the ATP-binding site in the NACHT domain. It is believed that they may interfere directly with ATP hydrolysis or interfere indirectly with the conformational switch, suggesting that this would allow excessive signaling due to a reduced disassembly of NOD2 signaling complexes. Outcome effects: The excessive signaling results in constitutively increased NF-kB activation, leading to abnormal inflammatory reaction. However, it is not completely clear how overactivation of the NOD2 protein causes the specific pattern of inflammation affecting the joints, eyes, and skin characteristic of Blau syndrome. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System hematological system PS:PMID 17223962 PS:PMID 20052476 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c75ce0e0-8b08-43b3-a1ae-3732a5948467 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-c75ce0e0-8b08-43b3-a1ae-3732a5948467 CCR1 Expression Targets uuid-c75ce0e0-8b08-43b3-a1ae-3732a5948467 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c75ce0e0-8b08-43b3-a1ae-3732a5948467 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Beta 2 microglobulin (B2M) is a protein found as a component of the major histocompatibility complex (MHC) class I on the surface of cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7680a4a-efaa-4663-b42f-5fa07ef0743e NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Beta 2 microglobulin (B2M) is a protein found as a component of the major histocompatibility complex (MHC) class I on the surface of cells. B2M protein is also known to be a mitogen and increases the growth of prostate cancer cells. The B2M gene has a putative androgen response element and is known to be overexpressed upon androgen stimulation. It is proposed that B2M can activate cAMP-dependent protein kinase A (PKA) possibly through the binding to G protein-coupled receptor. Outcome effects: Subsequent phosphorylation and activation of transcription factor CREB (cAMP responsive element binding protein 1) initiates the expression of cyclin A2 (CCNA2), cyclin D1 (CCND1) and vascular endothelial growth factor A (VEGFA), which increase cell proliferation, survival, and angiogenesis. B2M induces integrin-binding sialoprotein (IBSP) and bone gamma-carboxyglutamate (gla) protein (BGLAP) which are structural proteins of the bone matrix. The expression of IBSP and BGLAP is suggested to confer the ability of prostate cancer cells to grow and survive in the bone microenvironment which leads to bone metastasis. Organ: prostate Organ_System: urinary tract PMID: 16982753 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c7680a4a-efaa-4663-b42f-5fa07ef0743e Androgen Receptor/Beta-2-Microglobulin Signaling in Prostate Cancer uuid-c7680a4a-efaa-4663-b42f-5fa07ef0743e PS:CellType cancer cell PS:Description Beta 2 microglobulin (B2M) is a protein found as a component of the major histocompatibility complex (MHC) class I on the surface of cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7680a4a-efaa-4663-b42f-5fa07ef0743e PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Beta 2 microglobulin (B2M) is a protein found as a component of the major histocompatibility complex (MHC) class I on the surface of cells. B2M protein is also known to be a mitogen and increases the growth of prostate cancer cells. The B2M gene has a putative androgen response element and is known to be overexpressed upon androgen stimulation. It is proposed that B2M can activate cAMP-dependent protein kinase A (PKA) possibly through the binding to G protein-coupled receptor. Outcome effects: Subsequent phosphorylation and activation of transcription factor CREB (cAMP responsive element binding protein 1) initiates the expression of cyclin A2 (CCNA2), cyclin D1 (CCND1) and vascular endothelial growth factor A (VEGFA), which increase cell proliferation, survival, and angiogenesis. B2M induces integrin-binding sialoprotein (IBSP) and bone gamma-carboxyglutamate (gla) protein (BGLAP) which are structural proteins of the bone matrix. The expression of IBSP and BGLAP is suggested to confer the ability of prostate cancer cells to grow and survive in the bone microenvironment which leads to bone metastasis. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 16982753 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: The canonical WNT pathway has been found to be deregulated in mantle cell lymphoma (MCL). Nuclear expression of transcriptionally active CTNNB was detected in MCL and correlated with GSK3B inactivation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c76e7f94-a421-4475-b521-99594e3fe3f5 NodeType: Pathway Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: The canonical WNT pathway has been found to be deregulated in MCL. Nuclear expression of transcriptionally active beta-catenin (CTNNB1) was detected in MCL and correlated with glycogen synthase kinase-3 beta (GSK3B) inactivation. The high level of expression of several FZD receptors and LRP5 has been documented and indicates a possible autocrine loop of WNT signals. Furthermore, casein kinase II, which is constitutively phosphorylated in MCL, phosphorylates CTNNB1, thereby impeding its proteasomal degradation. Outcome effects: In conclusion, the disruption of canonical WNT signaling reduces proliferation and induces apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: lymph node Organ_System: lymphatic system PMID: 20940415 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-c76e7f94-a421-4475-b521-99594e3fe3f5 WNT Canonical Signaling in Mantle Cell Lymphoma uuid-c76e7f94-a421-4475-b521-99594e3fe3f5 PS:CellType B-cell PS:CellType cancer cell PS:Description The canonical WNT pathway has been found to be deregulated in mantle cell lymphoma (MCL). Nuclear expression of transcriptionally active CTNNB was detected in MCL and correlated with GSK3B inactivation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c76e7f94-a421-4475-b521-99594e3fe3f5 PS:NodeType Pathway PS:Notes Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description: The canonical WNT pathway has been found to be deregulated in MCL. Nuclear expression of transcriptionally active beta-catenin (CTNNB1) was detected in MCL and correlated with glycogen synthase kinase-3 beta (GSK3B) inactivation. The high level of expression of several FZD receptors and LRP5 has been documented and indicates a possible autocrine loop of WNT signals. Furthermore, casein kinase II, which is constitutively phosphorylated in MCL, phosphorylates CTNNB1, thereby impeding its proteasomal degradation. Outcome effects: In conclusion, the disruption of canonical WNT signaling reduces proliferation and induces apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 20940415 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: The E5 HPV protei is small protein that have many functions and not essential for the life cycle of virus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c772984a-98a5-4739-9292-e2502ab6e9d1 NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: These viruses encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2).The HPV16-E5 ORFs have been classified into four groups: alpha, beta, gamma and delta, which correlate with different clinical manifestations including oncogenic potential. The E5 ORF is absent in the genome of several HPVs including beta-, gamma- and mu-HPVs. This indicates that the protein is not essential for the life cycle of these viruses, but rather can provide some benefit in favor of infection and transformation. E5 is expressed during the early phases of the viral life cycle, but only as the fourth ORF on polycistronic transcripts. In contrast, during the epithelial-cell differentiation, E5 is expressed as the second ORF of late transcripts. E5 is a small protein (~85 a.a.), is extremely hydrophobic and has membrane localization. E5 is present in the endoplasmic reticulum, nuclear envelope, and Golgi apparatus, and, when overexpressed, on the plasma membrane. The C-terminal domain is localized in the cytoplasm and interacts with IPO5. Outcome effects: IPO5/E5 complex plays an important role in vesicle trafficking. E5 protein binds and inhibits the activity of ATP6V0C, which alters endosome transport. This causes altered endosomal acidification and degradation of EGFR, thus enhancing its recycling to the plasma membrane. E5 can also hinder EGFR degradation by interfering with membrane trafficking and the fusion of early and late endosomes. E5 impairs gap junction protein (GJA1), which is necessary for gap junction intercellular communication. In addition, E5 downregulates CDKN1A and CDKN1B, this leads to the reversal of the cell proliferation blockade. This action also occurs through the inhibition of ATP6V0C, which binds CERS2. This protein can inhibit cell proliferation and migration. The lack of EGFR degradation leads to the activation of EGFR/MAPK and PI3K/PKC signaling, which augments the JUN-FOS and MYC activation. This forces the cells through the cell cycle and stimulates transcription of the viral oncogenes E6 and E7. An additional pathway activated by EGFR is the PGE2 synthesis activation. PGE2 interacts with PTGER4 and initiates PKA activation, which leads to CREB1 phosphorylation. CREB1 initiates the transcription of PTGER4, BCL2, and VEGFA. MAPK and AKT1 signaling also elevates the VEGFA expression which leads to vascularization. E5 also enhances the effect of EDNRA signaling. EDNRA activates MAPK and AKT1 pathways and activates EGFR through SRC. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Exogenous protein is shown in grey. Organ: skin PMID: 11753669 PMID: 22078316 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-c772984a-98a5-4739-9292-e2502ab6e9d1 HPV E5 Regulates EDNRA and EGFR Signaling Pathway in Keratinocytes uuid-c772984a-98a5-4739-9292-e2502ab6e9d1 PS:CellType cancer cell PS:CellType keratinocyte PS:Description The E5 HPV protei is small protein that have many functions and not essential for the life cycle of virus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c772984a-98a5-4739-9292-e2502ab6e9d1 PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: These viruses encode six early viral proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2).The HPV16-E5 ORFs have been classified into four groups: alpha, beta, gamma and delta, which correlate with different clinical manifestations including oncogenic potential. The E5 ORF is absent in the genome of several HPVs including beta-, gamma- and mu-HPVs. This indicates that the protein is not essential for the life cycle of these viruses, but rather can provide some benefit in favor of infection and transformation. E5 is expressed during the early phases of the viral life cycle, but only as the fourth ORF on polycistronic transcripts. In contrast, during the epithelial-cell differentiation, E5 is expressed as the second ORF of late transcripts. E5 is a small protein (~85 a.a.), is extremely hydrophobic and has membrane localization. E5 is present in the endoplasmic reticulum, nuclear envelope, and Golgi apparatus, and, when overexpressed, on the plasma membrane. The C-terminal domain is localized in the cytoplasm and interacts with IPO5. Outcome effects: IPO5/E5 complex plays an important role in vesicle trafficking. E5 protein binds and inhibits the activity of ATP6V0C, which alters endosome transport. This causes altered endosomal acidification and degradation of EGFR, thus enhancing its recycling to the plasma membrane. E5 can also hinder EGFR degradation by interfering with membrane trafficking and the fusion of early and late endosomes. E5 impairs gap junction protein (GJA1), which is necessary for gap junction intercellular communication. In addition, E5 downregulates CDKN1A and CDKN1B, this leads to the reversal of the cell proliferation blockade. This action also occurs through the inhibition of ATP6V0C, which binds CERS2. This protein can inhibit cell proliferation and migration. The lack of EGFR degradation leads to the activation of EGFR/MAPK and PI3K/PKC signaling, which augments the JUN-FOS and MYC activation. This forces the cells through the cell cycle and stimulates transcription of the viral oncogenes E6 and E7. An additional pathway activated by EGFR is the PGE2 synthesis activation. PGE2 interacts with PTGER4 and initiates PKA activation, which leads to CREB1 phosphorylation. CREB1 initiates the transcription of PTGER4, BCL2, and VEGFA. MAPK and AKT1 signaling also elevates the VEGFA expression which leads to vascularization. E5 also enhances the effect of EDNRA signaling. EDNRA activates MAPK and AKT1 pathways and activates EGFR through SRC. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Exogenous protein is shown in grey. PS:Organ skin PS:PMID 11753669 PS:PMID 22078316 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7801d42-9ab9-4c24-a385-a89494b3af3f NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-c7801d42-9ab9-4c24-a385-a89494b3af3f Overview. Diseases of the eye (chapter 6) uuid-c7801d42-9ab9-4c24-a385-a89494b3af3f PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7801d42-9ab9-4c24-a385-a89494b3af3f PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: Congenital cataract (CC) is a common cause of visual disability in children. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7898796-67c1-4606-be7c-e81011d944f7 NodeType: Pathway Notes: Headnote: Cataract is clouding of the eye's lens that affects vision. Congenital cataract (CC) is a common cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents one third of all cases. Signaling description: At least 22 genes associated with isolated inherited cataract have been identified including crystallin genes, such as CRYAA, CRYAB, CRYBB1, CRYBB2, CRYGC, CRYGD, and CRYGS, four membrane protein genes including GJA3, GJA8, MIP, and LIM2, transcription factor genes such as MAF and HSF4, and cytoskeletal protein genes including BFSP1 and BFSP2. Outcome effects: The molecular mechanisms of CC are associated with either protein misfolding seen in the case of mutations in CRYBB1, CRYBB2, CRYGC, CRYGD, and CRYGS or their aggregation caused by mutations in CRYAA and/or CRYAB. In addition, impaired crystallin expression is observed when MAF is mutated. An additional mechanism of CC is based on the disruption of transport between lens cells due to mutations in the genes of aquaporin (MIP) and gap junction proteins such as GJA3 and GJA8. Mutations in these genes lead to reduced glutathione and ROS accumulation, which are the important mediators of different types of cataract including CC. Mutations in MIP gene lead to separation of the lens structural molecules due to water accumulation in the lens cells. Lastly, beaded filaments including BFSP1 and BFSP2 are lens cell-specific intermediate filaments, which help maintain lens transparency. Mutations in these genes lead to cytoskeleton disorganization and light scattering. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. Organ: eye Organ_System: sensory system PMID: 15110667 PMID: 15558493 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-c7898796-67c1-4606-be7c-e81011d944f7 Cataract, Congenital uuid-c7898796-67c1-4606-be7c-e81011d944f7 PS:CellType epithelial cell PS:Description Congenital cataract (CC) is a common cause of visual disability in children. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7898796-67c1-4606-be7c-e81011d944f7 PS:NodeType Pathway PS:Notes Headnote: Cataract is clouding of the eye's lens that affects vision. Congenital cataract (CC) is a common cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents one third of all cases. Signaling description: At least 22 genes associated with isolated inherited cataract have been identified including crystallin genes, such as CRYAA, CRYAB, CRYBB1, CRYBB2, CRYGC, CRYGD, and CRYGS, four membrane protein genes including GJA3, GJA8, MIP, and LIM2, transcription factor genes such as MAF and HSF4, and cytoskeletal protein genes including BFSP1 and BFSP2. Outcome effects: The molecular mechanisms of CC are associated with either protein misfolding seen in the case of mutations in CRYBB1, CRYBB2, CRYGC, CRYGD, and CRYGS or their aggregation caused by mutations in CRYAA and/or CRYAB. In addition, impaired crystallin expression is observed when MAF is mutated. An additional mechanism of CC is based on the disruption of transport between lens cells due to mutations in the genes of aquaporin (MIP) and gap junction proteins such as GJA3 and GJA8. Mutations in these genes lead to reduced glutathione and ROS accumulation, which are the important mediators of different types of cataract including CC. Mutations in MIP gene lead to separation of the lens structural molecules due to water accumulation in the lens cells. Lastly, beaded filaments including BFSP1 and BFSP2 are lens cell-specific intermediate filaments, which help maintain lens transparency. Mutations in these genes lead to cytoskeleton disorganization and light scattering. Highlighted proteins: Entities with increased level of activity are highlighted in red, and entities with decreased level of activity are highlighted in blue. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 15110667 PS:PMID 15558493 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7a932aa-58e9-4fff-8564-4b3cf227b724 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-c7a932aa-58e9-4fff-8564-4b3cf227b724 Proteins with Altered Expression in Melanoma uuid-c7a932aa-58e9-4fff-8564-4b3cf227b724 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7a932aa-58e9-4fff-8564-4b3cf227b724 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Activating germline mutations of ALK are responsible for the majority of hereditary neuroblastoma (NB) cases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7cd91e5-ec63-4e7b-934c-6eefefc4e8ef NodeType: Pathway Notes: Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain.Signaling descripton: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is normally expressed in neurons of the central and peripheral nervous systems at late embryonic stages and promotes cell growth and neurite outgrowth. Activating germline mutations of ALK are responsible for the majority of hereditary neuroblastoma (NB) cases. Moreover, ALK point mutations are often found in sporadic NB cases. ALK may function through the PI3K/AKT1, MAPK, and JAK/STAT signaling cascades. Outcome effects: The resulting signaling events lead to the upregulation of cell proliferation and inhibition of apoptosis. Mutated gene is shown in white-out style. Organ_System: nervous system PMID: 15226403 PMID: 15735675 PMID: 19737948 PMID: 21205076 PMID: 21295685 PMID: 22585002 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c7cd91e5-ec63-4e7b-934c-6eefefc4e8ef ALK Associated Neuroblastoma uuid-c7cd91e5-ec63-4e7b-934c-6eefefc4e8ef PS:CellType cancer cell PS:CellType neural stem cell PS:Description Activating germline mutations of ALK are responsible for the majority of hereditary neuroblastoma (NB) cases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7cd91e5-ec63-4e7b-934c-6eefefc4e8ef PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain.Signaling descripton: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is normally expressed in neurons of the central and peripheral nervous systems at late embryonic stages and promotes cell growth and neurite outgrowth. Activating germline mutations of ALK are responsible for the majority of hereditary neuroblastoma (NB) cases. Moreover, ALK point mutations are often found in sporadic NB cases. ALK may function through the PI3K/AKT1, MAPK, and JAK/STAT signaling cascades. Outcome effects: The resulting signaling events lead to the upregulation of cell proliferation and inhibition of apoptosis. Mutated gene is shown in white-out style. PS:Organ_System nervous system PS:PMID 15226403 PS:PMID 15735675 PS:PMID 19737948 PS:PMID 21205076 PS:PMID 21295685 PS:PMID 22585002 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7eb44ef-fd42-4154-ad26-260b0ae09af2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c7eb44ef-fd42-4154-ad26-260b0ae09af2 Histidine degradation template uuid-c7eb44ef-fd42-4154-ad26-260b0ae09af2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c7eb44ef-fd42-4154-ad26-260b0ae09af2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c805d2dc-bb26-45ef-9e2d-0296f0602227 NodeType: Pathway Organ: generic Organ_System: generic PMID: 24388967 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-c805d2dc-bb26-45ef-9e2d-0296f0602227 KRAS Signaling uuid-c805d2dc-bb26-45ef-9e2d-0296f0602227 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c805d2dc-bb26-45ef-9e2d-0296f0602227 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 24388967 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c828a912-9394-4aea-9e0b-ace7e89e6d90 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c828a912-9394-4aea-9e0b-ace7e89e6d90 Proteins Involved in Vascular Dementia uuid-c828a912-9394-4aea-9e0b-ace7e89e6d90 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c828a912-9394-4aea-9e0b-ace7e89e6d90 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c82c54b5-f428-4b7d-9f70-978f38f2673f NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c82c54b5-f428-4b7d-9f70-978f38f2673f CD80 -> AP-1 Expression Targets uuid-c82c54b5-f428-4b7d-9f70-978f38f2673f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c82c54b5-f428-4b7d-9f70-978f38f2673f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c82c800c-db89-4cc5-ba47-949426385ab8 NodeType: Pathway Notes: Headnote: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT), which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Mutant HTT (mHTT) can disrupt binding of the HAP1/DCTN1 complex to microtubules and motor complexes and thereby can depress BDNF axonal transport and release. mHTT binds more strongly to beta-tubulin (microtibules) than does wild-type HTT, thereby accumulating over time on the microtubules. This causes a physical block to transport and gradually makes intracellular transport less efficient. Signaling description: HAP1, a HTT interacting protein, facilitates the interaction of HTT with dynactin 1 (p150Glued, DCTN1), an accessory partner of dynein/dynactin motor protein complex. HTT/DCTN1/HAP1 protein complex interacts with microtubules to facilitate transport of the vesicle along the axon. It appears that HAP1 acts as a BDNF cargo-carrying molecule. Pro-BDNF forms a complex with HAP1 and sortilin that modulates pro-BDNF trafficking, degradation, and processing. Reduced association among pro-BDNF, HAP1 and SORT1 is observed in the Huntington disease (HD), which may result in impaired BDNF transport. HAP1 is involved in the internalization and recycling of the GABAA receptor. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mHTT. HAP1 regulates trafficking is of membrane receptors NTRK1, NTRK2 and EGFR, which can be attenuated by mHTT.HTT function in vesicle trafficking is also mediated by palmitoylation. Palmitoylation of HTT by HIP14 (ZDHHC17) is essential for its trafficking and function; it influences HTT localization and protects it from aggregation. Palmitoylation of SNAP25 (a protein, taking part in vesicle fusion and docking) by ZDHHC17 is potentiated in the presence of wild-type HTT. mHTT has prominently reduced affinity to ZDHHC17 that results in a marked reduction in palmitoylation. mHTT also impairs vesicle-mediated transport via interaction with RAB11A, HIP1 and HAP40 (F8A1). 14-3-3 protein interacts with HAP1 and regulates its trafficking. Duo (KALRN) binds to HAP1-binding proteins and regulates cytoskeleton (actin) organization and endocytosis. HAP1 also interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), which plays a role in the regulation of vesicular trafficking and signal transduction.Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 16339760 PMID: 16699508 PMID: 19262167 PMID: 20152113 PMID: 21882412 PMID: 22633949 PMID: 22921535 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-c82c800c-db89-4cc5-ba47-949426385ab8 Axonal Transport Impairment in Hungtington Disease uuid-c82c800c-db89-4cc5-ba47-949426385ab8 PS:CellType neuron PS:Description Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c82c800c-db89-4cc5-ba47-949426385ab8 PS:NodeType Pathway PS:Notes Headnote: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HGT), which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Normal huntingtin (HTT) was shown to play a role in fast axonal transport. Mutant HTT (mHTT) can disrupt binding of the HAP1/DCTN1 complex to microtubules and motor complexes and thereby can depress BDNF axonal transport and release. mHTT binds more strongly to beta-tubulin (microtibules) than does wild-type HTT, thereby accumulating over time on the microtubules. This causes a physical block to transport and gradually makes intracellular transport less efficient. Signaling description: HAP1, a HTT interacting protein, facilitates the interaction of HTT with dynactin 1 (p150Glued, DCTN1), an accessory partner of dynein/dynactin motor protein complex. HTT/DCTN1/HAP1 protein complex interacts with microtubules to facilitate transport of the vesicle along the axon. It appears that HAP1 acts as a BDNF cargo-carrying molecule. Pro-BDNF forms a complex with HAP1 and sortilin that modulates pro-BDNF trafficking, degradation, and processing. Reduced association among pro-BDNF, HAP1 and SORT1 is observed in the Huntington disease (HD), which may result in impaired BDNF transport. HAP1 is involved in the internalization and recycling of the GABAA receptor. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mHTT. HAP1 regulates trafficking is of membrane receptors NTRK1, NTRK2 and EGFR, which can be attenuated by mHTT.HTT function in vesicle trafficking is also mediated by palmitoylation. Palmitoylation of HTT by HIP14 (ZDHHC17) is essential for its trafficking and function; it influences HTT localization and protects it from aggregation. Palmitoylation of SNAP25 (a protein, taking part in vesicle fusion and docking) by ZDHHC17 is potentiated in the presence of wild-type HTT. mHTT has prominently reduced affinity to ZDHHC17 that results in a marked reduction in palmitoylation. mHTT also impairs vesicle-mediated transport via interaction with RAB11A, HIP1 and HAP40 (F8A1). 14-3-3 protein interacts with HAP1 and regulates its trafficking. Duo (KALRN) binds to HAP1-binding proteins and regulates cytoskeleton (actin) organization and endocytosis. HAP1 also interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), which plays a role in the regulation of vesicular trafficking and signal transduction.Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 16339760 PS:PMID 16699508 PS:PMID 19262167 PS:PMID 20152113 PS:PMID 21882412 PS:PMID 22633949 PS:PMID 22921535 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c88e01a2-ccff-4d2a-8c0f-db0361add8b1 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-c88e01a2-ccff-4d2a-8c0f-db0361add8b1 CD8 -> NF-kB Expression Targets uuid-c88e01a2-ccff-4d2a-8c0f-db0361add8b1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c88e01a2-ccff-4d2a-8c0f-db0361add8b1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8a002fc-cb40-4e9c-ae9a-314dca69784e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-c8a002fc-cb40-4e9c-ae9a-314dca69784e FGFs stabilize RUNX2 uuid-c8a002fc-cb40-4e9c-ae9a-314dca69784e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8a002fc-cb40-4e9c-ae9a-314dca69784e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast CellType: keratinocyte Description: Androgens are major regulators of human androgen-dependent pigmented terminal hair follicle growth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b560bc-8513-496a-9498-9451a7fb7f74 NodeType: Pathway Notes: Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: Androgens are major regulators of human androgen-dependent pigmented terminal hair follicle growth such as beard. At the same time, there are androgen-independent hair follicles such as eyelashes. Scalp follicles from frontal and parietal areas of the scalp are considered androgen-sensitive. In androgenetic alopecia (AGA), androgens have paradoxically different effects on hair follicles depending on body site, stimulating androgen-dependent beard growth while inducing regression of follicles from frontal and parietal areas of the scalp. Dermal papilla (DP) cells can synthesize androgens. All types of hair follicle DP cells, including beard, pubic, and scalp, contain testosterone and androstenedione. Normally, only beard cells produce the more potent androgen, dihydrotestosterone by SRD5A2. In AGA, DP cells from androgen-sensitive frontal scalp contain more SRD5A2 than those from androgen-insensitive occipital scalp. Steroid sulfatase, STS in the DP of human terminal hair follicles hydrolyzes dehydroepiandrosterone sulfate (DHEA-sulfate) to DHEA. The follicle DP appears to be the site of androgen action. Outcome effects: In hair follicles, androgen receptors (ARs) are only found in DP cells. In AGA, DP cells from balding scalp express higher levels of ARs than non-balding scalp cells. AR gene isoforms or functional mutations near the AR gene may explain the aberrant expression of AR protein in the balding scalp and AGA onset and development. Of the many AR gene polymorphisms known, the G allele of StuI and polyQ polymorphisms has the most significant association with AGA, especially in white populations. DNA methylation of the AR promoter is increased in hair follicles from occipital scalp compared with those from vertex AGA scalp, indicating the importance of DNA methylation for protecting occipital hair follicles against AR expression. In AGA, there is simultaneous androgen-dependent stimulation of beard hair growth and the regression of scalp hair which are explained by the difference in DP cell gene expression status due to different schemes of their embryogenesis. In beard and bald frontal scalp, DP cell expression of TGFB1I1 mRNA is higher than in cells from the occipital scalp. TGFB1I1 is a coactivator of AR. TGFB1 can enhance androgen sensitivity in balding DP cells through SMAD3 signaling and checked by TGFB1I1 in an autocrine manner. The expression of NCOA4, a cell growth promoter, has been shown to be reduced in DP of balding areas. The DP and hair bulb express only the short (beta), but not the long (alpha) form of NCOA4. Studies indicate that AR competes with AHR, VDR, and PPARG/ retinoid-X receptor for NCOA4 availability. In addition, in scalp DP cells of AGA patients, increased levels of DNA damage and androgen-accelerated premature senescence (loss of proliferative capacity) induction are observed. The loss of proliferative capacity of balding DP cells is associated with higher expression of CDKN2A, ATM, ATR, HSPB1, SOD; and lower expression of BMI1 and PCNA. CDKN2A protein levels are upregulated in response to androgen and the knockdown of AR diminishes the effects of androgen. Two important DNA damage sensors, H2AFX-ATM and ATR are detected only in balding DP cells. The expression levels of H2AFX proteins are further increased with AR overexpression. In prostate cancer cell lines, androgen signaling has been reported to induce the recruitment of TOP2B complex, which catalyzes DNA double-strand breaks (DSBs) at regulatory regions of AR target ge Organ: skin Organ_System: integumentary system PMID: 12015971 PMID: 17508020 PMID: 17989730 PMID: 20601956 PMID: 21981665 PMID: 22562579 PMID: 22829074 PMID: 24244503 PMID: 9284093 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: dermis urn:agi-pathway:uuid-c8b560bc-8513-496a-9498-9451a7fb7f74 Androgens Promote Scalp Dermal Papilla Regression uuid-c8b560bc-8513-496a-9498-9451a7fb7f74 PS:CellType fibroblast PS:CellType keratinocyte PS:Description Androgens are major regulators of human androgen-dependent pigmented terminal hair follicle growth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b560bc-8513-496a-9498-9451a7fb7f74 PS:NodeType Pathway PS:Notes Headnote: Androgenetic alopecia refers to hereditary androgen-dependent hair loss that affects both man and women. The process is characterized by moderate to severe hair loss. Androgenetic alopecia (AGA), as well as some other cutaneous diseases including seborrhea, acne, and hirsutism, is the prominent symptom of peripheral androgen excess. Androgen excess occurs by the increased synthesis of androgens in the skin called hyperandrogenism. Signaling description: Androgens are major regulators of human androgen-dependent pigmented terminal hair follicle growth such as beard. At the same time, there are androgen-independent hair follicles such as eyelashes. Scalp follicles from frontal and parietal areas of the scalp are considered androgen-sensitive. In androgenetic alopecia (AGA), androgens have paradoxically different effects on hair follicles depending on body site, stimulating androgen-dependent beard growth while inducing regression of follicles from frontal and parietal areas of the scalp. Dermal papilla (DP) cells can synthesize androgens. All types of hair follicle DP cells, including beard, pubic, and scalp, contain testosterone and androstenedione. Normally, only beard cells produce the more potent androgen, dihydrotestosterone by SRD5A2. In AGA, DP cells from androgen-sensitive frontal scalp contain more SRD5A2 than those from androgen-insensitive occipital scalp. Steroid sulfatase, STS in the DP of human terminal hair follicles hydrolyzes dehydroepiandrosterone sulfate (DHEA-sulfate) to DHEA. The follicle DP appears to be the site of androgen action. Outcome effects: In hair follicles, androgen receptors (ARs) are only found in DP cells. In AGA, DP cells from balding scalp express higher levels of ARs than non-balding scalp cells. AR gene isoforms or functional mutations near the AR gene may explain the aberrant expression of AR protein in the balding scalp and AGA onset and development. Of the many AR gene polymorphisms known, the G allele of StuI and polyQ polymorphisms has the most significant association with AGA, especially in white populations. DNA methylation of the AR promoter is increased in hair follicles from occipital scalp compared with those from vertex AGA scalp, indicating the importance of DNA methylation for protecting occipital hair follicles against AR expression. In AGA, there is simultaneous androgen-dependent stimulation of beard hair growth and the regression of scalp hair which are explained by the difference in DP cell gene expression status due to different schemes of their embryogenesis. In beard and bald frontal scalp, DP cell expression of TGFB1I1 mRNA is higher than in cells from the occipital scalp. TGFB1I1 is a coactivator of AR. TGFB1 can enhance androgen sensitivity in balding DP cells through SMAD3 signaling and checked by TGFB1I1 in an autocrine manner. The expression of NCOA4, a cell growth promoter, has been shown to be reduced in DP of balding areas. The DP and hair bulb express only the short (beta), but not the long (alpha) form of NCOA4. Studies indicate that AR competes with AHR, VDR, and PPARG/ retinoid-X receptor for NCOA4 availability. In addition, in scalp DP cells of AGA patients, increased levels of DNA damage and androgen-accelerated premature senescence (loss of proliferative capacity) induction are observed. The loss of proliferative capacity of balding DP cells is associated with higher expression of CDKN2A, ATM, ATR, HSPB1, SOD; and lower expression of BMI1 and PCNA. CDKN2A protein levels are upregulated in response to androgen and the knockdown of AR diminishes the effects of androgen. Two important DNA damage sensors, H2AFX-ATM and ATR are detected only in balding DP cells. The expression levels of H2AFX proteins are further increased with AR overexpression. In prostate cancer cell lines, androgen signaling has been reported to induce the recruitment of TOP2B complex, which catalyzes DNA double-strand breaks (DSBs) at regulatory regions of AR target ge PS:Organ skin PS:Organ_System integumentary system PS:PMID 12015971 PS:PMID 17508020 PS:PMID 17989730 PS:PMID 20601956 PS:PMID 21981665 PS:PMID 22562579 PS:PMID 22829074 PS:PMID 24244503 PS:PMID 9284093 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue dermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b7d9ef-9bea-4188-a014-f266a37fe28e NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-c8b7d9ef-9bea-4188-a014-f266a37fe28e Proteins with Altered Expression in Cancer-Associated Histone Deacetylation uuid-c8b7d9ef-9bea-4188-a014-f266a37fe28e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b7d9ef-9bea-4188-a014-f266a37fe28e PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b881b2-6d75-4423-90a7-dfd45e9382cb NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c8b881b2-6d75-4423-90a7-dfd45e9382cb TLR1 -> 2/6 Expression Targets uuid-c8b881b2-6d75-4423-90a7-dfd45e9382cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8b881b2-6d75-4423-90a7-dfd45e9382cb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8d857b3-97dd-4e4f-a736-2589450939a9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-c8d857b3-97dd-4e4f-a736-2589450939a9 CCL7 Expression Target uuid-c8d857b3-97dd-4e4f-a736-2589450939a9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8d857b3-97dd-4e4f-a736-2589450939a9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8e6cbfd-9c98-44d3-90ed-07c671bedf30 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-c8e6cbfd-9c98-44d3-90ed-07c671bedf30 Bile Acid Metabolism (Alternative Pathway) uuid-c8e6cbfd-9c98-44d3-90ed-07c671bedf30 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c8e6cbfd-9c98-44d3-90ed-07c671bedf30 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c918b5e4-d029-4d20-bbca-4012453367f0 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c918b5e4-d029-4d20-bbca-4012453367f0 ARDS genetic predisposition uuid-c918b5e4-d029-4d20-bbca-4012453367f0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c918b5e4-d029-4d20-bbca-4012453367f0 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: In humans, there are two subtypes of melatonin receptors including MTNR1A and MTNR1B. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c91e2846-2b6d-4ec9-92bf-773d2f29efae NodeType: Pathway Notes: Headnote: In humans, there are two subtypes of melatonin receptors including MTNR1A and MTNR1B. These are G protein-coupled receptors and are expressed in various tissues of the body, as a group or individually. Signaling description: Melatonin activates a variety of second messenger cascades following binding to membrane receptors contingent on the specific cell and species. The activation of MTNR1A and MTNR1B inhibits adenylyl cyclase (ADCY) and its inhibition causes a rippling effect of non-activation, which commences with the decreased formation of cAMP and then progressing to diminished PKA activity, which in turn hinders the phosphorylation of CREB1. MTNR1A also activates PLCB1. Outcome effects: The main effect of MTNR1A receptor activation is the inhibition of cAMP accumulation, however in different cell types melatonin may cause either inhibition or stimulation of cAMP. Melatonin has both receptor-mediated and receptor-independent actions. Nuclear binding sites are members of the retinoic acid receptor superfamily and include RORA and RORB. Glutamate activates N-methyl-D-aspartate selective glutamate receptor-induced calcium (Ca2+) influx which, along with other second messengers, triggers the activation of diverse signal transduction cascades including neuronal nitric oxide synthase (NOS1) activity, guanylate cyclase, and CREB1, which in turn activates PER1 and PER2 transcription. Mitogen-activated protein kinases (MAPKs) in suprachiasmatic nucleus (SCN) neurons are activated by light-induced neurotransmission and/or extracellular signals including trophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). MAPKs regulate the activity of CLOCK, ARNTL, and other circadian rhythm proteins. The activation of MTNR1A increases potassium (K+) conductance by activating KCNJ3-inward rectifier K channels via Gb/g proteins. This may play a role in the inhibition of neuronal firing in the SCN. In addition, melatonin interacts with intracellular proteins such as calmodulin and antagonizes the binding of Ca2+ to calmodulin. Organ: brain Organ_System: nervous system PMID: 16527442 PMID: 16817850 PMID: 18571301 PMID: 21193011 PMID: 22986412 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-c91e2846-2b6d-4ec9-92bf-773d2f29efae Circadian Clock Genes in Suprachiasmatic Nuclei Neurons uuid-c91e2846-2b6d-4ec9-92bf-773d2f29efae PS:CellType neuron PS:Description In humans, there are two subtypes of melatonin receptors including MTNR1A and MTNR1B. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c91e2846-2b6d-4ec9-92bf-773d2f29efae PS:NodeType Pathway PS:Notes Headnote: In humans, there are two subtypes of melatonin receptors including MTNR1A and MTNR1B. These are G protein-coupled receptors and are expressed in various tissues of the body, as a group or individually. Signaling description: Melatonin activates a variety of second messenger cascades following binding to membrane receptors contingent on the specific cell and species. The activation of MTNR1A and MTNR1B inhibits adenylyl cyclase (ADCY) and its inhibition causes a rippling effect of non-activation, which commences with the decreased formation of cAMP and then progressing to diminished PKA activity, which in turn hinders the phosphorylation of CREB1. MTNR1A also activates PLCB1. Outcome effects: The main effect of MTNR1A receptor activation is the inhibition of cAMP accumulation, however in different cell types melatonin may cause either inhibition or stimulation of cAMP. Melatonin has both receptor-mediated and receptor-independent actions. Nuclear binding sites are members of the retinoic acid receptor superfamily and include RORA and RORB. Glutamate activates N-methyl-D-aspartate selective glutamate receptor-induced calcium (Ca2+) influx which, along with other second messengers, triggers the activation of diverse signal transduction cascades including neuronal nitric oxide synthase (NOS1) activity, guanylate cyclase, and CREB1, which in turn activates PER1 and PER2 transcription. Mitogen-activated protein kinases (MAPKs) in suprachiasmatic nucleus (SCN) neurons are activated by light-induced neurotransmission and/or extracellular signals including trophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). MAPKs regulate the activity of CLOCK, ARNTL, and other circadian rhythm proteins. The activation of MTNR1A increases potassium (K+) conductance by activating KCNJ3-inward rectifier K channels via Gb/g proteins. This may play a role in the inhibition of neuronal firing in the SCN. In addition, melatonin interacts with intracellular proteins such as calmodulin and antagonizes the binding of Ca2+ to calmodulin. PS:Organ brain PS:Organ_System nervous system PS:PMID 16527442 PS:PMID 16817850 PS:PMID 18571301 PS:PMID 21193011 PS:PMID 22986412 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage CellType: monocyte CellType: neutrophil Description: Glomerulonephritis is an immune-mediated renal disease characterized by inflammation of the glomeruli and small blood vessels and glomerular antibody deposition. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c926ea2b-76bd-4c34-824a-fcdee787eeb4 NodeType: Pathway Notes: Glomerulonephritis is an immune-mediated renal disease characterized by inflammation of the glomeruli and small blood vessels and glomerular antibody deposition. Coagulation factors and plasminogen are important players in inflammation. Organ: kidney Organ_System: urinary tract PMID: 15034086 PMID: 18982158 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-c926ea2b-76bd-4c34-824a-fcdee787eeb4 Plasmin Role in Glomerulonephritis uuid-c926ea2b-76bd-4c34-824a-fcdee787eeb4 PS:CellType macrophage PS:CellType monocyte PS:CellType neutrophil PS:Description Glomerulonephritis is an immune-mediated renal disease characterized by inflammation of the glomeruli and small blood vessels and glomerular antibody deposition. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c926ea2b-76bd-4c34-824a-fcdee787eeb4 PS:NodeType Pathway PS:Notes Glomerulonephritis is an immune-mediated renal disease characterized by inflammation of the glomeruli and small blood vessels and glomerular antibody deposition. Coagulation factors and plasminogen are important players in inflammation. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 15034086 PS:PMID 18982158 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Prostaglandin E2 (PGE2) is a prostanoid produced from arachidonic acid in the cell membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c92ac527-8874-43bb-9488-26d4eff34bed NodeType: Pathway Notes: Headnote: Prostaglandin E2 (PGE2) is a prostanoid produced from arachidonic acid in the cell membrane. Prostanoids, including PGG2, PGH2, PGI2, and TXA2, are degraded into inactive products within several minutes. Due to this instability, it is believed that their physiological activity is restricted around the region where they are produced. PGE2 mediates fever generation in response to inflammation by acting primarily through prostaglandin E2 receptor EP3 subtype (PTGER3), which is expressed abundantly in the brain. Signaling description: The preoptic area of the hypothalamus has been shown to contain a thermocenter since the destruction of this region leads to the inability to generate fever and the preoptic area is sensitive to PGE2-induced fever. In the hypothalamus, PTGER3 mRNA is expressed in neurons in the medial and median preoptic nuclei, especially in neurons surrounding the organum vasculosum lamina terminalis (OVLT). Circulating pyrogens, lipopolysaccharide (LPS), or inflammatory cytokines have easy access to the OVLT since it lacks a blood-brain barrier. Pyrogens induce PTGS2 expression in the OVLT region, which may generate PGE2. It is possible that TNFSF11/TNFRSF11A signaling in astrocytes of the septal/preoptic area region in the hypothalamus mediates the induction of PTGS2/PGE2 generation, most likely through NF-kB signaling activation. PGE2 acts as a final mediator in the induction of fever. PGE2 inhibits GABAergic activity of PTGER3-expressing neurons, which allows the excitation of raphe pallidus neurons in the brain stem and leads to stimulation of thermogenic sympathetic nerves. In addition, GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter in the mammalian central nervous system. GABA binds to ligand-activated chloride (Cl-) channel transmembrane receptors (GABA-A receptors) in both pre- and post-synaptic neurons. This binding results in a negative change in the transmembrane potential, which usually causes hyperpolarization. Raphe pallidus neurons activate sympathetic nerves responsible for increasing thermoregulatory muscle tone, muscle tremors, and the reduction of heat transfer rate due to vasoconstriction on the body surface. The precise molecular signaling remains unknown following PTGER3 activation via PGE2 in preoptic area neurons which leads to fever generation. Outcome effects: PTGER3 primarily signals through GNAI1, which leads to decreased cAMP levels. PGE2/PTGER3 signaling rapidly down-regulates the protein expression of GABA-A receptor alpha-2 subunit (GABRA2) in preoptic area neurons. PTGER3-expressing neurons are most likely GABAergic themselves. When cytokine signals stimulate PGE2 production within the preoptic area, PGE2 inhibits GABAergic activity of PTGER3-expressing neurons. Organ: generic Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-c92ac527-8874-43bb-9488-26d4eff34bed Prostaglandin E2 Receptor Signaling in Neurons uuid-c92ac527-8874-43bb-9488-26d4eff34bed PS:CellType neuron PS:Description Prostaglandin E2 (PGE2) is a prostanoid produced from arachidonic acid in the cell membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c92ac527-8874-43bb-9488-26d4eff34bed PS:NodeType Pathway PS:Notes Headnote: Prostaglandin E2 (PGE2) is a prostanoid produced from arachidonic acid in the cell membrane. Prostanoids, including PGG2, PGH2, PGI2, and TXA2, are degraded into inactive products within several minutes. Due to this instability, it is believed that their physiological activity is restricted around the region where they are produced. PGE2 mediates fever generation in response to inflammation by acting primarily through prostaglandin E2 receptor EP3 subtype (PTGER3), which is expressed abundantly in the brain. Signaling description: The preoptic area of the hypothalamus has been shown to contain a thermocenter since the destruction of this region leads to the inability to generate fever and the preoptic area is sensitive to PGE2-induced fever. In the hypothalamus, PTGER3 mRNA is expressed in neurons in the medial and median preoptic nuclei, especially in neurons surrounding the organum vasculosum lamina terminalis (OVLT). Circulating pyrogens, lipopolysaccharide (LPS), or inflammatory cytokines have easy access to the OVLT since it lacks a blood-brain barrier. Pyrogens induce PTGS2 expression in the OVLT region, which may generate PGE2. It is possible that TNFSF11/TNFRSF11A signaling in astrocytes of the septal/preoptic area region in the hypothalamus mediates the induction of PTGS2/PGE2 generation, most likely through NF-kB signaling activation. PGE2 acts as a final mediator in the induction of fever. PGE2 inhibits GABAergic activity of PTGER3-expressing neurons, which allows the excitation of raphe pallidus neurons in the brain stem and leads to stimulation of thermogenic sympathetic nerves. In addition, GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter in the mammalian central nervous system. GABA binds to ligand-activated chloride (Cl-) channel transmembrane receptors (GABA-A receptors) in both pre- and post-synaptic neurons. This binding results in a negative change in the transmembrane potential, which usually causes hyperpolarization. Raphe pallidus neurons activate sympathetic nerves responsible for increasing thermoregulatory muscle tone, muscle tremors, and the reduction of heat transfer rate due to vasoconstriction on the body surface. The precise molecular signaling remains unknown following PTGER3 activation via PGE2 in preoptic area neurons which leads to fever generation. Outcome effects: PTGER3 primarily signals through GNAI1, which leads to decreased cAMP levels. PGE2/PTGER3 signaling rapidly down-regulates the protein expression of GABA-A receptor alpha-2 subunit (GABRA2) in preoptic area neurons. PTGER3-expressing neurons are most likely GABAergic themselves. When cytokine signals stimulate PGE2 production within the preoptic area, PGE2 inhibits GABAergic activity of PTGER3-expressing neurons. PS:Organ generic PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c93a8ab4-f240-44a5-9c82-5d08899b0971 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-c93a8ab4-f240-44a5-9c82-5d08899b0971 Compensation mechanisms in Huntington uuid-c93a8ab4-f240-44a5-9c82-5d08899b0971 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c93a8ab4-f240-44a5-9c82-5d08899b0971 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c94cb4a3-c62c-461e-8f5c-79f64aa314a4 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-c94cb4a3-c62c-461e-8f5c-79f64aa314a4 CD19 -> NF-kB Signaling uuid-c94cb4a3-c62c-461e-8f5c-79f64aa314a4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c94cb4a3-c62c-461e-8f5c-79f64aa314a4 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c950ae24-b947-4118-b685-00d87d0a3543 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c950ae24-b947-4118-b685-00d87d0a3543 Sucrose import (cell wall) template uuid-c950ae24-b947-4118-b685-00d87d0a3543 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c950ae24-b947-4118-b685-00d87d0a3543 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9764912-d11f-48fb-b263-766bfde7bfd3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-c9764912-d11f-48fb-b263-766bfde7bfd3 TORC1-|Apoptosis uuid-c9764912-d11f-48fb-b263-766bfde7bfd3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9764912-d11f-48fb-b263-766bfde7bfd3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c98a5c01-dff7-4c54-91d3-e714b824c2e3 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-c98a5c01-dff7-4c54-91d3-e714b824c2e3 Collagen expressed in cornea uuid-c98a5c01-dff7-4c54-91d3-e714b824c2e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c98a5c01-dff7-4c54-91d3-e714b824c2e3 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9a8310b-9fc1-45ac-b891-41348f24dab4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-c9a8310b-9fc1-45ac-b891-41348f24dab4 acetyl-CoA biosynthesis template uuid-c9a8310b-9fc1-45ac-b891-41348f24dab4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9a8310b-9fc1-45ac-b891-41348f24dab4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Ulcerative colitis (UC) is a form of inflammatory bowel disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9ad2fdd-73d7-44fe-91be-dc6b36d44936 NodeType: Pathway Notes: Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: UC is a form of IBD traditionally related to a Th2-cytokine profile mediated by IL-13, IL-10, IL-4 where immune homeostasis of the gastrointestinal tract is compromised. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 18500230 PMID: 22914297 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-c9ad2fdd-73d7-44fe-91be-dc6b36d44936 Th2-Cell Function in Ulcerative Colitis uuid-c9ad2fdd-73d7-44fe-91be-dc6b36d44936 PS:CellType T-cell PS:Description Ulcerative colitis (UC) is a form of inflammatory bowel disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9ad2fdd-73d7-44fe-91be-dc6b36d44936 PS:NodeType Pathway PS:Notes Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: UC is a form of IBD traditionally related to a Th2-cytokine profile mediated by IL-13, IL-10, IL-4 where immune homeostasis of the gastrointestinal tract is compromised. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 18500230 PS:PMID 22914297 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The vesicle tethering is a step of exocytosis, links the vesicles to the cell membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9b295b0-e5b8-443b-bf4d-9e5515aefac8 NodeType: Pathway Notes: Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle tethering links the vesicles to the cell membrane at half the diameter of a vesicle. Signaling description: The tethering of the secretory vesicle before docking and fusion with the targeted plasma membrane is mediated by the exocyst complex, an evolutionary conserved octameric protein complex which consists of EXOC1-8. Exocyst proteins on the plasma membrane (EXOC1 and EXOC7) bind vesicular exocyst proteins, bringing the vesicle very close to the plasma membrane. The exocyst is regulated by activated GTPases, such as RHOA, CDC42, RHOQ (TC10), RALA, and the scaffolding protein IQGAP1, responsible for controlling the activity of the cytoskeleton. Several tethering factors interact with specific Rab GTPases which regulate vesicle transport to the plasma membrane from recycling endosomes during cell surface remodeling and spreading. Prior to SNARE-mediated fusion, the exocyst interacts with the SNAREs and regulates SNARE assembly. The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: Exocyst proteins provide interaction between the vesicles and the acceptor membrane, regulate cytoskeleton reorganization and mediate SNARE assembly due to tethering of exocytosis. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 17488620 PMID: 19473826 PMID: 21997494 PMID: 22420621 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-c9b295b0-e5b8-443b-bf4d-9e5515aefac8 Exocytosis: Vesicle Tethering uuid-c9b295b0-e5b8-443b-bf4d-9e5515aefac8 PS:CellType generic PS:Description The vesicle tethering is a step of exocytosis, links the vesicles to the cell membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9b295b0-e5b8-443b-bf4d-9e5515aefac8 PS:NodeType Pathway PS:Notes Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. Vesicle tethering links the vesicles to the cell membrane at half the diameter of a vesicle. Signaling description: The tethering of the secretory vesicle before docking and fusion with the targeted plasma membrane is mediated by the exocyst complex, an evolutionary conserved octameric protein complex which consists of EXOC1-8. Exocyst proteins on the plasma membrane (EXOC1 and EXOC7) bind vesicular exocyst proteins, bringing the vesicle very close to the plasma membrane. The exocyst is regulated by activated GTPases, such as RHOA, CDC42, RHOQ (TC10), RALA, and the scaffolding protein IQGAP1, responsible for controlling the activity of the cytoskeleton. Several tethering factors interact with specific Rab GTPases which regulate vesicle transport to the plasma membrane from recycling endosomes during cell surface remodeling and spreading. Prior to SNARE-mediated fusion, the exocyst interacts with the SNAREs and regulates SNARE assembly. The described mechanism of molecular signaling is known in general terms and is described on the pathway. Outcome effects: Exocyst proteins provide interaction between the vesicles and the acceptor membrane, regulate cytoskeleton reorganization and mediate SNARE assembly due to tethering of exocytosis. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17488620 PS:PMID 19473826 PS:PMID 21997494 PS:PMID 22420621 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072). Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9d72648-43e0-4ce0-8b85-50da8dedb087 NodeType: Pathway Notes: Gangliosides are membrane-bound glycosphingolipids containing sialic acid. Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-c9d72648-43e0-4ce0-8b85-50da8dedb087 Ganglioside-Type Glycosphingolipid Biosynthesis uuid-c9d72648-43e0-4ce0-8b85-50da8dedb087 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072). PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9d72648-43e0-4ce0-8b85-50da8dedb087 PS:NodeType Pathway PS:Notes Gangliosides are membrane-bound glycosphingolipids containing sialic acid. PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9e02543-16cb-42c4-b7b2-e9ec81d4739a NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-c9e02543-16cb-42c4-b7b2-e9ec81d4739a Fatty Acid Biosynthesis uuid-c9e02543-16cb-42c4-b7b2-e9ec81d4739a PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9e02543-16cb-42c4-b7b2-e9ec81d4739a PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9e5210c-c1dc-4911-b686-c7d99a111459 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-c9e5210c-c1dc-4911-b686-c7d99a111459 BSG(CD147) signalling uuid-c9e5210c-c1dc-4911-b686-c7d99a111459 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c9e5210c-c1dc-4911-b686-c7d99a111459 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca3f4569-5c1f-4379-b7c1-bb9390cdcc48 NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-ca3f4569-5c1f-4379-b7c1-bb9390cdcc48 Proteins Involved in Psoriasis uuid-ca3f4569-5c1f-4379-b7c1-bb9390cdcc48 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca3f4569-5c1f-4379-b7c1-bb9390cdcc48 PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Adipose tissue is now regarded as an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of adipokines. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca542e5d-f367-4785-acd2-e55f6ca0870b NodeType: Pathway Notes: Headnote: Adipose tissue was traditionally considered only as energy storage depot in the form of triglycerides. It is now regarded as an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of adipokines (including chemokines, cytokines and hormones) modulating hemostasis. In obesity linked insulin resistance, adiponectin is downregulated. ADIPOQ is a well-known adipose-specific adipokine that produces insulin-sensitizing effects. Signaling description: Adipokines include leptin (LEP), adiponectin (ADIPOQ), resistin (RETN), visfatin (NAMPT), chemerin (RARRES2), adipsin (CFD), intelectin (ITLN1), retinol binding protein 4 (RBP4), vaspin (SERPINA12), TNF, IL6, IL1B, CCl2 and others. In obese subjects LEP, RETN, TNF, IL6, CCL2, IL1B, RBP4 are upregulated, ADIPOQ is downregulated. LEP is a "satiety hormone" and is abundantly expressed in adipose tissue. It inhibits appetite and food intake and stimulates energy expenditure. However, circulating leptin level is increased in obese subjects due to the existence of leptin resistance. Both TNF-alpha and IL-6, the most widely studied cytokines produced by adipose tissue, were reported to modulate insulin resistance.Proteins with increased expression or activity are highlighted in red and protein with decreased expression or activity is highlighted in blue. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. Organ_System: endocrine system PMID: 16166564 PMID: 19009016 PMID: 19682539 PMID: 23316186 PMID: 24733068 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-ca542e5d-f367-4785-acd2-e55f6ca0870b Adipokines Production by Adipocyte Impaired in Obesity uuid-ca542e5d-f367-4785-acd2-e55f6ca0870b PS:CellType adipocyte PS:Description Adipose tissue is now regarded as an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of adipokines. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca542e5d-f367-4785-acd2-e55f6ca0870b PS:NodeType Pathway PS:Notes Headnote: Adipose tissue was traditionally considered only as energy storage depot in the form of triglycerides. It is now regarded as an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of adipokines (including chemokines, cytokines and hormones) modulating hemostasis. In obesity linked insulin resistance, adiponectin is downregulated. ADIPOQ is a well-known adipose-specific adipokine that produces insulin-sensitizing effects. Signaling description: Adipokines include leptin (LEP), adiponectin (ADIPOQ), resistin (RETN), visfatin (NAMPT), chemerin (RARRES2), adipsin (CFD), intelectin (ITLN1), retinol binding protein 4 (RBP4), vaspin (SERPINA12), TNF, IL6, IL1B, CCl2 and others. In obese subjects LEP, RETN, TNF, IL6, CCL2, IL1B, RBP4 are upregulated, ADIPOQ is downregulated. LEP is a "satiety hormone" and is abundantly expressed in adipose tissue. It inhibits appetite and food intake and stimulates energy expenditure. However, circulating leptin level is increased in obese subjects due to the existence of leptin resistance. Both TNF-alpha and IL-6, the most widely studied cytokines produced by adipose tissue, were reported to modulate insulin resistance.Proteins with increased expression or activity are highlighted in red and protein with decreased expression or activity is highlighted in blue. Highlighted proteins: Proteins with increased expression or activity are highlighted in red and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System endocrine system PS:PMID 16166564 PS:PMID 19009016 PS:PMID 19682539 PS:PMID 23316186 PS:PMID 24733068 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue adipose tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell Description: Dendritic cells (DCs) have been identified in atherosclerotic plaques and are thought to play an important role in atherogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca60bf3d-1470-4ce0-b48b-abe8af2d0244 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Dendritic cells (DCs) have been identified in atherosclerotic plaques and are thought to have an important role in atherogenesis. Signaling description: DCs are a heterogeneous population that includes conventional dendritic cells (cDCs) subdivided into lymphoid-tissue-resident or migratory subtypes, plasmacytoid DCs (pDCs), and inflammatory DCs, which are not found in steady states. Lesional DCs take up lipids, produce proinflammatory cytokines, and polarize CD4 T-cells to atherogenic Th1 responses, all contributing to their proatherogenic character. Although DCs are antigen-presenting cells, they can also engulf lipids so they share phenotypic and functional features with macrophages. Therefore, the exact distinction between macrophages and DCs remains controversial and confounded by their plasticity. In addition, DCs may be ideally positioned at the crossroads of innate and adaptive immunity, translating innate damage signals, such as oxidized LDL, into an enhanced adaptive immune response. Outcome effects: Oxidized LDL bind CD36, inducing intracellular CD36-TLR4-TLR6 heterotrimerization, which activates NF-kB and chemokine expression. In advanced plaques, CCL17 DCs limit regulatory T (Treg) cell expansion and exert local immune-regulatory functions by recruiting and activating CD4 T-cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: blood vessel Organ_System: cardiovascular system PMID: 22064431 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-ca60bf3d-1470-4ce0-b48b-abe8af2d0244 Dendritic Cells Function in Atherosclerosis uuid-ca60bf3d-1470-4ce0-b48b-abe8af2d0244 PS:CellType dendritic cell PS:Description Dendritic cells (DCs) have been identified in atherosclerotic plaques and are thought to play an important role in atherogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca60bf3d-1470-4ce0-b48b-abe8af2d0244 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Dendritic cells (DCs) have been identified in atherosclerotic plaques and are thought to have an important role in atherogenesis. Signaling description: DCs are a heterogeneous population that includes conventional dendritic cells (cDCs) subdivided into lymphoid-tissue-resident or migratory subtypes, plasmacytoid DCs (pDCs), and inflammatory DCs, which are not found in steady states. Lesional DCs take up lipids, produce proinflammatory cytokines, and polarize CD4 T-cells to atherogenic Th1 responses, all contributing to their proatherogenic character. Although DCs are antigen-presenting cells, they can also engulf lipids so they share phenotypic and functional features with macrophages. Therefore, the exact distinction between macrophages and DCs remains controversial and confounded by their plasticity. In addition, DCs may be ideally positioned at the crossroads of innate and adaptive immunity, translating innate damage signals, such as oxidized LDL, into an enhanced adaptive immune response. Outcome effects: Oxidized LDL bind CD36, inducing intracellular CD36-TLR4-TLR6 heterotrimerization, which activates NF-kB and chemokine expression. In advanced plaques, CCL17 DCs limit regulatory T (Treg) cell expansion and exert local immune-regulatory functions by recruiting and activating CD4 T-cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 22064431 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca6604f8-9049-413e-a282-2b01105d2938 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ca6604f8-9049-413e-a282-2b01105d2938 Overview. Diseases of circulatory system (chapter 8) uuid-ca6604f8-9049-413e-a282-2b01105d2938 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca6604f8-9049-413e-a282-2b01105d2938 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca66f1c6-0064-4db1-baa9-d883db56093b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ca66f1c6-0064-4db1-baa9-d883db56093b Keratan sulfate II (skeletal) biosynthesis template uuid-ca66f1c6-0064-4db1-baa9-d883db56093b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca66f1c6-0064-4db1-baa9-d883db56093b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca922f04-e864-441e-9540-85000d1986f8 NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-ca922f04-e864-441e-9540-85000d1986f8 Frizzled Receptors -> ARRB1/ARRB2 non-Canonical Signaling uuid-ca922f04-e864-441e-9540-85000d1986f8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca922f04-e864-441e-9540-85000d1986f8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca9cb5d1-c8bf-4409-9d24-f6ecef7b90a5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ca9cb5d1-c8bf-4409-9d24-f6ecef7b90a5 CSH1/PRLR Expression Targets uuid-ca9cb5d1-c8bf-4409-9d24-f6ecef7b90a5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ca9cb5d1-c8bf-4409-9d24-f6ecef7b90a5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-caf78346-9435-4bcb-ac8c-1f493e0fa6ef NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: NFSF8 activates human cultured mast cells to release chemokines such as IL8 and CCL2 without histamine and without degranulation. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-caf78346-9435-4bcb-ac8c-1f493e0fa6ef Mast-Cell Activation without Degranulation through TNFSF8 Signaling uuid-caf78346-9435-4bcb-ac8c-1f493e0fa6ef PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-caf78346-9435-4bcb-ac8c-1f493e0fa6ef PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: NFSF8 activates human cultured mast cells to release chemokines such as IL8 and CCL2 without histamine and without degranulation. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb2bb006-9c38-4d76-957c-59779322ffde NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cb2bb006-9c38-4d76-957c-59779322ffde Aminobenzoate degradation template uuid-cb2bb006-9c38-4d76-957c-59779322ffde PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb2bb006-9c38-4d76-957c-59779322ffde PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Tissue CellType: generic Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb5914e5-ba7c-459b-b6f6-060f2958bd17 NodeType: Pathway Organ: generic Organ_System: generic PMID: 20599420 PMID: 25100021 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: generic urn:agi-pathway:uuid-cb5914e5-ba7c-459b-b6f6-060f2958bd17 ER Associated Protein Degradation in Vesicular Transport uuid-cb5914e5-ba7c-459b-b6f6-060f2958bd17 PS:CellType generic PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb5914e5-ba7c-459b-b6f6-060f2958bd17 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 20599420 PS:PMID 25100021 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb68c681-1be9-4b72-b2a0-b63368a72cb1 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-cb68c681-1be9-4b72-b2a0-b63368a72cb1 T-Cell Receptor -> AP-1 Signaling uuid-cb68c681-1be9-4b72-b2a0-b63368a72cb1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb68c681-1be9-4b72-b2a0-b63368a72cb1 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb894cea-2f90-4f48-adeb-27ffafb684d2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cb894cea-2f90-4f48-adeb-27ffafb684d2 PI remodelling in ER (Land cycle) template uuid-cb894cea-2f90-4f48-adeb-27ffafb684d2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb894cea-2f90-4f48-adeb-27ffafb684d2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb9eb40f-de8f-4186-924f-73b222084453 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: stomach Organ_System: digestive system PMID: 14755326 PMID: 16954210 PMID: 20938460 PMID: 22044679 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-cb9eb40f-de8f-4186-924f-73b222084453 CagA Phosphorylation Independent Signaling uuid-cb9eb40f-de8f-4186-924f-73b222084453 PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cb9eb40f-de8f-4186-924f-73b222084453 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ stomach PS:Organ_System digestive system PS:PMID 14755326 PS:PMID 16954210 PS:PMID 20938460 PS:PMID 22044679 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cba470af-7b56-4935-8fbf-68647a95dff9 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-cba470af-7b56-4935-8fbf-68647a95dff9 Glyoxylate and Glycerate Metabolism uuid-cba470af-7b56-4935-8fbf-68647a95dff9 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cba470af-7b56-4935-8fbf-68647a95dff9 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cba79dd6-0eff-4458-b3d3-2e6cfbe889e6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-cba79dd6-0eff-4458-b3d3-2e6cfbe889e6 IL11 Expression Targets uuid-cba79dd6-0eff-4458-b3d3-2e6cfbe889e6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cba79dd6-0eff-4458-b3d3-2e6cfbe889e6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Detumescense is subsidence of erection. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbaf158a-563e-4d25-84ff-6d3a911c782f NodeType: Pathway Notes: Headnote: Detumescense is subsidence of erection. There is a number of stimuli, including norepinephrine, endothelin 1 (EDN1), angiotensin II regulating the transition from erection to detumescense. Signaling description: The intracellular mechanism in the absence of arousal stimuli, initiates with activation of G proteins following ligand binding to membrane receptors in order to keep cavernosal arterioles and sinuses constricted, maintaining the penis in the non-erect state. Subsequently to G protein activation, two signaling pathways are brought into play to cause smooth muscle contraction in the arterioles and cavernosum: Ca+2 dependent pathway (phopholipase C, PKC) and RHOA/ROCK pathway. Another significant function of EDN1 and angiotensin II is to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, increasing reactive oxygen species (ROS) production. ROS rapidly react with NO, reducing its bioavailability, and also stimulate RHOA/ROCK activity. Outcome effects: The levels of circulating EDN1 and angiotensin II and sympathetic nervous system activity are increased in hypertension making an impact in erectile dysfunction.Proteins with increased expression or activity are highlighted in red. Compounds with elevated level are highlighted in red and compound with reduced level is highlighted in blue. Organ: penis Organ_System: reproductive system PMID: 16411892 PMID: 18208505 PMID: 22240443 PMID: 23817801 PMID: 24468580 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-cbaf158a-563e-4d25-84ff-6d3a911c782f Penile Detumescense Augmentation Mechanisms uuid-cbaf158a-563e-4d25-84ff-6d3a911c782f PS:CellType vascular smooth muscle cell PS:Description Detumescense is subsidence of erection. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbaf158a-563e-4d25-84ff-6d3a911c782f PS:NodeType Pathway PS:Notes Headnote: Detumescense is subsidence of erection. There is a number of stimuli, including norepinephrine, endothelin 1 (EDN1), angiotensin II regulating the transition from erection to detumescense. Signaling description: The intracellular mechanism in the absence of arousal stimuli, initiates with activation of G proteins following ligand binding to membrane receptors in order to keep cavernosal arterioles and sinuses constricted, maintaining the penis in the non-erect state. Subsequently to G protein activation, two signaling pathways are brought into play to cause smooth muscle contraction in the arterioles and cavernosum: Ca+2 dependent pathway (phopholipase C, PKC) and RHOA/ROCK pathway. Another significant function of EDN1 and angiotensin II is to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, increasing reactive oxygen species (ROS) production. ROS rapidly react with NO, reducing its bioavailability, and also stimulate RHOA/ROCK activity. Outcome effects: The levels of circulating EDN1 and angiotensin II and sympathetic nervous system activity are increased in hypertension making an impact in erectile dysfunction.Proteins with increased expression or activity are highlighted in red. Compounds with elevated level are highlighted in red and compound with reduced level is highlighted in blue. PS:Organ penis PS:Organ_System reproductive system PS:PMID 16411892 PS:PMID 18208505 PS:PMID 22240443 PS:PMID 23817801 PS:PMID 24468580 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbbb6e92-07d0-433a-a032-e4304d40a494 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-cbbb6e92-07d0-433a-a032-e4304d40a494 Aspartate Metabolism uuid-cbbb6e92-07d0-433a-a032-e4304d40a494 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbbb6e92-07d0-433a-a032-e4304d40a494 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbbf2da1-66e7-4011-8a2c-07ed45f1553c NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cbbf2da1-66e7-4011-8a2c-07ed45f1553c Pantothenate-CoA biosynthesis template uuid-cbbf2da1-66e7-4011-8a2c-07ed45f1553c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbbf2da1-66e7-4011-8a2c-07ed45f1553c PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbd3882b-ad05-480e-879c-731a9355f747 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-cbd3882b-ad05-480e-879c-731a9355f747 mTOR signaling in fibrosis uuid-cbd3882b-ad05-480e-879c-731a9355f747 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbd3882b-ad05-480e-879c-731a9355f747 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbe3f8ff-8203-4741-844a-0afbe2067f18 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-cbe3f8ff-8203-4741-844a-0afbe2067f18 SARS->Golgi transport uuid-cbe3f8ff-8203-4741-844a-0afbe2067f18 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbe3f8ff-8203-4741-844a-0afbe2067f18 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbf05bbb-e028-4b8d-9599-ffaa38ee32cb NodeType: Pathway Organ: bone Organ: joint Organ: skin Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone tissue urn:agi-pathway:uuid-cbf05bbb-e028-4b8d-9599-ffaa38ee32cb Proteins Involved in Psoriatic Arthritis uuid-cbf05bbb-e028-4b8d-9599-ffaa38ee32cb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbf05bbb-e028-4b8d-9599-ffaa38ee32cb PS:NodeType Pathway PS:Organ bone PS:Organ joint PS:Organ skin PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbfcf014-7c06-499f-b826-7d4e94846a18 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cbfcf014-7c06-499f-b826-7d4e94846a18 Keratan sulfate I biosynthesis template uuid-cbfcf014-7c06-499f-b826-7d4e94846a18 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cbfcf014-7c06-499f-b826-7d4e94846a18 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc0b896f-430d-4128-a08c-9a7bfa407476 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Source: Diseases urn:agi-pathway:uuid-cc0b896f-430d-4128-a08c-9a7bfa407476 Proteins Involved in Alzheimer's Disease uuid-cc0b896f-430d-4128-a08c-9a7bfa407476 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc0b896f-430d-4128-a08c-9a7bfa407476 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc201b42-62b9-43cb-8a7c-8211df28bbbf NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. G1 is the first phase of the new cell cycle during which the cell is preparing for DNA synthesis. The resting phase in which the cell has left the cycle and is not going to divide is called G0. Signaling description: The G0/G1 transition starts with the activation of growth factor receptors and focal adhesion receptors by extracellular signals. Activation of Ras/PI3K/Raf and Rho leads to the transcriptional induction of D-type cyclins (CycD) in early G1. Also, the expression of CycD may be activated through the MAPK cascade (via SP1, c-Fos, c-Jun) and/or through the NF-KB pathway. In addition, AKT may inhibit GSK3 beta, thus preventing the degradation of CycD. The eukaryotic cell cycle is dependent upon the activities of CDKs (Cyclin Dependent Kinases). CDK activity is controlled by fluctuations in levels of cyclins and cell cycle kinase inhibitors (CDKN), and by reversible phosphorylation. In mammalian cells, CycD - CDK4/6 complex is involved in the regulation of G1 phase progression. The accumulation of CycD - CDK4/6 complexes is activated via the phosphorylation of CDKs by the CAK complex.CAK is composed of three subunits: CDK7, CycH and MAT1. Along with six other subunits, CAK is also a part of the general transcription factor TFIIH. Outcome effects: CycD - CDK4/6 complex is responsible for the first phosphorylation of RB1 in G1 phase thereby, liberating E2Fs (for example, E2F1 or E2F4). E2Fs form a heterodimeric complex of the E2F polypeptide and TFDPs. E2F-TFDPs complex induces the expression of Cyclin E, Cyclin A, DNA polymerase, thymidine kinase and some other proteins that are required in S phase. Organ: generic Organ_System: generic PMID: 12814430 PMID: 17386261 PMID: 23861057 PMID: 24130333 PMID: 25658582 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-cc201b42-62b9-43cb-8a7c-8211df28bbbf G0/G1 Phase Transition uuid-cc201b42-62b9-43cb-8a7c-8211df28bbbf PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc201b42-62b9-43cb-8a7c-8211df28bbbf PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. G1 is the first phase of the new cell cycle during which the cell is preparing for DNA synthesis. The resting phase in which the cell has left the cycle and is not going to divide is called G0. Signaling description: The G0/G1 transition starts with the activation of growth factor receptors and focal adhesion receptors by extracellular signals. Activation of Ras/PI3K/Raf and Rho leads to the transcriptional induction of D-type cyclins (CycD) in early G1. Also, the expression of CycD may be activated through the MAPK cascade (via SP1, c-Fos, c-Jun) and/or through the NF-KB pathway. In addition, AKT may inhibit GSK3 beta, thus preventing the degradation of CycD. The eukaryotic cell cycle is dependent upon the activities of CDKs (Cyclin Dependent Kinases). CDK activity is controlled by fluctuations in levels of cyclins and cell cycle kinase inhibitors (CDKN), and by reversible phosphorylation. In mammalian cells, CycD - CDK4/6 complex is involved in the regulation of G1 phase progression. The accumulation of CycD - CDK4/6 complexes is activated via the phosphorylation of CDKs by the CAK complex.CAK is composed of three subunits: CDK7, CycH and MAT1. Along with six other subunits, CAK is also a part of the general transcription factor TFIIH. Outcome effects: CycD - CDK4/6 complex is responsible for the first phosphorylation of RB1 in G1 phase thereby, liberating E2Fs (for example, E2F1 or E2F4). E2Fs form a heterodimeric complex of the E2F polypeptide and TFDPs. E2F-TFDPs complex induces the expression of Cyclin E, Cyclin A, DNA polymerase, thymidine kinase and some other proteins that are required in S phase. PS:Organ generic PS:Organ_System generic PS:PMID 12814430 PS:PMID 17386261 PS:PMID 23861057 PS:PMID 24130333 PS:PMID 25658582 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc27ba0d-c35c-410c-b9b9-2f1fd9999268 NodeType: Pathway Notes: Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. The family of neurotrophin receptors includes neurotrophic tyrosine kinase receptor type 1, 2, and 3 (NTRK1/2/3). The ligands of NTRK include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 and 4 (NTF3/4). These ligand-receptor interactions induce PI3K/AKT1 and Ras/MAPK signaling pathwyas. Another transmembrane receptor known as nerve growth factor receptor (NGFR) binds all members of the neurotrophin family with low affinity. This receptor is a member of the tumor necrosis factor receptor (TNFR) or death receptor family. NGFR could lead to either cell death or differentiation in response to the ligand depending on whether NTRK receptors were co-expressed. Outcome effects: High levels of NTRK1 in association with very low/no MYCN expression are detected in favorable neuroblastoma (NB) tumors which often spontaneously regress. These favorable NB tumor cells usually express a small amount of NGF as do some of the surrounding cells. Cells that express the most NGFs are thought to undergo differentiation, while those that express less NGF undergo apoptosis. NTRK1 expression is dramatically decreased in MYCN-amplified NB tumors. In contrast, NTRK2 is preferentially expressed in clinically unfavorable NB tumors and the expression of NTRK2 strongly correlates with MYCN amplification. BDNF is also highly expressed in these tumors. NTRK3 is commonly expressed in favorable NB tumors. These tumors also express very limited amounts of NTF3 and co-express NTRK1. In addition to NGFs, other growth factors are also significant in the development of sympathoadrenal lineage cells and transformed neuroblasts. This includes EGF which is expressed in neural crest cells and is thought to contribute to the formation of neurons, in addition to VEGFA which is expressed by surrounding cells and IGF1/2 which is expressed in the neural crest, dorsal root, sympathetic ganglia, and adrenal medulla. Overall, these growth factors promote cell survival and proliferation. Organ_System: nervous system PMID: 12612655 PMID: 14699954 PMID: 19417027 PMID: 21295685 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-cc27ba0d-c35c-410c-b9b9-2f1fd9999268 Growth Factor Signaling in Neuroblastoma uuid-cc27ba0d-c35c-410c-b9b9-2f1fd9999268 PS:CellType cancer cell PS:CellType neural stem cell PS:Description Neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc27ba0d-c35c-410c-b9b9-2f1fd9999268 PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Neurotrophin receptor signaling was found to be important in malignant transformation of sympathetic neuroblasts. The family of neurotrophin receptors includes neurotrophic tyrosine kinase receptor type 1, 2, and 3 (NTRK1/2/3). The ligands of NTRK include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 and 4 (NTF3/4). These ligand-receptor interactions induce PI3K/AKT1 and Ras/MAPK signaling pathwyas. Another transmembrane receptor known as nerve growth factor receptor (NGFR) binds all members of the neurotrophin family with low affinity. This receptor is a member of the tumor necrosis factor receptor (TNFR) or death receptor family. NGFR could lead to either cell death or differentiation in response to the ligand depending on whether NTRK receptors were co-expressed. Outcome effects: High levels of NTRK1 in association with very low/no MYCN expression are detected in favorable neuroblastoma (NB) tumors which often spontaneously regress. These favorable NB tumor cells usually express a small amount of NGF as do some of the surrounding cells. Cells that express the most NGFs are thought to undergo differentiation, while those that express less NGF undergo apoptosis. NTRK1 expression is dramatically decreased in MYCN-amplified NB tumors. In contrast, NTRK2 is preferentially expressed in clinically unfavorable NB tumors and the expression of NTRK2 strongly correlates with MYCN amplification. BDNF is also highly expressed in these tumors. NTRK3 is commonly expressed in favorable NB tumors. These tumors also express very limited amounts of NTF3 and co-express NTRK1. In addition to NGFs, other growth factors are also significant in the development of sympathoadrenal lineage cells and transformed neuroblasts. This includes EGF which is expressed in neural crest cells and is thought to contribute to the formation of neurons, in addition to VEGFA which is expressed by surrounding cells and IGF1/2 which is expressed in the neural crest, dorsal root, sympathetic ganglia, and adrenal medulla. Overall, these growth factors promote cell survival and proliferation. PS:Organ_System nervous system PS:PMID 12612655 PS:PMID 14699954 PS:PMID 19417027 PS:PMID 21295685 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: The initial binding of HPV capsid to the cell surface is mediated by L1. Conformational changes and proteolytic cleavage of L2 then occurs which is essential for successful infection. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc51d797-1593-4bf0-99a8-83a467429b37 NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: The virus genome encodes six early proteins and two late proteins. The early proteins are required for viral replication (E1 and E2), virus particle release (E4), blocking of host immune response (E5), and host cell proliferation (E6 and E7). The late viral proteins (L1 and L2) are necessary for viral capsid formation.The HPV genome is surrounded by an icosahedral capsid consisting of two structural proteins: the major protein L1 and the minor capsid protein L2. The L1 proteins are highly conserved and form 72 five-fold capsomers. The L2 protein binds viral DNA. The L2 protein is an internally located multifunctional protein which takes part in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions, and nuclear transport of the HPV genome. The proteinaceous coat of HPVs encases and protects the viral nucleic acid and provides the initial interaction site of the viral particle with the host cell. Following receptor engagement, the virus is internalized and its coat is disassembled to permit the encapsidated genome access to the cellular transcription and replication machinery. The initial binding to the cell surface is mediated by L1 which interacts with heparan sulfate proteoglycans (HSPGs). L1 can also bind laminin-332 and syndecan-1 (SDC1). Next, conformational changes and proteolytic cleavage of L2 take place, which is essential for successful infection. Outcome effects: The internalization of virus can occur via different pathways including clathrin and/or caveolae dependent /independent and lipid raft independent routes. L2 then travels with the viral genome to the nucleus, where it accumulates at ND-10 domains. In addition, L2 can interact with karyopherins (importins) and the viral DNA may enter the nucleus via import pathways mediated by karyopherins. The karyopherin beta/importin beta superfamily proteins interact with nucleoporins at the nuclear pore complex to transport the proteins into the nucleus. Organ: skin PMID: 16733063 PMID: 20089191 PMID: 23689062 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-cc51d797-1593-4bf0-99a8-83a467429b37 HPV Entry into the Keratinocyte uuid-cc51d797-1593-4bf0-99a8-83a467429b37 PS:CellType cancer cell PS:CellType keratinocyte PS:Description The initial binding of HPV capsid to the cell surface is mediated by L1. Conformational changes and proteolytic cleavage of L2 then occurs which is essential for successful infection. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc51d797-1593-4bf0-99a8-83a467429b37 PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: The virus genome encodes six early proteins and two late proteins. The early proteins are required for viral replication (E1 and E2), virus particle release (E4), blocking of host immune response (E5), and host cell proliferation (E6 and E7). The late viral proteins (L1 and L2) are necessary for viral capsid formation.The HPV genome is surrounded by an icosahedral capsid consisting of two structural proteins: the major protein L1 and the minor capsid protein L2. The L1 proteins are highly conserved and form 72 five-fold capsomers. The L2 protein binds viral DNA. The L2 protein is an internally located multifunctional protein which takes part in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions, and nuclear transport of the HPV genome. The proteinaceous coat of HPVs encases and protects the viral nucleic acid and provides the initial interaction site of the viral particle with the host cell. Following receptor engagement, the virus is internalized and its coat is disassembled to permit the encapsidated genome access to the cellular transcription and replication machinery. The initial binding to the cell surface is mediated by L1 which interacts with heparan sulfate proteoglycans (HSPGs). L1 can also bind laminin-332 and syndecan-1 (SDC1). Next, conformational changes and proteolytic cleavage of L2 take place, which is essential for successful infection. Outcome effects: The internalization of virus can occur via different pathways including clathrin and/or caveolae dependent /independent and lipid raft independent routes. L2 then travels with the viral genome to the nucleus, where it accumulates at ND-10 domains. In addition, L2 can interact with karyopherins (importins) and the viral DNA may enter the nucleus via import pathways mediated by karyopherins. The karyopherin beta/importin beta superfamily proteins interact with nucleoporins at the nuclear pore complex to transport the proteins into the nucleus. PS:Organ skin PS:PMID 16733063 PS:PMID 20089191 PS:PMID 23689062 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc865e3e-f418-489a-a694-19459a9a1b7a NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G2/M DNA damage checkpoint prevents the cell from entering mitosis if the genome is damaged. Signaling description: DNA damage up-regulates the ATM/ATR which leads to the activation of p53, Chk1 and Chk2. Further, Chks phosphorylates CDC25C. The phosphorylated, 14-3-3-bound form of CDC25C is prohibited from dephosphorylating and activating the mitotic CyclB-CDC2 kinase. The phosphorylation of p53 activates its DNA binding activity. The genes that are turned on by p53 include GADD45 which apparently binds to and dissociates the CycB-CDC2 kinase. Outcome effects: As a result, the damaged cells are effectively blocked from entering mitosis. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-cc865e3e-f418-489a-a694-19459a9a1b7a G2/M Damage Checkpoint uuid-cc865e3e-f418-489a-a694-19459a9a1b7a PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc865e3e-f418-489a-a694-19459a9a1b7a PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G2/M DNA damage checkpoint prevents the cell from entering mitosis if the genome is damaged. Signaling description: DNA damage up-regulates the ATM/ATR which leads to the activation of p53, Chk1 and Chk2. Further, Chks phosphorylates CDC25C. The phosphorylated, 14-3-3-bound form of CDC25C is prohibited from dephosphorylating and activating the mitotic CyclB-CDC2 kinase. The phosphorylation of p53 activates its DNA binding activity. The genes that are turned on by p53 include GADD45 which apparently binds to and dissociates the CycB-CDC2 kinase. Outcome effects: As a result, the damaged cells are effectively blocked from entering mitosis. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc923b59-dd53-4dbf-b22b-527631c729ed NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-cc923b59-dd53-4dbf-b22b-527631c729ed CD Markers -> Expression Targets in Lymphoid System and Blood uuid-cc923b59-dd53-4dbf-b22b-527631c729ed PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cc923b59-dd53-4dbf-b22b-527631c729ed PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccbae216-d46b-4eae-aa76-c9244ea8a614 NodeType: Pathway Notes: Headnote: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. MALT lymphoma is a low grade B-cell neoplasm and is the third most common form of non-Hodgkin lymphoma. It occurs at different extra-nodal sites with the most common being the gastrointestinal (GI) tract, (50% of all cases), and within the GI tract, the stomach is the most common location (85% of GI MALT lymphomas). Other sites include small intestine, salivary glands, lungs, ocular adnexa, skin, thyroid, and breast. Signaling description: The development of MALT lymphoma is a multi-stage process which is best understood in the gastric form of disease. The first stage of MALT lymphoma development is associated with chronic infection and inflammation or autoimmune disorders. MALT lymphoma of the stomach is linked to Helicobacter pylori (H. pylori) infection and eradication of the bacterium with antibiotics leads to long-term regression of the disease in about 70% of cases. Campylobacter jejuni, Borrelia burgdorferi, and Chlamydia psittaci are associated with MALT lymphoma of the small intestine, skin, and ocular adnexa, respectively. In gastric MALT lymphoma, it has been shown that H. pylori stimulates lymphoma B-cells through tumor infiltrating T-cells involving CD40LG/CD40, CD86/CD28, and ICOSLG/ICOS interactions, CD209 (DC-SIGN receptor), Toll-like receptors, and direct antigen stimulation via B-cell receptor which also plays a role in pathogenesis. The overexpression of CCR7, CCR5, CCR2, CXCR4, and their ligands were also shown in MALT lymphoma. The second stage is characterized by the gain of chromosomal translocations, autonomous growth ability, and lack of response to antibacterial therapy. There are four common translocations occurring at variable incidences in MALT lymphomas of different locations including t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, t(14;18)/IGH-MALT1, and t(3;14)/IGH-FOXP1. The first three translocations drive the constant activation of NF-kB pathway. The final stage of MALT lymphoma is the transformation to high-grade lymphoma (most often to diffuse B-cell large cell lymphoma) and is associated with inactivating mutations of TP53, CDKN2A, TNFAIP3, and FAS. Outcome effects: Constant activation of NF-kB pathway leads to block of apoptosis. However, the exact mechanism of IGH-FOXP1 transcript action is not well known; however it may have an antiapoptotic effect through BCL2 activation by overexpressed FOXP1. Mutated genes: Mutated genes are shown in white-out style. Organ: intestine Organ: stomach Organ_System: lymphatic system PMID: 15286744 PMID: 16395399 PMID: 18040143 PMID: 20431728 PMID: 22044597 PMID: 22224767 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ccbae216-d46b-4eae-aa76-c9244ea8a614 Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma uuid-ccbae216-d46b-4eae-aa76-c9244ea8a614 PS:CellType B-cell PS:CellType cancer cell PS:Description Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccbae216-d46b-4eae-aa76-c9244ea8a614 PS:NodeType Pathway PS:Notes Headnote: Marginal zone lymphoma (MZL) is subdivided into three clinically and biologically distinct subtypes including splenic, nodal MZL, and mucosa-associated lymphoid tissue (MALT) lymphoma. MALT lymphoma is a low grade B-cell neoplasm and is the third most common form of non-Hodgkin lymphoma. It occurs at different extra-nodal sites with the most common being the gastrointestinal (GI) tract, (50% of all cases), and within the GI tract, the stomach is the most common location (85% of GI MALT lymphomas). Other sites include small intestine, salivary glands, lungs, ocular adnexa, skin, thyroid, and breast. Signaling description: The development of MALT lymphoma is a multi-stage process which is best understood in the gastric form of disease. The first stage of MALT lymphoma development is associated with chronic infection and inflammation or autoimmune disorders. MALT lymphoma of the stomach is linked to Helicobacter pylori (H. pylori) infection and eradication of the bacterium with antibiotics leads to long-term regression of the disease in about 70% of cases. Campylobacter jejuni, Borrelia burgdorferi, and Chlamydia psittaci are associated with MALT lymphoma of the small intestine, skin, and ocular adnexa, respectively. In gastric MALT lymphoma, it has been shown that H. pylori stimulates lymphoma B-cells through tumor infiltrating T-cells involving CD40LG/CD40, CD86/CD28, and ICOSLG/ICOS interactions, CD209 (DC-SIGN receptor), Toll-like receptors, and direct antigen stimulation via B-cell receptor which also plays a role in pathogenesis. The overexpression of CCR7, CCR5, CCR2, CXCR4, and their ligands were also shown in MALT lymphoma. The second stage is characterized by the gain of chromosomal translocations, autonomous growth ability, and lack of response to antibacterial therapy. There are four common translocations occurring at variable incidences in MALT lymphomas of different locations including t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, t(14;18)/IGH-MALT1, and t(3;14)/IGH-FOXP1. The first three translocations drive the constant activation of NF-kB pathway. The final stage of MALT lymphoma is the transformation to high-grade lymphoma (most often to diffuse B-cell large cell lymphoma) and is associated with inactivating mutations of TP53, CDKN2A, TNFAIP3, and FAS. Outcome effects: Constant activation of NF-kB pathway leads to block of apoptosis. However, the exact mechanism of IGH-FOXP1 transcript action is not well known; however it may have an antiapoptotic effect through BCL2 activation by overexpressed FOXP1. Mutated genes: Mutated genes are shown in white-out style. PS:Organ intestine PS:Organ stomach PS:Organ_System lymphatic system PS:PMID 15286744 PS:PMID 16395399 PS:PMID 18040143 PS:PMID 20431728 PS:PMID 22044597 PS:PMID 22224767 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Myocardial reperfusion injury (RI) results from pathological processes such as the return of blood supply after a period of ischemia. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccf9af08-f29a-4542-bab0-2b51188b3be1 NodeType: Pathway Notes: Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: Cardiomyocytes are very sensitive to ischemic injury. During I/R in humans, 5-30% of cardiac myocytes in the area at risk undergo apoptosis within 16 hours. ROS are critical mediators of I/R injury, which is also associated with intracellular Ca2+ overload in cardiomyocytes. During ischemia, intracellular Ca2+ is elevated with further increase during reperfusion. ROS also participates in lipid hyperoxidation, DNA degradation, and necrotic cell death. Outcome effects: Ischaemic/hypoxic heart disease induces rapid changes in all membrane systems and causes reversible or irreversible injury including necrotic and apoptotic cell death. Mitochondria play an important role in transmitting and amplifying the death signals. The most important mitochondrial events during apoptosis are structural and functional remodeling of this organelle and subsequent release of apoptogenic proteins into the cytosol and nucleus, such as ENDOG, which activates DNA degradation in the nucleus. In addition, proteins associated with mitochondrial permeability transition pore (mPTP) including VDAC1, SLC25A4, and PPID are also involved in these processes. Channel activity is regulated by interactions of BAX and BAK1 with the outer mitochondrial membrane. The mPTPs are regulated by BCL2 proteins and are opened by Ca2+ ionophores and oxidative stress. The mPTPs open under conditions of ischemia reperfusion when matrix Ca2+ levels increase above a certain threshold. Lastly, HMGB1 is a nuclear protein, which acts as a chromatin-binding factor and also functions as an extracellular signaling molecule, which is released into the blood from cardiomyocytes and associated with inflammation and cardiomyocyte necrosis. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. Organ: heart Organ_System: cardiovascular system PMID: 15539639 PMID: 18391174 PMID: 24224132 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-ccf9af08-f29a-4542-bab0-2b51188b3be1 Reperfusion Injury in Myocardial ischemia uuid-ccf9af08-f29a-4542-bab0-2b51188b3be1 PS:CellType cardiac myocyte PS:Description Myocardial reperfusion injury (RI) results from pathological processes such as the return of blood supply after a period of ischemia. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccf9af08-f29a-4542-bab0-2b51188b3be1 PS:NodeType Pathway PS:Notes Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Signaling description: Cardiomyocytes are very sensitive to ischemic injury. During I/R in humans, 5-30% of cardiac myocytes in the area at risk undergo apoptosis within 16 hours. ROS are critical mediators of I/R injury, which is also associated with intracellular Ca2+ overload in cardiomyocytes. During ischemia, intracellular Ca2+ is elevated with further increase during reperfusion. ROS also participates in lipid hyperoxidation, DNA degradation, and necrotic cell death. Outcome effects: Ischaemic/hypoxic heart disease induces rapid changes in all membrane systems and causes reversible or irreversible injury including necrotic and apoptotic cell death. Mitochondria play an important role in transmitting and amplifying the death signals. The most important mitochondrial events during apoptosis are structural and functional remodeling of this organelle and subsequent release of apoptogenic proteins into the cytosol and nucleus, such as ENDOG, which activates DNA degradation in the nucleus. In addition, proteins associated with mitochondrial permeability transition pore (mPTP) including VDAC1, SLC25A4, and PPID are also involved in these processes. Channel activity is regulated by interactions of BAX and BAK1 with the outer mitochondrial membrane. The mPTPs are regulated by BCL2 proteins and are opened by Ca2+ ionophores and oxidative stress. The mPTPs open under conditions of ischemia reperfusion when matrix Ca2+ levels increase above a certain threshold. Lastly, HMGB1 is a nuclear protein, which acts as a chromatin-binding factor and also functions as an extracellular signaling molecule, which is released into the blood from cardiomyocytes and associated with inflammation and cardiomyocyte necrosis. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 15539639 PS:PMID 18391174 PS:PMID 24224132 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: Histological examinations of lungs have shown that the alveolar walls in emphysema appear to be remarkably thin and almost avascular. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccfa874c-a39f-4a67-91aa-08775fd17371 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The two major types of COPD are chronic bronchitis and emphysema. Signaling description: Histological examinations of lungs have shown that the alveolar walls in emphysema appear to be remarkably thin and almost avascular. In endothelial cells, the synthesis of prostacyclin (PGI2) and nitric oxide (NO) is an outcome of KDR activation. Outcome effects: Normally, NO and PGI2 promote endothelial cell survival. Reactive oxygen species (ROS) can damage the promoter region of the VEGFA gene, and thus impair VEGFA transcription leading to the lack of NO and PGI2 as well as capillary loss. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 16403941 PMID: 17968307 PMID: 18246188 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ccfa874c-a39f-4a67-91aa-08775fd17371 VEGFA High Expression Level in Pulmonary Emphysema uuid-ccfa874c-a39f-4a67-91aa-08775fd17371 PS:CellType endothelial cell PS:Description Histological examinations of lungs have shown that the alveolar walls in emphysema appear to be remarkably thin and almost avascular. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccfa874c-a39f-4a67-91aa-08775fd17371 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The two major types of COPD are chronic bronchitis and emphysema. Signaling description: Histological examinations of lungs have shown that the alveolar walls in emphysema appear to be remarkably thin and almost avascular. In endothelial cells, the synthesis of prostacyclin (PGI2) and nitric oxide (NO) is an outcome of KDR activation. Outcome effects: Normally, NO and PGI2 promote endothelial cell survival. Reactive oxygen species (ROS) can damage the promoter region of the VEGFA gene, and thus impair VEGFA transcription leading to the lack of NO and PGI2 as well as capillary loss. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16403941 PS:PMID 17968307 PS:PMID 18246188 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccfe3b69-dd28-47ee-b352-993e586cfa31 NodeType: Pathway Notes: Diabetes mellitus type 2 is a pathology that slowly develops over time. Each stage of T2D is characterized by abnormalities on the cellular and tissue levels. At the prediabetes stages, a significant number of pancreatic beta cells become dysfunctional although they still secrete sufficient levels of insulin. Functional endopeptidases cleave proinsulin to release a fragment called the C-peptide (connecting peptide) and two other peptide chains, B- and A-, which together comprise the mature insulin. Insulin, C-peptide, and IAPP are then stored in the secretory granules in the beta cell. Insulin is stored as a crystal chelated with Zn2 in large dense-core secretory granules known as beta-granules. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ccfe3b69-dd28-47ee-b352-993e586cfa31 1_1_Insulin synthesis and secretion: insulin processing and storage uuid-ccfe3b69-dd28-47ee-b352-993e586cfa31 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ccfe3b69-dd28-47ee-b352-993e586cfa31 PS:NodeType Pathway PS:Notes Diabetes mellitus type 2 is a pathology that slowly develops over time. Each stage of T2D is characterized by abnormalities on the cellular and tissue levels. At the prediabetes stages, a significant number of pancreatic beta cells become dysfunctional although they still secrete sufficient levels of insulin. Functional endopeptidases cleave proinsulin to release a fragment called the C-peptide (connecting peptide) and two other peptide chains, B- and A-, which together comprise the mature insulin. Insulin, C-peptide, and IAPP are then stored in the secretory granules in the beta cell. Insulin is stored as a crystal chelated with Zn2 in large dense-core secretory granules known as beta-granules. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd111c3d-47b5-42c2-926c-5172d74056be NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-cd111c3d-47b5-42c2-926c-5172d74056be Proteins Involved in Phelan-McDermid Syndrome uuid-cd111c3d-47b5-42c2-926c-5172d74056be PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd111c3d-47b5-42c2-926c-5172d74056be PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd1a16b6-29eb-4469-a61b-875af5449805 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cd1a16b6-29eb-4469-a61b-875af5449805 TDP-rhamnose biosynthesis template uuid-cd1a16b6-29eb-4469-a61b-875af5449805 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd1a16b6-29eb-4469-a61b-875af5449805 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd1ad284-b5b9-4787-8c85-35114133d43c NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-cd1ad284-b5b9-4787-8c85-35114133d43c IGF1R -> ELK/SRF/HIF1A/MYC/SREBF Signaling uuid-cd1ad284-b5b9-4787-8c85-35114133d43c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd1ad284-b5b9-4787-8c85-35114133d43c PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd4db9a5-333f-4ef3-aabe-97274b2793ff NodeType: Pathway Notes: Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. Oxidative stress in neurons and Schwann cells is implicated in DN. Signaling description: High intracellular causes the formation of diacylglycerol and activates PRKCA which stimulates NOX4; whereas, high extracellular glucose induces the formation of advanced glycation end products (AGEs) which activate a specific cell-surface receptor (AGER). In addition, hyperglycemia causes an increase in glucose flux through the hexosamine pathway. Glucose-6-phosphate is converted to fructose-6-phosphate by GPI.GFPT1 then catalyzes the conversion of glucosamine-6-phosphate: GNPNAT1 converts it to N-acetyl-glucosamine-6-phosphate; PGM3 converts N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, which is converted to UDP-GlcNAc by UAP1. UDP-GlcNAc stimulates SP1 transcription factor, which regulates the expression of PARP1. Outcome effects: Following its activation by AGEs, AGER induces NOX4, which is involved in reactive oxygen species (ROS) production. In turn, PARP1 is a nuclear enzyme closely associated with oxidative-nitrosative stress. Highlighted proteins: Small molecules with elevated level are highlighted in red. Small molecules with decreased level are highlighted in blue. Organ_System: urinary tract PMID: 18616962 PMID: 24954624 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-cd4db9a5-333f-4ef3-aabe-97274b2793ff Oxidative Stress in Diabetic Neuropathy uuid-cd4db9a5-333f-4ef3-aabe-97274b2793ff PS:CellType neuron PS:Description Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd4db9a5-333f-4ef3-aabe-97274b2793ff PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. Oxidative stress in neurons and Schwann cells is implicated in DN. Signaling description: High intracellular causes the formation of diacylglycerol and activates PRKCA which stimulates NOX4; whereas, high extracellular glucose induces the formation of advanced glycation end products (AGEs) which activate a specific cell-surface receptor (AGER). In addition, hyperglycemia causes an increase in glucose flux through the hexosamine pathway. Glucose-6-phosphate is converted to fructose-6-phosphate by GPI.GFPT1 then catalyzes the conversion of glucosamine-6-phosphate: GNPNAT1 converts it to N-acetyl-glucosamine-6-phosphate; PGM3 converts N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, which is converted to UDP-GlcNAc by UAP1. UDP-GlcNAc stimulates SP1 transcription factor, which regulates the expression of PARP1. Outcome effects: Following its activation by AGEs, AGER induces NOX4, which is involved in reactive oxygen species (ROS) production. In turn, PARP1 is a nuclear enzyme closely associated with oxidative-nitrosative stress. Highlighted proteins: Small molecules with elevated level are highlighted in red. Small molecules with decreased level are highlighted in blue. PS:Organ_System urinary tract PS:PMID 18616962 PS:PMID 24954624 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: antigen-presenting cell CellType: dendritic cell CellType: macrophage Description: Major histocompatibility complex (MHC) 1 is a cell surface molecule that is responsible for the transmission of intracellular antigens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd5518aa-29f8-42f4-bd25-8d018f72140d NodeType: Pathway Notes: Headnote: Major histocompatibility complex (MHC) 1 is a cell surface molecule that is responsible for the transmission of intracellular antigens. Antigens are fragments of proteins from other organisms or self-proteins in the case of autoimmune diseases. Signaling description: Intracellular antigens are mainly produced by viruses replicating within a host cell and synthesized proteins such as self-antigens and cancer antigens. The process of MHC1-mediated antigen presentation is initiated when the cell takes over antigens and degrades them into peptides in the proteasome. Proteasomal action alone is not sufficient for peptide generation, therefore TPP2 is also required. Peptides are transported into the endoplasmic reticulum (ER) by TAP1 and TAP2. TAPs deliver the peptides to the ER for binding to the MHC1 groove. The chaperones, calnexin (CANX) and calreticulin (CALR) bind to MHC1 and the peptide complex assembly. Other chaperones maintain MHC1 as it binds to the TAP complex via tapasin (TAPBP). Outcome effects: Subsequently, MHC1 and the peptide complex migrate through Golgi vesicles to the outer cell membrane. Cell surface MHC1 and the peptide complex, when connected to the CD8 and NK cells, activate their differentiation and mediate apoptosis of the infected target cell. Organ: generic Organ_System: hematological system PMID: 12200053 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-cd5518aa-29f8-42f4-bd25-8d018f72140d MHC1-Mediated Antigen Presentation uuid-cd5518aa-29f8-42f4-bd25-8d018f72140d PS:CellType T-cell PS:CellType antigen-presenting cell PS:CellType dendritic cell PS:CellType macrophage PS:Description Major histocompatibility complex (MHC) 1 is a cell surface molecule that is responsible for the transmission of intracellular antigens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd5518aa-29f8-42f4-bd25-8d018f72140d PS:NodeType Pathway PS:Notes Headnote: Major histocompatibility complex (MHC) 1 is a cell surface molecule that is responsible for the transmission of intracellular antigens. Antigens are fragments of proteins from other organisms or self-proteins in the case of autoimmune diseases. Signaling description: Intracellular antigens are mainly produced by viruses replicating within a host cell and synthesized proteins such as self-antigens and cancer antigens. The process of MHC1-mediated antigen presentation is initiated when the cell takes over antigens and degrades them into peptides in the proteasome. Proteasomal action alone is not sufficient for peptide generation, therefore TPP2 is also required. Peptides are transported into the endoplasmic reticulum (ER) by TAP1 and TAP2. TAPs deliver the peptides to the ER for binding to the MHC1 groove. The chaperones, calnexin (CANX) and calreticulin (CALR) bind to MHC1 and the peptide complex assembly. Other chaperones maintain MHC1 as it binds to the TAP complex via tapasin (TAPBP). Outcome effects: Subsequently, MHC1 and the peptide complex migrate through Golgi vesicles to the outer cell membrane. Cell surface MHC1 and the peptide complex, when connected to the CD8 and NK cells, activate their differentiation and mediate apoptosis of the infected target cell. PS:Organ generic PS:Organ_System hematological system PS:PMID 12200053 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: hepatocyte Description: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is recognized as a major public health problem across the world. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd58cfdb-f457-47ba-9bbd-b2d8af413450 NodeType: Pathway Notes: Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. NAFLD involves decreased fatty acid oxidation which leads to the accumulation of triglycerides in hepatocytes. Signaling description: Obesity and NAFLD are interconnected. Hypertrophic adipocytes release proinflammatory cytokines such as TNF and IL6. TNF promotes inflammatory responses to injury and regulates insulin resistance. The overexpression of TNF plays an important role in the development and progression of metabolic disorders in humans via the following mechanism. Activated TNFRSF1A binds to TRADD/RIPK1/TRAF2 and via MAPKs activates NF-kB. Activated IL6ST and IL6R via JAK1 stimulate STAT3 which promotes CEBPB. CEBPB binds NF-kB and activates HIF1A which inhibits PPARA. Outcome effects: PPARA is responsible for the induction of ACADM, ACADL, PC, ACOT2, HADH, PDK2/4, ACADVL, CPT2, and ACSL1 all of which are involved in fatty acid oxidation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: liver Organ_System: digestive system PMID: 23394097 PMID: 25045276 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-cd58cfdb-f457-47ba-9bbd-b2d8af413450 Oxidation of Fatty Acid in non-Alcoholic Fatty Liver Disease uuid-cd58cfdb-f457-47ba-9bbd-b2d8af413450 PS:CellType adipocyte PS:CellType hepatocyte PS:Description Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is recognized as a major public health problem across the world. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd58cfdb-f457-47ba-9bbd-b2d8af413450 PS:NodeType Pathway PS:Notes Headnote: Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver diseases characterized by abnormal deposition of lipids (triglycerides) in hepatocytes. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) which can have different degrees of fibrosis and progress to liver cirrhosis and hepatocellular carcinoma. Type 2 diabetes, obesity, metabolic syndrome, and NAFLD are closely interconnected. NAFLD involves decreased fatty acid oxidation which leads to the accumulation of triglycerides in hepatocytes. Signaling description: Obesity and NAFLD are interconnected. Hypertrophic adipocytes release proinflammatory cytokines such as TNF and IL6. TNF promotes inflammatory responses to injury and regulates insulin resistance. The overexpression of TNF plays an important role in the development and progression of metabolic disorders in humans via the following mechanism. Activated TNFRSF1A binds to TRADD/RIPK1/TRAF2 and via MAPKs activates NF-kB. Activated IL6ST and IL6R via JAK1 stimulate STAT3 which promotes CEBPB. CEBPB binds NF-kB and activates HIF1A which inhibits PPARA. Outcome effects: PPARA is responsible for the induction of ACADM, ACADL, PC, ACOT2, HADH, PDK2/4, ACADVL, CPT2, and ACSL1 all of which are involved in fatty acid oxidation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ liver PS:Organ_System digestive system PS:PMID 23394097 PS:PMID 25045276 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd699f6c-0543-48f9-8aba-2995c5dc81cf NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-cd699f6c-0543-48f9-8aba-2995c5dc81cf Proteins with Altered Expression in Acne Vulgaris uuid-cd699f6c-0543-48f9-8aba-2995c5dc81cf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd699f6c-0543-48f9-8aba-2995c5dc81cf PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd7b3cba-20ec-4c94-a89b-07399621efa9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-cd7b3cba-20ec-4c94-a89b-07399621efa9 Brassinosteroid biosynthesis template uuid-cd7b3cba-20ec-4c94-a89b-07399621efa9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd7b3cba-20ec-4c94-a89b-07399621efa9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Normally, autonomic neuron development is controlled by a network of transcription factors which includes PHOX2A, PHOX2B, ASCL1, HAND2, and GATA3. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd91288a-c71b-41af-869e-6bc945346ab3 NodeType: Pathway Notes: Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Normally, autonomic neuron development is controlled by a network of transcription factors which includes PHOX2A, PHOX2B, ASCL1, HAND2, and GATA3. These transcription factors are essential for the initial differentiation of autonomic neurons and also directly activate genes of the noradrenalin synthesis route such as dopamine beta hydroxylase (DBH) and tyrosine hydroxylase (TH). The expression of PHOX2B, PHOX2A, ASCL1, and HAND2 is controlled by bone morphogenetic proteins (BMP2/4/7) and Notch signaling. Mutations in PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma (NB). NB patients with PHOX2B mutations may also have familial disorders of the neural crest such as Hirschsprung disease and congenital central hypoventilation syndrome. Outcome effects: Mutated PHOX2B fails to inactivate SOX10, which normally blocks differentiation. Mutations disrupt the interaction of PHOX2B with the neuronal calcium sensor, HPCAL1 and thereby also impede cellular differentiation in NB. In addition, PHOX2B downregulates MSX1, which in turn upregulates Notch pathway genes including DLK1, NOTCH3, and HEY1 and downregulates NEUROD1. Finally, PHOX2B mutations lead to block of differentiation and activation of proliferation. It may also lead to the impairment of sympathoadrenal ganglia formation as observed in Hirschsprung disease. In NB, neuroblasts often retain the ability to secrete noradrenaline (norepinephrine). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ_System: nervous system PMID: 15288262 PMID: 16084642 PMID: 18201699 PMID: 20089899 PMID: 21295685 PMID: 22922260 PMID: 22922261 PMID: 23873030 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-cd91288a-c71b-41af-869e-6bc945346ab3 PHOX2B Effects in Neuroblastoma uuid-cd91288a-c71b-41af-869e-6bc945346ab3 PS:CellType cancer cell PS:CellType neural stem cell PS:Description Normally, autonomic neuron development is controlled by a network of transcription factors which includes PHOX2A, PHOX2B, ASCL1, HAND2, and GATA3. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd91288a-c71b-41af-869e-6bc945346ab3 PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is derived from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Normally, autonomic neuron development is controlled by a network of transcription factors which includes PHOX2A, PHOX2B, ASCL1, HAND2, and GATA3. These transcription factors are essential for the initial differentiation of autonomic neurons and also directly activate genes of the noradrenalin synthesis route such as dopamine beta hydroxylase (DBH) and tyrosine hydroxylase (TH). The expression of PHOX2B, PHOX2A, ASCL1, and HAND2 is controlled by bone morphogenetic proteins (BMP2/4/7) and Notch signaling. Mutations in PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma (NB). NB patients with PHOX2B mutations may also have familial disorders of the neural crest such as Hirschsprung disease and congenital central hypoventilation syndrome. Outcome effects: Mutated PHOX2B fails to inactivate SOX10, which normally blocks differentiation. Mutations disrupt the interaction of PHOX2B with the neuronal calcium sensor, HPCAL1 and thereby also impede cellular differentiation in NB. In addition, PHOX2B downregulates MSX1, which in turn upregulates Notch pathway genes including DLK1, NOTCH3, and HEY1 and downregulates NEUROD1. Finally, PHOX2B mutations lead to block of differentiation and activation of proliferation. It may also lead to the impairment of sympathoadrenal ganglia formation as observed in Hirschsprung disease. In NB, neuroblasts often retain the ability to secrete noradrenaline (norepinephrine). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ_System nervous system PS:PMID 15288262 PS:PMID 16084642 PS:PMID 18201699 PS:PMID 20089899 PS:PMID 21295685 PS:PMID 22922260 PS:PMID 22922261 PS:PMID 23873030 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd9245fd-4007-4808-8b44-dd656337a01a NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-cd9245fd-4007-4808-8b44-dd656337a01a Proteins Involved in Glaucoma uuid-cd9245fd-4007-4808-8b44-dd656337a01a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd9245fd-4007-4808-8b44-dd656337a01a PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: epithelial cell Description: Multiple mechanisms are involved in ovarian cancer pathogenesis, including EGFR and PTAFR signaling, leading to uncontrolled cell proliferation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd9ac37e-25a3-4b62-948b-571489ef3c94 NodeType: Pathway Notes: Headnote: Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, or a red scaly patch of skin. Multiple pathways are involved in ovarian cancer pathogenesis, including the EGFR and PTAFR signaling. In ovarian cancer EGFR and PTAFR are cross talking and activating each other leading to uncontrolled cell proliferation. Signaling description: EGFR is activated by EGF and HBEGF and lead to downstream RAS-MAPK signaling. PTAFR is activated by 1-O-Stearoyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet activating factor) leading to GNAQ - PLCB1 - RAS - MAPK signaling. EGFR and PTAFR are cross talking and activating each other. MAPK1 and MAPK3 may also activate phospholipase A2, leading to hyper production of 1-O-Stearoyl-2-acetyl-sn-glyceryl-3-phosphorylcholine and forming a vicious circle. Proteins EGF, HBEGF, EGFR and PTAFR with red highlights have increased expression in ovarian cancer cells. Organ: ovary Organ_System: reproductive system PMID: 24721622 PMID: 25261977 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-cd9ac37e-25a3-4b62-948b-571489ef3c94 EGFR and PTAFR Signaling in Ovarian Cancer uuid-cd9ac37e-25a3-4b62-948b-571489ef3c94 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Multiple mechanisms are involved in ovarian cancer pathogenesis, including EGFR and PTAFR signaling, leading to uncontrolled cell proliferation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cd9ac37e-25a3-4b62-948b-571489ef3c94 PS:NodeType Pathway PS:Notes Headnote: Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, or a red scaly patch of skin. Multiple pathways are involved in ovarian cancer pathogenesis, including the EGFR and PTAFR signaling. In ovarian cancer EGFR and PTAFR are cross talking and activating each other leading to uncontrolled cell proliferation. Signaling description: EGFR is activated by EGF and HBEGF and lead to downstream RAS-MAPK signaling. PTAFR is activated by 1-O-Stearoyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet activating factor) leading to GNAQ - PLCB1 - RAS - MAPK signaling. EGFR and PTAFR are cross talking and activating each other. MAPK1 and MAPK3 may also activate phospholipase A2, leading to hyper production of 1-O-Stearoyl-2-acetyl-sn-glyceryl-3-phosphorylcholine and forming a vicious circle. Proteins EGF, HBEGF, EGFR and PTAFR with red highlights have increased expression in ovarian cancer cells. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 24721622 PS:PMID 25261977 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdad2570-df93-4d74-9b9f-5c8c380850aa NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-cdad2570-df93-4d74-9b9f-5c8c380850aa TGFb+>apoptosis uuid-cdad2570-df93-4d74-9b9f-5c8c380850aa PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdad2570-df93-4d74-9b9f-5c8c380850aa PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdbb1795-0530-46e1-b460-1b902d1527ee NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-cdbb1795-0530-46e1-b460-1b902d1527ee Calveolin-| EMT in lipid rafts uuid-cdbb1795-0530-46e1-b460-1b902d1527ee PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdbb1795-0530-46e1-b460-1b902d1527ee PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdc369a1-d308-44ea-b1f6-4641b8ab6ac7 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: aorta Organ_System: cardiovascular system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-cdc369a1-d308-44ea-b1f6-4641b8ab6ac7 Elevated Receptors -> Expression Targets in Aorta uuid-cdc369a1-d308-44ea-b1f6-4641b8ab6ac7 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cdc369a1-d308-44ea-b1f6-4641b8ab6ac7 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ aorta PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce0ce105-ff93-4200-8a01-28fff921d3b2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ce0ce105-ff93-4200-8a01-28fff921d3b2 Formalin and formate degradation template uuid-ce0ce105-ff93-4200-8a01-28fff921d3b2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce0ce105-ff93-4200-8a01-28fff921d3b2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: kidney mesangial cell Description: Diabetic nephropathy (DN), also known as Kimmelstiel-Wilson syndrome, nodular diabetic glomerulosclerosis, and intercapillary glomerulonephritis, is a major complication of diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce12703f-bdfb-49bd-abcc-d742265c671c NodeType: Pathway Notes: Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Clinically progressive DN is characterized by the decrease in glomerular filtration and albuminuria which are associated with the development of characteristic histopathologic features including the thickening of the glomerular basement membrane and mesangial expansion due to the accumulation of extracellular matrix proteins. As albuminuria progresses and renal insufficiency ensues, glomerulosclerosis, arteriolar hyalinosis, and interstitial fibrosis develop. Signaling description: The enhanced expression of TGFB1 in renal cells can lead to glomerular mesangial cell hypertrophy and glomerular fibrosis by extracellular matrix degradation. Mesangial expansion and the degree of fibrosis correlate inversely with glomerular filtration rate in humans with diabetic kidney disease and appear to be critical steps in the progression of diabetic nephropathy to end-stage renal disease. Mesangial cells are specialized cells around blood vessels of the glomeruli which offer structural support and regulate filtration rate. High glucose levels increase the transcription of TGFB1 in the kidney and activate TGFBR2 which interacts with SMAD 2/3/4 to form a heterotetrameric complex that translocates to the nucleus and regulates target genes such as transcription factor SP1 involved in cell proliferation. Activated TGFBR2 mediates mitogen-activated protein kinases (MAPK) and stress-activated protein kinases (SAPK) cascades. Mesangial cells express angiotensin II receptors (AGTR1). The overactivation of AGTR1 leads to the activation of the MAPK cascade. Outcome effects: MAP kinases regulate the transcription of fibronectin (FN1) and matrix metallopeptidases (MMP 2, 3, 9, and 12) which are involved in extracellular matrix degradation and inflammation via IL6 and TNF. Diabetes is associated with an increase in PRKCB activity related to increased glucose-induced formation of diacylglycerol (DAG). Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER, via PI3K, activates AKT1 which induces cell growth. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: kidney Organ_System: urinary tract PMID: 18726161 PMID: 20224802 PMID: 20716934 PMID: 21261520 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-ce12703f-bdfb-49bd-abcc-d742265c671c Mesangial Cell Dysfunction in Diabetic Nephropathy uuid-ce12703f-bdfb-49bd-abcc-d742265c671c PS:CellType kidney mesangial cell PS:Description Diabetic nephropathy (DN), also known as Kimmelstiel-Wilson syndrome, nodular diabetic glomerulosclerosis, and intercapillary glomerulonephritis, is a major complication of diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce12703f-bdfb-49bd-abcc-d742265c671c PS:NodeType Pathway PS:Notes Headnote: Diabetic nephropathy (DN) is a major diabetic complication. It is the leading cause of end-stage renal disease and a contributor to significant mortality in patients with diabetes. The exact mechanisms leading to the development and progression of renal injury in diabetes are not well understood. Clinically progressive DN is characterized by the decrease in glomerular filtration and albuminuria which are associated with the development of characteristic histopathologic features including the thickening of the glomerular basement membrane and mesangial expansion due to the accumulation of extracellular matrix proteins. As albuminuria progresses and renal insufficiency ensues, glomerulosclerosis, arteriolar hyalinosis, and interstitial fibrosis develop. Signaling description: The enhanced expression of TGFB1 in renal cells can lead to glomerular mesangial cell hypertrophy and glomerular fibrosis by extracellular matrix degradation. Mesangial expansion and the degree of fibrosis correlate inversely with glomerular filtration rate in humans with diabetic kidney disease and appear to be critical steps in the progression of diabetic nephropathy to end-stage renal disease. Mesangial cells are specialized cells around blood vessels of the glomeruli which offer structural support and regulate filtration rate. High glucose levels increase the transcription of TGFB1 in the kidney and activate TGFBR2 which interacts with SMAD 2/3/4 to form a heterotetrameric complex that translocates to the nucleus and regulates target genes such as transcription factor SP1 involved in cell proliferation. Activated TGFBR2 mediates mitogen-activated protein kinases (MAPK) and stress-activated protein kinases (SAPK) cascades. Mesangial cells express angiotensin II receptors (AGTR1). The overactivation of AGTR1 leads to the activation of the MAPK cascade. Outcome effects: MAP kinases regulate the transcription of fibronectin (FN1) and matrix metallopeptidases (MMP 2, 3, 9, and 12) which are involved in extracellular matrix degradation and inflammation via IL6 and TNF. Diabetes is associated with an increase in PRKCB activity related to increased glucose-induced formation of diacylglycerol (DAG). Advanced glycation end products (AGEs) activate advanced glycosylation end product-specific receptor (AGER). AGER, via PI3K, activates AKT1 which induces cell growth. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 18726161 PS:PMID 20224802 PS:PMID 20716934 PS:PMID 21261520 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce390446-fad4-4009-9d74-9da2c81bf225 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ce390446-fad4-4009-9d74-9da2c81bf225 Monoterpenoid biosynthesis template uuid-ce390446-fad4-4009-9d74-9da2c81bf225 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce390446-fad4-4009-9d74-9da2c81bf225 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce3d9177-5d7e-45f5-8aee-bdb13e0afee9 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-ce3d9177-5d7e-45f5-8aee-bdb13e0afee9 Proteins with Altered Expression in Pyelonephritis uuid-ce3d9177-5d7e-45f5-8aee-bdb13e0afee9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce3d9177-5d7e-45f5-8aee-bdb13e0afee9 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce4985b9-7035-49a4-981e-b94b36f8f2ec NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ce4985b9-7035-49a4-981e-b94b36f8f2ec NOTCH -> RBPJ/HES/HEY Signaling uuid-ce4985b9-7035-49a4-981e-b94b36f8f2ec PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce4985b9-7035-49a4-981e-b94b36f8f2ec PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce4baadc-280e-49eb-99fa-cc050d2cd05b NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ce4baadc-280e-49eb-99fa-cc050d2cd05b IL12R -> NF-kB/NFATC Signaling uuid-ce4baadc-280e-49eb-99fa-cc050d2cd05b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce4baadc-280e-49eb-99fa-cc050d2cd05b PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce5f49b7-3289-4d56-aac3-7dd6b86db769 NodeType: Pathway Notes: During inflammation, cytokines and structural-functional impairments of the microcirculation and the tubular epithelium lead to extracellular matrix degradation and kidney fibrosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ce5f49b7-3289-4d56-aac3-7dd6b86db769 3_The role of interstitial fibroblasts in pyelonephritis uuid-ce5f49b7-3289-4d56-aac3-7dd6b86db769 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce5f49b7-3289-4d56-aac3-7dd6b86db769 PS:NodeType Pathway PS:Notes During inflammation, cytokines and structural-functional impairments of the microcirculation and the tubular epithelium lead to extracellular matrix degradation and kidney fibrosis. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce82aa0d-4bc9-4f2d-a52d-88cc5f2426b6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ce82aa0d-4bc9-4f2d-a52d-88cc5f2426b6 IL31 Expression Targets uuid-ce82aa0d-4bc9-4f2d-a52d-88cc5f2426b6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ce82aa0d-4bc9-4f2d-a52d-88cc5f2426b6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: M2 macrophage CellType: cancer cell CellType: cancer stem cell CellType: tumor infiltrating macrophage Description: Tumor-associated macrophages act as protumoral cells with M2 phenotype contributing to tumor immune escape, tumor cell proliferation, angiogenesis, matrix remodeling and invasion. They play major role in cancer-associated inflammation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceacde7c-f419-448d-94ea-351df0a10ed3 NodeType: Pathway Notes: Headnote: Tumor-associated macrophages (TAMs) represent the major inflammatory component of the stroma of many tumors, and can affect different aspects of the neoplastic tissue. TAMs express several M2-associated pro-tumoral functions, including promotion of angiogenesis, matrix remodeling and suppression of adaptive immunity. Signaling description: TAMs are recruited to the tumor, activated and switched to the M2 phenotype via several effectors, including IL10, IL13, IL4, IL1B, TGFB1, CCL2/5, VEGFA, CSF1 and others. The corresponding signaling routes are activated in TAMs for the induction of transcription factors NF-kB, STAT3/6, HIF1A and some others (not shown on the pathway). TAMs produce a number of proteolytic molecules, such as plasmin, PLAU CTSB/S and matrix metalloproteases (MMPs) which may remodel the extracellular matrix and potentiate tumor cell invasion. TAMs promote tumor angiogenesis via the expression of VEGFA/C, PDGFB, TYMP, CCL18, CXCL8 which are directly or indirectly involved in new vessel formation and sprouting. TAMs express immunosuppressive molecules CD274, VTCN1, CD276 which inhibit T-cell activation. TAMs also cause immunosuppression via the production of IL10, IL13, TGFB1, CCL22. They express ARG1 that catabolizes arginine, deplete their environment of arginine and limit arginine availability to T-cells. TAMs also express IDO1 that produces kynurenine, inhibiting T-cell activation and proliferation and inducing apoptosis of T-cells. TAMs potentiate tumor cell proliferation producing EGF, FGF2, IL-6, PDGFB and some other molecules. Outcome effects: TAMs promote tumor immune escape, tumor cell proliferation, angiogenesis and tumor invasion. Organ_System: lymphatic system PMID: 16520032 PMID: 17913510 PMID: 18467122 PMID: 19741157 PMID: 23891329 PMID: 24213109 PMID: 25035953 PMID: 25220733 PMID: 26998515 PMID: 28241846 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-ceacde7c-f419-448d-94ea-351df0a10ed3 Tumor Infiltrating Macrophages in Cancer Progression and Immune Escape uuid-ceacde7c-f419-448d-94ea-351df0a10ed3 PS:CellType M2 macrophage PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType tumor infiltrating macrophage PS:Description Tumor-associated macrophages act as protumoral cells with M2 phenotype contributing to tumor immune escape, tumor cell proliferation, angiogenesis, matrix remodeling and invasion. They play major role in cancer-associated inflammation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceacde7c-f419-448d-94ea-351df0a10ed3 PS:NodeType Pathway PS:Notes Headnote: Tumor-associated macrophages (TAMs) represent the major inflammatory component of the stroma of many tumors, and can affect different aspects of the neoplastic tissue. TAMs express several M2-associated pro-tumoral functions, including promotion of angiogenesis, matrix remodeling and suppression of adaptive immunity. Signaling description: TAMs are recruited to the tumor, activated and switched to the M2 phenotype via several effectors, including IL10, IL13, IL4, IL1B, TGFB1, CCL2/5, VEGFA, CSF1 and others. The corresponding signaling routes are activated in TAMs for the induction of transcription factors NF-kB, STAT3/6, HIF1A and some others (not shown on the pathway). TAMs produce a number of proteolytic molecules, such as plasmin, PLAU CTSB/S and matrix metalloproteases (MMPs) which may remodel the extracellular matrix and potentiate tumor cell invasion. TAMs promote tumor angiogenesis via the expression of VEGFA/C, PDGFB, TYMP, CCL18, CXCL8 which are directly or indirectly involved in new vessel formation and sprouting. TAMs express immunosuppressive molecules CD274, VTCN1, CD276 which inhibit T-cell activation. TAMs also cause immunosuppression via the production of IL10, IL13, TGFB1, CCL22. They express ARG1 that catabolizes arginine, deplete their environment of arginine and limit arginine availability to T-cells. TAMs also express IDO1 that produces kynurenine, inhibiting T-cell activation and proliferation and inducing apoptosis of T-cells. TAMs potentiate tumor cell proliferation producing EGF, FGF2, IL-6, PDGFB and some other molecules. Outcome effects: TAMs promote tumor immune escape, tumor cell proliferation, angiogenesis and tumor invasion. PS:Organ_System lymphatic system PS:PMID 16520032 PS:PMID 17913510 PS:PMID 18467122 PS:PMID 19741157 PS:PMID 23891329 PS:PMID 24213109 PS:PMID 25035953 PS:PMID 25220733 PS:PMID 26998515 PS:PMID 28241846 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: This pathway illustrates key process in vasospasm development: calcium, noradrenaline, serotonin, thromboxane A2, endothelin 1 and 3, and leukotrienes B activates vascular contraction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceb223b0-0208-4f75-bfdb-5ea307b2476a NodeType: Pathway Notes: Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. Increased calcium (Ca2+), noradrenaline, serotonin, thromboxane A2 (TXA2), endothelin 1 and 3 (EDN1 and EDN3), and leukotriene B (LTB4) activate vascular contraction. The receptors for these mediators are G protein-coupled receptors (GPCRs). Once they are activated, their action leads to an increase in intracellular Ca2+ via the IP3 pathway and the activation of protein kinase C (PKC). This activates calmodulin and Ras proteins. Outcome effects: Ras proteins activate the pathway, which results in the CALD1 phosphorylation, required for actin stabilization in the smooth muscle. Calmodulin activates myosin light chain kinase (MYLK), resulting in smooth muscle contraction. G-proteins are also capable of inhibiting protein kinase A (PKA) (through cAMP), which may suppress the activity of MYLK and RHOA. The activation of RHOA via the guanine nucleotide exchange factors RASGRF1 and RASGRP1, leads to the inhibition of MYLK and results in the arrest of smooth muscle relaxation. Thus, increased Ca2+, noradrenaline, serotonin, TXA2, EDN1, EDN3, and LTB4 lead to vasoconstriction following SAH. Vasoconstriction results in a decreased cellular nutrition along with dysfunction and death of endothelial cells. The depletion of ATP reduces the activity of myosin light chain phosphatase (MLCP), providing further vasoconstriction. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: cardiovascular system PMID: 15795160 PMID: 15927823 PMID: 18173899 PMID: 23050638 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-ceb223b0-0208-4f75-bfdb-5ea307b2476a Contraction Due Vasospasm uuid-ceb223b0-0208-4f75-bfdb-5ea307b2476a PS:CellType vascular smooth muscle cell PS:Description This pathway illustrates key process in vasospasm development: calcium, noradrenaline, serotonin, thromboxane A2, endothelin 1 and 3, and leukotrienes B activates vascular contraction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceb223b0-0208-4f75-bfdb-5ea307b2476a PS:NodeType Pathway PS:Notes Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. Increased calcium (Ca2+), noradrenaline, serotonin, thromboxane A2 (TXA2), endothelin 1 and 3 (EDN1 and EDN3), and leukotriene B (LTB4) activate vascular contraction. The receptors for these mediators are G protein-coupled receptors (GPCRs). Once they are activated, their action leads to an increase in intracellular Ca2+ via the IP3 pathway and the activation of protein kinase C (PKC). This activates calmodulin and Ras proteins. Outcome effects: Ras proteins activate the pathway, which results in the CALD1 phosphorylation, required for actin stabilization in the smooth muscle. Calmodulin activates myosin light chain kinase (MYLK), resulting in smooth muscle contraction. G-proteins are also capable of inhibiting protein kinase A (PKA) (through cAMP), which may suppress the activity of MYLK and RHOA. The activation of RHOA via the guanine nucleotide exchange factors RASGRF1 and RASGRP1, leads to the inhibition of MYLK and results in the arrest of smooth muscle relaxation. Thus, increased Ca2+, noradrenaline, serotonin, TXA2, EDN1, EDN3, and LTB4 lead to vasoconstriction following SAH. Vasoconstriction results in a decreased cellular nutrition along with dysfunction and death of endothelial cells. The depletion of ATP reduces the activity of myosin light chain phosphatase (MLCP), providing further vasoconstriction. Highlighted proteins: Entities with increased level or acitivity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 15795160 PS:PMID 15927823 PS:PMID 18173899 PS:PMID 23050638 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: CFTR is ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceb75183-93f4-4d01-a648-df9e78881a49 NodeType: Pathway Notes: Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: There are more than a thousand mutations in the CFTR gene and the diversity of mutations explains the penetrance of the disease. The mutations are divided into 5 classes. Class I CFTR mutations affect its biosynthesis. This type of mutations includes the most severe CF phenotypes since no protein is being synthesized. The most common mutations are G542X, which prevent the synthesis of a stable CFTR protein or result in the production of a truncated protein due to the creation of a premature termination codon. The truncated proteins are usually unstable, rapidly degraded, and recognized by chaperone proteins in the endoplasmic reticulum (ER). IL1B receptors and beta-2-adrenergic receptor (ADRB2) stimulate the expression of CFTR via NF-kB and CREB1. The exact signaling leading to CFTR expression is poorly understood. This pathway illustrates the classic signaling route activated by IL1R1 and ADRB2. Outcome effects: P2RY2 activates Ca2+-dependent signaling that leads to membrane hyperpolarization, CFTR secretion, and possibly CFTR expression activation. Mutated proteins: Mutated gene is shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 12940920 PMID: 23630497 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ceb75183-93f4-4d01-a648-df9e78881a49 CFTR Expression in Epithelial Cells (Class I Mutations) uuid-ceb75183-93f4-4d01-a648-df9e78881a49 PS:CellType epithelial cell PS:Description CFTR is ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ceb75183-93f4-4d01-a648-df9e78881a49 PS:NodeType Pathway PS:Notes Headnote: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR is a cyclic AMP (cAMP)-regulated, ATP-gated chloride (Cl-) channel located in the apical membrane of epithelial cells lining the airways, intestines, ducts of the pancreas, and sweat glands. Lung disease is the major cause of mortality of CF. Signaling description: There are more than a thousand mutations in the CFTR gene and the diversity of mutations explains the penetrance of the disease. The mutations are divided into 5 classes. Class I CFTR mutations affect its biosynthesis. This type of mutations includes the most severe CF phenotypes since no protein is being synthesized. The most common mutations are G542X, which prevent the synthesis of a stable CFTR protein or result in the production of a truncated protein due to the creation of a premature termination codon. The truncated proteins are usually unstable, rapidly degraded, and recognized by chaperone proteins in the endoplasmic reticulum (ER). IL1B receptors and beta-2-adrenergic receptor (ADRB2) stimulate the expression of CFTR via NF-kB and CREB1. The exact signaling leading to CFTR expression is poorly understood. This pathway illustrates the classic signaling route activated by IL1R1 and ADRB2. Outcome effects: P2RY2 activates Ca2+-dependent signaling that leads to membrane hyperpolarization, CFTR secretion, and possibly CFTR expression activation. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 12940920 PS:PMID 23630497 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced3ae9d-b289-4e0c-a7dd-a980f364670b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ced3ae9d-b289-4e0c-a7dd-a980f364670b FGF2 -> FOXO3A Expression Targets uuid-ced3ae9d-b289-4e0c-a7dd-a980f364670b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced3ae9d-b289-4e0c-a7dd-a980f364670b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced84230-6428-446b-bd4d-821d3e01d661 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-ced84230-6428-446b-bd4d-821d3e01d661 HTR1 -> IL6 Production uuid-ced84230-6428-446b-bd4d-821d3e01d661 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced84230-6428-446b-bd4d-821d3e01d661 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Copper (Cu), iron (Fe) and zinc (Zn) ions are believed to play a role in the pathogenesis of Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced9a5b3-9e90-4fce-bc91-666e8b1e4c5d NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Metals are believed to have a role in the pathogenesis of AD. Signaling description: Abeta protein monomers can bind to copper (Cu), iron (Fe), and zinc (Zn) ions and enzymatically decrease their valence by oxidation. Abeta-Cu2 exhibits both antioxidant activity and prooxidant activity depending on the conditions. In the early stages of AD, monomeric Abeta may protect neurons by binding to potentially toxic Cu2 released at the synapse. In long-term AD, oligomeric Abeta could concentrate the redox-active form of Cu2 at the membrane and cause lipid peroxidation and eventually cell death. Similar to Cu, Fe interacts with Abeta. Fe2 and Fe3 accumulate in senile plaques in patients with AD and can lead to the generation of free radicals. In addition, Zn2 also binds to Abeta and accelerates its aggregation. Zn is a competitive inhibitor of Cu uptake, while Cu competes for Zn uptake. Oxidized Cu and Fe anions participate in the Fenton reaction that results in the formation of reactive oxygen species (ROS). In addition, aluminum (Al) induces a conformational change in Abeta which has been shown to inhibit the degradation of Abeta. Abeta coupled with Al is more toxic than normal Abeta, causing membrane disruption or perturbation of neural Ca2 homeostasis and mitochondrial respiration. Furthermore, selenium (Se) protects against 4-hydroxynonenal and Abeta-mediated toxicity in neurons. A deficiency in Se intake was largely observed in patients with AD. Outcome effects: One of general effects of ROS inside a cell is the peroxidation of lipids in cellular membranes. In turn, lipid peroxidation causes the release of 4-hydroxynonenal or propanedial, which is toxic to the cell. The activation of JUN N-terminal kinases and p38 pathways mediate the 4-hydroxynonenal dependent up-regulation of BACE-1 expression. 4-hydroxynonenal, an oxidative stress mediator, was detected in vivo in the brains of AD patients. HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients with AD were found to be up-regulated. In conclusion, the interaction of Abeta and redox-active metals enhances Abeta aggregation or facilitates the generation of ROS, and causes neuronal death and the activation of an inflammatory mechanism in the brain. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 15910549 PMID: 19601593 PMID: 20026385 PMID: 21423554 PMID: 21696420 PMID: 22166855 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ced9a5b3-9e90-4fce-bc91-666e8b1e4c5d Metals and Amyloid beta Toxicity in Alzheimer's Disease uuid-ced9a5b3-9e90-4fce-bc91-666e8b1e4c5d PS:CellType neuron PS:Description Copper (Cu), iron (Fe) and zinc (Zn) ions are believed to play a role in the pathogenesis of Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ced9a5b3-9e90-4fce-bc91-666e8b1e4c5d PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Metals are believed to have a role in the pathogenesis of AD. Signaling description: Abeta protein monomers can bind to copper (Cu), iron (Fe), and zinc (Zn) ions and enzymatically decrease their valence by oxidation. Abeta-Cu2 exhibits both antioxidant activity and prooxidant activity depending on the conditions. In the early stages of AD, monomeric Abeta may protect neurons by binding to potentially toxic Cu2 released at the synapse. In long-term AD, oligomeric Abeta could concentrate the redox-active form of Cu2 at the membrane and cause lipid peroxidation and eventually cell death. Similar to Cu, Fe interacts with Abeta. Fe2 and Fe3 accumulate in senile plaques in patients with AD and can lead to the generation of free radicals. In addition, Zn2 also binds to Abeta and accelerates its aggregation. Zn is a competitive inhibitor of Cu uptake, while Cu competes for Zn uptake. Oxidized Cu and Fe anions participate in the Fenton reaction that results in the formation of reactive oxygen species (ROS). In addition, aluminum (Al) induces a conformational change in Abeta which has been shown to inhibit the degradation of Abeta. Abeta coupled with Al is more toxic than normal Abeta, causing membrane disruption or perturbation of neural Ca2 homeostasis and mitochondrial respiration. Furthermore, selenium (Se) protects against 4-hydroxynonenal and Abeta-mediated toxicity in neurons. A deficiency in Se intake was largely observed in patients with AD. Outcome effects: One of general effects of ROS inside a cell is the peroxidation of lipids in cellular membranes. In turn, lipid peroxidation causes the release of 4-hydroxynonenal or propanedial, which is toxic to the cell. The activation of JUN N-terminal kinases and p38 pathways mediate the 4-hydroxynonenal dependent up-regulation of BACE-1 expression. 4-hydroxynonenal, an oxidative stress mediator, was detected in vivo in the brains of AD patients. HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients with AD were found to be up-regulated. In conclusion, the interaction of Abeta and redox-active metals enhances Abeta aggregation or facilitates the generation of ROS, and causes neuronal death and the activation of an inflammatory mechanism in the brain. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 15910549 PS:PMID 19601593 PS:PMID 20026385 PS:PMID 21423554 PS:PMID 21696420 PS:PMID 22166855 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cedc2592-7745-46d4-a491-b2232a3e686b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-cedc2592-7745-46d4-a491-b2232a3e686b HGF->EMT uuid-cedc2592-7745-46d4-a491-b2232a3e686b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cedc2592-7745-46d4-a491-b2232a3e686b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: pituitary cell Description: The activity of the thyroid gland is predominantly regulated by the concentration of the pituitary glycoprotein hormone, thyroid stimulating hormone (TSH). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cef38fcd-142a-46fd-be15-6a2fbce625b2 NodeType: Pathway Notes: Headnote: Hypothyroidism is a pathological state in which the thyroid gland does not produce a sufficient amount of thyroid hormones. About 95% of hypothyroidism cases are caused by changes which occur in the thyroid gland. Signaling description: The activity of the thyroid gland is predominantly regulated by the concentration of the pituitary glycoprotein hormone, thyroid stimulating hormone (TSH). TSH is a heterodimer consisting of alpha and beta subunits tightly, but non-covalently, bound. Both thyroid hormones (via their nuclear receptors (THRB and THRA)) directly inhibit the synthesis and release of TSH in pituitary cells. Primary hypothyroidism is the most common cause of elevated serum TSH. In the case of hypothyroidism, the reduced level of thyroid hormones enhances the level of TSH. Thyroid hormones can indirectly affect TSH synthesis via their effects on TRH synthesis and leptin (LEP) synthesis in adipocytes. The second major regulator of TSH production is the thyrotropin-releasing hormone (TRH). TRH is the major positive regulator of TSH beta gene expression and mainly acts by activating the thyrotropin-releasing hormone receptor (TRHR) which is a G protein-coupled receptor that activates the inositol phospholipid-calcium-protein kinase C transduction pathway upon the binding of TRH. TSH secretion in humans is pulsatile. The pulse frequency is slightly less than 2 hours. Dopamine plays a major role in the cyclic secretion of TSH. In addition, cold stress may play an important role in the regulation of TSH secretion by pituitary cells. The best known mechanism is adrenergic receptor signaling activation. Other hormones/factors such as CCK, GCG, AVP, GAL, GRP, and steroid hormones are also implicated in the complex regulation of TSH beta gene expression. Outcome effects: Several inherited TSH-beta gene mutations are responsible for familial isolated central hypothyroidism. . Highlighted proteins: Entities with increased level or activity are highlighted in red and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Koreaki Sugimoto and Kouki Mori (2012) Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism, Hypothyroidism - Influences and Treatments, Dr. Drahomira Springer (Ed.), ISBN: 978-953-51-0021-8, InTech, Available from: http://www.intechopen.com/books/hypothyroidism-influences-andtreatments/thyroid-stimulating-hormone-regulation-and-transcription-in-hypothyroidism 2). Mariotti S (2011) Physiology of the Hypothalamic-Pituitary Thyroidal System. Available from: www.thyroidmanager.org. Published by ENDOCRINE EDUCATION Inc, South Dartmouth, MA 02748 Organ: brain Organ: liver Organ_System: endocrine system PMID: 21062194 PMID: 25905193 PMID: 8387773 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: adipose tissue urn:agi-pathway:uuid-cef38fcd-142a-46fd-be15-6a2fbce625b2 Thyroid Stimulating Hormone (TSH) Secretion in Overt Hypothyroidism uuid-cef38fcd-142a-46fd-be15-6a2fbce625b2 PS:CellType adipocyte PS:CellType pituitary cell PS:Description The activity of the thyroid gland is predominantly regulated by the concentration of the pituitary glycoprotein hormone, thyroid stimulating hormone (TSH). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cef38fcd-142a-46fd-be15-6a2fbce625b2 PS:NodeType Pathway PS:Notes Headnote: Hypothyroidism is a pathological state in which the thyroid gland does not produce a sufficient amount of thyroid hormones. About 95% of hypothyroidism cases are caused by changes which occur in the thyroid gland. Signaling description: The activity of the thyroid gland is predominantly regulated by the concentration of the pituitary glycoprotein hormone, thyroid stimulating hormone (TSH). TSH is a heterodimer consisting of alpha and beta subunits tightly, but non-covalently, bound. Both thyroid hormones (via their nuclear receptors (THRB and THRA)) directly inhibit the synthesis and release of TSH in pituitary cells. Primary hypothyroidism is the most common cause of elevated serum TSH. In the case of hypothyroidism, the reduced level of thyroid hormones enhances the level of TSH. Thyroid hormones can indirectly affect TSH synthesis via their effects on TRH synthesis and leptin (LEP) synthesis in adipocytes. The second major regulator of TSH production is the thyrotropin-releasing hormone (TRH). TRH is the major positive regulator of TSH beta gene expression and mainly acts by activating the thyrotropin-releasing hormone receptor (TRHR) which is a G protein-coupled receptor that activates the inositol phospholipid-calcium-protein kinase C transduction pathway upon the binding of TRH. TSH secretion in humans is pulsatile. The pulse frequency is slightly less than 2 hours. Dopamine plays a major role in the cyclic secretion of TSH. In addition, cold stress may play an important role in the regulation of TSH secretion by pituitary cells. The best known mechanism is adrenergic receptor signaling activation. Other hormones/factors such as CCK, GCG, AVP, GAL, GRP, and steroid hormones are also implicated in the complex regulation of TSH beta gene expression. Outcome effects: Several inherited TSH-beta gene mutations are responsible for familial isolated central hypothyroidism. . Highlighted proteins: Entities with increased level or activity are highlighted in red and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. References: 1). Koreaki Sugimoto and Kouki Mori (2012) Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism, Hypothyroidism - Influences and Treatments, Dr. Drahomira Springer (Ed.), ISBN: 978-953-51-0021-8, InTech, Available from: http://www.intechopen.com/books/hypothyroidism-influences-andtreatments/thyroid-stimulating-hormone-regulation-and-transcription-in-hypothyroidism 2). Mariotti S (2011) Physiology of the Hypothalamic-Pituitary Thyroidal System. Available from: www.thyroidmanager.org. Published by ENDOCRINE EDUCATION Inc, South Dartmouth, MA 02748 PS:Organ brain PS:Organ liver PS:Organ_System endocrine system PS:PMID 21062194 PS:PMID 25905193 PS:PMID 8387773 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue adipose tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf029f89-35b7-4098-ac1a-1b91583f65e1 NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: mouth Organ_System: digestive system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-cf029f89-35b7-4098-ac1a-1b91583f65e1 Acinar Cells in the Saliva Formation uuid-cf029f89-35b7-4098-ac1a-1b91583f65e1 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf029f89-35b7-4098-ac1a-1b91583f65e1 PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Megakaryocytes are large, multinucleate cells that are the precursors of thrombocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf047ec7-5523-4141-b4be-d04ca95a99a3 NodeType: Pathway Notes: Headnote: Megakaryocytes are large, multinucleate cells that are the precursors of thrombocytes. Thrombocytes lack nuclei and have no genes that need to be transcribed. The primary physiological function of platelets is to form hemostatic thrombi, which prevent blood loss and maintain vascular integrity. Signaling description: Upon activation due to damage or inflammation, thrombocytes change their shape, release the contents of granules, and become clustered forming hemostatic thrombus. The maturation of thrombocytes consists of two phases, which begins when proplatelets are formed. In the first phase, there is nuclear proliferation to the enlargement of the megakaryocyte cytoplasm as it is filled with cytoskeletal proteins, platelet-specific granules, and granule contents. This phase occurs over a period of days and requires induction by megakaryocyte-specific growth factors. Proplatelets are extended in the second phase and platelets are released. Large proplatelets are released in the bloodstream where they form platelets by fragmentation at their bulbous ends. This phase is completed in several hours. THPO is the main factor of megakaryocyte maturation. In thrombocytes, THPO activates the secretion of alpha granules through PI3K-dependent signaling. THPO acts on the synthesis of thrombocyte-specific proteins via MPL receptor and its signaling. Other factors that are important for thrombocyte maturation are CSF2, IL6, VWF, IL11, and EPO. EPO affects platelet production but its precise role in homeostatic platelet production is unknown. Megakaryocytes mature in the osteoblastic niche and migrate to the vascular niche under a CXCL12 gradient. Some of the strong inhibitors of megakaryocyte differentiation are PACAP, VIP, and PF4. GATA1 and ZFPM1 are considered key transcription factors in the maturation process of thrombocytes. The initial event in megakaryocyte differentiation is the simultaneous inhibition of SPI1 and activation of GATA1. Further, GATA1, FLI1, and KLF1 may be involved in the transcription of megakaryocyte and proplatelet-specific genes. NFE2, MKL1, and RUNX1 control late stages of differentiation, which includes the formation of prothrombocytes and thrombocytes. Signaling description: As a megakaryocyte begins to migrate towards the endothelium, it interacts with other compounds of the extracellular matrix (ECM) such as fibrinogen or VWF which may increase proplatelet formation. The late stages of differentiation may be regulated by ITGA2B/ITGB3 and GP1BA. In order to migrate through endothelial cells, megakaryocytes require the synthesis of matrix metallopeptidases (MMPs) such as MMP2 or MMP9. In addition, myosin II is crucial in the control of proplatelet formation. It is likely that myosin II interacts with microtubules to generate the forces that impair the protrusion necessary for proplatelet formation. The sliding of overlapping microtubules acts as a primary motor for proplatelet elongation. Furthermore, proteins contained in alpha granules, which are specialized secretory granules, in mature platelets can be synthesized or endocytosed during proplatelet maturation. Most specific proteins, such as PF4 or VWF, are synthesized early in differentiation and localize into alpha granules. Other proteins bind to membrane receptors, such as fibrinogen to ITGA2B/ITGB3, and are endocytosed and packaged into alpha granules. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: blood urn:agi-pathway:uuid-cf047ec7-5523-4141-b4be-d04ca95a99a3 Proplatelet Maturation uuid-cf047ec7-5523-4141-b4be-d04ca95a99a3 PS:CellType blood platelet PS:Description Megakaryocytes are large, multinucleate cells that are the precursors of thrombocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf047ec7-5523-4141-b4be-d04ca95a99a3 PS:NodeType Pathway PS:Notes Headnote: Megakaryocytes are large, multinucleate cells that are the precursors of thrombocytes. Thrombocytes lack nuclei and have no genes that need to be transcribed. The primary physiological function of platelets is to form hemostatic thrombi, which prevent blood loss and maintain vascular integrity. Signaling description: Upon activation due to damage or inflammation, thrombocytes change their shape, release the contents of granules, and become clustered forming hemostatic thrombus. The maturation of thrombocytes consists of two phases, which begins when proplatelets are formed. In the first phase, there is nuclear proliferation to the enlargement of the megakaryocyte cytoplasm as it is filled with cytoskeletal proteins, platelet-specific granules, and granule contents. This phase occurs over a period of days and requires induction by megakaryocyte-specific growth factors. Proplatelets are extended in the second phase and platelets are released. Large proplatelets are released in the bloodstream where they form platelets by fragmentation at their bulbous ends. This phase is completed in several hours. THPO is the main factor of megakaryocyte maturation. In thrombocytes, THPO activates the secretion of alpha granules through PI3K-dependent signaling. THPO acts on the synthesis of thrombocyte-specific proteins via MPL receptor and its signaling. Other factors that are important for thrombocyte maturation are CSF2, IL6, VWF, IL11, and EPO. EPO affects platelet production but its precise role in homeostatic platelet production is unknown. Megakaryocytes mature in the osteoblastic niche and migrate to the vascular niche under a CXCL12 gradient. Some of the strong inhibitors of megakaryocyte differentiation are PACAP, VIP, and PF4. GATA1 and ZFPM1 are considered key transcription factors in the maturation process of thrombocytes. The initial event in megakaryocyte differentiation is the simultaneous inhibition of SPI1 and activation of GATA1. Further, GATA1, FLI1, and KLF1 may be involved in the transcription of megakaryocyte and proplatelet-specific genes. NFE2, MKL1, and RUNX1 control late stages of differentiation, which includes the formation of prothrombocytes and thrombocytes. Signaling description: As a megakaryocyte begins to migrate towards the endothelium, it interacts with other compounds of the extracellular matrix (ECM) such as fibrinogen or VWF which may increase proplatelet formation. The late stages of differentiation may be regulated by ITGA2B/ITGB3 and GP1BA. In order to migrate through endothelial cells, megakaryocytes require the synthesis of matrix metallopeptidases (MMPs) such as MMP2 or MMP9. In addition, myosin II is crucial in the control of proplatelet formation. It is likely that myosin II interacts with microtubules to generate the forces that impair the protrusion necessary for proplatelet formation. The sliding of overlapping microtubules acts as a primary motor for proplatelet elongation. Furthermore, proteins contained in alpha granules, which are specialized secretory granules, in mature platelets can be synthesized or endocytosed during proplatelet maturation. Most specific proteins, such as PF4 or VWF, are synthesized early in differentiation and localize into alpha granules. Other proteins bind to membrane receptors, such as fibrinogen to ITGA2B/ITGB3, and are endocytosed and packaged into alpha granules. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf148e31-74ca-4fc6-9a1c-a38aad777887 NodeType: Pathway Notes: During the overt (clear/apparent) stages of diabetes, defects in insulin receptor signaling and impaired insulin sensitivity (insulin resistance) develop throughout the whole body. Most older adults have some insulin resistance, but lifestyle and weight gain make it worse, greatly increasing the likelihood of developing T2D. Pathway 4. Insulin resistance: Insulin signaling (Fig. 7). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-cf148e31-74ca-4fc6-9a1c-a38aad777887 4_1_Insulin resistance: insulin signaling uuid-cf148e31-74ca-4fc6-9a1c-a38aad777887 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf148e31-74ca-4fc6-9a1c-a38aad777887 PS:NodeType Pathway PS:Notes During the overt (clear/apparent) stages of diabetes, defects in insulin receptor signaling and impaired insulin sensitivity (insulin resistance) develop throughout the whole body. Most older adults have some insulin resistance, but lifestyle and weight gain make it worse, greatly increasing the likelihood of developing T2D. Pathway 4. Insulin resistance: Insulin signaling (Fig. 7). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf1b1de5-d836-4ff8-a52c-0950c6455cf0 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-cf1b1de5-d836-4ff8-a52c-0950c6455cf0 Wilson's Disease Anatomy and Molecular Biomarkers uuid-cf1b1de5-d836-4ff8-a52c-0950c6455cf0 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf1b1de5-d836-4ff8-a52c-0950c6455cf0 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into extracellular space. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a NodeType: Pathway Notes: Headnote: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into the surrounding extracellular space. This usually occurs under conditions of extreme damage such as ischemia or trauma when apoptosis fails to occur. Signaling description: An important consequence of necrotic cell death is the loss of plasma membrane integrity, thereby allowing the escape of intracellular material from the cell. Mechanical damage of membranes leads to the release of free radicals of hydrogen, oxygen, and others. Superoxide radical is the major initial free radical species, which can be converted into other reactive species. In the mitochondria, superoxide radical is generated by the capture of electrons in the mitochondrial electron transport chain escaping from the electron transport chain by molecular oxygen (O2). Superoxide can be rapidly converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1), which can be reused to generate superoxide radicals. H2O2 diffuses freely across cellular membranes and can interact with iron (Fe2+) in the Fenton reaction in the lysosomes since they are rich in free Fe2+ and lack H2O2-detoxifying enzymes. In the presence of transition metals such as Fe2+, H2O2 can be converted into hydroxyl radicals that are highly reactive and can cause damage to lipids, proteins, and DNA. Nitric oxide (NO) is a reactive radical produced from arginine by nitric oxide synthase (NOS). NO has a very short half-life and can react with superoxide to form peroxynitrite. Outcome effects: The targets of ROS are proteins and the polyunsaturated fatty acid residues in the membrane phospholipids which are extremely sensitive to oxidation. Free radicals lead to lipid peroxidation and the destruction of cellular membranes. Oxidative stress directly leads to damage of cellular macromolecules including DNA, proteins, and lipids. Furthermore, extensive DNA damage during necrosis causes hyperactivation of PARP1 and leads to necrotic cell death. When DNA damage is moderate, PARP1 participates in DNA repair processes. However, excessive PARP1 activation is involved in catalyzing the hydrolysis of NAD into nicotinamide and poly(ADPribose) (PAR) which leads to ATP depletion, irreversible cellular energy failure, and necrotic cell death. PARP1-mediated cell death requires the activation of RIPK1 and TRAF2. Necrosis can be classified as either stochastic or programmed (necroptosis). Necroptosis has now been established as a regulated necrotic cell death pathway controlled by TNF, RIPK1 and RIPK3 kinases. Necrosis causes lipid peroxidation of intracellular membranes of endoplasmic reticulum, lysosomes, and mitochondria and leads to the release of calcium (Ca2+) and proteolytic enzymes into the cytoplasm where they further digest cellular content and expose it to extracellular space. The molecules that are released after necrotic cell death and may cause inflammation are called damage-associated molecular patterns (DAMPs). There are also extracellular DAMPs which are released after the degradation of extracellular matrix caused by injury. For example, fragments of hyaluronan, heparin sulfate, and biglycan are generated as a result of proteolysis catalyzed either by enzymes released from dying cells or by proteases activated to promote tissue repair and remodeling. Highlighted proteins: Entities with elevated level are highlighted in red, and entities with reduced level are highlighted in blue. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a Necrosis uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a PS:CellType generic PS:Description Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into extracellular space. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a PS:NodeType Pathway PS:Notes Headnote: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into the surrounding extracellular space. This usually occurs under conditions of extreme damage such as ischemia or trauma when apoptosis fails to occur. Signaling description: An important consequence of necrotic cell death is the loss of plasma membrane integrity, thereby allowing the escape of intracellular material from the cell. Mechanical damage of membranes leads to the release of free radicals of hydrogen, oxygen, and others. Superoxide radical is the major initial free radical species, which can be converted into other reactive species. In the mitochondria, superoxide radical is generated by the capture of electrons in the mitochondrial electron transport chain escaping from the electron transport chain by molecular oxygen (O2). Superoxide can be rapidly converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1), which can be reused to generate superoxide radicals. H2O2 diffuses freely across cellular membranes and can interact with iron (Fe2+) in the Fenton reaction in the lysosomes since they are rich in free Fe2+ and lack H2O2-detoxifying enzymes. In the presence of transition metals such as Fe2+, H2O2 can be converted into hydroxyl radicals that are highly reactive and can cause damage to lipids, proteins, and DNA. Nitric oxide (NO) is a reactive radical produced from arginine by nitric oxide synthase (NOS). NO has a very short half-life and can react with superoxide to form peroxynitrite. Outcome effects: The targets of ROS are proteins and the polyunsaturated fatty acid residues in the membrane phospholipids which are extremely sensitive to oxidation. Free radicals lead to lipid peroxidation and the destruction of cellular membranes. Oxidative stress directly leads to damage of cellular macromolecules including DNA, proteins, and lipids. Furthermore, extensive DNA damage during necrosis causes hyperactivation of PARP1 and leads to necrotic cell death. When DNA damage is moderate, PARP1 participates in DNA repair processes. However, excessive PARP1 activation is involved in catalyzing the hydrolysis of NAD into nicotinamide and poly(ADPribose) (PAR) which leads to ATP depletion, irreversible cellular energy failure, and necrotic cell death. PARP1-mediated cell death requires the activation of RIPK1 and TRAF2. Necrosis can be classified as either stochastic or programmed (necroptosis). Necroptosis has now been established as a regulated necrotic cell death pathway controlled by TNF, RIPK1 and RIPK3 kinases. Necrosis causes lipid peroxidation of intracellular membranes of endoplasmic reticulum, lysosomes, and mitochondria and leads to the release of calcium (Ca2+) and proteolytic enzymes into the cytoplasm where they further digest cellular content and expose it to extracellular space. The molecules that are released after necrotic cell death and may cause inflammation are called damage-associated molecular patterns (DAMPs). There are also extracellular DAMPs which are released after the degradation of extracellular matrix caused by injury. For example, fragments of hyaluronan, heparin sulfate, and biglycan are generated as a result of proteolysis catalyzed either by enzymes released from dying cells or by proteases activated to promote tissue repair and remodeling. Highlighted proteins: Entities with elevated level are highlighted in red, and entities with reduced level are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: Periodontitis is a set of inflammatory diseases affecting the periodontium. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf33a767-dde5-4ab5-a278-dce74a899e72 NodeType: Pathway Notes: Headnote: Periodontitis is a chronic inflammatory disease involving interactions between complex microbial biofilms, many cell populations and inflammatory mediators, leading to the destruction of the tooth-supporting structures like the periodontal ligament and the alveolar bone. Chronic periodontitis is initiated by colonization with a broad array of bacteria and is perpetuated by an immune-inflammatory response to the changing biofilm. Host recognition of microbes is largely mediated by toll-like receptors (TLRs). Signaling description: Lipopolysaccharides (LPS) and other virulence factors of gram-negative periodontal bacteria increase the gene expression of TLR2 and TLR4 that play a crucial role in mediating tissue immune responses to periodontitis. These two receptors are expressed in the cells of periodontal tissues such as gingival epithelial cells, gingival fibroblasts, periodontal ligament cells and highly-expressed TLR2 and TLR4 are detected in infected gingival tissues. Mechanism of the molecular signaling of this pathway is known. When virulence factors produced by periodontal pathogens bind to TLRs, they recruit adapter proteins (TICAM1/2, TIRAP, MYD88) and via protein kinases (IKBKE, IRAK1/4, TBK1) and other downstream proteins activate transcription factors NF-kB and IRF3 that induce production of proinflammatory cytokines, chemokine and interferons (IL1B, IL2, IL6, TNF, CXCL8, IFNA1, IFNB1). Outcome effects: Increased expressions of TLRs participate and persist in inflammatory responses and immune responses following stimulation by bacteria in periodontal tissues. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: mouth Organ: periodontal ligament Organ: periodontium Organ_System: digestive system PMID: 15195695 PMID: 20528699 PMID: 23679005 PMID: 25624622 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: connective tissue Tissue: epithelium urn:agi-pathway:uuid-cf33a767-dde5-4ab5-a278-dce74a899e72 Toll-like Receptors (TLR) in Periodontitis uuid-cf33a767-dde5-4ab5-a278-dce74a899e72 PS:CellType fibroblast PS:Description Periodontitis is a set of inflammatory diseases affecting the periodontium. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf33a767-dde5-4ab5-a278-dce74a899e72 PS:NodeType Pathway PS:Notes Headnote: Periodontitis is a chronic inflammatory disease involving interactions between complex microbial biofilms, many cell populations and inflammatory mediators, leading to the destruction of the tooth-supporting structures like the periodontal ligament and the alveolar bone. Chronic periodontitis is initiated by colonization with a broad array of bacteria and is perpetuated by an immune-inflammatory response to the changing biofilm. Host recognition of microbes is largely mediated by toll-like receptors (TLRs). Signaling description: Lipopolysaccharides (LPS) and other virulence factors of gram-negative periodontal bacteria increase the gene expression of TLR2 and TLR4 that play a crucial role in mediating tissue immune responses to periodontitis. These two receptors are expressed in the cells of periodontal tissues such as gingival epithelial cells, gingival fibroblasts, periodontal ligament cells and highly-expressed TLR2 and TLR4 are detected in infected gingival tissues. Mechanism of the molecular signaling of this pathway is known. When virulence factors produced by periodontal pathogens bind to TLRs, they recruit adapter proteins (TICAM1/2, TIRAP, MYD88) and via protein kinases (IKBKE, IRAK1/4, TBK1) and other downstream proteins activate transcription factors NF-kB and IRF3 that induce production of proinflammatory cytokines, chemokine and interferons (IL1B, IL2, IL6, TNF, CXCL8, IFNA1, IFNB1). Outcome effects: Increased expressions of TLRs participate and persist in inflammatory responses and immune responses following stimulation by bacteria in periodontal tissues. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ mouth PS:Organ periodontal ligament PS:Organ periodontium PS:Organ_System digestive system PS:PMID 15195695 PS:PMID 20528699 PS:PMID 23679005 PS:PMID 25624622 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue connective tissue PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf395372-923d-4157-8f4f-54ca9136c17c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-cf395372-923d-4157-8f4f-54ca9136c17c ORF7a inhibitors uuid-cf395372-923d-4157-8f4f-54ca9136c17c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf395372-923d-4157-8f4f-54ca9136c17c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Arterial hypertension (AH) is characterized by constant high blood pressure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf533842-a3f0-45c2-bbd8-6ebaadd27191 NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone and angiotensin (AGT) have a central role in the neuro-endocrine regulation of blood pressure. Chronic activation of the angiotensin-aldosterone system (AAS) is a major contributing factor to the pathogenesis and progression of arterial hypertension. Signaling description: The classic AAS is a cascade, which involves several distinct components. The juxtaglomerular apparatus in the kidney secretes renin (REN). REN cleaves an inactive angiotensinogen (AGT), a high molecular weight protein released from the liver, converting it into angiotensin I, which is then converted into angiotensin II by angiotensin-converting enzyme (ACE). The angiotensin II receptors are located in the arterioles, adrenal gland, and circumventricular regions of the brain. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone. These effects include constriction of blood vessels resulting in increased blood pressure, stimulation of aldosterone synthesis and release, and induction of thirst and salt appetite. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, which is involved in the control of extracellular fluid volume and electrolyte homeostasis. CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is then hydroxylated to desoxycorticosterone by CYP21A2, while CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, which is hydroxylated to 17alpha-hydroxyprogesterone by HSD3B2. CYP21A2 hydroxylates 17alpha-hydroxyprogesterone to 11-deoxycortisol. CYP11B1 converts 11-deoxycortisol to cortisol. Outcome effects: Aldosterone and cortisol act on the kidney tubules causing them to reabsorb more Na+ and water from urine. K+ is secreted into the tubules in exchange for Na+, which is excreted. This increases the volume of fluid in the body and increases the blood pressure. In addition, aldosterone production is stimulated by adrenocorticotropic hormone (ACTH). ACTH is synthesized from proopiomelanocortin (POMC) in the anterior pituitary gland. Precursor polypeptide POMC is cleaved to ACTH and other hormones. Corticotropin-releasing hormone (CRH) is produced by parvocellular neuroendocrine cells of the hypothalamus and released into the primary capillary plexus of the hypothalamo-hypophyseal portal system, where it regulates the production of ACTH. The latter binds MC2R, which activates ADCY, and ADCY produces the second messenger cAMP, thereby stimulating the activity of PKA, which phosphorylates and activates STAR, a crucial protein for the transport of cholesterol mitochondria, where the biosynthesis of steroids is initiated. Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in nephrons and is responsible for Na+ reabsorption into plasma and K+ excretion in the distal renal tubule. The transport of Na+ and K+ has a dominant role in blood pressure homeostasis and excessive levels of Na+ in the plasma causes arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. Organ: adrenal gland Organ: brain Organ: hypothalamus Organ: kidney Organ: pituitary gland Organ: zona glomerulosa Organ_System: endocrine system PMID: 19225145 PMID: 23378101 PMID: 24399884 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-cf533842-a3f0-45c2-bbd8-6ebaadd27191 Angiotensin-Aldosterone System Activation Scheme uuid-cf533842-a3f0-45c2-bbd8-6ebaadd27191 PS:Description Arterial hypertension (AH) is characterized by constant high blood pressure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf533842-a3f0-45c2-bbd8-6ebaadd27191 PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone and angiotensin (AGT) have a central role in the neuro-endocrine regulation of blood pressure. Chronic activation of the angiotensin-aldosterone system (AAS) is a major contributing factor to the pathogenesis and progression of arterial hypertension. Signaling description: The classic AAS is a cascade, which involves several distinct components. The juxtaglomerular apparatus in the kidney secretes renin (REN). REN cleaves an inactive angiotensinogen (AGT), a high molecular weight protein released from the liver, converting it into angiotensin I, which is then converted into angiotensin II by angiotensin-converting enzyme (ACE). The angiotensin II receptors are located in the arterioles, adrenal gland, and circumventricular regions of the brain. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone. These effects include constriction of blood vessels resulting in increased blood pressure, stimulation of aldosterone synthesis and release, and induction of thirst and salt appetite. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, which is involved in the control of extracellular fluid volume and electrolyte homeostasis. CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is then hydroxylated to desoxycorticosterone by CYP21A2, while CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, which is hydroxylated to 17alpha-hydroxyprogesterone by HSD3B2. CYP21A2 hydroxylates 17alpha-hydroxyprogesterone to 11-deoxycortisol. CYP11B1 converts 11-deoxycortisol to cortisol. Outcome effects: Aldosterone and cortisol act on the kidney tubules causing them to reabsorb more Na+ and water from urine. K+ is secreted into the tubules in exchange for Na+, which is excreted. This increases the volume of fluid in the body and increases the blood pressure. In addition, aldosterone production is stimulated by adrenocorticotropic hormone (ACTH). ACTH is synthesized from proopiomelanocortin (POMC) in the anterior pituitary gland. Precursor polypeptide POMC is cleaved to ACTH and other hormones. Corticotropin-releasing hormone (CRH) is produced by parvocellular neuroendocrine cells of the hypothalamus and released into the primary capillary plexus of the hypothalamo-hypophyseal portal system, where it regulates the production of ACTH. The latter binds MC2R, which activates ADCY, and ADCY produces the second messenger cAMP, thereby stimulating the activity of PKA, which phosphorylates and activates STAR, a crucial protein for the transport of cholesterol mitochondria, where the biosynthesis of steroids is initiated. Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in nephrons and is responsible for Na+ reabsorption into plasma and K+ excretion in the distal renal tubule. The transport of Na+ and K+ has a dominant role in blood pressure homeostasis and excessive levels of Na+ in the plasma causes arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style. PS:Organ adrenal gland PS:Organ brain PS:Organ hypothalamus PS:Organ kidney PS:Organ pituitary gland PS:Organ zona glomerulosa PS:Organ_System endocrine system PS:PMID 19225145 PS:PMID 23378101 PS:PMID 24399884 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf779014-322e-48fb-8062-7778834a5cf7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-cf779014-322e-48fb-8062-7778834a5cf7 WNT3A Expression Targets uuid-cf779014-322e-48fb-8062-7778834a5cf7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf779014-322e-48fb-8062-7778834a5cf7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: cancer cell Description: Several recurrent genetic alterations have been identified in T-cell acute lymphoblastic leukemia (T-ALL). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf85d983-43e0-4554-a648-854872e8d2cc NodeType: Pathway Notes: Headnote: T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15% of childhood and 25% of adult ALL cases. T-ALL patients frequently present high peripheral blast counts, central nervous system dissemination, and larger mediastinal masses at diagnosis. Several recurrent genetic alterations have been identified in T-ALL. Signaling description: Several recurrent genetic alterations have been identified in T-cell acute lymphoblastic leukemia (T-ALL). Chromosomal translocations occur in about 20% of cases and result in either fusions between the coding regions of two genes which leads to chimeric protein expression, or fusions between proto-oncogenes and T-cell receptor (TCR) loci which triggers oncogene overexpression (e.g., TAL1, TAL2, TLX1, TLX3, HOXA, LMO1, LMO2, MYB, and others). Aberrations involving TCR gene regions can be detected in 35% of patients. Outcome effects: The described genetic rearrangements directly or indirectly lead to block of differentiation and uncontrolled proliferation of leukemia T-cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PMID: 16826225 PMID: 18379008 PMID: 18691165 PMID: 19181788 PMID: 20800819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-cf85d983-43e0-4554-a648-854872e8d2cc T-Cell Genetic Rearrangements in Acute Lymphoblastic Leukemia uuid-cf85d983-43e0-4554-a648-854872e8d2cc PS:CellType T-cell PS:CellType cancer cell PS:Description Several recurrent genetic alterations have been identified in T-cell acute lymphoblastic leukemia (T-ALL). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf85d983-43e0-4554-a648-854872e8d2cc PS:NodeType Pathway PS:Notes Headnote: T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of T-cells and represents 15% of childhood and 25% of adult ALL cases. T-ALL patients frequently present high peripheral blast counts, central nervous system dissemination, and larger mediastinal masses at diagnosis. Several recurrent genetic alterations have been identified in T-ALL. Signaling description: Several recurrent genetic alterations have been identified in T-cell acute lymphoblastic leukemia (T-ALL). Chromosomal translocations occur in about 20% of cases and result in either fusions between the coding regions of two genes which leads to chimeric protein expression, or fusions between proto-oncogenes and T-cell receptor (TCR) loci which triggers oncogene overexpression (e.g., TAL1, TAL2, TLX1, TLX3, HOXA, LMO1, LMO2, MYB, and others). Aberrations involving TCR gene regions can be detected in 35% of patients. Outcome effects: The described genetic rearrangements directly or indirectly lead to block of differentiation and uncontrolled proliferation of leukemia T-cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:PMID 16826225 PS:PMID 18379008 PS:PMID 18691165 PS:PMID 19181788 PS:PMID 20800819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: S-cell Description: Release of secretin by S-cells inhibits stomach acid secretion and activates bile acid secretion. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf92d781-15b2-49de-ab41-77bbb36cdfbf NodeType: Pathway Notes: Headnote: S-cells are located in the proximal small intestine and release secretin (SCT) in response to stomach acid. Signaling description: Stomach acid activates the acid sensing ion channels in the proximal small intestine. These channels, in turn activate calcium channels. Both types of channels are responsible for calcium influx within the cell and activate phospholipase A2, which leads to secretin release. Overall, the details of SCT expression activation are poorly understood. Secretin initiates HCO3- anion secretion leading to pH increase. Outcome effects: Secretin release from S-cells leads to the inhibition of stomach acid secretion and activation of the bile acid secretion. Organ: duodenum Organ: jejunum Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-cf92d781-15b2-49de-ab41-77bbb36cdfbf S-cell: Secretin Production uuid-cf92d781-15b2-49de-ab41-77bbb36cdfbf PS:CellType S-cell PS:Description Release of secretin by S-cells inhibits stomach acid secretion and activates bile acid secretion. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf92d781-15b2-49de-ab41-77bbb36cdfbf PS:NodeType Pathway PS:Notes Headnote: S-cells are located in the proximal small intestine and release secretin (SCT) in response to stomach acid. Signaling description: Stomach acid activates the acid sensing ion channels in the proximal small intestine. These channels, in turn activate calcium channels. Both types of channels are responsible for calcium influx within the cell and activate phospholipase A2, which leads to secretin release. Overall, the details of SCT expression activation are poorly understood. Secretin initiates HCO3- anion secretion leading to pH increase. Outcome effects: Secretin release from S-cells leads to the inhibition of stomach acid secretion and activation of the bile acid secretion. PS:Organ duodenum PS:Organ jejunum PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfa5f50a-0fe1-447c-92d3-0249a1a7f68d NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-cfa5f50a-0fe1-447c-92d3-0249a1a7f68d IL27R -> STAT Signaling uuid-cfa5f50a-0fe1-447c-92d3-0249a1a7f68d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfa5f50a-0fe1-447c-92d3-0249a1a7f68d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfacb5b4-b619-4b84-97f8-4e97c882f9a2 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: lung Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-cfacb5b4-b619-4b84-97f8-4e97c882f9a2 NOTCH Receptors -> Receptors Expression Targets in Lung uuid-cfacb5b4-b619-4b84-97f8-4e97c882f9a2 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfacb5b4-b619-4b84-97f8-4e97c882f9a2 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfae980c-27dd-4ce6-8187-75f8ee101c23 NodeType: Pathway Notes: Iodine and hormones released by the hypothalamus and the pituitary gland are primary regulators of thyroid gland function. However, other triggers also may affect the function of thyroid follicular cells leading to decreased secretion of the thyroid hormones, namely, triiodothyronine (T3) and thyroxine (T4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-cfae980c-27dd-4ce6-8187-75f8ee101c23 1_Decreased secretion of thyroid hormones uuid-cfae980c-27dd-4ce6-8187-75f8ee101c23 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfae980c-27dd-4ce6-8187-75f8ee101c23 PS:NodeType Pathway PS:Notes Iodine and hormones released by the hypothalamus and the pituitary gland are primary regulators of thyroid gland function. However, other triggers also may affect the function of thyroid follicular cells leading to decreased secretion of the thyroid hormones, namely, triiodothyronine (T3) and thyroxine (T4). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top most studied mutated genes assotiated with disease Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfb9e822-5a97-4879-a132-6d493c6146b5 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-cfb9e822-5a97-4879-a132-6d493c6146b5 Usher Syndrome Mutated Genes uuid-cfb9e822-5a97-4879-a132-6d493c6146b5 PS:Description Top most studied mutated genes assotiated with disease PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfb9e822-5a97-4879-a132-6d493c6146b5 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfc5990f-298a-4ea6-aba1-7b476df69152 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-cfc5990f-298a-4ea6-aba1-7b476df69152 IL16 -> NF-kB Expression Targets uuid-cfc5990f-298a-4ea6-aba1-7b476df69152 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cfc5990f-298a-4ea6-aba1-7b476df69152 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d01785f7-2b6e-4861-9b31-5be0a2c17dd2 NodeType: Pathway Notes: Dopamine regulates motivated behavior, release of hormones and other biological functions. The effect of dopamine action is dependent upon the types of receptors present on the cell membrane. Organ: generic Organ_System: generic Organ_System: nervous system PMID: 15521361 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-d01785f7-2b6e-4861-9b31-5be0a2c17dd2 Dopamine Receptors Signaling uuid-d01785f7-2b6e-4861-9b31-5be0a2c17dd2 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d01785f7-2b6e-4861-9b31-5be0a2c17dd2 PS:NodeType Pathway PS:Notes Dopamine regulates motivated behavior, release of hormones and other biological functions. The effect of dopamine action is dependent upon the types of receptors present on the cell membrane. PS:Organ generic PS:Organ_System generic PS:Organ_System nervous system PS:PMID 15521361 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d04dbfb2-cecc-4618-bc3d-1be9668fcc09 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: Thrombin (F2) and KITLG cause the selective secretion of IL6 in mast cells without degranulation. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-d04dbfb2-cecc-4618-bc3d-1be9668fcc09 Mast-Cell Activation without Degranulation through KIT/F2R Signaling uuid-d04dbfb2-cecc-4618-bc3d-1be9668fcc09 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d04dbfb2-cecc-4618-bc3d-1be9668fcc09 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: Thrombin (F2) and KITLG cause the selective secretion of IL6 in mast cells without degranulation. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d05fc0b8-dcf6-4fbf-a0ac-9d1be0ed4085 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d05fc0b8-dcf6-4fbf-a0ac-9d1be0ed4085 NSP13 interactions uuid-d05fc0b8-dcf6-4fbf-a0ac-9d1be0ed4085 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d05fc0b8-dcf6-4fbf-a0ac-9d1be0ed4085 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d060d71a-9ec0-4456-8de9-66b886cd8d16 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d060d71a-9ec0-4456-8de9-66b886cd8d16 SARS induces Stress Granule and P-body formation uuid-d060d71a-9ec0-4456-8de9-66b886cd8d16 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d060d71a-9ec0-4456-8de9-66b886cd8d16 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d073003d-bfd1-48f4-a81e-15fbd978f5d8 NodeType: Pathway Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-d073003d-bfd1-48f4-a81e-15fbd978f5d8 ADORA3 -> Mast-Cell Degranulation uuid-d073003d-bfd1-48f4-a81e-15fbd978f5d8 PS:CellType mast cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d073003d-bfd1-48f4-a81e-15fbd978f5d8 PS:NodeType Pathway PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d08c3c51-d19b-4d6a-9761-c6271bfed1f1 NodeType: Pathway Notes: Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located at the uppermost portion of the lateral plasma membrane apical to adherens junctions, and serve to hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each cell surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Junctional adhesion molecules (JAMs) are found at tight junctions of polarized epithelial and endothelial cells. JAMs are characterized by the molecular structure composed of two extracellular immunoglobulin loops, a single transmembrane domain, and a cytoplasmic domain with a PDZ binding motif. In addition, other cell adhesion regulators such as TJP1, CSDA, EPB41, MLLT4, spectrin/fodrin, TJAP1, CGN, CASK, MAGI1, F-actin, and myosin also form plaques near the cytoplasmic domains of JAMs to promote firm adhesions. Outcome effects: The PARD3/PARD6A/ atypical PKC complex that is adjacent to JAMs regulates epithelial polarization. PARD3 regulates tight junction assembly through a PARD6A/ atypical PKC-independent mechanism by regulating RAC1 activation through TIAM1 to induce F-actin/myosin binding and cell adhesion. Atypical PKC and CDC42 regulate vesicular trafficking, organization of the microtubule network, and polarized membrane traffic. The JAMs/CGN complex contributes to the regulation of RHOA signaling and this influences cell migration and cell cycle progression. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-d08c3c51-d19b-4d6a-9761-c6271bfed1f1 Tight Junction Assembly (JAMs) uuid-d08c3c51-d19b-4d6a-9761-c6271bfed1f1 PS:CellType generic PS:Description Junctions between adjacent cells may be gap junctions, desmosomes, adherens junctions, or tight junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d08c3c51-d19b-4d6a-9761-c6271bfed1f1 PS:NodeType Pathway PS:Notes Headnote: Junctions between adjacent cells include gap junctions, desmosomes, adherens junctions, or tight junctions. The tight junctions are located at the uppermost portion of the lateral plasma membrane apical to adherens junctions, and serve to hold cells together, act as a barrier, and prevent the lateral diffusion of membrane proteins between the apical and lateral/basal surfaces which allows the specialized functions of each cell surface, endocytosis at the apical surface and exocytosis at the basolateral surface, to be preserved. Signaling description: Tight junctions are represented by linear co-polymerized molecules of occluding, claudins, and junctional adhesion molecules that have a high affinity for the C-terminal sequences of PDZ domain-containing cytoplasmic proteins. Junctional adhesion molecules (JAMs) are found at tight junctions of polarized epithelial and endothelial cells. JAMs are characterized by the molecular structure composed of two extracellular immunoglobulin loops, a single transmembrane domain, and a cytoplasmic domain with a PDZ binding motif. In addition, other cell adhesion regulators such as TJP1, CSDA, EPB41, MLLT4, spectrin/fodrin, TJAP1, CGN, CASK, MAGI1, F-actin, and myosin also form plaques near the cytoplasmic domains of JAMs to promote firm adhesions. Outcome effects: The PARD3/PARD6A/ atypical PKC complex that is adjacent to JAMs regulates epithelial polarization. PARD3 regulates tight junction assembly through a PARD6A/ atypical PKC-independent mechanism by regulating RAC1 activation through TIAM1 to induce F-actin/myosin binding and cell adhesion. Atypical PKC and CDC42 regulate vesicular trafficking, organization of the microtubule network, and polarized membrane traffic. The JAMs/CGN complex contributes to the regulation of RHOA signaling and this influences cell migration and cell cycle progression. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell CellType: smooth muscle myocyte Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d08faa22-f6fc-4f83-a3fb-ccc4255e0879 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-d08faa22-f6fc-4f83-a3fb-ccc4255e0879 SARS+>blood clotting uuid-d08faa22-f6fc-4f83-a3fb-ccc4255e0879 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d08faa22-f6fc-4f83-a3fb-ccc4255e0879 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Ethanol is metabolized in the liver to produce acetaldehyde followed by acetate with the consumption of NAD and production of NADH. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0ac8fc0-e529-4898-827b-49c8dc70149f NodeType: Pathway Notes: Headnote: Ethanol is metabolized in the liver to produce acetaldehyde and then acetate with the consumption of NAD and production of NADH. Signaling description: Therefore, in the case of systematic alcohol abuse, the pool of NAD is exhausted, while NADH concentration increases. This shifts the equilibrium in many metabolic reactions. Outcome effects: In particular, this results in the inversion of lipid beta-oxidation and promotes the biosynthesis of triacylglycerols. Conversely, in mitochondria, acetaldehyde promotes ROS production and this leads to lipid peroxidation. The overproduction of NADH also promotes lactate synthesis and accumulation which provides the condition for acidosis. Moreover, it is known that in hepatocytes, ethanol upregulates TGFB1 pathway, which induces collagen and fibronectin (FN1) production leading to fibrosis. Highlighted proteins: Entities with elevated level are highlighted in red. Organ: liver Organ_System: digestive system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-d0ac8fc0-e529-4898-827b-49c8dc70149f Ethanol Induced Hepatotoxicity uuid-d0ac8fc0-e529-4898-827b-49c8dc70149f PS:CellType hepatocyte PS:Description Ethanol is metabolized in the liver to produce acetaldehyde followed by acetate with the consumption of NAD and production of NADH. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0ac8fc0-e529-4898-827b-49c8dc70149f PS:NodeType Pathway PS:Notes Headnote: Ethanol is metabolized in the liver to produce acetaldehyde and then acetate with the consumption of NAD and production of NADH. Signaling description: Therefore, in the case of systematic alcohol abuse, the pool of NAD is exhausted, while NADH concentration increases. This shifts the equilibrium in many metabolic reactions. Outcome effects: In particular, this results in the inversion of lipid beta-oxidation and promotes the biosynthesis of triacylglycerols. Conversely, in mitochondria, acetaldehyde promotes ROS production and this leads to lipid peroxidation. The overproduction of NADH also promotes lactate synthesis and accumulation which provides the condition for acidosis. Moreover, it is known that in hepatocytes, ethanol upregulates TGFB1 pathway, which induces collagen and fibronectin (FN1) production leading to fibrosis. Highlighted proteins: Entities with elevated level are highlighted in red. PS:Organ liver PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0e59d8b-d970-4dfd-8c3d-30344b725542 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-d0e59d8b-d970-4dfd-8c3d-30344b725542 CHRNA7 -> IL8 Production uuid-d0e59d8b-d970-4dfd-8c3d-30344b725542 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0e59d8b-d970-4dfd-8c3d-30344b725542 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Mutations in genes responsible for cell cycle transition cause uncontrolled cancer cell proliferation Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0f76646-a8fd-4fda-ab10-67df8b36f06d NodeType: Pathway Notes: Headnote: The G0/G1 cell cycle transition phase is the transition from quiescence to interphase. Mutations in genes responsible for cell cycle transition are common in cancers and cause uncontrolled malignant cell proliferation. Signaling description: Cyclin D1 (CCND1), cyclin-dependent kinases and E2F1/2/3 transcription factors are activated due to mutations or amplifications. Cyclin-dependent kinase inhibitors and RB1 are inactivated due to mutations or have decreased expression. Many viral proteins promote oncogenesis through the activation of cell cycle machinery, including the adenovirus protein E1A, polyomavirus large T antigen, KSHV protein ORF72, HPV Protein HPV16-E7. Outcome effects: Cyclins CCNA1/2, CCNE1/2 and cyclin-dependent kinase 2 (CDK2) are activated promoting uncontrolled cell proliferation. Animal data: The experimental data were obtained both from animal models and human cancer cell lines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Proteins with decreased expression or activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: E1A, large T antigen, ORF72, HPV16-E7 shown in grey are viral proteins. Organ: oncogenic Organ_System: oncogenic PMID: 19851314 PMID: 21734724 PMID: 23842645 PMID: 23934193 PMID: 26315616 PMID: 26658964 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-d0f76646-a8fd-4fda-ab10-67df8b36f06d G0/G1 Cell Cycle Phase Transition Activation in Cancer uuid-d0f76646-a8fd-4fda-ab10-67df8b36f06d PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Mutations in genes responsible for cell cycle transition cause uncontrolled cancer cell proliferation PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0f76646-a8fd-4fda-ab10-67df8b36f06d PS:NodeType Pathway PS:Notes Headnote: The G0/G1 cell cycle transition phase is the transition from quiescence to interphase. Mutations in genes responsible for cell cycle transition are common in cancers and cause uncontrolled malignant cell proliferation. Signaling description: Cyclin D1 (CCND1), cyclin-dependent kinases and E2F1/2/3 transcription factors are activated due to mutations or amplifications. Cyclin-dependent kinase inhibitors and RB1 are inactivated due to mutations or have decreased expression. Many viral proteins promote oncogenesis through the activation of cell cycle machinery, including the adenovirus protein E1A, polyomavirus large T antigen, KSHV protein ORF72, HPV Protein HPV16-E7. Outcome effects: Cyclins CCNA1/2, CCNE1/2 and cyclin-dependent kinase 2 (CDK2) are activated promoting uncontrolled cell proliferation. Animal data: The experimental data were obtained both from animal models and human cancer cell lines. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Proteins with decreased expression or activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Description of viral proteins: E1A, large T antigen, ORF72, HPV16-E7 shown in grey are viral proteins. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 19851314 PS:PMID 21734724 PS:PMID 23842645 PS:PMID 23934193 PS:PMID 26315616 PS:PMID 26658964 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Classical phenylketonuria (PKU) is inherited in a strictly autosomal recessive manner and is the result of mutations in the PAH gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0f82c2d-12ea-4d23-afcd-b15ee3ebea7d NodeType: Pathway Notes: Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. Signaling description: The conversion of L-phenylalanine to L-tyrosine catalyzed by PAH requires a tetrahydrobiopterin cofactor which converts to dihydrobiopterin in the reaction. Dihydrobiopterin is recycled to tetrahydrobiopterin by the enzyme ihydropteridine reductase (QDPR). Tetrahydrobiopterin deficiency caused by a lack of function mutation in the QDPR gene results in tetrahydrobiopterin-deficient hyperphenylalaninemia. Elevated intracellular L-phenylalanine is metabolized by different routes. First, it can be converted to phenylacetate by the consequential action of DDC and MAOB. Secondly, it can be converted to phenylpyruvate by aromatic-amino-acid-glyoxylate transaminase. Outcome effects: Phenylpyruvate enters neurons where it exerts its toxic effect. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: liver Organ_System: digestive system PMID: 11043156 PMID: 20123477 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d0f82c2d-12ea-4d23-afcd-b15ee3ebea7d Phenylalanine Metabolism Disruption in Phenylketonuria uuid-d0f82c2d-12ea-4d23-afcd-b15ee3ebea7d PS:CellType hepatocyte PS:Description Classical phenylketonuria (PKU) is inherited in a strictly autosomal recessive manner and is the result of mutations in the PAH gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d0f82c2d-12ea-4d23-afcd-b15ee3ebea7d PS:NodeType Pathway PS:Notes Headnote: Phenylketonuria (PKU) is an inherited disorder characterized by increased levels of phenylalanine in the blood. Classical PKU is inherited in a strictly autosomal recessive manner and results from mutations in the PAH (phenylalanine hydroxylase) gene. PAH is responsible for the conversion of L-phenylalanine to L-tyrosine. Low levels of PAH result in the accumulation of dietary phenylalanine in the blood. PKU if left untreated leads to intellectual disability, seizures and behavioral problems. Brain dysfunction in PKU occurs due to phenylalanine toxicity to neurons. Signaling description: The conversion of L-phenylalanine to L-tyrosine catalyzed by PAH requires a tetrahydrobiopterin cofactor which converts to dihydrobiopterin in the reaction. Dihydrobiopterin is recycled to tetrahydrobiopterin by the enzyme ihydropteridine reductase (QDPR). Tetrahydrobiopterin deficiency caused by a lack of function mutation in the QDPR gene results in tetrahydrobiopterin-deficient hyperphenylalaninemia. Elevated intracellular L-phenylalanine is metabolized by different routes. First, it can be converted to phenylacetate by the consequential action of DDC and MAOB. Secondly, it can be converted to phenylpyruvate by aromatic-amino-acid-glyoxylate transaminase. Outcome effects: Phenylpyruvate enters neurons where it exerts its toxic effect. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 11043156 PS:PMID 20123477 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Diabetic neuropathy (DN) is a major complication in diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1202542-f532-4876-a65f-2b463b65fe25 NodeType: Pathway Notes: Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. DN is characterized by microvascular injury which involves small blood vessels which supply the nerves (vasa nervorum) and results from chronic hyperglycemia. Microangiopathy is a major initiating factor in the pathogenesis of nerve ischemia. Signaling description: Endothelial dysfunction has been implicated as a key mechanism for chronic microangiopathy in diabetic patients. High intracellular glucose causes the formation of diacylglycerol and activates PRKCB which stimulates AKT1. In addition, high extracellular glucose induces the formation of advanced glycation end products (AGEs). AGEs activate advanced glycosylation end product-specific receptor (AGER), which stimulates mitogen-activated protein kinase (MAPK) pathway and activates AKT1/NF-kB signaling pathway via PI3K. Outcome effects: The activation of these pathways leads to the overexpression of VEGFA, TGFB1, adhesion molecules (ICAM1 and VCAM1), interleukins (IL6, IL1A), and endothelin 1 (EDN1). TGFB1 and VEGFA increase blood vessel permeability and endothelial cell proliferation. Further, ICAM1 and VCAM1 mediate leukocyte-endothelial cell adhesion; while, interleukins mediate macrophage chemotaxis. Finally, EDN1 is responsible for vasoconstriction which results in microangiopathy. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ_System: nervous system PMID: 18616962 PMID: 24954624 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-d1202542-f532-4876-a65f-2b463b65fe25 Microangiopathy in Diabetic Neuropathy uuid-d1202542-f532-4876-a65f-2b463b65fe25 PS:CellType neuron PS:Description Diabetic neuropathy (DN) is a major complication in diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1202542-f532-4876-a65f-2b463b65fe25 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus is the leading cause of diabetic neuropathy (DN), resulting in significant morbidity and increased mortality. DN is characterized by a progressive loss of nerve fiber function. Clinically peripheral DN is characterized by pain or burning sensations, numbness, or tingling of limbs. DN is implicated in 50-75% of non-traumatic amputations. DN is characterized by microvascular injury which involves small blood vessels which supply the nerves (vasa nervorum) and results from chronic hyperglycemia. Microangiopathy is a major initiating factor in the pathogenesis of nerve ischemia. Signaling description: Endothelial dysfunction has been implicated as a key mechanism for chronic microangiopathy in diabetic patients. High intracellular glucose causes the formation of diacylglycerol and activates PRKCB which stimulates AKT1. In addition, high extracellular glucose induces the formation of advanced glycation end products (AGEs). AGEs activate advanced glycosylation end product-specific receptor (AGER), which stimulates mitogen-activated protein kinase (MAPK) pathway and activates AKT1/NF-kB signaling pathway via PI3K. Outcome effects: The activation of these pathways leads to the overexpression of VEGFA, TGFB1, adhesion molecules (ICAM1 and VCAM1), interleukins (IL6, IL1A), and endothelin 1 (EDN1). TGFB1 and VEGFA increase blood vessel permeability and endothelial cell proliferation. Further, ICAM1 and VCAM1 mediate leukocyte-endothelial cell adhesion; while, interleukins mediate macrophage chemotaxis. Finally, EDN1 is responsible for vasoconstriction which results in microangiopathy. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ_System nervous system PS:PMID 18616962 PS:PMID 24954624 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell CellType: retinal rod photoreceptor cell Description: Netrin-1 (NTN1) was shown to make impact in age-related macular degeneration via activation of DCC / cAMP / PRKAR2B / Ca2 / calcineurin / NFAT3 axis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d16da759-a49d-4fbf-af5f-031c3201e081 NodeType: Pathway Notes: Netrin-1 (NTN1) was shown to make impact in age-related macular degeneration via activation of DCC/cAMP/PRKAR2B/Ca2+ /calcineurin/NFAT3 axis. NFAT was shown to control expression of pro-angiogenic VEGA and FLT1 and matrix metallopeptidases 2 and 9 (MMP2 and 9), which contribute to degradation of Bruch's membrane. Organ: eye Organ_System: sensory system PMID: 24052639 PMID: 25950802 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d16da759-a49d-4fbf-af5f-031c3201e081 Netrin-1 Signaling in Age-Related Macular Degeneration uuid-d16da759-a49d-4fbf-af5f-031c3201e081 PS:CellType epithelial cell PS:CellType retinal rod photoreceptor cell PS:Description Netrin-1 (NTN1) was shown to make impact in age-related macular degeneration via activation of DCC / cAMP / PRKAR2B / Ca2 / calcineurin / NFAT3 axis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d16da759-a49d-4fbf-af5f-031c3201e081 PS:NodeType Pathway PS:Notes Netrin-1 (NTN1) was shown to make impact in age-related macular degeneration via activation of DCC/cAMP/PRKAR2B/Ca2+ /calcineurin/NFAT3 axis. NFAT was shown to control expression of pro-angiogenic VEGA and FLT1 and matrix metallopeptidases 2 and 9 (MMP2 and 9), which contribute to degradation of Bruch's membrane. PS:Organ eye PS:Organ_System sensory system PS:PMID 24052639 PS:PMID 25950802 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d17c6727-f60f-4196-8a8f-1bd26ea39238 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d17c6727-f60f-4196-8a8f-1bd26ea39238 Molting hormone biosynthesis template uuid-d17c6727-f60f-4196-8a8f-1bd26ea39238 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d17c6727-f60f-4196-8a8f-1bd26ea39238 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1a8fa6d-2f9f-42f3-adce-dc63620c7b67 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-d1a8fa6d-2f9f-42f3-adce-dc63620c7b67 Proteins Involved in Glioma uuid-d1a8fa6d-2f9f-42f3-adce-dc63620c7b67 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1a8fa6d-2f9f-42f3-adce-dc63620c7b67 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Several members of single-strand base excision DNA repair machinery can be mutated and dysregulated in cancer. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1c75a4f-5fe4-44b1-a344-3046d3cfe805 NodeType: Pathway Notes: Headnote: Several members of single-strand base excision DNA repair machinery can be mutated and dysregulated in cancer including MUTYH, OGG1, POLB/E, FEN1. UNG can be down-regulated by MIR16-1/34C. Signaling description: Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of a DNA base itself. BER facilitates the repair of damaged DNA via two general pathways including short-patch and long-patch, both of which are initiated by a DNA glycosylase. These DNA glycosylases specifically hydrolyze the N-glycosylic bond of the target base which causes the release of the ineligible base while keeping the sugar phosphate backbone of the DNA intact. Glycosylase action creates an apurinic/apyrimidinic site (AP) or abasic site, which is processed by APEX1, which cleaves the phosphodiester backbone immediately 5' to the AP site, resulting in a 3' hydroxyl group and a transient 5' abasic deoxyribose phosphate (dRP). In the short-patch pathway, the removal of the dRP is accomplished by the action of POLB which adds one nucleotide to the 3' end of the nick and removes the dRP moiety through its associated AP lyase activity. The integrity of the DNA is then restored by DNA ligase (LIG3) which seals the strand nick. POLB and LIG3 are brought together at the site of repair by means of XRCC1 that acts as a scaffold protein. In the long-patch pathway, DNA synthesis of multiple nucleotides occurs and the displaced oligonucleotide is removed by the FEN1 endonuclease. The strand integrity is finally restored by a DNA ligase (LIG1). Outcome effects: The deregulation of single-strand base excision DNA repair machinery leads to genomic instability in cancer cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20965415 PMID: 24947262 PMID: 25017190 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-d1c75a4f-5fe4-44b1-a344-3046d3cfe805 Single Strand Base Excision DNA Repair Impairment in Cancer uuid-d1c75a4f-5fe4-44b1-a344-3046d3cfe805 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Several members of single-strand base excision DNA repair machinery can be mutated and dysregulated in cancer. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1c75a4f-5fe4-44b1-a344-3046d3cfe805 PS:NodeType Pathway PS:Notes Headnote: Several members of single-strand base excision DNA repair machinery can be mutated and dysregulated in cancer including MUTYH, OGG1, POLB/E, FEN1. UNG can be down-regulated by MIR16-1/34C. Signaling description: Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to deamination, oxidation, alkylation, or spontaneous loss of a DNA base itself. BER facilitates the repair of damaged DNA via two general pathways including short-patch and long-patch, both of which are initiated by a DNA glycosylase. These DNA glycosylases specifically hydrolyze the N-glycosylic bond of the target base which causes the release of the ineligible base while keeping the sugar phosphate backbone of the DNA intact. Glycosylase action creates an apurinic/apyrimidinic site (AP) or abasic site, which is processed by APEX1, which cleaves the phosphodiester backbone immediately 5' to the AP site, resulting in a 3' hydroxyl group and a transient 5' abasic deoxyribose phosphate (dRP). In the short-patch pathway, the removal of the dRP is accomplished by the action of POLB which adds one nucleotide to the 3' end of the nick and removes the dRP moiety through its associated AP lyase activity. The integrity of the DNA is then restored by DNA ligase (LIG3) which seals the strand nick. POLB and LIG3 are brought together at the site of repair by means of XRCC1 that acts as a scaffold protein. In the long-patch pathway, DNA synthesis of multiple nucleotides occurs and the displaced oligonucleotide is removed by the FEN1 endonuclease. The strand integrity is finally restored by a DNA ligase (LIG1). Outcome effects: The deregulation of single-strand base excision DNA repair machinery leads to genomic instability in cancer cells. Highlighted proteins: Proteins with red highlights have increased expression/activity. Proteins with blue highlight have decreased expression / activity. See pathway "Proteins with Altered Expression Associated with Impaired DNA Repair in Cancer" for details. Mutated proteins: Mutated proteins are shown in white-out style. See pathway "Genes with Mutation Associated with Impaired DNA Repair in Cancer" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20965415 PS:PMID 24947262 PS:PMID 25017190 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1d87fa3-e40b-408d-956b-e71f3731f963 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-d1d87fa3-e40b-408d-956b-e71f3731f963 Lymphangiogenesis uuid-d1d87fa3-e40b-408d-956b-e71f3731f963 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1d87fa3-e40b-408d-956b-e71f3731f963 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Cystic Kidney Disease (CKD) is a group of genetic diseases in which multiple cysts are formed in the kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1e51ab8-6fa7-4ccc-a075-8dafc8342282 NodeType: Pathway Notes: Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Medullary Sponge Kidney (MSK), Nephronophthisis. Hereditary factors account for the majority of CKD types. ADPKD and ARPKD are the two most common types of CKD with different modes of inheritance. Nephronophthisis is a rare autosomal recessive disorder; however, it is the most frequent monogenic cause of the end stage renal disease in children. Pathology of CKD may be related to defects in planar cell polarity. Signaling description: Mutations in PKD1/2 and PKHD1 genes are associated with ADPKD and ARPKD. Mutations in the INVS gene are associated with nephronophthisis. Both PKD1 and INVS proteins interact with the WNT-signaling pathway leading to cyst formation and renal disease. Precise molecular mechanisms of this process are largely unknown. One of hypotheses is depicted on the pathway. The canonical WNT-signaling pathway initiates when WNT4/5A binds to FZD4 receptor in the presence of LRP5/6, resulting in the activation of DVL1/2. The destruction complex comprising GSK3ß, APC, Axin and CK1 proteins is inhibited by DVL1/2. When this pathway is inactive, the destruction complex targets CTNNB1 for proteosomal degradation. When the pathway is active, such destruction is inhibited, resulting in the accumulation of CTNNB1 in the cytosol with subsequent transcriptional activation of target genes. The non-canonical WNT-pathway initiates when WNT4/5A/9B/11 binds to FZD3/4/5/6 receptors leading to the activation of DVL1/2/3, RHOA, RAC1 and downstream signaling cascade, resulting in cytoskeletal rearrangements and cell polarity regulation. Outcome effects: In the kidney, the interaction of INVS and PKD1 with CTNNB1 functions as a molecular switch between the WNT-signaling pathways. The impaired balance between the WNT/ß-catenin and non-canonical WNT-pathways disturbs planar cell polarity and causes cyst formation. Mutated proteins: Mutated PKD1, PKD2, PKHD1, and INVS are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 14992727 PMID: 15640349 PMID: 22016823 PMID: 23652676 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-d1e51ab8-6fa7-4ccc-a075-8dafc8342282 WNT Signaling in Cystic Kidney Disease uuid-d1e51ab8-6fa7-4ccc-a075-8dafc8342282 PS:CellType epithelial cell PS:Description Cystic Kidney Disease (CKD) is a group of genetic diseases in which multiple cysts are formed in the kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1e51ab8-6fa7-4ccc-a075-8dafc8342282 PS:NodeType Pathway PS:Notes Headnote: Cystic Kidney Disease (CKD) refers to a large group of diseases in which abnormal cysts are formed in the kidneys. The cysts interfere with normal kidney function and may cause kidney failure. CKD includes Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Medullary Sponge Kidney (MSK), Nephronophthisis. Hereditary factors account for the majority of CKD types. ADPKD and ARPKD are the two most common types of CKD with different modes of inheritance. Nephronophthisis is a rare autosomal recessive disorder; however, it is the most frequent monogenic cause of the end stage renal disease in children. Pathology of CKD may be related to defects in planar cell polarity. Signaling description: Mutations in PKD1/2 and PKHD1 genes are associated with ADPKD and ARPKD. Mutations in the INVS gene are associated with nephronophthisis. Both PKD1 and INVS proteins interact with the WNT-signaling pathway leading to cyst formation and renal disease. Precise molecular mechanisms of this process are largely unknown. One of hypotheses is depicted on the pathway. The canonical WNT-signaling pathway initiates when WNT4/5A binds to FZD4 receptor in the presence of LRP5/6, resulting in the activation of DVL1/2. The destruction complex comprising GSK3ß, APC, Axin and CK1 proteins is inhibited by DVL1/2. When this pathway is inactive, the destruction complex targets CTNNB1 for proteosomal degradation. When the pathway is active, such destruction is inhibited, resulting in the accumulation of CTNNB1 in the cytosol with subsequent transcriptional activation of target genes. The non-canonical WNT-pathway initiates when WNT4/5A/9B/11 binds to FZD3/4/5/6 receptors leading to the activation of DVL1/2/3, RHOA, RAC1 and downstream signaling cascade, resulting in cytoskeletal rearrangements and cell polarity regulation. Outcome effects: In the kidney, the interaction of INVS and PKD1 with CTNNB1 functions as a molecular switch between the WNT-signaling pathways. The impaired balance between the WNT/ß-catenin and non-canonical WNT-pathways disturbs planar cell polarity and causes cyst formation. Mutated proteins: Mutated PKD1, PKD2, PKHD1, and INVS are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 14992727 PS:PMID 15640349 PS:PMID 22016823 PS:PMID 23652676 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1fb3b70-6e68-4fb6-851f-03909de6a89c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d1fb3b70-6e68-4fb6-851f-03909de6a89c FASLG Expression Targets uuid-d1fb3b70-6e68-4fb6-851f-03909de6a89c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d1fb3b70-6e68-4fb6-851f-03909de6a89c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d211807a-496f-45bf-b9f9-52b33e78f01a NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-d211807a-496f-45bf-b9f9-52b33e78f01a HTR4/6/7 -> Cation Channels uuid-d211807a-496f-45bf-b9f9-52b33e78f01a PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d211807a-496f-45bf-b9f9-52b33e78f01a PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte CellType: striated muscle cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2307771-97bc-416d-bb33-5b21658f8538 NodeType: Pathway Notes: The sarcomere this the force-generating structure in cardiomyocytes. The sarcomere is comprised of several proteins, including cardiac actin (encoded by ACTC1), myosin-binding protein C (MYBPC3), myosin heavy chains (MYH6, MYH7), myosin light chains (MYL2). Organ: heart Organ_System: cardiovascular system PMID: 23900355 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-d2307771-97bc-416d-bb33-5b21658f8538 Sarcomere in Cardiomyocyte in Dilated Cardiomyopathy uuid-d2307771-97bc-416d-bb33-5b21658f8538 PS:CellType cardiac myocyte PS:CellType striated muscle cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2307771-97bc-416d-bb33-5b21658f8538 PS:NodeType Pathway PS:Notes The sarcomere this the force-generating structure in cardiomyocytes. The sarcomere is comprised of several proteins, including cardiac actin (encoded by ACTC1), myosin-binding protein C (MYBPC3), myosin heavy chains (MYH6, MYH7), myosin light chains (MYL2). PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 23900355 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d24a7278-5e0f-495d-9a9b-76d6e0bed05d NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-d24a7278-5e0f-495d-9a9b-76d6e0bed05d Proteins Involved in Cystic Kidney Disease uuid-d24a7278-5e0f-495d-9a9b-76d6e0bed05d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d24a7278-5e0f-495d-9a9b-76d6e0bed05d PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d24ae446-d30a-41b5-bbc5-951d51e310aa NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-d24ae446-d30a-41b5-bbc5-951d51e310aa Rett Syndrome Clinical Trials uuid-d24ae446-d30a-41b5-bbc5-951d51e310aa PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d24ae446-d30a-41b5-bbc5-951d51e310aa PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d26a07a9-fd93-46e3-8ee5-a51e07286d0f NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-d26a07a9-fd93-46e3-8ee5-a51e07286d0f Proteins Involved in Frontotemporal Dementia uuid-d26a07a9-fd93-46e3-8ee5-a51e07286d0f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d26a07a9-fd93-46e3-8ee5-a51e07286d0f PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2988c94-bd8d-4a2b-982a-b5a29d9c16cc NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d2988c94-bd8d-4a2b-982a-b5a29d9c16cc Ubiquinone-7 biosynthesis template uuid-d2988c94-bd8d-4a2b-982a-b5a29d9c16cc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2988c94-bd8d-4a2b-982a-b5a29d9c16cc PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2bec693-2228-49c2-88bd-a6af74632639 NodeType: Pathway Organ_System: reproductive system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d2bec693-2228-49c2-88bd-a6af74632639 Genes with Mutations Associated with Testicular Male Infertility uuid-d2bec693-2228-49c2-88bd-a6af74632639 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2bec693-2228-49c2-88bd-a6af74632639 PS:NodeType Pathway PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2bff055-fdc4-4928-a024-c405d602d1e1 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-d2bff055-fdc4-4928-a024-c405d602d1e1 TCR -> AP-1 Expression Targets uuid-d2bff055-fdc4-4928-a024-c405d602d1e1 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2bff055-fdc4-4928-a024-c405d602d1e1 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The vesicle docking is a step of exocytosis which represents the molecular interactions underlying the tight association of a vesicle with its target membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2c09b71-bd2c-4def-9d98-437794c637d0 NodeType: Pathway Notes: Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. During vesicle docking, the two membranes are held within a bilayer's distance of one another. Signaling description: Vesicle docking includes molecular interactions underlying the close and tight association of a vesicle with its target and may include the molecular rearrangements needed to trigger bilayer fusion. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex. SNARE proteins (soluble NSF attachment receptor) can be divided into two categories: vesicle or v-SNAREs, which are incorporated into the membranes of transport vesicles (synaptobrevin or VAMPs), and target or t-SNAREs, which are located in the membranes of target compartments (syntaxin 1 or STX1A and SNAP25). The described mechanism of the molecular signaling is known in general terms and is described on the pathway. Outcome effects: Assembly of the SNAREs into the ""trans"" complexes likely bridges the opposing membranes belonging to cell and secretory granule, bringing them in proximity and inducing their fusion. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 17110340 PMID: 24363652 PMID: 26498108 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-d2c09b71-bd2c-4def-9d98-437794c637d0 Exocytosis: Vesicle Docking uuid-d2c09b71-bd2c-4def-9d98-437794c637d0 PS:CellType generic PS:Description The vesicle docking is a step of exocytosis which represents the molecular interactions underlying the tight association of a vesicle with its target membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2c09b71-bd2c-4def-9d98-437794c637d0 PS:NodeType Pathway PS:Notes Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. During vesicle docking, the two membranes are held within a bilayer's distance of one another. Signaling description: Vesicle docking includes molecular interactions underlying the close and tight association of a vesicle with its target and may include the molecular rearrangements needed to trigger bilayer fusion. Docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex. SNARE proteins (soluble NSF attachment receptor) can be divided into two categories: vesicle or v-SNAREs, which are incorporated into the membranes of transport vesicles (synaptobrevin or VAMPs), and target or t-SNAREs, which are located in the membranes of target compartments (syntaxin 1 or STX1A and SNAP25). The described mechanism of the molecular signaling is known in general terms and is described on the pathway. Outcome effects: Assembly of the SNAREs into the ""trans"" complexes likely bridges the opposing membranes belonging to cell and secretory granule, bringing them in proximity and inducing their fusion. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17110340 PS:PMID 24363652 PS:PMID 26498108 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2e435e9-8c79-4680-b559-0c5a6bf6addc NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-d2e435e9-8c79-4680-b559-0c5a6bf6addc VEGFR -> FOXO3A Signaling uuid-d2e435e9-8c79-4680-b559-0c5a6bf6addc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2e435e9-8c79-4680-b559-0c5a6bf6addc PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: The activation of autoreactive CD8 T-lymphocytes in type1 diabetes mellitus occurs by T-cell receptor (TCR) recognition of self-determinants. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2e5efde-15d2-4210-9edf-0924bd40d545 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type diabetes. Signaling description: The activation of autoreactive CD8 T-lymphocytes in type1 diabetes mellitus occurs by T-cell receptor (TCR) recognition of self-determinants. A viral infection may initiate an autoimmune reaction against pancreatic beta-cells and trigger type 1 diabetes mellitus. TCR, which consists of TRA@, TRB@, CD3E, CD3D, CD3G, CD247, and FCER1G, interacts with MHC class I protein complex of the host cell containing self-antigens. The coreceptor, CD8A is necessary for the successful T-cell activation. After binding to an antigen, LCK and intracellular TCR domains phosphorylate and activate ZAP70. ZAP70 transduces the signal to PLCG1 through LAT. Outcome effects: PLCG1 is responsible for the bulk of antigen-stimulated IP3 production in T-cells. IP3 provokes calcium efflux from endoplasmic reticulum and interacts with calmodulin-calcineurin resulting in NF-AT activation. NF-AT is a transcription factor for IFNG and FASLG which are the main T-cell produced substances involved in T-cell killing mechanisms. PMID: 15035967 PMID: 19111164 PMID: 19693476 PMID: 21181304 PMID: 9609134 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d2e5efde-15d2-4210-9edf-0924bd40d545 CD8+ T-Cell Response to Self-Determinants in Diabetes uuid-d2e5efde-15d2-4210-9edf-0924bd40d545 PS:CellType T-cell PS:Description The activation of autoreactive CD8 T-lymphocytes in type1 diabetes mellitus occurs by T-cell receptor (TCR) recognition of self-determinants. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d2e5efde-15d2-4210-9edf-0924bd40d545 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type diabetes. Signaling description: The activation of autoreactive CD8 T-lymphocytes in type1 diabetes mellitus occurs by T-cell receptor (TCR) recognition of self-determinants. A viral infection may initiate an autoimmune reaction against pancreatic beta-cells and trigger type 1 diabetes mellitus. TCR, which consists of TRA@, TRB@, CD3E, CD3D, CD3G, CD247, and FCER1G, interacts with MHC class I protein complex of the host cell containing self-antigens. The coreceptor, CD8A is necessary for the successful T-cell activation. After binding to an antigen, LCK and intracellular TCR domains phosphorylate and activate ZAP70. ZAP70 transduces the signal to PLCG1 through LAT. Outcome effects: PLCG1 is responsible for the bulk of antigen-stimulated IP3 production in T-cells. IP3 provokes calcium efflux from endoplasmic reticulum and interacts with calmodulin-calcineurin resulting in NF-AT activation. NF-AT is a transcription factor for IFNG and FASLG which are the main T-cell produced substances involved in T-cell killing mechanisms. PS:PMID 15035967 PS:PMID 19111164 PS:PMID 19693476 PS:PMID 21181304 PS:PMID 9609134 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:NodeType PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Source: Atlas urn:agi-pathway:uuid-d307d943-c7e9-4733-853d-eb13336d39d8 1_levothyroxine clinical effects uuid-d307d943-c7e9-4733-853d-eb13336d39d8 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d30b5808-7b41-4e2b-b9ac-28c5d0712f76 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Pathological Process urn:agi-pathway:uuid-d30b5808-7b41-4e2b-b9ac-28c5d0712f76 Chemoresistance uuid-d30b5808-7b41-4e2b-b9ac-28c5d0712f76 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d30b5808-7b41-4e2b-b9ac-28c5d0712f76 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3195467-38ce-4c88-854b-e36a2ace226b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-d3195467-38ce-4c88-854b-e36a2ace226b ROS+>Apoptosis uuid-d3195467-38ce-4c88-854b-e36a2ace226b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3195467-38ce-4c88-854b-e36a2ace226b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:ObjectType PS:ParentFolder PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d325d20a-d15b-4a16-ad7c-060a107fa62e NodeType: Pathway ObjectType: Pathway ParentFolder: Panic Disorder PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-d325d20a-d15b-4a16-ad7c-060a107fa62e Panic Disorder: Posible Action of CO2 in Panic Attack Induction uuid-d325d20a-d15b-4a16-ad7c-060a107fa62e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d325d20a-d15b-4a16-ad7c-060a107fa62e PS:NodeType Pathway PS:ObjectType Pathway PS:ParentFolder Panic Disorder PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d347fc92-b247-43e8-afa1-cd5ed840a537 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-d347fc92-b247-43e8-afa1-cd5ed840a537 ADRA1 -> Prostaglandin Generation uuid-d347fc92-b247-43e8-afa1-cd5ed840a537 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d347fc92-b247-43e8-afa1-cd5ed840a537 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d36eb577-6267-459c-9142-870b5e765e60 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d36eb577-6267-459c-9142-870b5e765e60 TLR5 Expression Targets uuid-d36eb577-6267-459c-9142-870b5e765e60 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d36eb577-6267-459c-9142-870b5e765e60 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Mutagenic activation of the MAPK pathway is observed in up to 90 percent of melanoma cases and is achieved via mutations in NRAS or BRAF. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d38c1912-08a7-409a-9d3d-efbab6c67287 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Dysregulation of cell cycle is a key point in melanomagenesis. Signaling description: Many melanocytic signaling pathways are initiated through the activation of the KIT receptor, which in turn triggers MAPK and PI3K pathways activation. Notably, KIT aberrations are found in 28-39% of melanoma cases, while the mutagenic activation of the MAPK pathway is observed in up to 90% of melanoma cases and is most commonly achieved via mutations in NRAS or BRAF. The latter occur at the stage of the benign nevus. As a result, constant MAPK activation drives cell cycle progression. MAPK may also be activated via UV/ROS-induced PKC-activation. In addition, 43-50% of melanoma cases have selective constitutive activity in AKT3 due to a mutation or gene amplification. Furthermore, CDKN2A and CDK4 mutations are associated with the familial form of melanoma, while CCND1 and CDKN2B may be sporadically mutated. Lastly, MITF directly binds to the promoter regions of CDKN2A, CDKN1A, and CCND1 and positively regulates their transcription. Outcome effects: Defects in cell cycle checkpoint control are associated with the pathogenesis of melanoma. As a result of NRAS and BRAF gene mutations frequently found in melanoma cells, constant MAPK activation drives cell cycle progression. Genes directly involved in cell cycle G1-S transition including CDKN2A, CDK4, CCND1, and CDKN2B are often mutated in melanoma. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Genes mutated in melanoma are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 16822996 PMID: 18927540 PMID: 19571822 PMID: 20067521 PMID: 20629085 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d38c1912-08a7-409a-9d3d-efbab6c67287 Cell Cycle Dysregulation in Melanoma uuid-d38c1912-08a7-409a-9d3d-efbab6c67287 PS:CellType cancer cell PS:CellType melanocyte PS:Description Mutagenic activation of the MAPK pathway is observed in up to 90 percent of melanoma cases and is achieved via mutations in NRAS or BRAF. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d38c1912-08a7-409a-9d3d-efbab6c67287 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Dysregulation of cell cycle is a key point in melanomagenesis. Signaling description: Many melanocytic signaling pathways are initiated through the activation of the KIT receptor, which in turn triggers MAPK and PI3K pathways activation. Notably, KIT aberrations are found in 28-39% of melanoma cases, while the mutagenic activation of the MAPK pathway is observed in up to 90% of melanoma cases and is most commonly achieved via mutations in NRAS or BRAF. The latter occur at the stage of the benign nevus. As a result, constant MAPK activation drives cell cycle progression. MAPK may also be activated via UV/ROS-induced PKC-activation. In addition, 43-50% of melanoma cases have selective constitutive activity in AKT3 due to a mutation or gene amplification. Furthermore, CDKN2A and CDK4 mutations are associated with the familial form of melanoma, while CCND1 and CDKN2B may be sporadically mutated. Lastly, MITF directly binds to the promoter regions of CDKN2A, CDKN1A, and CCND1 and positively regulates their transcription. Outcome effects: Defects in cell cycle checkpoint control are associated with the pathogenesis of melanoma. As a result of NRAS and BRAF gene mutations frequently found in melanoma cells, constant MAPK activation drives cell cycle progression. Genes directly involved in cell cycle G1-S transition including CDKN2A, CDK4, CCND1, and CDKN2B are often mutated in melanoma. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Genes mutated in melanoma are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 16822996 PS:PMID 18927540 PS:PMID 19571822 PS:PMID 20067521 PS:PMID 20629085 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d393da37-f6db-453d-bd97-dacbb71719d4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d393da37-f6db-453d-bd97-dacbb71719d4 Tubular ER formation in axons uuid-d393da37-f6db-453d-bd97-dacbb71719d4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d393da37-f6db-453d-bd97-dacbb71719d4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3abb958-f846-434b-a466-40fed7e8f40f NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d3abb958-f846-434b-a466-40fed7e8f40f Raffinose degradation template uuid-d3abb958-f846-434b-a466-40fed7e8f40f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3abb958-f846-434b-a466-40fed7e8f40f PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3ac5ae6-1620-41da-b7a1-14f8b36b9e37 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d3ac5ae6-1620-41da-b7a1-14f8b36b9e37 TGFA -> HIF1A Expression Targets uuid-d3ac5ae6-1620-41da-b7a1-14f8b36b9e37 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3ac5ae6-1620-41da-b7a1-14f8b36b9e37 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: adipocyte CellType: cardiac myocyte CellType: chromaffin cell CellType: endometrium cell CellType: epithelial cell CellType: kidney cell CellType: muscle cell CellType: neuroendocrine cell CellType: neuron CellType: pneumocyte CellType: vascular smooth muscle cell Description: The adrenergic receptors regulate many key physiological function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3beab6e-ac01-48e1-aeee-2efbd260db0e NodeType: Pathway Notes: Headnote: The adrenergic receptors (adrenoceptors, AR) are a family prototypic G protein-coupled regulatory receptors. They include three alpha-1-AR subtypes (ADRA1A, ADRA1B, and ADRA1D), three alpha-2-AR (ADRA2A, ADRA2B, and ADRA2C) subtypes and beta-2-ARs (ADRB1, ADRB2, and ADRB3). Outcome effects: Alpha-1-ARs activate mitogenic responses, regulate growth and proliferation of many cells, and mediate vasoconstriction. Alpha-2-ARs regulate presynaptic control of transmitter release from sympathetic nerves, vasoconstriction, and blood clotting. Beta-2ARs is involved in the regulation of lipid metabolism, thermogenesis, hippocampal function, vasodilation, heart muscle contractility, myometrium and bronchi contraction, memory, and kidney excretion. PMID: 27062709 PMID: 27398826 PMID: 27902931 PMID: 28836008 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-d3beab6e-ac01-48e1-aeee-2efbd260db0e Adrenoceptors Physiological Effects uuid-d3beab6e-ac01-48e1-aeee-2efbd260db0e PS:CellType adipocyte PS:CellType cardiac myocyte PS:CellType chromaffin cell PS:CellType endometrium cell PS:CellType epithelial cell PS:CellType kidney cell PS:CellType muscle cell PS:CellType neuroendocrine cell PS:CellType neuron PS:CellType pneumocyte PS:CellType vascular smooth muscle cell PS:Description The adrenergic receptors regulate many key physiological function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3beab6e-ac01-48e1-aeee-2efbd260db0e PS:NodeType Pathway PS:Notes Headnote: The adrenergic receptors (adrenoceptors, AR) are a family prototypic G protein-coupled regulatory receptors. They include three alpha-1-AR subtypes (ADRA1A, ADRA1B, and ADRA1D), three alpha-2-AR (ADRA2A, ADRA2B, and ADRA2C) subtypes and beta-2-ARs (ADRB1, ADRB2, and ADRB3). Outcome effects: Alpha-1-ARs activate mitogenic responses, regulate growth and proliferation of many cells, and mediate vasoconstriction. Alpha-2-ARs regulate presynaptic control of transmitter release from sympathetic nerves, vasoconstriction, and blood clotting. Beta-2ARs is involved in the regulation of lipid metabolism, thermogenesis, hippocampal function, vasodilation, heart muscle contractility, myometrium and bronchi contraction, memory, and kidney excretion. PS:PMID 27062709 PS:PMID 27398826 PS:PMID 27902931 PS:PMID 28836008 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Cyclosporine and tacrolimus are immunosuppressive drugs that may cause post-transplant diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3d81c48-de9a-4aec-a816-77c799c10cd1 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Cyclosporine and tacrolimus are immunosuppressive drugs that may cause post-transplant diabetes. Signaling description: In animal models, tacrolimus-induced decrease of beta-cell proliferation may be related to CRTC2/CCND1 signaling. In mouse model, calcineurin inhibition leads to age-dependent diabetes which is also characterized by decreased beta-cell proliferation and mass. Tacrolimus and cyclosporine inhibit the calcineurin/NFAT signaling pathway in rodent beta-cells. In a rat insulinoma cell line (INS-1E cells), both drugs equally impair insulin secretion and inhibition of calcineurin activity. In rat islet beta-cells, IRS2 and INS expression is mediated by Ca2 /calcineurin/NFAT pathway. However, in rat cells no transcriptional repression of NFATC1-C4 isoforms was observed despite calcineurin inhibition. CCNDs, which are downstream targets of AKT1, are reduced in rodent islets following calcineurin inhibition. GCG enhances insulin promoter activity via NFAT in rodents. Glucose metabolism activates NFAT pathway by increasing voltage-gated Ca2 channel by affecting the electrical activity of the cell. In rat cells, cyclosporine significantly up-regulates SREBF1 which suppresses genes essential for beta-cell function and proliferation. The role of calcineurin in beta-cell apoptosis is controversial. In rat beta-cells, cyclosporine is connected to the BAX/ BCL2-related apoptotic mechanism. In human islet beta cells, calcineurin has anti-apoptotic effects. Outcome effects: Cyclosporine and tacrolimus have been shown to impair insulin secretion, decrease insulin content of human pancreatic beta cells, and impair insulin transcription. Tacrolimus works to induce beta cell apoptosis, decrease insulin exocytosis, and reduce insulin gene transcription which ultimately leads to impaired functional beta-cell mass following pancreas transplantation. Animal data: rodent model Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: pancreas Organ_System: endocrine system PMID: 11872668 PMID: 16988714 PMID: 20825407 PMID: 20943662 PMID: 21940781 PMID: 25255841 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d3d81c48-de9a-4aec-a816-77c799c10cd1 beta-Cell Function Inhibition by Ciclosporine and Tacrolimus (Rodent Model) uuid-d3d81c48-de9a-4aec-a816-77c799c10cd1 PS:CellType insulin-secreting cell PS:Description Cyclosporine and tacrolimus are immunosuppressive drugs that may cause post-transplant diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3d81c48-de9a-4aec-a816-77c799c10cd1 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Cytokine-mediated destruction of beta cells is central in the development of type 1 diabetes. Cyclosporine and tacrolimus are immunosuppressive drugs that may cause post-transplant diabetes. Signaling description: In animal models, tacrolimus-induced decrease of beta-cell proliferation may be related to CRTC2/CCND1 signaling. In mouse model, calcineurin inhibition leads to age-dependent diabetes which is also characterized by decreased beta-cell proliferation and mass. Tacrolimus and cyclosporine inhibit the calcineurin/NFAT signaling pathway in rodent beta-cells. In a rat insulinoma cell line (INS-1E cells), both drugs equally impair insulin secretion and inhibition of calcineurin activity. In rat islet beta-cells, IRS2 and INS expression is mediated by Ca2 /calcineurin/NFAT pathway. However, in rat cells no transcriptional repression of NFATC1-C4 isoforms was observed despite calcineurin inhibition. CCNDs, which are downstream targets of AKT1, are reduced in rodent islets following calcineurin inhibition. GCG enhances insulin promoter activity via NFAT in rodents. Glucose metabolism activates NFAT pathway by increasing voltage-gated Ca2 channel by affecting the electrical activity of the cell. In rat cells, cyclosporine significantly up-regulates SREBF1 which suppresses genes essential for beta-cell function and proliferation. The role of calcineurin in beta-cell apoptosis is controversial. In rat beta-cells, cyclosporine is connected to the BAX/ BCL2-related apoptotic mechanism. In human islet beta cells, calcineurin has anti-apoptotic effects. Outcome effects: Cyclosporine and tacrolimus have been shown to impair insulin secretion, decrease insulin content of human pancreatic beta cells, and impair insulin transcription. Tacrolimus works to induce beta cell apoptosis, decrease insulin exocytosis, and reduce insulin gene transcription which ultimately leads to impaired functional beta-cell mass following pancreas transplantation. Animal data: rodent model Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 11872668 PS:PMID 16988714 PS:PMID 20825407 PS:PMID 20943662 PS:PMID 21940781 PS:PMID 25255841 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3e14a8f-bddf-46cd-b40e-abe4ff95d59b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d3e14a8f-bddf-46cd-b40e-abe4ff95d59b AREG -> STAT Expression Targets uuid-d3e14a8f-bddf-46cd-b40e-abe4ff95d59b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d3e14a8f-bddf-46cd-b40e-abe4ff95d59b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Myocardial infarction results from prolonged ischemia or the interruption of coronary blood supply to a part of the heart resulting in death of the heart muscle. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d40d1d40-940f-4dfd-8c48-1fbc7c92bda7 NodeType: Pathway Notes: Headnote: Myocardial infarction (MI) results from prolonged ischemia or the interruption of coronary blood supply to a part of the heart resulting in death of the heart muscle. If blood flow is not restored to the heart muscle within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Signaling description: Following MI, the dead heart muscle is eventually replaced by scar tissue. The maintenance of cardiac function is determined by cardiomyocyte death and recovery.The most common symptom of a heart attack is chest pain and important risk factors include: previous cardiovascular disease, older age, tobacco smoking, high blood pressure, high levels of cholesterol, diabetes, lack of physical activity and obesity, chronic kidney disease, excessive alcohol consumption, and long-term stress. Necrosis, apoptosis, and autophagy contribute to the death of cardiomyocytes. Apoptosis is a highly regulated process activated via death receptors in the plasma membrane or mitochondria permeabilization. Necrosis is generally an uncontrolled process that leads to mitochondrial swelling, cell rupture, and subsequent inflammation. Mitochondria play an important role in both apoptosis and necrosis and changes in their morphology can affect the susceptibility of cardiomyocytes to stress. Autophagy is an intracellular lysosomal degradative process. Ischemia leads to myocardial injury, and the following rapid release of HSPD1 and HMGB1from myocardium activate TLR4 and the advanced glycosylation end product specific receptor (AGER) signaling. Outcome effects: TLR4 signaling triggers the expression of a number of genes through the MYD88-dependent and TICAM-dependent pathways. TLR4-MYD88 signaling pathway leads to NF-kB activation via the IRAK4/IRAK1/TRAF6 axis. Further, NF-kB activates the BIRC2/BIRC3/BIRC5/XIAP complex, which prevents apoptosis; however, the activated DIABLO inhibits BIRC2 and XIAP, thus inducing apoptosis. In addition, the TLR4-TICAM and TNFRSF1A signaling pathways result in the activation of CASP9/CASP3 via MAP kinases (MAPKs). Outcome effects: Activated AGER participates in cardiomyocyte apoptosis through the activation of MAPK3/MAPK1 and autophagy through the activation of ATG13. Oxidative stress and acidification induce Ca2+ release, which, in turn induces oxidative stress leading to the generation of ROS, opening of mitochondrial permeability transition pores (mPTP), loss of mitochondrial membrane potential, release of CYCS from mitochondria, and activation of CASP9 and CASP3 involved in cardiomyocyte apoptosis and necrosis. In addition, ischemia and the presense of unfolded proteins promote endoplasmic reticulum (ER) stress. ER stress plays an important role in the progression of cardiovascular diseases including ischemic MI, as it causes the accumulation of misfolded proteins in the ER lumen, which attract chaperones such as HSPA5. Then, HSPA5 interacts with important ER transmembrane proteins including HSP90B1, EIF2AK3, ATF6, and ERN1. HSP90B1 facilitates ER-associated protein degradation via CANX. EIF2AK3, ATF6, and ERN1 induce apoptosis via ATF4 and XBP1. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. Organ: heart Organ_System: cardiovascular system PMID: 15539639 PMID: 17991891 PMID: 21091074 PMID: 23824949 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-d40d1d40-940f-4dfd-8c48-1fbc7c92bda7 Myocardial Infarction uuid-d40d1d40-940f-4dfd-8c48-1fbc7c92bda7 PS:CellType cardiac myocyte PS:Description Myocardial infarction results from prolonged ischemia or the interruption of coronary blood supply to a part of the heart resulting in death of the heart muscle. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d40d1d40-940f-4dfd-8c48-1fbc7c92bda7 PS:NodeType Pathway PS:Notes Headnote: Myocardial infarction (MI) results from prolonged ischemia or the interruption of coronary blood supply to a part of the heart resulting in death of the heart muscle. If blood flow is not restored to the heart muscle within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Signaling description: Following MI, the dead heart muscle is eventually replaced by scar tissue. The maintenance of cardiac function is determined by cardiomyocyte death and recovery.The most common symptom of a heart attack is chest pain and important risk factors include: previous cardiovascular disease, older age, tobacco smoking, high blood pressure, high levels of cholesterol, diabetes, lack of physical activity and obesity, chronic kidney disease, excessive alcohol consumption, and long-term stress. Necrosis, apoptosis, and autophagy contribute to the death of cardiomyocytes. Apoptosis is a highly regulated process activated via death receptors in the plasma membrane or mitochondria permeabilization. Necrosis is generally an uncontrolled process that leads to mitochondrial swelling, cell rupture, and subsequent inflammation. Mitochondria play an important role in both apoptosis and necrosis and changes in their morphology can affect the susceptibility of cardiomyocytes to stress. Autophagy is an intracellular lysosomal degradative process. Ischemia leads to myocardial injury, and the following rapid release of HSPD1 and HMGB1from myocardium activate TLR4 and the advanced glycosylation end product specific receptor (AGER) signaling. Outcome effects: TLR4 signaling triggers the expression of a number of genes through the MYD88-dependent and TICAM-dependent pathways. TLR4-MYD88 signaling pathway leads to NF-kB activation via the IRAK4/IRAK1/TRAF6 axis. Further, NF-kB activates the BIRC2/BIRC3/BIRC5/XIAP complex, which prevents apoptosis; however, the activated DIABLO inhibits BIRC2 and XIAP, thus inducing apoptosis. In addition, the TLR4-TICAM and TNFRSF1A signaling pathways result in the activation of CASP9/CASP3 via MAP kinases (MAPKs). Outcome effects: Activated AGER participates in cardiomyocyte apoptosis through the activation of MAPK3/MAPK1 and autophagy through the activation of ATG13. Oxidative stress and acidification induce Ca2+ release, which, in turn induces oxidative stress leading to the generation of ROS, opening of mitochondrial permeability transition pores (mPTP), loss of mitochondrial membrane potential, release of CYCS from mitochondria, and activation of CASP9 and CASP3 involved in cardiomyocyte apoptosis and necrosis. In addition, ischemia and the presense of unfolded proteins promote endoplasmic reticulum (ER) stress. ER stress plays an important role in the progression of cardiovascular diseases including ischemic MI, as it causes the accumulation of misfolded proteins in the ER lumen, which attract chaperones such as HSPA5. Then, HSPA5 interacts with important ER transmembrane proteins including HSP90B1, EIF2AK3, ATF6, and ERN1. HSP90B1 facilitates ER-associated protein degradation via CANX. EIF2AK3, ATF6, and ERN1 induce apoptosis via ATF4 and XBP1. Highlighted proteins: Entities with increased levels are highlighted in red, and entities with decreased levels are highlighted in blue. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 15539639 PS:PMID 17991891 PS:PMID 21091074 PS:PMID 23824949 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet CellType: stem cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d40ded4c-bb1c-47be-af61-e54ca75e6078 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-d40ded4c-bb1c-47be-af61-e54ca75e6078 Megakaryocyte -> Platelet Precursor Cell Surface Expression Markers uuid-d40ded4c-bb1c-47be-af61-e54ca75e6078 PS:CellType blood platelet PS:CellType stem cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d40ded4c-bb1c-47be-af61-e54ca75e6078 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d41971e7-1683-4ad8-9c8f-cb8b37f6388d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d41971e7-1683-4ad8-9c8f-cb8b37f6388d PECAM1 Expression Targets uuid-d41971e7-1683-4ad8-9c8f-cb8b37f6388d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d41971e7-1683-4ad8-9c8f-cb8b37f6388d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d448581b-15e5-41c3-8102-3aa216b53281 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d448581b-15e5-41c3-8102-3aa216b53281 Proteins Involved in Pulmonary Hypertension uuid-d448581b-15e5-41c3-8102-3aa216b53281 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d448581b-15e5-41c3-8102-3aa216b53281 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: mammary epithelial cell Description: One of the more aggressive types of breast cancer is basal breast cancer (BBC). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d46f99a0-e29c-4dcf-8a31-4a8ec99b0a4b NodeType: Pathway Notes: Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. One of the major molecular subtypes of BC is basal breast cancer (BBC). Signaling description: BBC has cells with features similar to those of the outer (basal) cells lining the mammary ducts. Most BBCs are triple-negative breast cancers (TNBC). However, not all TNBCs are basal-like and not all BBCs are triple-negative. TNBC/BBC has estrogen receptor negative, progesterone receptor negative, human epidermal growth factor receptor 2 (HER2/neu) negative (ER-, PR-, ERBB2-) status. These are high-grade cancers that tend to grow quickly and have a poor prognosis. TNBC/BBC demonstrates overexpression of EGFR (epidermal growth factor receptor), VEGFRs (vascular endothelial growth factor receptors) including VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), LRP6 (low-density lipoprotein receptor-related protein 6), FZD7, KIT (c-kit receptor tyrosine kinase), TNFRSF10A (tumor necrosis factor receptor superfamily, member 10a), TGFBR1 (receptor 1 of transforming growth factor beta), and NOTCH1. In addition, there may be mutations in TP53, PTEN (antagonist of PIK3CA and suppressor of AKT1-mediated signaling pathways), and in DNA repair genes such as BRCA1, BRCA2, PALB2, RAD51, NBN, BRIP1, PARP1, and MLH1. This type of BC is more common among women with BRCA1 gene mutations. Hormone therapy is not effective against TNBC/BBC. This cancer is generally resistant to standard therapy, although chemotherapy may be helpful. MTOR inhibitors (Everolimus and Temsirolimus), inhibitor of SRC (Dasatinib), inhibitors of EGFR (Iressa (Gefitinib), Lapatinib and Cetuximab), inhibitors of KDR (Bevacizumab and Sutent (Sunitinib)), inhibitor of VEGFA (Bevacizumab), and inhibitors of KIT (Dasatinib and Imatinib) are used for the treatment of BC. The crucial pathogenic processes involved in TNBC/BBC are cell proliferation, block of apoptosis, cell invasion, chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. Outcome effects: The overexpression of EGFR and VEGFRs causes constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that result in block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. The overexpression of KIT and TGFBR1 triggers the activation of Janus kinases 1/2 (JAK1/2) and SMAD family members 2/3/4 (SMAD2/3/4) complexes, respectively which are involved in cell proliferation. The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. The overexpression of FZD7 and LRP6 causes the constitutive activation of WNT/CTNNB1 signaling pathway resulting in loss of differentiation, redundant cell proliferation, and migration. The overexpression of TNFRSF10A over-activates NF-kB which participates in blocking apoptosis. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2 via NBN. Mutations in these genes lead to block of DNA repair and dysfunction in response to DNA damage. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: breast Organ_System: integumentary system PMID: 18779615 PMID: 19729680 PMID: 21076464 PMID: 22082486 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-d46f99a0-e29c-4dcf-8a31-4a8ec99b0a4b Breast Cancer uuid-d46f99a0-e29c-4dcf-8a31-4a8ec99b0a4b PS:CellType cancer cell PS:CellType mammary epithelial cell PS:Description One of the more aggressive types of breast cancer is basal breast cancer (BBC). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d46f99a0-e29c-4dcf-8a31-4a8ec99b0a4b PS:NodeType Pathway PS:Notes Headnote: Breast cancer (BC) is the most commonly diagnosed cancer in women (excluding skin cancer) and the second leading cause of cancer death in women. Men may also develop BC, but this accounts for less than 1% of all BCs. One of the major molecular subtypes of BC is basal breast cancer (BBC). Signaling description: BBC has cells with features similar to those of the outer (basal) cells lining the mammary ducts. Most BBCs are triple-negative breast cancers (TNBC). However, not all TNBCs are basal-like and not all BBCs are triple-negative. TNBC/BBC has estrogen receptor negative, progesterone receptor negative, human epidermal growth factor receptor 2 (HER2/neu) negative (ER-, PR-, ERBB2-) status. These are high-grade cancers that tend to grow quickly and have a poor prognosis. TNBC/BBC demonstrates overexpression of EGFR (epidermal growth factor receptor), VEGFRs (vascular endothelial growth factor receptors) including VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), LRP6 (low-density lipoprotein receptor-related protein 6), FZD7, KIT (c-kit receptor tyrosine kinase), TNFRSF10A (tumor necrosis factor receptor superfamily, member 10a), TGFBR1 (receptor 1 of transforming growth factor beta), and NOTCH1. In addition, there may be mutations in TP53, PTEN (antagonist of PIK3CA and suppressor of AKT1-mediated signaling pathways), and in DNA repair genes such as BRCA1, BRCA2, PALB2, RAD51, NBN, BRIP1, PARP1, and MLH1. This type of BC is more common among women with BRCA1 gene mutations. Hormone therapy is not effective against TNBC/BBC. This cancer is generally resistant to standard therapy, although chemotherapy may be helpful. MTOR inhibitors (Everolimus and Temsirolimus), inhibitor of SRC (Dasatinib), inhibitors of EGFR (Iressa (Gefitinib), Lapatinib and Cetuximab), inhibitors of KDR (Bevacizumab and Sutent (Sunitinib)), inhibitor of VEGFA (Bevacizumab), and inhibitors of KIT (Dasatinib and Imatinib) are used for the treatment of BC. The crucial pathogenic processes involved in TNBC/BBC are cell proliferation, block of apoptosis, cell invasion, chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. Outcome effects: The overexpression of EGFR and VEGFRs causes constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling cascades that result in block of apoptosis, loss of differentiation, proliferation, and migration of mammary epithelial cells. The overexpression of KIT and TGFBR1 triggers the activation of Janus kinases 1/2 (JAK1/2) and SMAD family members 2/3/4 (SMAD2/3/4) complexes, respectively which are involved in cell proliferation. The constitutive activation of NOTCH signaling leads to loss of differentiation and hyperplastic growth of mammary epithelial cells. The overexpression of FZD7 and LRP6 causes the constitutive activation of WNT/CTNNB1 signaling pathway resulting in loss of differentiation, redundant cell proliferation, and migration. The overexpression of TNFRSF10A over-activates NF-kB which participates in blocking apoptosis. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with DNA mismatch repair protein complex MLH1/MSH2/MSH3/MSH6 and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2 via NBN. Mutations in these genes lead to block of DNA repair and dysfunction in response to DNA damage. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ breast PS:Organ_System integumentary system PS:PMID 18779615 PS:PMID 19729680 PS:PMID 21076464 PS:PMID 22082486 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Gastric acid secretion represents an important non-immunological first line of defense against ingested microbes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d474cb99-8654-4bda-a74d-06e47528dcef NodeType: Pathway Notes: Headnote: Gastric acid secretion represents an important non-immunological first line of defense against ingested microbes. Histamine is also produced by enterochromaffin-like (ECL) cells of the stomach, where it controls hydrochloric acid synthesis in neighboring parietal cells through histamine receptor H2 (HRH2) receptor signaling. Signaling description: Histamine synthesis may be induced by various combinations of stimuli; however it is largely unknown how the tissue-specific expression of histidine decarboxylase (HDC) is regulated. HRH2 activates H /K -exchanging ATPase in the luminal membrane of parietal cells which drives H+ ions into the glandular lumen in exchange for K+. For every H+ ion which is secreted, one HCO3- ion leaves the blood side of the cell and is exchanged for a Cl- ion via an anion exchanger. The HCO3- ions are obtained from CO2 OH-, a reaction catalyzed by CA1. This results in the intracellular accumulation of Cl- ions, which diffuse out of the cell into the lumen via Cl- channels. Outcome effects: Thus, one Cl- ion reaches the lumen for each H+ ion secreted. PGE2, via PTGER1, induces hydrochloric acid secretions in the stomach and inhibits it via PTGER3/PTGER4 receptors in the duodenum. PGI2 decreases hydrochloric acid secretions indirectly. Organ: stomach Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-d474cb99-8654-4bda-a74d-06e47528dcef Prostaglandin E2 and Histamine in Gastric Acid Secretion uuid-d474cb99-8654-4bda-a74d-06e47528dcef PS:Description Gastric acid secretion represents an important non-immunological first line of defense against ingested microbes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d474cb99-8654-4bda-a74d-06e47528dcef PS:NodeType Pathway PS:Notes Headnote: Gastric acid secretion represents an important non-immunological first line of defense against ingested microbes. Histamine is also produced by enterochromaffin-like (ECL) cells of the stomach, where it controls hydrochloric acid synthesis in neighboring parietal cells through histamine receptor H2 (HRH2) receptor signaling. Signaling description: Histamine synthesis may be induced by various combinations of stimuli; however it is largely unknown how the tissue-specific expression of histidine decarboxylase (HDC) is regulated. HRH2 activates H /K -exchanging ATPase in the luminal membrane of parietal cells which drives H+ ions into the glandular lumen in exchange for K+. For every H+ ion which is secreted, one HCO3- ion leaves the blood side of the cell and is exchanged for a Cl- ion via an anion exchanger. The HCO3- ions are obtained from CO2 OH-, a reaction catalyzed by CA1. This results in the intracellular accumulation of Cl- ions, which diffuse out of the cell into the lumen via Cl- channels. Outcome effects: Thus, one Cl- ion reaches the lumen for each H+ ion secreted. PGE2, via PTGER1, induces hydrochloric acid secretions in the stomach and inhibits it via PTGER3/PTGER4 receptors in the duodenum. PGI2 decreases hydrochloric acid secretions indirectly. PS:Organ stomach PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4859071-080e-438d-9632-b87b6676c134 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d4859071-080e-438d-9632-b87b6676c134 VEGFA -> STAT Expression Targets uuid-d4859071-080e-438d-9632-b87b6676c134 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4859071-080e-438d-9632-b87b6676c134 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4a3a56b-bb61-4a69-9468-4effc2f6af78 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19931639 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-d4a3a56b-bb61-4a69-9468-4effc2f6af78 Androgen Receptor Genomic Signaling uuid-d4a3a56b-bb61-4a69-9468-4effc2f6af78 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4a3a56b-bb61-4a69-9468-4effc2f6af78 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19931639 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4acba90-47a9-4240-826f-0ba17726a6a9 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d4acba90-47a9-4240-826f-0ba17726a6a9 PLG -> AP-1/CREB/ELK/SRF/SP1 Expression Targets uuid-d4acba90-47a9-4240-826f-0ba17726a6a9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4acba90-47a9-4240-826f-0ba17726a6a9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4addbbb-70cc-4252-a814-1282b45b94a6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d4addbbb-70cc-4252-a814-1282b45b94a6 DLL4 Expression Targets uuid-d4addbbb-70cc-4252-a814-1282b45b94a6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4addbbb-70cc-4252-a814-1282b45b94a6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4bffaed-9067-4839-a956-8f7dd3cc4133 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d4bffaed-9067-4839-a956-8f7dd3cc4133 Prostaglandin F Expression Targets uuid-d4bffaed-9067-4839-a956-8f7dd3cc4133 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d4bffaed-9067-4839-a956-8f7dd3cc4133 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d542798c-32a6-40b0-8a78-24e9aeff7271 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d542798c-32a6-40b0-8a78-24e9aeff7271 Glutathione metabolism template uuid-d542798c-32a6-40b0-8a78-24e9aeff7271 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d542798c-32a6-40b0-8a78-24e9aeff7271 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d55d8ccc-b193-44c0-aaab-05368f3075fd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d55d8ccc-b193-44c0-aaab-05368f3075fd IFNG/IFNR Expression Targets uuid-d55d8ccc-b193-44c0-aaab-05368f3075fd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d55d8ccc-b193-44c0-aaab-05368f3075fd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: blood platelet Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d56f2193-4682-461e-9951-2e0b4669fb0e NodeType: Pathway Notes: Headnote: Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Thrombophilia can be hereditary or acquired. Signaling description: The most common types of hereditary thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects. The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin (F2) G20210A mutation. F5 mutation is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. F2 mutation occurs at rates of 1-4% in the general population, 5-10% of people with thrombosis. Like F5, this abnormality is uncommon in Africans and Asians. The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. The main ones are antithrombin III (SERPINC1) deficiency, protein C (PROC) deficiency and protein S (PROS1) deficiency.SERPINC1 deficiency is present in 0.2% of the general population and 0.5-7.5% of people with venous thrombosis. PROC deficiency, too, is present in 0.2% of the population, and can be found in 2.5-6% of people with thrombosis. The exact prevalence of PROS1 deficiency in the population is unknown; it is found 1.3-5% of people with thrombosis. Milder rare congenital thrombophilias are factor XIII (F13A1) mutation and familial dysfibrinogenemia (an abnormal fibrinogen).Mutated genes are shown in white-out style. Organ_System: cardiovascular system PMID: 16968541 PMID: 21116184 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood urn:agi-pathway:uuid-d56f2193-4682-461e-9951-2e0b4669fb0e Thrombophilia Hereditary uuid-d56f2193-4682-461e-9951-2e0b4669fb0e PS:CellType blood platelet PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d56f2193-4682-461e-9951-2e0b4669fb0e PS:NodeType Pathway PS:Notes Headnote: Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Thrombophilia can be hereditary or acquired. Signaling description: The most common types of hereditary thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects. The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin (F2) G20210A mutation. F5 mutation is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. F2 mutation occurs at rates of 1-4% in the general population, 5-10% of people with thrombosis. Like F5, this abnormality is uncommon in Africans and Asians. The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. The main ones are antithrombin III (SERPINC1) deficiency, protein C (PROC) deficiency and protein S (PROS1) deficiency.SERPINC1 deficiency is present in 0.2% of the general population and 0.5-7.5% of people with venous thrombosis. PROC deficiency, too, is present in 0.2% of the population, and can be found in 2.5-6% of people with thrombosis. The exact prevalence of PROS1 deficiency in the population is unknown; it is found 1.3-5% of people with thrombosis. Milder rare congenital thrombophilias are factor XIII (F13A1) mutation and familial dysfibrinogenemia (an abnormal fibrinogen).Mutated genes are shown in white-out style. PS:Organ_System cardiovascular system PS:PMID 16968541 PS:PMID 21116184 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d571d9b7-9fd1-4e68-9204-91eaeecdf644 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d571d9b7-9fd1-4e68-9204-91eaeecdf644 ORF8 interactions uuid-d571d9b7-9fd1-4e68-9204-91eaeecdf644 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d571d9b7-9fd1-4e68-9204-91eaeecdf644 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: neuron Description: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d58f90ac-14ed-4127-b606-dc9f56ece190 NodeType: Pathway Notes: Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Loss-of-function mutations in either parkin (PARK2) or PTEN-induced putative kinase 1 (PINK1) can result in familial autosomal recessive forms of PD while a mutation in ubiquitin carboxyl-terminal esterase L1 (UCHL1) causes an autosomal dominant form. PARK2 is a component of the multiprotein ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in this gene lead to the accumulation of its substrates which causes neurodegeneration. Mutated PARK2 is unable to bind zinc finger protein 746 (ZNF746) which in free form represses the expression of the transcriptional co-activator, PGC-1-alpha (PPARGC1A) by binding to its promoter. Mutations in PARK2 impair normal mitochondrion organization and biogenesis. PINK1 and PARK2 act in concert to utilize the mitochondrial fission-fusion cycle to initiate the segregation and removal of irreversibly damaged/dysfunctional mitochondria with reduced mitochondrial membrane potential. Outcome effects: Such mitochondria accumulate PINK1 on the outer mitochondrial membrane which in turn recruits the cytosolic ubiquitin ligase, PARK2; therefore mutations in both genes disturb mitophagy. In addition, UCHL1 is an ubiquitin-recycling enzyme that cleaves the carboxy-terminal peptide bond of polyubiquitine chains. Thus, the supply of ubiquitin for 26S proteasome (PSMD4) may be reduced by mutations in UCHL1. Also, mutated UCHL1 cannot bind to LAMP2 which disrupts chaperone-mediated autophagy. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17017531 PMID: 17499497 PMID: 22257884 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-d58f90ac-14ed-4127-b606-dc9f56ece190 PARK2/PINK1/UCHL1 in Young Onset Parkinson's Disease uuid-d58f90ac-14ed-4127-b606-dc9f56ece190 PS:CellType neuron PS:Description Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d58f90ac-14ed-4127-b606-dc9f56ece190 PS:NodeType Pathway PS:Notes Headnote: Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system which generally affects the motor sphere. Early symptoms include involuntary shaking, muscle rigidity and movement slowness, with demetntia being more common in the advanced stages. PD is characterized by the dramatic loss of dopaminergic neurons in the substantia nigra. Signaling description: Loss-of-function mutations in either parkin (PARK2) or PTEN-induced putative kinase 1 (PINK1) can result in familial autosomal recessive forms of PD while a mutation in ubiquitin carboxyl-terminal esterase L1 (UCHL1) causes an autosomal dominant form. PARK2 is a component of the multiprotein ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in this gene lead to the accumulation of its substrates which causes neurodegeneration. Mutated PARK2 is unable to bind zinc finger protein 746 (ZNF746) which in free form represses the expression of the transcriptional co-activator, PGC-1-alpha (PPARGC1A) by binding to its promoter. Mutations in PARK2 impair normal mitochondrion organization and biogenesis. PINK1 and PARK2 act in concert to utilize the mitochondrial fission-fusion cycle to initiate the segregation and removal of irreversibly damaged/dysfunctional mitochondria with reduced mitochondrial membrane potential. Outcome effects: Such mitochondria accumulate PINK1 on the outer mitochondrial membrane which in turn recruits the cytosolic ubiquitin ligase, PARK2; therefore mutations in both genes disturb mitophagy. In addition, UCHL1 is an ubiquitin-recycling enzyme that cleaves the carboxy-terminal peptide bond of polyubiquitine chains. Thus, the supply of ubiquitin for 26S proteasome (PSMD4) may be reduced by mutations in UCHL1. Also, mutated UCHL1 cannot bind to LAMP2 which disrupts chaperone-mediated autophagy. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17017531 PS:PMID 17499497 PS:PMID 22257884 PS:PathwayType signaling PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d590e3ed-6cc1-458f-a90f-e1df3f3f34c7 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-d590e3ed-6cc1-458f-a90f-e1df3f3f34c7 EGFR/ERBB2 -> CTNNB Signaling uuid-d590e3ed-6cc1-458f-a90f-e1df3f3f34c7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d590e3ed-6cc1-458f-a90f-e1df3f3f34c7 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: In ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5b312e4-7a71-4b66-af6f-17c88e3f418c NodeType: Pathway Notes: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. In IBD, leukocytic infiltration of the mucosa is associated with epithelial damage. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 19915572 PMID: 20117335 PMID: 21319274 PMID: 22997506 PMID: 25634675 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-d5b312e4-7a71-4b66-af6f-17c88e3f418c Epithelial Cell in the Innate Immune Response in Ulcerative Colitis uuid-d5b312e4-7a71-4b66-af6f-17c88e3f418c PS:CellType epithelial cell PS:Description In ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5b312e4-7a71-4b66-af6f-17c88e3f418c PS:NodeType Pathway PS:Notes Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. In IBD, leukocytic infiltration of the mucosa is associated with epithelial damage. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 19915572 PS:PMID 20117335 PS:PMID 21319274 PS:PMID 22997506 PS:PMID 25634675 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5c65174-309e-4ea7-8d05-12e78c3c22c6 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-d5c65174-309e-4ea7-8d05-12e78c3c22c6 Sulfur Metabolism uuid-d5c65174-309e-4ea7-8d05-12e78c3c22c6 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5c65174-309e-4ea7-8d05-12e78c3c22c6 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell CellType: cancer cell Description: B-cell chronic lymphocytic leukemia (B-CLL) is a malignant lymphoproliferative disorder of mature non-functional B lymphocytes. B-CLL is the most common form of leukemia in Western countries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5d8e0b2-8ebf-4879-aced-e6755f334525 NodeType: Pathway Notes: Headnote: B-cell chronic lymphocytic leukemia (B-CLL) is a malignant lymphoproliferative disorder of mature non-functional B-lymphocytes. B-CLL is the most common form of leukemia in Western countries. It is a disease of adults, with most patients being over 50. Approximately 5-10% of patients report a family history of leukemia or lymphoma. The progressive accumulation of monoclonal B-lymphocytes leads to leukocytosis, lymphadenopathy, hepatosplenomegaly, bone marrow failure, recurrent infection and is sometimes associated with autoimmune disease (hemolytic anemia and autoimmune thrombocytopenia). Signaling description: There are two subsets of B-CLL cases that can be differentiated by the degree of somatic hypermutation (mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes) and have distinct clinical and biological behaviors. IGHV-mutated B-CLL group has low CD38 and ZAP70 expression, long telomeres, is less responsive to BCR stimulation, and is genetically stable with a favorable prognosis.IGHV-unmutated B-CLL has the opposite properties: it has high CD38 and ZAP70 expression, short telomeres, is responsive to BCR stimulation, and is genetically unstable with an unfavorable prognosis. Approximately 80% of CLLs show aberrations in a few frequently affected chromosomal regions, including 13q14 (MIR15A and MIR16-1), 11q23 (ataxia telangiectasia-mutated; ATM), trisomy 12 and 17p13 (TP53). Recurrent translocations are rare in CLL. The p53 tumor suppressor (TP53) gene is a transcription factor that is involved in cell cycle arrest and the induction of apoptosis in genetically damaged cells. B-CLL patients with a p53 deletion exhibit a very poor overall survival and often fail to respond to treatment. Therefore, p53 plays a central role in understanding the lack of response to therapy. Single nucleotide polymorphisms (SNPs) in the interferon regulatory factor 4 (IRF4) gene were shown to be associated with a predisposition to the familial form of B-CLL. IRF4 is a known regulator of lymphocyte development and proliferation. In addition, molecular interactions between CLL and microenvironment are considered important for B-CLL cell survival and proliferation. The contact between B-CLL cells and monocyte-derived nurse-like cells or stromal cells is established and maintained by chemokine receptors and adhesion molecules. B-CLL is a disease caused by a loss of appropriate apoptosis, rather than increased proliferation. The great majority (98%) of peripherally circulating B-CLL cells is arrested in G0 or the early G1 phase and has overexpression of antiapoptotic proteins. Circulating B-CLL cells can survive for a few months (as opposed to a few days for normal B-cells). CDKN1B has been shown to play a critical role in cell cycle arrest of B-CLL cells. There is only a small proliferative compartment of B-CLL cells in bone marrow. Outcome effects: TNFR, BCR, TLR signaling, as well as NF-kB, PI3K/Akt, RAS/MAPK and MTOR pathways are all involved in the pathogenesis of B-CLL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: lymphatic system PMID: 17707830 PMID: 18035318 PMID: 18059180 PMID: 19956173 PMID: 20863894 PMID: 21239773 PMID: 22160019 PMID: 22973499 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood Tissue: bone marrow urn:agi-pathway:uuid-d5d8e0b2-8ebf-4879-aced-e6755f334525 B-Cell Chronic Lymphocytic Leukemia uuid-d5d8e0b2-8ebf-4879-aced-e6755f334525 PS:CellType B-cell PS:CellType cancer cell PS:Description B-cell chronic lymphocytic leukemia (B-CLL) is a malignant lymphoproliferative disorder of mature non-functional B lymphocytes. B-CLL is the most common form of leukemia in Western countries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5d8e0b2-8ebf-4879-aced-e6755f334525 PS:NodeType Pathway PS:Notes Headnote: B-cell chronic lymphocytic leukemia (B-CLL) is a malignant lymphoproliferative disorder of mature non-functional B-lymphocytes. B-CLL is the most common form of leukemia in Western countries. It is a disease of adults, with most patients being over 50. Approximately 5-10% of patients report a family history of leukemia or lymphoma. The progressive accumulation of monoclonal B-lymphocytes leads to leukocytosis, lymphadenopathy, hepatosplenomegaly, bone marrow failure, recurrent infection and is sometimes associated with autoimmune disease (hemolytic anemia and autoimmune thrombocytopenia). Signaling description: There are two subsets of B-CLL cases that can be differentiated by the degree of somatic hypermutation (mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes) and have distinct clinical and biological behaviors. IGHV-mutated B-CLL group has low CD38 and ZAP70 expression, long telomeres, is less responsive to BCR stimulation, and is genetically stable with a favorable prognosis.IGHV-unmutated B-CLL has the opposite properties: it has high CD38 and ZAP70 expression, short telomeres, is responsive to BCR stimulation, and is genetically unstable with an unfavorable prognosis. Approximately 80% of CLLs show aberrations in a few frequently affected chromosomal regions, including 13q14 (MIR15A and MIR16-1), 11q23 (ataxia telangiectasia-mutated; ATM), trisomy 12 and 17p13 (TP53). Recurrent translocations are rare in CLL. The p53 tumor suppressor (TP53) gene is a transcription factor that is involved in cell cycle arrest and the induction of apoptosis in genetically damaged cells. B-CLL patients with a p53 deletion exhibit a very poor overall survival and often fail to respond to treatment. Therefore, p53 plays a central role in understanding the lack of response to therapy. Single nucleotide polymorphisms (SNPs) in the interferon regulatory factor 4 (IRF4) gene were shown to be associated with a predisposition to the familial form of B-CLL. IRF4 is a known regulator of lymphocyte development and proliferation. In addition, molecular interactions between CLL and microenvironment are considered important for B-CLL cell survival and proliferation. The contact between B-CLL cells and monocyte-derived nurse-like cells or stromal cells is established and maintained by chemokine receptors and adhesion molecules. B-CLL is a disease caused by a loss of appropriate apoptosis, rather than increased proliferation. The great majority (98%) of peripherally circulating B-CLL cells is arrested in G0 or the early G1 phase and has overexpression of antiapoptotic proteins. Circulating B-CLL cells can survive for a few months (as opposed to a few days for normal B-cells). CDKN1B has been shown to play a critical role in cell cycle arrest of B-CLL cells. There is only a small proliferative compartment of B-CLL cells in bone marrow. Outcome effects: TNFR, BCR, TLR signaling, as well as NF-kB, PI3K/Akt, RAS/MAPK and MTOR pathways are all involved in the pathogenesis of B-CLL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System lymphatic system PS:PMID 17707830 PS:PMID 18035318 PS:PMID 18059180 PS:PMID 19956173 PS:PMID 20863894 PS:PMID 21239773 PS:PMID 22160019 PS:PMID 22973499 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: monocyte Description: Toll-like receptors (TLRs) recognize small molecular motifs found on pathogens known as pathogen-associated molecular patterns (PAMPs) and activate innate immune responses. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5db399a-4a49-4b0f-b812-b3f3a66d5967 NodeType: Pathway Notes: Headnote: Toll-like receptors (TLRs) recognize small molecular motifs found on pathogens known as pathogen-associated molecular patterns (PAMPs) and activate innate immune responses protecting the organism from infection. Signaling description: There are four classes of viral PAMPs including double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), unmethylated CpG DNA, and envelope glycoproteins. TLR3 binds to dsRNA, TLR7/8 binds to ssRNA, TLR9 binds to unmethylated CpG DNA, and TLR2/TLR4 binds to envelope glycoproteins. In addition, both DDX58 and IFIH1 have been identified as cytoplasmic sensors of dsRNA. Outcome effects: TLRs act in a MYD88- and TICAM1-dependent manner and activate the expression of antiviral TNF and interferon I (IFNA1/IFNB1). Organ: generic Organ_System: generic PMID: 24316048 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-d5db399a-4a49-4b0f-b812-b3f3a66d5967 Antiviral Signaling through Pattern Recognition Receptors uuid-d5db399a-4a49-4b0f-b812-b3f3a66d5967 PS:CellType dendritic cell PS:CellType monocyte PS:Description Toll-like receptors (TLRs) recognize small molecular motifs found on pathogens known as pathogen-associated molecular patterns (PAMPs) and activate innate immune responses. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5db399a-4a49-4b0f-b812-b3f3a66d5967 PS:NodeType Pathway PS:Notes Headnote: Toll-like receptors (TLRs) recognize small molecular motifs found on pathogens known as pathogen-associated molecular patterns (PAMPs) and activate innate immune responses protecting the organism from infection. Signaling description: There are four classes of viral PAMPs including double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), unmethylated CpG DNA, and envelope glycoproteins. TLR3 binds to dsRNA, TLR7/8 binds to ssRNA, TLR9 binds to unmethylated CpG DNA, and TLR2/TLR4 binds to envelope glycoproteins. In addition, both DDX58 and IFIH1 have been identified as cytoplasmic sensors of dsRNA. Outcome effects: TLRs act in a MYD88- and TICAM1-dependent manner and activate the expression of antiviral TNF and interferon I (IFNA1/IFNB1). PS:Organ generic PS:Organ_System generic PS:PMID 24316048 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Top substances from published studies for Usher syndrome treatments Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5f07c94-f4f7-43ba-9fc6-829bb3194dbe NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d5f07c94-f4f7-43ba-9fc6-829bb3194dbe Usher Syndrome Drugs uuid-d5f07c94-f4f7-43ba-9fc6-829bb3194dbe PS:Description Top substances from published studies for Usher syndrome treatments PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5f07c94-f4f7-43ba-9fc6-829bb3194dbe PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5fd8cf0-ab40-4e95-90f9-baedf69ef40d NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d5fd8cf0-ab40-4e95-90f9-baedf69ef40d Proteins with Altered Expression in Cataract uuid-d5fd8cf0-ab40-4e95-90f9-baedf69ef40d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d5fd8cf0-ab40-4e95-90f9-baedf69ef40d PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Inhibition or mutations of caspases is one of the mechanisms of apoptosis impairment in cancer cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d604a0fd-5407-412e-8502-b9aa68cb039b NodeType: Pathway Notes: Headnote: Caspases are a family of protease enzymes with essential roles in programmed cell death and inflammation. Apoptopic caspases are subcategorized as initiator caspases (CASP2/8/9/10) and executioner caspases (CASP3/6/7). Signaling description: Impairment of caspase function may be either due to inactivating mutations (shown for CASP1/4/5/6/8/10) or inactivation by inhibitors of apoptosis (BIRCs, XIAP, CFLAR). Impairment of CASP3/9 activation may be also due to inactivating mutations of NTN1 and DCC which directly regulate these caspases. Outcome effects: Executioner caspases can't cleave cellular components and apoptosis is blocked. Animal data: some data are obtained in animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21943236 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-d604a0fd-5407-412e-8502-b9aa68cb039b Suppression of Caspase Activity in Cancer uuid-d604a0fd-5407-412e-8502-b9aa68cb039b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Inhibition or mutations of caspases is one of the mechanisms of apoptosis impairment in cancer cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d604a0fd-5407-412e-8502-b9aa68cb039b PS:NodeType Pathway PS:Notes Headnote: Caspases are a family of protease enzymes with essential roles in programmed cell death and inflammation. Apoptopic caspases are subcategorized as initiator caspases (CASP2/8/9/10) and executioner caspases (CASP3/6/7). Signaling description: Impairment of caspase function may be either due to inactivating mutations (shown for CASP1/4/5/6/8/10) or inactivation by inhibitors of apoptosis (BIRCs, XIAP, CFLAR). Impairment of CASP3/9 activation may be also due to inactivating mutations of NTN1 and DCC which directly regulate these caspases. Outcome effects: Executioner caspases can't cleave cellular components and apoptosis is blocked. Animal data: some data are obtained in animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21943236 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d60c5751-ba43-4d72-a679-8fcbd9256ffe NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d60c5751-ba43-4d72-a679-8fcbd9256ffe NRG1 -> FOXO3A Expression Targets uuid-d60c5751-ba43-4d72-a679-8fcbd9256ffe PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d60c5751-ba43-4d72-a679-8fcbd9256ffe PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Argininosuccinic aciduria (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the ASL gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d624847f-8687-4d6c-9bb9-6bf75ae887bd NodeType: Pathway Notes: Argininosuccinic aciduria (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the ASL gene. Organ: liver PMID: 20301396 PMID: 21290785 PMID: 24772957 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-d624847f-8687-4d6c-9bb9-6bf75ae887bd Argininosuccinic Aciduria in Urea Cycle Disorders uuid-d624847f-8687-4d6c-9bb9-6bf75ae887bd PS:CellType hepatocyte PS:Description Argininosuccinic aciduria (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the ASL gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d624847f-8687-4d6c-9bb9-6bf75ae887bd PS:NodeType Pathway PS:Notes Argininosuccinic aciduria (ICD10 - E72.2) is an autosomal-recessive disease that caused by a mutation in the ASL gene. PS:Organ liver PS:PMID 20301396 PS:PMID 21290785 PS:PMID 24772957 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d64e4d76-57fa-4793-9e4c-262154bf491c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d64e4d76-57fa-4793-9e4c-262154bf491c FGF9 -> AP-1/CREB/MYC Expression Targets uuid-d64e4d76-57fa-4793-9e4c-262154bf491c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d64e4d76-57fa-4793-9e4c-262154bf491c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d67eee6d-fe82-4b71-bedc-6329144dc345 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d67eee6d-fe82-4b71-bedc-6329144dc345 Dopamine/Gi Expression Targets uuid-d67eee6d-fe82-4b71-bedc-6329144dc345 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d67eee6d-fe82-4b71-bedc-6329144dc345 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d68d8297-335c-4ce5-8a72-28f6a2db1621 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d68d8297-335c-4ce5-8a72-28f6a2db1621 VEGFA -> NCOR2 Expression Target uuid-d68d8297-335c-4ce5-8a72-28f6a2db1621 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d68d8297-335c-4ce5-8a72-28f6a2db1621 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d68faae5-00d8-4259-a358-64673aaec6c4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-d68faae5-00d8-4259-a358-64673aaec6c4 Paracrine-+>IR uuid-d68faae5-00d8-4259-a358-64673aaec6c4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d68faae5-00d8-4259-a358-64673aaec6c4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6de99e7-f8da-470d-8c26-934351a6833b NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-d6de99e7-f8da-470d-8c26-934351a6833b NMDA Receptor -> Synaptic Excitation uuid-d6de99e7-f8da-470d-8c26-934351a6833b PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6de99e7-f8da-470d-8c26-934351a6833b PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6e49292-3f90-42f5-8343-95c1aa141d25 NodeType: Pathway Organ: Parathyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-d6e49292-3f90-42f5-8343-95c1aa141d25 Proteins Involved in Hypogonadotropic Hypogonadism uuid-d6e49292-3f90-42f5-8343-95c1aa141d25 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6e49292-3f90-42f5-8343-95c1aa141d25 PS:NodeType Pathway PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6f7b62f-2be3-412e-8cfc-bf75c59aadc5 NodeType: Pathway Organ_System: hematological system Organ_System: reproductive system PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: blood urn:agi-pathway:uuid-d6f7b62f-2be3-412e-8cfc-bf75c59aadc5 Estrogens Procoagulant Effect uuid-d6f7b62f-2be3-412e-8cfc-bf75c59aadc5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d6f7b62f-2be3-412e-8cfc-bf75c59aadc5 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d736dc88-7619-4e3b-857a-659bd1c58c53 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-d736dc88-7619-4e3b-857a-659bd1c58c53 Lysine Metabolsm uuid-d736dc88-7619-4e3b-857a-659bd1c58c53 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d736dc88-7619-4e3b-857a-659bd1c58c53 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: The formation of neurofibrillary tangles (NFTs) impair cytoskeleton organization and disrupt intracellular trafficking in Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d7407b17-a53e-4c51-b219-1c6026ff1090 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The neurofibrillary tangles (NFTs) impair cytoskeleton organization and disrupt intracellular trafficking.NFT formation occurs by several mechanisms: Ca2+ activation of calpain cleaves CDK5R1 (p35) to give rise to CDK5 and p25, and thus controls CDK5 activation. CDK5 then phosphorylates MAPT, which is also phosphorylated by CASP3 and GSK3B. There is a high level of GSK3B expression in the neurons, increased by the APP intracellular domain (AICD) which is formed during gamma-secretase cleavage of APP. NFTs are formed when MAPT becomes pathologically hyper-phosphorylated and dissociates from microtubules which then depolymerize. Outcome effects: The hyper-phosphorylated MAPT self-aggregates and accumulates in the cell body where it forms paired-helical filaments (NFTs). The hyper-phosphorylated MAPT binds MAP2 and forms insoluble complexes and is cross-linked by the enzymatic activity of TGM2. In addition, heat shock protein 27 (HSPB1) preferentially binds hyper-phosphorylated MAPT and paired helical filaments directly. The formation of this complex alters the conformation of the hyper-phosphorylated MAPT and reduces its concentration by facilitating its degradation and dephosphorylation. MAPT is also dephosphorylated by PPP2CB, but its expression is decreased in AD. Finally, NFTs cause a disruption in intracellular transport and dendrite degradation triggering cell death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 20658991 PMID: 20942789 PMID: 22720188 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d7407b17-a53e-4c51-b219-1c6026ff1090 Neurofibrillary Tangle Formation uuid-d7407b17-a53e-4c51-b219-1c6026ff1090 PS:CellType neuron PS:Description The formation of neurofibrillary tangles (NFTs) impair cytoskeleton organization and disrupt intracellular trafficking in Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d7407b17-a53e-4c51-b219-1c6026ff1090 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The neurofibrillary tangles (NFTs) impair cytoskeleton organization and disrupt intracellular trafficking.NFT formation occurs by several mechanisms: Ca2+ activation of calpain cleaves CDK5R1 (p35) to give rise to CDK5 and p25, and thus controls CDK5 activation. CDK5 then phosphorylates MAPT, which is also phosphorylated by CASP3 and GSK3B. There is a high level of GSK3B expression in the neurons, increased by the APP intracellular domain (AICD) which is formed during gamma-secretase cleavage of APP. NFTs are formed when MAPT becomes pathologically hyper-phosphorylated and dissociates from microtubules which then depolymerize. Outcome effects: The hyper-phosphorylated MAPT self-aggregates and accumulates in the cell body where it forms paired-helical filaments (NFTs). The hyper-phosphorylated MAPT binds MAP2 and forms insoluble complexes and is cross-linked by the enzymatic activity of TGM2. In addition, heat shock protein 27 (HSPB1) preferentially binds hyper-phosphorylated MAPT and paired helical filaments directly. The formation of this complex alters the conformation of the hyper-phosphorylated MAPT and reduces its concentration by facilitating its degradation and dephosphorylation. MAPT is also dephosphorylated by PPP2CB, but its expression is decreased in AD. Finally, NFTs cause a disruption in intracellular transport and dendrite degradation triggering cell death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 20658991 PS:PMID 20942789 PS:PMID 22720188 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Tryptophan (trp) metabolites are important endogenous AHR ligands. Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d75038b4-97b9-4c61-bf58-cd87f3b9491d NodeType: Pathway Notes: Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Tryptophan (trp) metabolites are important endogenous AHR ligands. Most of the free trp in mammals is oxidized along the kynurenine pathway. The first and rate-limiting step in this series of reactions is catalyzed by indoleamine 2,3-dioxygenase 1/2 (IDO1/2) and tryptophan 2,3-dioxygenase (TDO2), which produce AHR ligand kynurenine. Importantly, IDO1 and IDO2 can be upregulated upon AHR suggesting that AHR activation may result in a positive feedback loop that prolongs and/or amplifies AHR signaling. The downstream metabolites kynurenic acid and xanthurenic acid also act as AHR ligands. The IDO/TDO-independent tryptamine pathway, catalyzed by tryptophan hydroxylase (TPH1/2), and dopamine decarboxylase (DDC) also has been implicated in AHR activation. The most proximal metabolite in that pathway, tryptamine, is a potent AHR activator and may be both a direct AHR ligand and a precursor of a downstream AHR ligands. Of note, tryptamine is a competitive CYP1A1 substrate, a result consistent with the prediction that endogenous AHR ligand is degraded by CYP1 enzymes. In addition, the serotonin pathway is connected to AHR activation. 5-Hydroxytryptophan, a proximal serotonin metabolite, is an AHR agonist of modest potency. Serotonin itself is a weak AHR activator. 6-formylindolo[3,2-b]carbazole (FICZ) and 1-(2H-Indol-3-yl)-9H-pyrido(3,4-b)indole (eudistomin U) are photoproducts of trp and act as AHR ligands. Outcome effects: FICZ is readily metabolized by CYP1A1, CYP1A2, and CYP1B1. DAO and aspartate aminotransferase take part in metabolizing of trp to indolyl-3-pyruvate, AHR ligand. In the gut, the indole derivative 3-Formylindole, which is generated through conversion from dietary tryptophan by commensal lactobacilli, acts as endogenous ligand for AHR. Other tryptophan metabolites produced by commensal gut flora also may act as AHR ligands. PMID: 19054769 PMID: 19860415 PMID: 21722628 PMID: 23908379 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-d75038b4-97b9-4c61-bf58-cd87f3b9491d Aryl Hydrocarbon Receptor/Tryptophan Metabolites Signaling uuid-d75038b4-97b9-4c61-bf58-cd87f3b9491d PS:Description Tryptophan (trp) metabolites are important endogenous AHR ligands. Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d75038b4-97b9-4c61-bf58-cd87f3b9491d PS:NodeType Pathway PS:Notes Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons Signaling description: Tryptophan (trp) metabolites are important endogenous AHR ligands. Most of the free trp in mammals is oxidized along the kynurenine pathway. The first and rate-limiting step in this series of reactions is catalyzed by indoleamine 2,3-dioxygenase 1/2 (IDO1/2) and tryptophan 2,3-dioxygenase (TDO2), which produce AHR ligand kynurenine. Importantly, IDO1 and IDO2 can be upregulated upon AHR suggesting that AHR activation may result in a positive feedback loop that prolongs and/or amplifies AHR signaling. The downstream metabolites kynurenic acid and xanthurenic acid also act as AHR ligands. The IDO/TDO-independent tryptamine pathway, catalyzed by tryptophan hydroxylase (TPH1/2), and dopamine decarboxylase (DDC) also has been implicated in AHR activation. The most proximal metabolite in that pathway, tryptamine, is a potent AHR activator and may be both a direct AHR ligand and a precursor of a downstream AHR ligands. Of note, tryptamine is a competitive CYP1A1 substrate, a result consistent with the prediction that endogenous AHR ligand is degraded by CYP1 enzymes. In addition, the serotonin pathway is connected to AHR activation. 5-Hydroxytryptophan, a proximal serotonin metabolite, is an AHR agonist of modest potency. Serotonin itself is a weak AHR activator. 6-formylindolo[3,2-b]carbazole (FICZ) and 1-(2H-Indol-3-yl)-9H-pyrido(3,4-b)indole (eudistomin U) are photoproducts of trp and act as AHR ligands. Outcome effects: FICZ is readily metabolized by CYP1A1, CYP1A2, and CYP1B1. DAO and aspartate aminotransferase take part in metabolizing of trp to indolyl-3-pyruvate, AHR ligand. In the gut, the indole derivative 3-Formylindole, which is generated through conversion from dietary tryptophan by commensal lactobacilli, acts as endogenous ligand for AHR. Other tryptophan metabolites produced by commensal gut flora also may act as AHR ligands. PS:PMID 19054769 PS:PMID 19860415 PS:PMID 21722628 PS:PMID 23908379 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d76dcf08-4a1b-4d66-908a-fedff76e60fb NodeType: Pathway Notes: Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G2/M checkpoint occurs at the end of G2 phase, triggering the start of mitosis. Signaling description: The mitotic entry is determined by activation of the CycB - CDK1 complex. CycB is absent in G1 and accumulates in S/G2/M phases of the cycle. CycB - CDK1 activities are held in check until DNA synthesis is completed. During the S/G2/M state CycA - CDK2 turns off FZR1, allowing CycB to accumulate, so that the cell will eventually be able to enter mitosis. Wee1 and PKMYT1 phosphorylate and inhibit CDK1. Further, CDK1 is dephosphorylated primarily by Cdc25. Multiple feedback loops function in parallel to enhance the CycB - CDK1 activation. For example, CycB - CDK1-mediated activation of Plk1 increases the production of several CycB - CDK1 activators, thereby further stimulating CycB - CDK1 activation. FOXM1 is a critical regulator of G2/M cell cycle transitions. FoxM1 stimulates the expression of multiple proteins in the mitotic entry network including CycB. FOXM1 regulates Cdc25B and Cdc25c genes transcription via direct promoter binding. Cdc25B has a role in activating the mitotic kinase CycB - CDK1 in the cytoplasm. Active CycB - CDK1 then phosphorylates and activates Cdc25C leading to a positive feedback mechanism and to entry into mitosis. Outcome effects: The CycB - CDK1 complex phosphorylates many targets in preparation for mitosis, including Histone H1, nuclear lamins, centrosomal proteins. CycB - CDK1 complex induces chromosome condensation, assembly of the mitotic spindle apparatus, and alignment of condensed chromosomes at the metaphase plate. During the G2-phase, CDC2 is maintained in an inactive state by the kinases Wee1 and Myt1. As cells approach the M-phase, the phosphatase CDC25 is activated by PLK1. CDC25 then activates CDC2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. 14-3-3 proteins bind to the phosphorylated CycB-CDC2 kinase and export it from the nucleus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-d76dcf08-4a1b-4d66-908a-fedff76e60fb G2/M Phase Transition uuid-d76dcf08-4a1b-4d66-908a-fedff76e60fb PS:CellType generic PS:Description The mammalian cell cycle divides into two stages: mitosis (M) - the process of nuclear division and interphase.Interphase is the interlude between two M phases. Interphase includes G1, S and G 2 phases. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d76dcf08-4a1b-4d66-908a-fedff76e60fb PS:NodeType Pathway PS:Notes Headnote: In eukaryotes, the cell cycle consists of two major phases: the mitotic (M) phase (the process of nuclear division) and interphase (the interlude between two M phases). The interphase is further divided into three periods G1, S and G 2 phases. The G2/M checkpoint occurs at the end of G2 phase, triggering the start of mitosis. Signaling description: The mitotic entry is determined by activation of the CycB - CDK1 complex. CycB is absent in G1 and accumulates in S/G2/M phases of the cycle. CycB - CDK1 activities are held in check until DNA synthesis is completed. During the S/G2/M state CycA - CDK2 turns off FZR1, allowing CycB to accumulate, so that the cell will eventually be able to enter mitosis. Wee1 and PKMYT1 phosphorylate and inhibit CDK1. Further, CDK1 is dephosphorylated primarily by Cdc25. Multiple feedback loops function in parallel to enhance the CycB - CDK1 activation. For example, CycB - CDK1-mediated activation of Plk1 increases the production of several CycB - CDK1 activators, thereby further stimulating CycB - CDK1 activation. FOXM1 is a critical regulator of G2/M cell cycle transitions. FoxM1 stimulates the expression of multiple proteins in the mitotic entry network including CycB. FOXM1 regulates Cdc25B and Cdc25c genes transcription via direct promoter binding. Cdc25B has a role in activating the mitotic kinase CycB - CDK1 in the cytoplasm. Active CycB - CDK1 then phosphorylates and activates Cdc25C leading to a positive feedback mechanism and to entry into mitosis. Outcome effects: The CycB - CDK1 complex phosphorylates many targets in preparation for mitosis, including Histone H1, nuclear lamins, centrosomal proteins. CycB - CDK1 complex induces chromosome condensation, assembly of the mitotic spindle apparatus, and alignment of condensed chromosomes at the metaphase plate. During the G2-phase, CDC2 is maintained in an inactive state by the kinases Wee1 and Myt1. As cells approach the M-phase, the phosphatase CDC25 is activated by PLK1. CDC25 then activates CDC2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. 14-3-3 proteins bind to the phosphorylated CycB-CDC2 kinase and export it from the nucleus. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: keratinocyte CellType: monocyte Description: Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacterium that plays a role in the development of inflammatory acne lesions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d76ed1c5-509e-4edb-a9e3-2d3aed6977c3 NodeType: Pathway Notes: Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of the hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacterium which plays a role in the development of inflammatory acne lesions. Signaling description: P. acnes induces TLR2 signaling activation and provokes the inflammasome activation. The inflammasome is a protein complex comprised of NLRP3, PYCARD, and other proteins which promotes CASP1 activation. CASP1 cleaves pro-IL1B to generate its active form. TNF and IL1B play an important role in the inflammatory reaction in acne. They bind to their receptors on the cell surface and mediate inflammation through MAPK pathway. Outcome effects: JUN/FOS induction leads to MMP synthesis and ECM degradation. In addition, NF-kB activation causes TNF and IL8 synthesis, which promotes neutrophil recruitment in the foci and also initiates IL1B, DEFB4A, IL12A, and IL12B transcription causing an immune response, contributing to the formation of acne lesions. Organ: skin Organ_System: integumentary system PMID: 15788147 PMID: 19555434 PMID: 19588637 PMID: 24575836 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-d76ed1c5-509e-4edb-a9e3-2d3aed6977c3 Inflammatory Reaction in Acne Vulgaris uuid-d76ed1c5-509e-4edb-a9e3-2d3aed6977c3 PS:CellType keratinocyte PS:CellType monocyte PS:Description Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacterium that plays a role in the development of inflammatory acne lesions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d76ed1c5-509e-4edb-a9e3-2d3aed6977c3 PS:NodeType Pathway PS:Notes Headnote: Acne vulgaris is a chronic inflammatory skin disorder which occurs due to the blockage of the hair follicles and their accompanying sebaceous glands with excess sebum and dead keratinocytes. Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacterium which plays a role in the development of inflammatory acne lesions. Signaling description: P. acnes induces TLR2 signaling activation and provokes the inflammasome activation. The inflammasome is a protein complex comprised of NLRP3, PYCARD, and other proteins which promotes CASP1 activation. CASP1 cleaves pro-IL1B to generate its active form. TNF and IL1B play an important role in the inflammatory reaction in acne. They bind to their receptors on the cell surface and mediate inflammation through MAPK pathway. Outcome effects: JUN/FOS induction leads to MMP synthesis and ECM degradation. In addition, NF-kB activation causes TNF and IL8 synthesis, which promotes neutrophil recruitment in the foci and also initiates IL1B, DEFB4A, IL12A, and IL12B transcription causing an immune response, contributing to the formation of acne lesions. PS:Organ skin PS:Organ_System integumentary system PS:PMID 15788147 PS:PMID 19555434 PS:PMID 19588637 PS:PMID 24575836 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Tangier disease (E78.6) is a rare, inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d78be8fd-f437-474d-bac8-a810f9b5bbe5 NodeType: Pathway Notes: Headnote: Tangier disease (E78.6) is a rare, inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. Symptoms of Tangier disease include enlarged, orange-colored tonsils, a slightly elevated amount of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). Other features of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (corneal clouding), and type 2 diabetes. In addition, affected individuals often develop atherosclerosis, which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries. Signaling description: HDL transports cholesterol and phospholipids from the body's tissues to the liver, where they are removed from the blood. Mutations in ABCA1 gene are associated with Tangier disease. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway. Mutations in ABCA1 gene prevent the release of cholesterol and phospholipids from the cells. Outcome effects: As a result, cholesterol and phospholipids accumulate within the cells and cause certain body tissues to enlarge and the tonsils to acquire a yellowish-orange color. A buildup of cholesterol can be toxic to cells and lead to impaired cell function or cell death. In addition, the inability to transport cholesterol and phospholipids out of the cells results in very low HDL levels, which increases the risk of cardiovascular disease. These combined factors cause the symptoms of Tangier disease. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ_System: hematological system PMID: 11483617 PMID: 16235041 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: blood urn:agi-pathway:uuid-d78be8fd-f437-474d-bac8-a810f9b5bbe5 Tangier Disease Overwiew uuid-d78be8fd-f437-474d-bac8-a810f9b5bbe5 PS:Description Tangier disease (E78.6) is a rare, inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d78be8fd-f437-474d-bac8-a810f9b5bbe5 PS:NodeType Pathway PS:Notes Headnote: Tangier disease (E78.6) is a rare, inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. Symptoms of Tangier disease include enlarged, orange-colored tonsils, a slightly elevated amount of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). Other features of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (corneal clouding), and type 2 diabetes. In addition, affected individuals often develop atherosclerosis, which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries. Signaling description: HDL transports cholesterol and phospholipids from the body's tissues to the liver, where they are removed from the blood. Mutations in ABCA1 gene are associated with Tangier disease. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway. Mutations in ABCA1 gene prevent the release of cholesterol and phospholipids from the cells. Outcome effects: As a result, cholesterol and phospholipids accumulate within the cells and cause certain body tissues to enlarge and the tonsils to acquire a yellowish-orange color. A buildup of cholesterol can be toxic to cells and lead to impaired cell function or cell death. In addition, the inability to transport cholesterol and phospholipids out of the cells results in very low HDL levels, which increases the risk of cardiovascular disease. These combined factors cause the symptoms of Tangier disease. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System hematological system PS:PMID 11483617 PS:PMID 16235041 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d7f3f5a1-c7b5-4027-99fe-2e10467ce64a NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-d7f3f5a1-c7b5-4027-99fe-2e10467ce64a Huntington's Disease Clinical Trials uuid-d7f3f5a1-c7b5-4027-99fe-2e10467ce64a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d7f3f5a1-c7b5-4027-99fe-2e10467ce64a PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Beta-catenin (CTNNB1) and alpha-catenins (CTNNAs) are proteins that constitute adherens junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d802e459-62ec-4393-ae16-2b51f4e15ef9 NodeType: Pathway Notes: Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Beta-catenin (CTNNB1) and alpha-catenins (CTNNAs) are proteins that constitute adherens junctions. The catenins associated with E-cadherin (CDH1) play a critical role in the regulation of cell-cell adhesion and cell growth. It has been demonstrated that the loss of E-cadherin promotes prostate cancer. The WNT/beta-catenin (WNT/CTNNB1) signaling pathway is important since it controls various cellular functions including proliferation, differentiation, and migration. In particular, WNT/CTNNB1 signaling has been implicated in prostate carcinogenesis. In the absence of WNT proteins, beta-catenin is associated with a complex that consists of the adenomatous polyposis coli (APC) tumor suppressor, AXIN2, glycogen synthase kinase-3 beta (GSK3B) and casein kinase 1 (CSNK1A1). This complex formation induces the phosphorylation of beta-catenin by CSNK1A1 and GSK3B, which leads to the ubiquitination and degradation of beta-catenin by the proteasome. When WNT proteins bind to low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) and frizzled receptor (FZD), scaffold protein dishevelled (DVL1/2) is activated and inhibits GSK3B, which results in the stabilization of cytosolic beta-catenin. Outcome effects: The activated beta-catenin translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. In addition, beta-catenin activates androgen receptor (AR) that binds with TCF4 and HNF1 homeobox A (HNF1A) inducing cyclin D1 (CCDN1). Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. Organ: prostate Organ_System: urinary tract PMID: 15809669 PMID: 16741972 PMID: 18566211 PMID: 21756376 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d802e459-62ec-4393-ae16-2b51f4e15ef9 beta-Catenin/Androgen Receptor Signaling in Prostate Cancer uuid-d802e459-62ec-4393-ae16-2b51f4e15ef9 PS:CellType cancer cell PS:Description Beta-catenin (CTNNB1) and alpha-catenins (CTNNAs) are proteins that constitute adherens junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d802e459-62ec-4393-ae16-2b51f4e15ef9 PS:NodeType Pathway PS:Notes Headnote: Prostate cancer is a cancer that develops in the prostate gland. Prostate cancer cases are characterized by considerable heterogeneity especially during the progression to hormone-refractory status. It is generally accepted that androgen receptor (AR) plays a significant role in prostate cancer even upon transition to an androgen-independent state. Signaling description: Beta-catenin (CTNNB1) and alpha-catenins (CTNNAs) are proteins that constitute adherens junctions. The catenins associated with E-cadherin (CDH1) play a critical role in the regulation of cell-cell adhesion and cell growth. It has been demonstrated that the loss of E-cadherin promotes prostate cancer. The WNT/beta-catenin (WNT/CTNNB1) signaling pathway is important since it controls various cellular functions including proliferation, differentiation, and migration. In particular, WNT/CTNNB1 signaling has been implicated in prostate carcinogenesis. In the absence of WNT proteins, beta-catenin is associated with a complex that consists of the adenomatous polyposis coli (APC) tumor suppressor, AXIN2, glycogen synthase kinase-3 beta (GSK3B) and casein kinase 1 (CSNK1A1). This complex formation induces the phosphorylation of beta-catenin by CSNK1A1 and GSK3B, which leads to the ubiquitination and degradation of beta-catenin by the proteasome. When WNT proteins bind to low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) and frizzled receptor (FZD), scaffold protein dishevelled (DVL1/2) is activated and inhibits GSK3B, which results in the stabilization of cytosolic beta-catenin. Outcome effects: The activated beta-catenin translocates into the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) to induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and migration. In addition, beta-catenin activates androgen receptor (AR) that binds with TCF4 and HNF1 homeobox A (HNF1A) inducing cyclin D1 (CCDN1). Highlighted proteins: Protein with decreased expression or activity is highlighted in blue. PS:Organ prostate PS:Organ_System urinary tract PS:PMID 15809669 PS:PMID 16741972 PS:PMID 18566211 PS:PMID 21756376 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: fibroblast Description: Synovial tissue in normal joints has few resident immune cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8085542-84b1-46ab-b6da-181a8b523406 NodeType: Pathway Notes: Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Signaling description: Synovial tissue in normal joints has few resident immune cells. It consists of an intimal lining layer made up of fibroblast-like synoviocytes and intimal lining layer of macrophages, resting on a subsynovial layer of loose connective tissue, which contains blood vessels, nerve endings, fibroblasts and adipocytes. Inflamed joints are characterised by increased synovial lining cell numbers, increased sublining vascularity, with large numbers of cells within this sub-synovial layer, including fibroblasts. TNF, IL17 and IL1B are the main cytokines that promote cell activation. There are increased levels of TNF and IL17 in the synovium of rheumatoid arthritis patients. Cytokines bind to their receptors on the synovial fibroblast surface and promote JUN, FOS, and NF-kB activation. TNF signaling involves TRAF2 which provides NF-kB activation through the MAPK14 and NF-kB pathway. TRAF2 activates MAPK9 (through MAP3K1), which interacts with JUN and FOS transcription factors. IL1B affects the same pathways through the MYD88/IRAK axis. TRAF3IP2 encodes the TRAF3 interacting protein 2 or NFkB activator 1, which is essential for Th-17 cell-mediated inflammatory responses, and its dysregulation may affect both IL-17 and NFkB signaling cascades. Outcome effects: JUN, FOS, and NF-kB transcription factors promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), IL8 (recruitment of inflammatory cells in the synovium that leads to pannus formation), IL6 (osteoclast activation and bone resorption), and VEGFA (new vessel growth). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: skeletal system PMID: 17370327 PMID: 19182814 PMID: 22064628 PMID: 22541888 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-d8085542-84b1-46ab-b6da-181a8b523406 Synovial Fibroblast Activation in Psoriatic Arthritis uuid-d8085542-84b1-46ab-b6da-181a8b523406 PS:CellType fibroblast PS:Description Synovial tissue in normal joints has few resident immune cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8085542-84b1-46ab-b6da-181a8b523406 PS:NodeType Pathway PS:Notes Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Our understanding of psoriasis and PsA pathogenesis has evolved due to new knowledge on their immunopathology. Psoriasis and PsA, often termed 'psoriatic disease' are currently considered autoimmune diseases which share certain similar pathological events and clinical features. PsA is a seronegative autoimmune inflammatory joint disease that develops in approximately 25 % of psoriasis patients usually within 10 years of the start of skin manifestations. Signaling description: Synovial tissue in normal joints has few resident immune cells. It consists of an intimal lining layer made up of fibroblast-like synoviocytes and intimal lining layer of macrophages, resting on a subsynovial layer of loose connective tissue, which contains blood vessels, nerve endings, fibroblasts and adipocytes. Inflamed joints are characterised by increased synovial lining cell numbers, increased sublining vascularity, with large numbers of cells within this sub-synovial layer, including fibroblasts. TNF, IL17 and IL1B are the main cytokines that promote cell activation. There are increased levels of TNF and IL17 in the synovium of rheumatoid arthritis patients. Cytokines bind to their receptors on the synovial fibroblast surface and promote JUN, FOS, and NF-kB activation. TNF signaling involves TRAF2 which provides NF-kB activation through the MAPK14 and NF-kB pathway. TRAF2 activates MAPK9 (through MAP3K1), which interacts with JUN and FOS transcription factors. IL1B affects the same pathways through the MYD88/IRAK axis. TRAF3IP2 encodes the TRAF3 interacting protein 2 or NFkB activator 1, which is essential for Th-17 cell-mediated inflammatory responses, and its dysregulation may affect both IL-17 and NFkB signaling cascades. Outcome effects: JUN, FOS, and NF-kB transcription factors promote the expression of a wide range of cytokines such as MMPs (cartilage erosion), IL8 (recruitment of inflammatory cells in the synovium that leads to pannus formation), IL6 (osteoclast activation and bone resorption), and VEGFA (new vessel growth). Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System skeletal system PS:PMID 17370327 PS:PMID 19182814 PS:PMID 22064628 PS:PMID 22541888 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8181f21-8a68-4f99-b1a2-cea5ff1682a4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d8181f21-8a68-4f99-b1a2-cea5ff1682a4 phytosiderophore biosynthesis template uuid-d8181f21-8a68-4f99-b1a2-cea5ff1682a4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8181f21-8a68-4f99-b1a2-cea5ff1682a4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8254ff6-b15b-4ad1-8015-2b64e00d7937 NodeType: Pathway Organ: generic Organ_System: generic PMID: 24470019 PMID: 8286433 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-d8254ff6-b15b-4ad1-8015-2b64e00d7937 HRAS Signaling uuid-d8254ff6-b15b-4ad1-8015-2b64e00d7937 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8254ff6-b15b-4ad1-8015-2b64e00d7937 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 24470019 PS:PMID 8286433 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8319760-93f5-4c5b-b1b6-12b7f48ce5b8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d8319760-93f5-4c5b-b1b6-12b7f48ce5b8 Drugs->Autophagy uuid-d8319760-93f5-4c5b-b1b6-12b7f48ce5b8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8319760-93f5-4c5b-b1b6-12b7f48ce5b8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d870039e-a082-4335-8428-c3ebd43d2557 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-d870039e-a082-4335-8428-c3ebd43d2557 Lipoyl-Protein Complex Biosynthesis I uuid-d870039e-a082-4335-8428-c3ebd43d2557 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d870039e-a082-4335-8428-c3ebd43d2557 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d870b0bc-e8b7-4335-be5e-44e062649898 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-d870b0bc-e8b7-4335-be5e-44e062649898 PTPRC -> BCL6 Signaling uuid-d870b0bc-e8b7-4335-be5e-44e062649898 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d870b0bc-e8b7-4335-be5e-44e062649898 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: hepatocyte Description: Cocaine participates in several metabolic pathways in the liver. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d871e5e0-f1ef-4b60-8465-c35b4a01abb0 NodeType: Pathway Notes: Headnote: Cocaine participates in several metabolic pathways in the liver. Signaling description: One of them (the activation pathway) is catalyzed by the cytochrome P450 superfamily proteins, primarily CYP3A, as well as monooxygenases, which activate the production of N-hydroxynorcocaine and norcocaine nitroxide. Outcome effects: N-hydroxynorcocaine and norcocaine nitroxide compounds exist in a dynamic equilibrium and both are sources of ROS production, which in turn leads to oxidative stress, mitochondrial damage, and necrosis of hepatocytes. These consequences are the major hepatotoxic effects of cocaine abuse. Organ: liver Organ_System: digestive system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-d871e5e0-f1ef-4b60-8465-c35b4a01abb0 Cocaine Induced Hepatotoxicity uuid-d871e5e0-f1ef-4b60-8465-c35b4a01abb0 PS:CellType hepatocyte PS:Description Cocaine participates in several metabolic pathways in the liver. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d871e5e0-f1ef-4b60-8465-c35b4a01abb0 PS:NodeType Pathway PS:Notes Headnote: Cocaine participates in several metabolic pathways in the liver. Signaling description: One of them (the activation pathway) is catalyzed by the cytochrome P450 superfamily proteins, primarily CYP3A, as well as monooxygenases, which activate the production of N-hydroxynorcocaine and norcocaine nitroxide. Outcome effects: N-hydroxynorcocaine and norcocaine nitroxide compounds exist in a dynamic equilibrium and both are sources of ROS production, which in turn leads to oxidative stress, mitochondrial damage, and necrosis of hepatocytes. These consequences are the major hepatotoxic effects of cocaine abuse. PS:Organ liver PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8b6552e-a728-4bc6-ad40-b0ff653d53c4 NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Primary GBM is the most frequent type of glioblastoma and develops rapidly following a short clinical history and without evidence of a less malignant precursor. Signaling description: The central signaling systems deregulated in GBM are receptor tyrosine kinase (RTK), TP53, and RB1 pathways. The amplification and/or activating mutations of the gene that encodes EGFR are the most frequent genetic defects that is associated with GBM. Also, other RTKs such as PDGFRA, FGFR, IGF1R, and MET are abnormally expressed in GBM. RTKs activate proliferation via PI3K/AKT1/MTOR and Ras/MAPK pathways. MAPK activation results in the activation of various transcription factors such as ELK1, MYC, ETS1, and STAT1/3 which induce cell transformation and inhibit apoptosis. TP53 pathway is disrupted through the deletion of CDKN2A or amplification of MDM2 and MDM4. TP53 mutations may occur as well. The disruption of the RB1 pathway occurs through deletions of CDK4 or CDKN2A. In addition, PIK3CA and PIK3R1, which are members of the PI3K family, and PTEN may be mutated. Furthermore, mutations and/or deletions in NF1 are present in 15-18% of GBM cases. Outcome effects: In conclusion, all of these genetic events ultimately lead to the activation of proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 19737147 PMID: 19777070 PMID: 20414201 PMID: 23183634 PMID: 24212955 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-d8b6552e-a728-4bc6-ad40-b0ff653d53c4 Glioblastoma, Primary uuid-d8b6552e-a728-4bc6-ad40-b0ff653d53c4 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8b6552e-a728-4bc6-ad40-b0ff653d53c4 PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Primary GBM is the most frequent type of glioblastoma and develops rapidly following a short clinical history and without evidence of a less malignant precursor. Signaling description: The central signaling systems deregulated in GBM are receptor tyrosine kinase (RTK), TP53, and RB1 pathways. The amplification and/or activating mutations of the gene that encodes EGFR are the most frequent genetic defects that is associated with GBM. Also, other RTKs such as PDGFRA, FGFR, IGF1R, and MET are abnormally expressed in GBM. RTKs activate proliferation via PI3K/AKT1/MTOR and Ras/MAPK pathways. MAPK activation results in the activation of various transcription factors such as ELK1, MYC, ETS1, and STAT1/3 which induce cell transformation and inhibit apoptosis. TP53 pathway is disrupted through the deletion of CDKN2A or amplification of MDM2 and MDM4. TP53 mutations may occur as well. The disruption of the RB1 pathway occurs through deletions of CDK4 or CDKN2A. In addition, PIK3CA and PIK3R1, which are members of the PI3K family, and PTEN may be mutated. Furthermore, mutations and/or deletions in NF1 are present in 15-18% of GBM cases. Outcome effects: In conclusion, all of these genetic events ultimately lead to the activation of proliferation and block of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 19737147 PS:PMID 19777070 PS:PMID 20414201 PS:PMID 23183634 PS:PMID 24212955 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8bdceb0-be3f-4347-9814-19b9a3a13474 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-d8bdceb0-be3f-4347-9814-19b9a3a13474 EGFR -> AP-1/ATF2 Signaling uuid-d8bdceb0-be3f-4347-9814-19b9a3a13474 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8bdceb0-be3f-4347-9814-19b9a3a13474 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: GIP and GCG potentiate as much as 70? of the meal-induced insulin secretion in beta cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8dade4c-c668-49e0-b842-b88f124d0c28 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: Beta-cell function may be improved by the activation of GCK. PFKFB2 acts as a glucose sensor and an endogenous GCK activator. The activation of GCK is promoted by glucose, resulting in an enhancement of insulin secretion. GCK activity is regulated by adaptive translocation between the nucleus and the cytoplasm through binding and dissociation from its regulatory protein (GCKR) in the nucleus. G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit from endoplasmic reticulum. Glucose-6-phosphatase catalyzes the dephosphorylation of glucose-6-phosphate to glucose, which is the process opposite to glucose utilization. G6PC2 inhibitors may be a new approach for the treatment of insulin secretion defects in type 2 diabetes. Further, GIP and GCG potentiate approximately 70% of the meal-induced insulin secretion in beta-cells. GCG is rapidly inactivated by the ubiquitous proteolytic enzyme DPP4, whose inhibition improves islet and beta-cell functions. Outcome effects: Mitochondrial respiratory chain is the main source of superoxide in pancreatic beta cells. The levels of reactive oxygen species (ROS)-inactivating enzymes, glutathione peroxidase and CAT are extremely low in pancreatic beta-cells. UCP2 may have an antioxidant role preventing excessive superoxide formation within the respiratory chain. An additional ROS source may be provided by CYP2E1 and the family of NADPH oxidases (NOX). Human beta-cells seem to be less prone to oxidative stress than rodent beta-cells, possibly due to greater catalase and SOD activities. Glutathione peroxidase activity is poorly detectable in human islets. NFE2L2 and PPARG increase antioxidant enzyme activity in beta-cells. Thiazolidinediones are drugs that activate the PPAR group with the highest specificity for PPARG. The activation of PPARG also prevents the NF-kB activation, and the loss of the ATP2A2 pump induced by high glucose concentration and IL1B. Organ: pancreas Organ_System: endocrine system PMID: 15180990 PMID: 20702580 PMID: 23274894 PMID: 24566088 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d8dade4c-c668-49e0-b842-b88f124d0c28 beta-Cell Recovery in Diabetes Mellitus uuid-d8dade4c-c668-49e0-b842-b88f124d0c28 PS:CellType insulin-secreting cell PS:Description GIP and GCG potentiate as much as 70? of the meal-induced insulin secretion in beta cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d8dade4c-c668-49e0-b842-b88f124d0c28 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Diabetes mellitus refers to a group of chronic diseases characterized by a high blood sugar levels over a prolonged period. Signaling description: Beta-cell function may be improved by the activation of GCK. PFKFB2 acts as a glucose sensor and an endogenous GCK activator. The activation of GCK is promoted by glucose, resulting in an enhancement of insulin secretion. GCK activity is regulated by adaptive translocation between the nucleus and the cytoplasm through binding and dissociation from its regulatory protein (GCKR) in the nucleus. G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit from endoplasmic reticulum. Glucose-6-phosphatase catalyzes the dephosphorylation of glucose-6-phosphate to glucose, which is the process opposite to glucose utilization. G6PC2 inhibitors may be a new approach for the treatment of insulin secretion defects in type 2 diabetes. Further, GIP and GCG potentiate approximately 70% of the meal-induced insulin secretion in beta-cells. GCG is rapidly inactivated by the ubiquitous proteolytic enzyme DPP4, whose inhibition improves islet and beta-cell functions. Outcome effects: Mitochondrial respiratory chain is the main source of superoxide in pancreatic beta cells. The levels of reactive oxygen species (ROS)-inactivating enzymes, glutathione peroxidase and CAT are extremely low in pancreatic beta-cells. UCP2 may have an antioxidant role preventing excessive superoxide formation within the respiratory chain. An additional ROS source may be provided by CYP2E1 and the family of NADPH oxidases (NOX). Human beta-cells seem to be less prone to oxidative stress than rodent beta-cells, possibly due to greater catalase and SOD activities. Glutathione peroxidase activity is poorly detectable in human islets. NFE2L2 and PPARG increase antioxidant enzyme activity in beta-cells. Thiazolidinediones are drugs that activate the PPAR group with the highest specificity for PPARG. The activation of PPARG also prevents the NF-kB activation, and the loss of the ATP2A2 pump induced by high glucose concentration and IL1B. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 15180990 PS:PMID 20702580 PS:PMID 23274894 PS:PMID 24566088 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d91aaeed-03c0-460f-bded-19397c274abd NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d91aaeed-03c0-460f-bded-19397c274abd TDGF1/ACVR2B Expression Targets uuid-d91aaeed-03c0-460f-bded-19397c274abd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d91aaeed-03c0-460f-bded-19397c274abd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d93bfdd6-0016-415f-aa86-10817f53fd69 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-d93bfdd6-0016-415f-aa86-10817f53fd69 CSF1 -> FOXO3A Expression Targets uuid-d93bfdd6-0016-415f-aa86-10817f53fd69 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d93bfdd6-0016-415f-aa86-10817f53fd69 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: The activation of CD4 may occur when Antigen-Presenting Cells, after endocytosis of dying Melanocytes, migrate to skin-draining lymph nodes to present peptides derived from Melanosomal Antigens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9430753-5054-4c08-bb99-8defa66b37af NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T-cells. Signaling description: The activation of CD4 may occur following the endocytosis of dying melanocytes, when antigen-presenting cells migrate to skin-draining lymph nodes to present peptides derived from melanosomal antigens. Outcome effects: Studies have shown that CD4+ T-cells directly target melanocytes for destruction leading the development of hypopigmented patches in vitiligo. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Vitiligo susceptibility genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 11886510 PMID: 23668538 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-d9430753-5054-4c08-bb99-8defa66b37af T-Cell Cytotoxic Response against Melanocytes in Vitiligo uuid-d9430753-5054-4c08-bb99-8defa66b37af PS:CellType T-cell PS:Description The activation of CD4 may occur when Antigen-Presenting Cells, after endocytosis of dying Melanocytes, migrate to skin-draining lymph nodes to present peptides derived from Melanosomal Antigens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9430753-5054-4c08-bb99-8defa66b37af PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. Cutaneous depigmentation in vitiligo involves cytotoxic activity of autoreactive T-cells. Signaling description: The activation of CD4 may occur following the endocytosis of dying melanocytes, when antigen-presenting cells migrate to skin-draining lymph nodes to present peptides derived from melanosomal antigens. Outcome effects: Studies have shown that CD4+ T-cells directly target melanocytes for destruction leading the development of hypopigmented patches in vitiligo. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Vitiligo susceptibility genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 11886510 PS:PMID 23668538 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Noradrenalin has an important role in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d956943a-72b4-4d31-84eb-dbbe973410bf NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: Noradrenalin has an important role in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Alpha-2-adrenergic receptor (ADRA2A) agonist and beta-1-adrenergic receptor (ADRB1) blockers are commonly used as anti-glaucoma treatment. Outcome effects: ADRA2A agonist activates presynaptic ADRA2A, thus inhibiting the release of noradrenalin. ADRB1 blockers act post-synaptically and inhibit cAMP production, thereby decreasing AH production. Organ: ciliary body Organ: eye Organ_System: sensory system PMID: 22699774 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-d956943a-72b4-4d31-84eb-dbbe973410bf Noradrenalin Signaling in Glaucoma uuid-d956943a-72b4-4d31-84eb-dbbe973410bf PS:CellType neuron PS:Description Noradrenalin has an important role in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d956943a-72b4-4d31-84eb-dbbe973410bf PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: Noradrenalin has an important role in the regulation of aqueous humor (AH) production by the ciliary body and intraocular pressure (IOP) regulation. Alpha-2-adrenergic receptor (ADRA2A) agonist and beta-1-adrenergic receptor (ADRB1) blockers are commonly used as anti-glaucoma treatment. Outcome effects: ADRA2A agonist activates presynaptic ADRA2A, thus inhibiting the release of noradrenalin. ADRB1 blockers act post-synaptically and inhibit cAMP production, thereby decreasing AH production. PS:Organ ciliary body PS:Organ eye PS:Organ_System sensory system PS:PMID 22699774 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9698b96-dd55-4b37-a1c0-0cda26d93411 NodeType: Pathway Organ: generic Organ_System: generic PMID: 11897488 PMID: 21962830 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-d9698b96-dd55-4b37-a1c0-0cda26d93411 TNF-alpha/TNFRSF1A Signaling uuid-d9698b96-dd55-4b37-a1c0-0cda26d93411 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9698b96-dd55-4b37-a1c0-0cda26d93411 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 11897488 PS:PMID 21962830 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9771594-72a6-4c61-89a8-83ac054b81ca NodeType: Pathway Notes: The penetration of HPVs into the cell occurs through the interaction of viral envelope proteins with the membrane proteins of the host cell. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organelle: nucleus Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-d9771594-72a6-4c61-89a8-83ac054b81ca 1_Human papilloma virus entry into the cell uuid-d9771594-72a6-4c61-89a8-83ac054b81ca PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9771594-72a6-4c61-89a8-83ac054b81ca PS:NodeType Pathway PS:Notes The penetration of HPVs into the cell occurs through the interaction of viral envelope proteins with the membrane proteins of the host cell. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organelle nucleus PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d98a5551-40e0-435a-9f6e-fb69692ec717 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-d98a5551-40e0-435a-9f6e-fb69692ec717 FynT Inhibits Autophagy in White Muscles uuid-d98a5551-40e0-435a-9f6e-fb69692ec717 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d98a5551-40e0-435a-9f6e-fb69692ec717 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9a41817-595d-47cd-a7ff-7f5dbcc53f64 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-d9a41817-595d-47cd-a7ff-7f5dbcc53f64 Flavonol biosynthesis template uuid-d9a41817-595d-47cd-a7ff-7f5dbcc53f64 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9a41817-595d-47cd-a7ff-7f5dbcc53f64 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Acetylcholine (ACh) is a neurotransmitter widely distributed in the central nervous system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9bf57ed-c81e-4793-a2df-52d1ddfb5565 NodeType: Pathway Notes: Headnote: Acetylcholine (ACh) is a neurotransmitter widely distributed in the central (and also peripheral, autonomic and enteric) nervous system (CNS). In the CNS, ACh facilitates many functions, such as learning, memory, attention, sleep regulation and motor control. Signaling description: Cholinesterase inhibitors are commonly used to treat memory loss and mental changes in individuals with Alzheimer's disease and other types of dementia. One of the main side effects of these drugs is sleep disturbance. These drugs inhibit acetylcholinesterase (ACHE), the enzyme that breaks down ACh and thus boosting the amount available to brain cells. Outcome effects: The excess of ACh in the synaptic cleft may lead to sleep disturbances. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: brain Organ_System: nervous system PMID: 15525294 PMID: 19813776 PMID: 19949165 PMID: 23410039 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-d9bf57ed-c81e-4793-a2df-52d1ddfb5565 Cholinesterase Inhibitors Induce Insomnia uuid-d9bf57ed-c81e-4793-a2df-52d1ddfb5565 PS:CellType neuron PS:Description Acetylcholine (ACh) is a neurotransmitter widely distributed in the central nervous system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9bf57ed-c81e-4793-a2df-52d1ddfb5565 PS:NodeType Pathway PS:Notes Headnote: Acetylcholine (ACh) is a neurotransmitter widely distributed in the central (and also peripheral, autonomic and enteric) nervous system (CNS). In the CNS, ACh facilitates many functions, such as learning, memory, attention, sleep regulation and motor control. Signaling description: Cholinesterase inhibitors are commonly used to treat memory loss and mental changes in individuals with Alzheimer's disease and other types of dementia. One of the main side effects of these drugs is sleep disturbance. These drugs inhibit acetylcholinesterase (ACHE), the enzyme that breaks down ACh and thus boosting the amount available to brain cells. Outcome effects: The excess of ACh in the synaptic cleft may lead to sleep disturbances. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ_System nervous system PS:PMID 15525294 PS:PMID 19813776 PS:PMID 19949165 PS:PMID 23410039 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9c08bbb-5d27-4db7-accb-b6732984c072 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-d9c08bbb-5d27-4db7-accb-b6732984c072 FrizzledR -> CTNNB Signaling uuid-d9c08bbb-5d27-4db7-accb-b6732984c072 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9c08bbb-5d27-4db7-accb-b6732984c072 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9d0bc5e-f773-4289-9c84-a752300e2a52 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-d9d0bc5e-f773-4289-9c84-a752300e2a52 SARS E protein inhibitors uuid-d9d0bc5e-f773-4289-9c84-a752300e2a52 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9d0bc5e-f773-4289-9c84-a752300e2a52 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: hepatocyte CellType: muscle cell Description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e0735b-b3d2-4fd6-b456-5018d0ea0627 NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. In addition, IL6 has emerged as a factor involved in insulin resistance. In obesity, adipose tissue infiltrated by immune cells starts producing excessive amount of IL6. In the liver, IL6 inhibits insulin signaling leading to insulin resistance. This effect is mediated through the JAK/STAT pathway. IL6-induced activation of STAT3 leads to the up-regulation of SOCS3. Outcome effects: SOCS3 is a negative regulator of insulin signaling. Some other downstream targets of IL6, such as MAPK8, NOS2, and PTPN1, can also affect activity of the immediate targets of the insulin receptor (insulin receptor substrates), blocking insulin's action. However, in muscles, IL6 can be beneficial for insulin signaling. Increased IL6 production caused by muscle contraction stimulates AMPK that can increase glucose uptake and repress MTOR, thereby abolishing its negative regulation of insulin receptor substrates. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-d9e0735b-b3d2-4fd6-b456-5018d0ea0627 IL6 and Insulin Resistance in Muscular Dystrophies uuid-d9e0735b-b3d2-4fd6-b456-5018d0ea0627 PS:CellType hepatocyte PS:CellType muscle cell PS:Description Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e0735b-b3d2-4fd6-b456-5018d0ea0627 PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. In addition, IL6 has emerged as a factor involved in insulin resistance. In obesity, adipose tissue infiltrated by immune cells starts producing excessive amount of IL6. In the liver, IL6 inhibits insulin signaling leading to insulin resistance. This effect is mediated through the JAK/STAT pathway. IL6-induced activation of STAT3 leads to the up-regulation of SOCS3. Outcome effects: SOCS3 is a negative regulator of insulin signaling. Some other downstream targets of IL6, such as MAPK8, NOS2, and PTPN1, can also affect activity of the immediate targets of the insulin receptor (insulin receptor substrates), blocking insulin's action. However, in muscles, IL6 can be beneficial for insulin signaling. Increased IL6 production caused by muscle contraction stimulates AMPK that can increase glucose uptake and repress MTOR, thereby abolishing its negative regulation of insulin receptor substrates. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e09416-0922-45a9-9654-23e9cf539f08 NodeType: Pathway Organ: colon Organ: intestine Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-d9e09416-0922-45a9-9654-23e9cf539f08 Genes with Susceptibility for Crohn's Disease and Ulcerative Colitis uuid-d9e09416-0922-45a9-9654-23e9cf539f08 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e09416-0922-45a9-9654-23e9cf539f08 PS:NodeType Pathway PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e5b30b-f75f-4e15-a4a7-a3a7071a11ea NodeType: Pathway Notes: In general the mechanisms promoting pain in DN are poorly understood. There is increasing evidence that alterations to the somatosensory nervous system drive sustained pain. Changes in nociceptors located in the skin and the associated activation of the brain leads to neuropathic pain. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-d9e5b30b-f75f-4e15-a4a7-a3a7071a11ea 3_Pain perception in diabetic neuropathy uuid-d9e5b30b-f75f-4e15-a4a7-a3a7071a11ea PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-d9e5b30b-f75f-4e15-a4a7-a3a7071a11ea PS:NodeType Pathway PS:Notes In general the mechanisms promoting pain in DN are poorly understood. There is increasing evidence that alterations to the somatosensory nervous system drive sustained pain. Changes in nociceptors located in the skin and the associated activation of the brain leads to neuropathic pain. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da047a39-c3e5-4ccf-a916-688247d1247c NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: nerve tissue urn:agi-pathway:uuid-da047a39-c3e5-4ccf-a916-688247d1247c PTGER4 -> Expression Targets in Nerve Tissue uuid-da047a39-c3e5-4ccf-a916-688247d1247c PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da047a39-c3e5-4ccf-a916-688247d1247c PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Cigarette smoke induces both autophagy and apoptosis in alveolar epithelial cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da0afc41-bca2-47fc-b7f4-4c64778191da NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: Cigarette smoke induces both autophagy and apoptosis in alveolar epithelial cells. In lung tissue from patients with chronic obstructive pulmonary disease (COPD), autophagy is promoted by increased autophagic vacuoles and activation of autophagic proteins such as ATG4B, ATG5-ATG12, and ATG7. Cigarette smoke induces endoplasmic reticulum (ER) stress response and autophagy through the activation of EIF2AK3, ATF4, and ATF6. The autophagic protein, MAP1LC3B has a pivotal role not only in autophagy, but also in apoptosis since it associates with the extrinsic apoptotic factor, FAS. The MAP1LC3B promoter has binding sites for EGR1 and E2F4 transcription factors. Both factors have been shown to bind to the MAP1LC3B promoter in response to cigarette smoke extract in epithelial cells. Outcome effects: BECN1 interacts with anti-apoptotic BCL2 family members including BCL2 and BCL2L1. The binding of BCL2 family proteins to BECN1 inhibits autophagy by preventing the association of BECN1 with PIK3C3. Autophagy induction correlates with the dissociation of BECN1 from BCL2 or BCL2L1. Organ: lung Organ_System: respiratory system PMID: 18079489 PMID: 18841140 PMID: 19066468 PMID: 20160144 PMID: 20923337 PMID: 21182587 PMID: 21311563 PMID: 21697995 PMID: 22697344 PMID: 23956502 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-da0afc41-bca2-47fc-b7f4-4c64778191da Alveolar Epithelial Cell Autophagy in COPD uuid-da0afc41-bca2-47fc-b7f4-4c64778191da PS:CellType epithelial cell PS:Description Cigarette smoke induces both autophagy and apoptosis in alveolar epithelial cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da0afc41-bca2-47fc-b7f4-4c64778191da PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: Cigarette smoke induces both autophagy and apoptosis in alveolar epithelial cells. In lung tissue from patients with chronic obstructive pulmonary disease (COPD), autophagy is promoted by increased autophagic vacuoles and activation of autophagic proteins such as ATG4B, ATG5-ATG12, and ATG7. Cigarette smoke induces endoplasmic reticulum (ER) stress response and autophagy through the activation of EIF2AK3, ATF4, and ATF6. The autophagic protein, MAP1LC3B has a pivotal role not only in autophagy, but also in apoptosis since it associates with the extrinsic apoptotic factor, FAS. The MAP1LC3B promoter has binding sites for EGR1 and E2F4 transcription factors. Both factors have been shown to bind to the MAP1LC3B promoter in response to cigarette smoke extract in epithelial cells. Outcome effects: BECN1 interacts with anti-apoptotic BCL2 family members including BCL2 and BCL2L1. The binding of BCL2 family proteins to BECN1 inhibits autophagy by preventing the association of BECN1 with PIK3C3. Autophagy induction correlates with the dissociation of BECN1 from BCL2 or BCL2L1. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18079489 PS:PMID 18841140 PS:PMID 19066468 PS:PMID 20160144 PS:PMID 20923337 PS:PMID 21182587 PS:PMID 21311563 PS:PMID 21697995 PS:PMID 22697344 PS:PMID 23956502 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: keratinocyte Description: E1 and E2 are early HPV proteins and their expression is required for the replication of viral DNA. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da1c1dbc-aabf-487a-8f0c-58e79578ee19 NodeType: Pathway Notes: Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode two viral oncogenes, HPV16-E6 and HPV16-E7, which can inhibit TP53 and RB1, respectively leading to dysregulation of cell proliferation. The transcription of E6 and E7 is negatively regulated by the viral HPV16-E2 protein, which binds directly to their promoter. In 62% of late stages of cervical carcinomas associated with HPV (types 16, 18, 31, 33, and 45), the viral DNA is integrated into the host cell genome and causes the disruption of the E2 open reading frame and uncontrolled E6 and E7 expression. E1 and E2 are early viral proteins and their expression is required for the replication of viral DNA. E1 binds to and recruits cellular replication proteins to the viral origin of replication, including alpha DNA polymeraseprimase, replication factor A, and human topoisomerase I (TOP1). E2 binds DNA as a homodimer, with a helix of each monomer contacting two consecutive major grooves of its target site. Strong interactions of high-risk HPV E2 with CDC20 and CDH1, the activators of APC/C, result in the stabilization of some APC/C substrates including CCNB2 and AURKA. Outcome effects: The overexpression of AURKA causes excessive centrosome duplication and genome instability. The blocking of APC/C by E2 also stabilizes SKP2 which leads to increased levels of SKP2 before the cell reaches the G1/S transition. Through negative feedback loop, the accumulation of SKP2 by E2 leads to E2 degradation via the SCF/SKP2 complex.SCF (SKP1/ CUL1/F-box) is a ring-finger ubiquitin ligase composed of four subunits: three invariable components (RBX1, CUL1, and SKP1) and one variable component, specifically, F-box protein SKP2, that binds directly to the substrates. The overexpression of SKP2 also leads to the activation of E2F transcription factors that are required for G1/S transition. The maximum expression of E2 is observed in the G1 phase. This change of E2 expression is explained by its degradation through SCF (SKP2) ubiquitin ligase in late G1 phase. Differentiated cells express SKP2, unlike proliferating cells. This explains why E2 accumulates in the granular layer of HPV-associated cervical intraepithelial neoplasia (CIN) cases and is not detected in proliferating cells of the basal layer. APC/C inhibition and thus stabilization of SKP2 are induced at very low levels of E2, whereas E2-induced apoptosis necessitates higher levels of expression. The interaction of E2 with BRD4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in HPV-infected cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Exogenous proteins are shown in grey. Organ: skin PMID: 19828607 PMID: 23263171 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-da1c1dbc-aabf-487a-8f0c-58e79578ee19 HPV E1 and E2 Expression in Early Phase of Cancer uuid-da1c1dbc-aabf-487a-8f0c-58e79578ee19 PS:CellType cancer cell PS:CellType keratinocyte PS:Description E1 and E2 are early HPV proteins and their expression is required for the replication of viral DNA. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da1c1dbc-aabf-487a-8f0c-58e79578ee19 PS:NodeType Pathway PS:Notes Headnote: Human papillomaviruses (HPVs) are small DNA viruses that infect differentiated stratified epithelia. They induce benign lesions such as cervical carcinomas depending on the HPV type. Signaling description: HPVs encode two viral oncogenes, HPV16-E6 and HPV16-E7, which can inhibit TP53 and RB1, respectively leading to dysregulation of cell proliferation. The transcription of E6 and E7 is negatively regulated by the viral HPV16-E2 protein, which binds directly to their promoter. In 62% of late stages of cervical carcinomas associated with HPV (types 16, 18, 31, 33, and 45), the viral DNA is integrated into the host cell genome and causes the disruption of the E2 open reading frame and uncontrolled E6 and E7 expression. E1 and E2 are early viral proteins and their expression is required for the replication of viral DNA. E1 binds to and recruits cellular replication proteins to the viral origin of replication, including alpha DNA polymeraseprimase, replication factor A, and human topoisomerase I (TOP1). E2 binds DNA as a homodimer, with a helix of each monomer contacting two consecutive major grooves of its target site. Strong interactions of high-risk HPV E2 with CDC20 and CDH1, the activators of APC/C, result in the stabilization of some APC/C substrates including CCNB2 and AURKA. Outcome effects: The overexpression of AURKA causes excessive centrosome duplication and genome instability. The blocking of APC/C by E2 also stabilizes SKP2 which leads to increased levels of SKP2 before the cell reaches the G1/S transition. Through negative feedback loop, the accumulation of SKP2 by E2 leads to E2 degradation via the SCF/SKP2 complex.SCF (SKP1/ CUL1/F-box) is a ring-finger ubiquitin ligase composed of four subunits: three invariable components (RBX1, CUL1, and SKP1) and one variable component, specifically, F-box protein SKP2, that binds directly to the substrates. The overexpression of SKP2 also leads to the activation of E2F transcription factors that are required for G1/S transition. The maximum expression of E2 is observed in the G1 phase. This change of E2 expression is explained by its degradation through SCF (SKP2) ubiquitin ligase in late G1 phase. Differentiated cells express SKP2, unlike proliferating cells. This explains why E2 accumulates in the granular layer of HPV-associated cervical intraepithelial neoplasia (CIN) cases and is not detected in proliferating cells of the basal layer. APC/C inhibition and thus stabilization of SKP2 are induced at very low levels of E2, whereas E2-induced apoptosis necessitates higher levels of expression. The interaction of E2 with BRD4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in HPV-infected cells. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Exogenous proteins are shown in grey. PS:Organ skin PS:PMID 19828607 PS:PMID 23263171 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da65e2df-10db-4f86-895e-11e938b068c3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-da65e2df-10db-4f86-895e-11e938b068c3 Phosphatidyl ethanolamine metabolism template uuid-da65e2df-10db-4f86-895e-11e938b068c3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da65e2df-10db-4f86-895e-11e938b068c3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: pituitary cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da6b55a7-ecea-4696-b055-215b64245749 NodeType: Pathway Notes: Headnote: Activins and inhibins are produced in the ovary. Activins and inhibins are structurally related complexes. Activin is a homodimer of two b subunits and antagonizes the effect of inhibin. Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB).The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. Outcome effects: Activins and inhibins play important role in regulating ovarian function either as modulators of pituitary FSH synthesis or as a paracrine factors in the ovary. Follistatin which is produced locally in pituitary gland blocks activin action. Organ: pituitary gland Organ_System: reproductive system PMID: 15451565 PMID: 16885530 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-da6b55a7-ecea-4696-b055-215b64245749 Activin, Inhibin and Follistatin Action on Pituitary Gland uuid-da6b55a7-ecea-4696-b055-215b64245749 PS:CellType pituitary cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da6b55a7-ecea-4696-b055-215b64245749 PS:NodeType Pathway PS:Notes Headnote: Activins and inhibins are produced in the ovary. Activins and inhibins are structurally related complexes. Activin is a homodimer of two b subunits and antagonizes the effect of inhibin. Inhibin consists of alpha (a) and beta (b) subunits. The b-subunit is of two types, A and B. Thus there are two forms of inhibin: inhibin A (a-bA) and inhibin B (a-bB).The genes INHA, INHBA and INHBB encode for inhibin a, inhibin bA and inhibin bB subunits, respectively. Outcome effects: Activins and inhibins play important role in regulating ovarian function either as modulators of pituitary FSH synthesis or as a paracrine factors in the ovary. Follistatin which is produced locally in pituitary gland blocks activin action. PS:Organ pituitary gland PS:Organ_System reproductive system PS:PMID 15451565 PS:PMID 16885530 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7182b6-fe92-4ec7-aa32-45bc4e92206f NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-da7182b6-fe92-4ec7-aa32-45bc4e92206f CD40 -> Expression Targets in Lymph Node uuid-da7182b6-fe92-4ec7-aa32-45bc4e92206f PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7182b6-fe92-4ec7-aa32-45bc4e92206f PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7435a7-339b-4c49-b7a3-832ce6061c93 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-da7435a7-339b-4c49-b7a3-832ce6061c93 GNRH1 Expression Targets uuid-da7435a7-339b-4c49-b7a3-832ce6061c93 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7435a7-339b-4c49-b7a3-832ce6061c93 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Melatonin is synthesized from L-tryptophan by the actions of four enzymes including TPH2, DDC, AANAT, and ASMT. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7d5645-fc6c-4a5c-98d2-c56065f2dbfa NodeType: Pathway Notes: Headnote: Melatonin is synthesized from L-tryptophan through the actions of four enzymes including TPH2, DDC, AANAT, and ASMT. Signaling description: TPH2 is responsible for the 5' hydroxylation of tryptophan yielding 5-hydroxytryptophan. DDC converts 5-hydroxytryptophan to 5-hydroxytryptamine, while AANAT acetylates serotonin to form N-acetylserotonin. ASMT catalyzes the conversion of N-acetylserotonin to melatonin. The 24-hour oscillations in AANAT activity and melatonin production are driven by the master circadian clock in the anterior hypothalamus, which is the suprachiasmatic nucleus (SCN). Outcome effects: At night during darkness, retinal ganglion cells send a signal to SCN and then SCN sends a signal to the paraventricular nucleus, intermediolateral cell column, and superior cervical ganglion. The signal comes to the pineal gland as a release of noradrenaline from post-ganglionic sympathetic nerve endings onto the pinealocytes, which initiates and sustains, primarily via ADRB1, elevated melatonin production. ADRB1 sends a signal to AANAT via GNAS, adenylate cyclase (ADCY), PKA, and CREB1. Following synthesis, melatonin is secreted from the pineal gland into the blood. Importantly, the pineal gland does not store residual amounts of its secretory product (melatonin) as other endocrine glands do. Organ: brain Organ_System: nervous system PMID: 20478436 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-da7d5645-fc6c-4a5c-98d2-c56065f2dbfa Melatonin Synthesis in Pinealocytes uuid-da7d5645-fc6c-4a5c-98d2-c56065f2dbfa PS:CellType neuron PS:Description Melatonin is synthesized from L-tryptophan by the actions of four enzymes including TPH2, DDC, AANAT, and ASMT. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da7d5645-fc6c-4a5c-98d2-c56065f2dbfa PS:NodeType Pathway PS:Notes Headnote: Melatonin is synthesized from L-tryptophan through the actions of four enzymes including TPH2, DDC, AANAT, and ASMT. Signaling description: TPH2 is responsible for the 5' hydroxylation of tryptophan yielding 5-hydroxytryptophan. DDC converts 5-hydroxytryptophan to 5-hydroxytryptamine, while AANAT acetylates serotonin to form N-acetylserotonin. ASMT catalyzes the conversion of N-acetylserotonin to melatonin. The 24-hour oscillations in AANAT activity and melatonin production are driven by the master circadian clock in the anterior hypothalamus, which is the suprachiasmatic nucleus (SCN). Outcome effects: At night during darkness, retinal ganglion cells send a signal to SCN and then SCN sends a signal to the paraventricular nucleus, intermediolateral cell column, and superior cervical ganglion. The signal comes to the pineal gland as a release of noradrenaline from post-ganglionic sympathetic nerve endings onto the pinealocytes, which initiates and sustains, primarily via ADRB1, elevated melatonin production. ADRB1 sends a signal to AANAT via GNAS, adenylate cyclase (ADCY), PKA, and CREB1. Following synthesis, melatonin is secreted from the pineal gland into the blood. Importantly, the pineal gland does not store residual amounts of its secretory product (melatonin) as other endocrine glands do. PS:Organ brain PS:Organ_System nervous system PS:PMID 20478436 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da963cfc-e06e-4158-841b-cc272308ea8c NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-da963cfc-e06e-4158-841b-cc272308ea8c AGTR1 -> ARRB1/ARRB2 Signaling uuid-da963cfc-e06e-4158-841b-cc272308ea8c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-da963cfc-e06e-4158-841b-cc272308ea8c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dacd0d07-a597-4e9c-9956-0a4be6433642 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-dacd0d07-a597-4e9c-9956-0a4be6433642 CD8 -> ATF/CREB/CREBBP Expression Targets uuid-dacd0d07-a597-4e9c-9956-0a4be6433642 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dacd0d07-a597-4e9c-9956-0a4be6433642 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-daff1562-19c6-4907-b97f-21bd9dc1f777 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Source: Diseases urn:agi-pathway:uuid-daff1562-19c6-4907-b97f-21bd9dc1f777 Proteins with Altered Expression in Polycystic Ovary Syndrome uuid-daff1562-19c6-4907-b97f-21bd9dc1f777 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-daff1562-19c6-4907-b97f-21bd9dc1f777 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Aldosterone regulates Na+ and Cl- reabsorption and K+ excretion in nephrons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db0a2b45-0cd7-49e3-bff2-d330d5823731 NodeType: Pathway Notes: Headnote: Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in nephrons and is responsible for Na+ reabsorption into plasma and K+ excretion in the distal renal tubule. The transport of Na+ and K+ has a dominant role in blood pressure regulation. Signaling description: Non-voltage gated sodium channels SCNN1A/1B/1G and kidney-specific SLC12A1/A3 and KCNJ1 play a key role in Na+, Cl-, and K+ ion homeostasis. These channels control electrolyte transport across epithelia in nephrons which are responsible for Na+ and Cl- reabsorption into plasma and K+ excretion. Aldosterone modulates the activity of these channels in kidney. Aldosterone binds to NR3C2, which interacts with NR3C1, and they both function as transcription factors that bind to corticoid response elements in the promoters of corticoid responsive genes to activate their transcription. NR3C1 promotes TSC22D3 which increases the transcription of SGK1. Subsequently, SGK1 phosphorylates NEDD4L which mediates the ubiquitination of multiple target substrates and has a critical role in epithelial Na+ transport. WNK1/4 control the transport of Na+ and Cl- ions via activation of STK39 and OXSR1 that stimulate SLC12A1 and SLC12A3. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Aldosterone regulates Na+ and Cl- reabsorption and K+ excretion in nephrons. Organ: collecting tubule Organ: kidney Organ: nephron Organ_System: urinary tract PMID: 19690383 PMID: 21436285 PMID: 28341694 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-db0a2b45-0cd7-49e3-bff2-d330d5823731 Aldosterone Renal Effects uuid-db0a2b45-0cd7-49e3-bff2-d330d5823731 PS:CellType epithelial cell PS:Description Aldosterone regulates Na+ and Cl- reabsorption and K+ excretion in nephrons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db0a2b45-0cd7-49e3-bff2-d330d5823731 PS:NodeType Pathway PS:Notes Headnote: Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in nephrons and is responsible for Na+ reabsorption into plasma and K+ excretion in the distal renal tubule. The transport of Na+ and K+ has a dominant role in blood pressure regulation. Signaling description: Non-voltage gated sodium channels SCNN1A/1B/1G and kidney-specific SLC12A1/A3 and KCNJ1 play a key role in Na+, Cl-, and K+ ion homeostasis. These channels control electrolyte transport across epithelia in nephrons which are responsible for Na+ and Cl- reabsorption into plasma and K+ excretion. Aldosterone modulates the activity of these channels in kidney. Aldosterone binds to NR3C2, which interacts with NR3C1, and they both function as transcription factors that bind to corticoid response elements in the promoters of corticoid responsive genes to activate their transcription. NR3C1 promotes TSC22D3 which increases the transcription of SGK1. Subsequently, SGK1 phosphorylates NEDD4L which mediates the ubiquitination of multiple target substrates and has a critical role in epithelial Na+ transport. WNK1/4 control the transport of Na+ and Cl- ions via activation of STK39 and OXSR1 that stimulate SLC12A1 and SLC12A3. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: Aldosterone regulates Na+ and Cl- reabsorption and K+ excretion in nephrons. PS:Organ collecting tubule PS:Organ kidney PS:Organ nephron PS:Organ_System urinary tract PS:PMID 19690383 PS:PMID 21436285 PS:PMID 28341694 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db11ebce-d037-41c9-959c-e842c4cff2d5 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-db11ebce-d037-41c9-959c-e842c4cff2d5 Genes with Mutations Associated with Osteoporosis uuid-db11ebce-d037-41c9-959c-e842c4cff2d5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db11ebce-d037-41c9-959c-e842c4cff2d5 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db692d42-17fa-4931-b88b-5579b19900e3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-db692d42-17fa-4931-b88b-5579b19900e3 Ubiquinone-8 biosynthesis template uuid-db692d42-17fa-4931-b88b-5579b19900e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db692d42-17fa-4931-b88b-5579b19900e3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db6fcd44-7029-45d5-8bf4-587f60cf3fd6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-db6fcd44-7029-45d5-8bf4-587f60cf3fd6 SARS hijacks cyclophilin A to enhance cell attachment uuid-db6fcd44-7029-45d5-8bf4-587f60cf3fd6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db6fcd44-7029-45d5-8bf4-587f60cf3fd6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db75c379-79c5-49c5-83bf-084431e791fc NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-db75c379-79c5-49c5-83bf-084431e791fc Hereditary Breast and Ovarian Cancer Syndrome Anatomy and Molecular Biomarkers uuid-db75c379-79c5-49c5-83bf-084431e791fc PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db75c379-79c5-49c5-83bf-084431e791fc PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Mutations in several genes including TARDBP, FUS, SETX, ANG, C9orf72, and TAF15 which are responsible for RNA transcription, processing, and splicing or DNA repair are involved in ALS pathogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db770053-933a-427c-bb51-6e78ddfa8e0f NodeType: Pathway Notes: Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Mutations in a number of genes including TARDBP, FUS, SETX, ANG, C9orf72, and TAF15 are related to ALS pathogenesis. TAR DNA-binding protein 43 (TARDBP) is implicated in multiple aspects of RNA processing including transcriptional regulation and alternative splicing via interactions with ADARB1, SRSF2, HNRNPA2B1, and other proteins. Fused in sarcoma protein (FUS) is an RNA-DNA-binding protein that is involved in transcriptional regulation and RNA processing. FUS associates with multiple splicing factors including YBX1, SRSF2, SRSF10, and HNRNPA1. FUS also associates with TBP, which is essential for RNA polymerase I, II, and III transcription activation. Both TARDBP and FUS are involved in microRNA processing. Both associate with DROSHA, the nuclear RNase III-type protein that mediates the first step in microRNA maturation. In addition, TARDBP may be involved in the cytoplasmic cleavage step of microRNA biogenesis by its association with DDX17. TARDBP and FUS also form insoluble toxic aggregates. It is unclear whether the motor neuron injury in ALS is caused by a loss of normal nuclear functions of TARDBP and FUS in RNA processing or by toxic gains of function or both. Senataxin (SETX) is a component of large ribonucleoprotein complexes and is involved in maintaining DNA repair and RNA processing. SETX mutation affects the function of RNA polymerase I and II. Furthermore, TAF15 interacts with the components of the RNA polymerase II complex. Angiogenin (ANG) acts as a transfer RNA-specific ribonuclease and regulates ribosomal RNA transcription; thereby ANG acts as a permissive factor for other angiogenic proteins. Outcome effects: A number of genes which are responsible for RNA transcription, processing, and splicing or DNA repair were shown to be mutated in ALS. Their association with ALS indicates an important role for these fundamental molecular processes in neurodegeneration. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ: spinal cord Organ_System: nervous system PMID: 16924260 PMID: 18781822 PMID: 20400460 PMID: 22051914 PMID: 22444279 PMID: 22482452 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-db770053-933a-427c-bb51-6e78ddfa8e0f RNA and DNA Metabolism Dysregulation uuid-db770053-933a-427c-bb51-6e78ddfa8e0f PS:CellType neuron PS:Description Mutations in several genes including TARDBP, FUS, SETX, ANG, C9orf72, and TAF15 which are responsible for RNA transcription, processing, and splicing or DNA repair are involved in ALS pathogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db770053-933a-427c-bb51-6e78ddfa8e0f PS:NodeType Pathway PS:Notes Headnote: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative lethal disorder of both the upper and lower motor neurons leading to progressive atrophy and paralysis of skeletal muscles. Signaling description: Mutations in a number of genes including TARDBP, FUS, SETX, ANG, C9orf72, and TAF15 are related to ALS pathogenesis. TAR DNA-binding protein 43 (TARDBP) is implicated in multiple aspects of RNA processing including transcriptional regulation and alternative splicing via interactions with ADARB1, SRSF2, HNRNPA2B1, and other proteins. Fused in sarcoma protein (FUS) is an RNA-DNA-binding protein that is involved in transcriptional regulation and RNA processing. FUS associates with multiple splicing factors including YBX1, SRSF2, SRSF10, and HNRNPA1. FUS also associates with TBP, which is essential for RNA polymerase I, II, and III transcription activation. Both TARDBP and FUS are involved in microRNA processing. Both associate with DROSHA, the nuclear RNase III-type protein that mediates the first step in microRNA maturation. In addition, TARDBP may be involved in the cytoplasmic cleavage step of microRNA biogenesis by its association with DDX17. TARDBP and FUS also form insoluble toxic aggregates. It is unclear whether the motor neuron injury in ALS is caused by a loss of normal nuclear functions of TARDBP and FUS in RNA processing or by toxic gains of function or both. Senataxin (SETX) is a component of large ribonucleoprotein complexes and is involved in maintaining DNA repair and RNA processing. SETX mutation affects the function of RNA polymerase I and II. Furthermore, TAF15 interacts with the components of the RNA polymerase II complex. Angiogenin (ANG) acts as a transfer RNA-specific ribonuclease and regulates ribosomal RNA transcription; thereby ANG acts as a permissive factor for other angiogenic proteins. Outcome effects: A number of genes which are responsible for RNA transcription, processing, and splicing or DNA repair were shown to be mutated in ALS. Their association with ALS indicates an important role for these fundamental molecular processes in neurodegeneration. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ spinal cord PS:Organ_System nervous system PS:PMID 16924260 PS:PMID 18781822 PS:PMID 20400460 PS:PMID 22051914 PS:PMID 22444279 PS:PMID 22482452 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db9bdd9c-11ff-4620-95dd-c6aec8e44011 NodeType: Pathway Notes: Headnote: Noise-induced hearing loss (NIHL) is the result of prolonged exposure to excessive noise that damages cochlear sensory hair cells. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. Genetic variations of PCDH15 are associated with susceptibility to NIHL. Outcome effects: K+ exits the hair cells through KCNQ4 and KCNMA1 channels, and single nucleotide polymorphisms (SNPs) in KCNQ4 are strongly associated with NIHL. Further, K+ is taken up via KCNJ10 by supporting Deiters cells and exported by SLC12A6 and SLC12A7. Fibrocytes in the lateral wall of the cochlea are connected by gap junctions. Most likely K+ is transported through these gap junctions from cell to cell. The common GJB2 (Connexin 26, gap junction protein) 35delG mutation might contribute to the development of age-related hearing impairment and NIHL. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. K+ exits through the apical channels KCNQ1 and KCNE1 back to the endolymph. SNPs in KCNQ1 and KCNE1 were shown to be strongly asscociated with NIHL. Organ: ear Organ_System: sensory system PMID: 16990454 PMID: 17670895 PMID: 17909436 PMID: 23207014 PMID: 25462672 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-db9bdd9c-11ff-4620-95dd-c6aec8e44011 Potassium Cycling in the Inner Ear (Noise-Induced) uuid-db9bdd9c-11ff-4620-95dd-c6aec8e44011 PS:CellType sensory hair cell PS:Description Hearing depends on a high K concentration in endolymph, bathing the apical membranes of sensory hair cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-db9bdd9c-11ff-4620-95dd-c6aec8e44011 PS:NodeType Pathway PS:Notes Headnote: Noise-induced hearing loss (NIHL) is the result of prolonged exposure to excessive noise that damages cochlear sensory hair cells. Signaling description: Hearing depends on a high K+ concentration in the endolymph bathing the apical membranes of sensory hair cells. During sound stimulation, K+ enters the hair cells via apical mechanoelectrical transducer channels (MTCs). TMC1, TMC2, LHFPL5, PCDH15 and TMIE proteins are likely to be involved in the organization of MTCs, although the exact molecular composition of the MTCs is yet to be completely elucidated. Genetic variations of PCDH15 are associated with susceptibility to NIHL. Outcome effects: K+ exits the hair cells through KCNQ4 and KCNMA1 channels, and single nucleotide polymorphisms (SNPs) in KCNQ4 are strongly associated with NIHL. Further, K+ is taken up via KCNJ10 by supporting Deiters cells and exported by SLC12A6 and SLC12A7. Fibrocytes in the lateral wall of the cochlea are connected by gap junctions. Most likely K+ is transported through these gap junctions from cell to cell. The common GJB2 (Connexin 26, gap junction protein) 35delG mutation might contribute to the development of age-related hearing impairment and NIHL. In strial vascularis marginal cells, SLC12A2 (NKCC1), ATP1A1 and ATP1A2 raise intracellular K+ concentration. In parallel, CLCNKA/ BSND and CLCNKB/ BSND channels recycle Cl-. K+ exits through the apical channels KCNQ1 and KCNE1 back to the endolymph. SNPs in KCNQ1 and KCNE1 were shown to be strongly asscociated with NIHL. PS:Organ ear PS:Organ_System sensory system PS:PMID 16990454 PS:PMID 17670895 PS:PMID 17909436 PS:PMID 23207014 PS:PMID 25462672 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: erythrocyte Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbb210c7-bf59-4438-afff-deb5b85f3f44 NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: bone marrow urn:agi-pathway:uuid-dbb210c7-bf59-4438-afff-deb5b85f3f44 Proerythroblast -> Erythrocyte Surface Expression Markers uuid-dbb210c7-bf59-4438-afff-deb5b85f3f44 PS:CellType erythrocyte PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbb210c7-bf59-4438-afff-deb5b85f3f44 PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue bone marrow PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbd9c8bf-bce0-44c6-add6-55a11cd38a7f NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: spleen Organ_System: lymphatic system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-dbd9c8bf-bce0-44c6-add6-55a11cd38a7f Elevated Receptors -> Expression Targets in Spleen uuid-dbd9c8bf-bce0-44c6-add6-55a11cd38a7f PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbd9c8bf-bce0-44c6-add6-55a11cd38a7f PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ spleen PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: GPCRs are able to utilize the EGFR as a downstream signalling partner in the generation of mitogenic signals Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbe0241d-5bd3-44ff-abc8-0fd4421336ff NodeType: Pathway Notes: Headnote: GPCRs (G-protein-coupled receptors) are able to utilize the EGFR (epidermal growth factor receptor) as a downstream signaling partner in mitogenic signal generation. Signaling description: The EGFR is essential for the regulation of normal cellular functions, as well as pathological processes that underlie the development of hyperproliferative diseases including cancer. GPCRs stimulation leads to activation of second messengers, such as PKC, SRC, PTK2B, Ca2+ and other molecules. GPCR signaling activates EGRF via the 'triple-membrane-passing-signaling' mechanism, in which second messengers activate membrane-bound MMPs (e. g. ADAM family members) which cleave EGF ligands that bind to EGFR (and other EGFR family members) and promote dimerization and activation of EGFR. Outcome effects: The activation of EGFR promotes the subsequent activation of signaling cascades including the MAPK pathway and the PI3K/AKT pathway, which ultimately stimulates essential cellular responses including cell proliferation, migration, invasion and survival (for details see the "EGFR Signaling" pathway). Animal data: Some data were obtained from animal experiments or human cancer lines. Analysis of GPCR-induced EGFR activation in more than 60 human carcinoma cell lines derived from different tissues has demonstrated broad relevance of this signaling mechanism in cancer. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 14641026 PMID: 23992425 PMID: 25563590 PMID: 26771606 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-dbe0241d-5bd3-44ff-abc8-0fd4421336ff EGFR Transactivation in Cancer and Non-Cancer Cells uuid-dbe0241d-5bd3-44ff-abc8-0fd4421336ff PS:CellType cancer cell PS:CellType cancer stem cell PS:Description GPCRs are able to utilize the EGFR as a downstream signalling partner in the generation of mitogenic signals PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbe0241d-5bd3-44ff-abc8-0fd4421336ff PS:NodeType Pathway PS:Notes Headnote: GPCRs (G-protein-coupled receptors) are able to utilize the EGFR (epidermal growth factor receptor) as a downstream signaling partner in mitogenic signal generation. Signaling description: The EGFR is essential for the regulation of normal cellular functions, as well as pathological processes that underlie the development of hyperproliferative diseases including cancer. GPCRs stimulation leads to activation of second messengers, such as PKC, SRC, PTK2B, Ca2+ and other molecules. GPCR signaling activates EGRF via the 'triple-membrane-passing-signaling' mechanism, in which second messengers activate membrane-bound MMPs (e. g. ADAM family members) which cleave EGF ligands that bind to EGFR (and other EGFR family members) and promote dimerization and activation of EGFR. Outcome effects: The activation of EGFR promotes the subsequent activation of signaling cascades including the MAPK pathway and the PI3K/AKT pathway, which ultimately stimulates essential cellular responses including cell proliferation, migration, invasion and survival (for details see the "EGFR Signaling" pathway). Animal data: Some data were obtained from animal experiments or human cancer lines. Analysis of GPCR-induced EGFR activation in more than 60 human carcinoma cell lines derived from different tissues has demonstrated broad relevance of this signaling mechanism in cancer. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 14641026 PS:PMID 23992425 PS:PMID 25563590 PS:PMID 26771606 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Neoplastic cells de-repress telomerase expression to support immortalization and tumor formation. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbe6c34b-b638-449b-9afa-bf21bc845b8e NodeType: Pathway Notes: Headnote: Telomerase (TERT) is an enzyme expressed during the embryonic development that catalyzes the addition of telomere repeats to chromosome ends. Most neoplastic cells de-repress telomerase expression to support immortalization and tumor formation, although some neoplastic cells use telomere recombination or the mechanism of alternative lengthening of telomeres (ALT). Signaling description: There exist multiple mechanisms of TERT re-activation. A number of transcription factors over-expressed in different tumors are responsible for TERT expression. These include MYC, SP1, STAT3, CTNNB2 and many others. Different oncogenic viral proteins participate in direct or indirect TERT re-activation, including HTLV-1 protein tax, EBV protein LMP1, HPV proteins HPV16-E6/7, KSHV protein ORF73, HBV protein HBx, HCMV protein UL123. In rare cancer cases, TERT may also have activating mutations. Outcome effects: TERT catalyzes the addition of telomere repeats to chromosome ends supporting cancer cell immortalization. Animal data: Some of the data were obtained from experiments on animals. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Enabling of Replicative Immortality" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21346783 PMID: 22381618 PMID: 23993966 PMID: 26846696 PMID: 27438857 PMID: 27483324 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-dbe6c34b-b638-449b-9afa-bf21bc845b8e TERT Activation in Cancer uuid-dbe6c34b-b638-449b-9afa-bf21bc845b8e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Neoplastic cells de-repress telomerase expression to support immortalization and tumor formation. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbe6c34b-b638-449b-9afa-bf21bc845b8e PS:NodeType Pathway PS:Notes Headnote: Telomerase (TERT) is an enzyme expressed during the embryonic development that catalyzes the addition of telomere repeats to chromosome ends. Most neoplastic cells de-repress telomerase expression to support immortalization and tumor formation, although some neoplastic cells use telomere recombination or the mechanism of alternative lengthening of telomeres (ALT). Signaling description: There exist multiple mechanisms of TERT re-activation. A number of transcription factors over-expressed in different tumors are responsible for TERT expression. These include MYC, SP1, STAT3, CTNNB2 and many others. Different oncogenic viral proteins participate in direct or indirect TERT re-activation, including HTLV-1 protein tax, EBV protein LMP1, HPV proteins HPV16-E6/7, KSHV protein ORF73, HBV protein HBx, HCMV protein UL123. In rare cancer cases, TERT may also have activating mutations. Outcome effects: TERT catalyzes the addition of telomere repeats to chromosome ends supporting cancer cell immortalization. Animal data: Some of the data were obtained from experiments on animals. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Enabling of Replicative Immortality" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Enabling of Replicative Immortality" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21346783 PS:PMID 22381618 PS:PMID 23993966 PS:PMID 26846696 PS:PMID 27438857 PS:PMID 27483324 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbfdc7c9-c4ad-456e-8915-d4a1ab89e783 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-dbfdc7c9-c4ad-456e-8915-d4a1ab89e783 CO2 fixation (Wood–Ljungdahl) template uuid-dbfdc7c9-c4ad-456e-8915-d4a1ab89e783 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbfdc7c9-c4ad-456e-8915-d4a1ab89e783 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: parathyroid cell Description: Germline-inactivating mutations in MEN1 are associated with familial form of primary hyperparathyroidism and Multiple Endocrine Neoplasia Type 1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbffc5cc-70a9-43eb-90a9-7fc02c017378 NodeType: Pathway Notes: Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-inactivating mutations in MEN1 are associated with familial form of primary hyperparathyroidism and multiple endocrine neoplasia type 1. Outcome effects: Mutations in MEN1 cause the disruption of DNA repair, chromatin remodeling and cell cycle regulation. Organ: Parathyroid gland Organ_System: endocrine system PMID: 14992727 PMID: 15640349 PMID: 22016823 PMID: 23652676 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-dbffc5cc-70a9-43eb-90a9-7fc02c017378 MEN1 Mutation in Hyperparathyroidism uuid-dbffc5cc-70a9-43eb-90a9-7fc02c017378 PS:CellType parathyroid cell PS:Description Germline-inactivating mutations in MEN1 are associated with familial form of primary hyperparathyroidism and Multiple Endocrine Neoplasia Type 1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dbffc5cc-70a9-43eb-90a9-7fc02c017378 PS:NodeType Pathway PS:Notes Headnote: Primary hyperparathyroidism is a common endocrine disorder caused primarily by tumors in the parathyroid glands. In primary hyperparathyroidism, the parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone (PTH). Signaling description: The most common cause of primary hyperparathyroidism is a mutation in one the following genes: menin (MEN1 syndrome), RET proto-oncogene (MEN2 syndrome) and HRPT2-parafibromin (hyperparathyroidism-jaw tumor syndrome). Germline-inactivating mutations in MEN1 are associated with familial form of primary hyperparathyroidism and multiple endocrine neoplasia type 1. Outcome effects: Mutations in MEN1 cause the disruption of DNA repair, chromatin remodeling and cell cycle regulation. PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PMID 14992727 PS:PMID 15640349 PS:PMID 22016823 PS:PMID 23652676 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Abnormal autophagy and proteins degradation by lysosome are documented in aging and lead to the accumulation of cross-linked products and cell damage. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc0e93a7-52d3-4534-a77e-9be87bde0eea NodeType: Pathway Notes: Headnote: Autophagy is the process of utilization of worn-out long-lived proteins and organelles. Abnormal autophagy and protein degradation by lysosomes are related to aging and lead to the accumulation of cross-linked products and cell damage. Signaling description: In chaperone-mediated autophagy (CMA), substrate proteins labeled with penta-peptide motif KFERQ and are directly transported to lysosomes by HSPA8. The activity of CMA was shown to decrease in old rodents and senescent human fibroblasts in culture. In macroautophagy, phagophora formed from ER surrounds and absorb part of the cytosol and mature to autophagosomes which then fuse with lysosome. Autophagy-related proteins (ATGs) and PIK3C3C with BECN1 induce formation of the autophagosome. Induction of autophagy is negatively regulated by mTOR. Microautophagy is a poorly understood process in mammals and is not shown on the pathway. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. Organ: generic Organ_System: generic PMID: 15325579 PMID: 21884931 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-dc0e93a7-52d3-4534-a77e-9be87bde0eea Autophagic-Lysosomal System Decline Associated with Aging uuid-dc0e93a7-52d3-4534-a77e-9be87bde0eea PS:CellType generic PS:Description Abnormal autophagy and proteins degradation by lysosome are documented in aging and lead to the accumulation of cross-linked products and cell damage. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc0e93a7-52d3-4534-a77e-9be87bde0eea PS:NodeType Pathway PS:Notes Headnote: Autophagy is the process of utilization of worn-out long-lived proteins and organelles. Abnormal autophagy and protein degradation by lysosomes are related to aging and lead to the accumulation of cross-linked products and cell damage. Signaling description: In chaperone-mediated autophagy (CMA), substrate proteins labeled with penta-peptide motif KFERQ and are directly transported to lysosomes by HSPA8. The activity of CMA was shown to decrease in old rodents and senescent human fibroblasts in culture. In macroautophagy, phagophora formed from ER surrounds and absorb part of the cytosol and mature to autophagosomes which then fuse with lysosome. Autophagy-related proteins (ATGs) and PIK3C3C with BECN1 induce formation of the autophagosome. Induction of autophagy is negatively regulated by mTOR. Microautophagy is a poorly understood process in mammals and is not shown on the pathway. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. For references see "Proteins with Altered Expression in Aging" pathway. PS:Organ generic PS:Organ_System generic PS:PMID 15325579 PS:PMID 21884931 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Cancer cells show increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc3d3606-4348-400c-8ef1-501d8e1dbd06 NodeType: Pathway Notes: Headnote: Cancer cells display increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle (TCA), nucleotide and fatty acid biosynthesis, and redox balance in cancer cells, activates mTOR signaling and promotes protein synthesis. Signaling description: Glutamine enters the cell through transporters such as SLC1A5 and SLC38A5. Glutamine first loses its amide group to form glutamate by glutaminase (GLS, GLS2), which then loses its amine group to form a-ketoglutarate by glutamate dehydrogenase (GLUD1/2 or GPT). Further, a-ketoglutarate enters TCA. Acetyl-CoA obtained in TCA can be used for fatty acid synthesis. To combat oxidative stress, glutamine can be converted directly into glutathione by the enzyme glutathione cysteine ligase (GCL). Glutathione is a tripeptide composed of glutamate, cysteine and glycine. The reduced form of glutathione has an antioxidant role and is important in controlling cellular redox homeostasis. Glutamate acts as a nitrogen donor for the transamination involved in the production of 'dispensable amino acids' aspartate, alanine and serine through the actions of glutamic-oxaloacetic transaminase (GOT1/2), glutamic pyruvate transaminase (GPT) and phosphoserine aminotransferase 1 (PSAT1), respectively. Glutamine can also act as a nitrogen donor for asparagine through asparagine synthetase (ASNS). In a reaction independent of transamination, proline can be synthesized by conversion of glutamate to pyrroline-5-carboxylate by pyrroline-5-carboxylate synthase (ALDH18A1) and subsequently to proline by pyrroline-5-carboxylate reductase 1 (PYCR1). Glutamate can be exchanged for cystine (which is quickly reduced to cysteine inside the cell) by SLC7A11. Glutamine controls MTOR through the synthesis of amino acids. Specifically, arginine and isoleucine are the two amino acids that can stimulate MTOR. Glutamine can contribute to MTOR activation by being exchanged for essential amino acids, including isoleucine, through the large neutral amino acid transporter 1 (LAT1; a heterodimer of SLC7A5 and SLC3A2). The oncogene MYC regulates several steps in the glutamine metabolism. It controls the expression of SLC1A5, SLC38A5, SLC3A2, SLC7A5, PYCR1, ALDH18A1 and GLS (through MIR23A/B). Overexpressed TP63 and TP73 control GLS2 expression. The inactivating mutations in SLC7A11 induce overexpression of SLC7A11, and inactivating mutations in RB1 induce SLC1A5 overexpression. NFE2L2 controls the expression of GCL enzymes. Outcome effects: Glutamine metabolism impacts the biosynthesis of amino acids and proteins, fatty acids and nucleotides, fuels TCA and regulates redox balance by influencing the glutathione level. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" for details. Organ: oncogenic Organ_System: oncogenic PMID: 20570523 PMID: 23071355 PMID: 23897900 PMID: 23999442 PMID: 24657017 PMID: 26583064 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-dc3d3606-4348-400c-8ef1-501d8e1dbd06 Glutamine in Cancer Metabolism uuid-dc3d3606-4348-400c-8ef1-501d8e1dbd06 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Cancer cells show increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc3d3606-4348-400c-8ef1-501d8e1dbd06 PS:NodeType Pathway PS:Notes Headnote: Cancer cells display increased consumption of and dependence on glutamine. Glutamine metabolism fuels the tricarboxylic acid cycle (TCA), nucleotide and fatty acid biosynthesis, and redox balance in cancer cells, activates mTOR signaling and promotes protein synthesis. Signaling description: Glutamine enters the cell through transporters such as SLC1A5 and SLC38A5. Glutamine first loses its amide group to form glutamate by glutaminase (GLS, GLS2), which then loses its amine group to form a-ketoglutarate by glutamate dehydrogenase (GLUD1/2 or GPT). Further, a-ketoglutarate enters TCA. Acetyl-CoA obtained in TCA can be used for fatty acid synthesis. To combat oxidative stress, glutamine can be converted directly into glutathione by the enzyme glutathione cysteine ligase (GCL). Glutathione is a tripeptide composed of glutamate, cysteine and glycine. The reduced form of glutathione has an antioxidant role and is important in controlling cellular redox homeostasis. Glutamate acts as a nitrogen donor for the transamination involved in the production of 'dispensable amino acids' aspartate, alanine and serine through the actions of glutamic-oxaloacetic transaminase (GOT1/2), glutamic pyruvate transaminase (GPT) and phosphoserine aminotransferase 1 (PSAT1), respectively. Glutamine can also act as a nitrogen donor for asparagine through asparagine synthetase (ASNS). In a reaction independent of transamination, proline can be synthesized by conversion of glutamate to pyrroline-5-carboxylate by pyrroline-5-carboxylate synthase (ALDH18A1) and subsequently to proline by pyrroline-5-carboxylate reductase 1 (PYCR1). Glutamate can be exchanged for cystine (which is quickly reduced to cysteine inside the cell) by SLC7A11. Glutamine controls MTOR through the synthesis of amino acids. Specifically, arginine and isoleucine are the two amino acids that can stimulate MTOR. Glutamine can contribute to MTOR activation by being exchanged for essential amino acids, including isoleucine, through the large neutral amino acid transporter 1 (LAT1; a heterodimer of SLC7A5 and SLC3A2). The oncogene MYC regulates several steps in the glutamine metabolism. It controls the expression of SLC1A5, SLC38A5, SLC3A2, SLC7A5, PYCR1, ALDH18A1 and GLS (through MIR23A/B). Overexpressed TP63 and TP73 control GLS2 expression. The inactivating mutations in SLC7A11 induce overexpression of SLC7A11, and inactivating mutations in RB1 induce SLC1A5 overexpression. NFE2L2 controls the expression of GCL enzymes. Outcome effects: Glutamine metabolism impacts the biosynthesis of amino acids and proteins, fatty acids and nucleotides, fuels TCA and regulates redox balance by influencing the glutathione level. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 20570523 PS:PMID 23071355 PS:PMID 23897900 PS:PMID 23999442 PS:PMID 24657017 PS:PMID 26583064 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Link PS:NodeType PS:Organ PS:PMID PS:Pathway_Author PS:Tissue CellType: fibroblast Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc70fe2c-24af-4076-b55d-42fc7f1b331f NodeType: Pathway Organ: skin PMID: 17133253 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Tissue: epidermis urn:agi-pathway:uuid-dc70fe2c-24af-4076-b55d-42fc7f1b331f Blood vessels mechanical stress->fibrosis uuid-dc70fe2c-24af-4076-b55d-42fc7f1b331f PS:CellType fibroblast PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dc70fe2c-24af-4076-b55d-42fc7f1b331f PS:NodeType Pathway PS:Organ skin PS:PMID 17133253 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: leukocyte Description: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dca49e57-5d82-426d-a7f6-f13ed9d92a53 NodeType: Pathway Notes: Headnote: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. In humans, ten functional receptors (TLR1-10) have been identified. TLR5 recognizes flagellin of bacterial flagella. TLR7 and TLR8 are found in membranes of endosomes and recognize single-stranded RNA from viruses. TLR9 is also found in the membrane of endosomes and recognizes unmethylated CpG islands in bacterial and viral DNA. Outcome effects: The specific signaling cascade activated by TLRs depends of the type of cytoplasmic adaptor molecules. TLR5, TLR7, TLR8, and TLR9 act through the MYD88 pathway. The MYD88-dependent pathway leads to the activation of NF-kB, MAPK1, MAPK8, p38 MAPK (MAPK14), IRF5, and IRF7 in addition to the transcription of inflammatory genes. The details of TLR5, TLR7, TLR8, and TLR9-related signaling remain unknown. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-dca49e57-5d82-426d-a7f6-f13ed9d92a53 Toll-like Receptors Act through MYD88 Signaling uuid-dca49e57-5d82-426d-a7f6-f13ed9d92a53 PS:CellType dendritic cell PS:CellType leukocyte PS:Description Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dca49e57-5d82-426d-a7f6-f13ed9d92a53 PS:NodeType Pathway PS:Notes Headnote: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs), which are small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. In humans, ten functional receptors (TLR1-10) have been identified. TLR5 recognizes flagellin of bacterial flagella. TLR7 and TLR8 are found in membranes of endosomes and recognize single-stranded RNA from viruses. TLR9 is also found in the membrane of endosomes and recognizes unmethylated CpG islands in bacterial and viral DNA. Outcome effects: The specific signaling cascade activated by TLRs depends of the type of cytoplasmic adaptor molecules. TLR5, TLR7, TLR8, and TLR9 act through the MYD88 pathway. The MYD88-dependent pathway leads to the activation of NF-kB, MAPK1, MAPK8, p38 MAPK (MAPK14), IRF5, and IRF7 in addition to the transcription of inflammatory genes. The details of TLR5, TLR7, TLR8, and TLR9-related signaling remain unknown. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dca6e879-8a95-4667-81f9-82fe6c9ed47e NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-dca6e879-8a95-4667-81f9-82fe6c9ed47e Genes with Mutations in Cancer-Associated Resisting to Cell Death uuid-dca6e879-8a95-4667-81f9-82fe6c9ed47e PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dca6e879-8a95-4667-81f9-82fe6c9ed47e PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcaaca76-329e-44ac-8e05-592b8f1cea99 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-dcaaca76-329e-44ac-8e05-592b8f1cea99 Cutin biosynthesis template uuid-dcaaca76-329e-44ac-8e05-592b8f1cea99 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcaaca76-329e-44ac-8e05-592b8f1cea99 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: CUL4/CRL complex regulates cell cycle progression, apoptosis, chromatin remodeling and DNA damage response. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcae430c-b0ae-490b-8cf6-baa0eea64c6d NodeType: Pathway Notes: Headnote: The CRL complex (Cullin-RING ubiquitin ligase, SCF4 complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in the cell cycle progression, apoptosis, chromatin remodeling and DNA damage response.The SCF4 complex consists of four components: three constant subunits CUL4, DDB1 and RBX, and a variable subunit which includes substrate-recognition proteins. CUL4 (Cullin) is the core subunit on which the RING-finger protein RBX1 and adaptor protein DDB1 are assembled. RBX1 connects to E2 and DDB1 binds to the substrate-recognition proteins. Each substrate-recognition protein binds to a specific substrate protein. In the CUL4/CRL complex, WDR5, DTL, DDB2 and RFWD2 act as the substrate recognition proteins. DDB1 can bind a substrate directly, and can function as both an adaptor and a substrate-recognition protein._ Signaling description: The core of CUL4/CRL related signaling through specific subset of substrate proteins regulates the cell cycle progression and DNA damage response. Precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: CUL4/CRL targets and degrades the DTL, a protein that controls cell cycle progression, DNA damage and DNA repair via CDKN1A, CDT1 and PCNA. Degradation of DDB2 and RFWD2 leads to control of DNA repair. CUL4/CRL complex degrades WDR5, a protein involved in a variety of cellular processes, including cell cycle progression and chromatin remodeling through the interaction of the HDAC1/2/3. CUL4/CRL can also promote degradation of DET1 required to apoptosis and chromatin remodeling. Animal data: Role of CUL4/CRL in the signaling was revealed partially from animal model experiments. Organ: generic Organ_System: generic PMID: 17041588 PMID: 17079684 PMID: 21212733 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-dcae430c-b0ae-490b-8cf6-baa0eea64c6d CUL4/CRL (SCF4) Complex uuid-dcae430c-b0ae-490b-8cf6-baa0eea64c6d PS:CellType generic PS:Description CUL4/CRL complex regulates cell cycle progression, apoptosis, chromatin remodeling and DNA damage response. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcae430c-b0ae-490b-8cf6-baa0eea64c6d PS:NodeType Pathway PS:Notes Headnote: The CRL complex (Cullin-RING ubiquitin ligase, SCF4 complex) is a multi-protein E3-ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in the cell cycle progression, apoptosis, chromatin remodeling and DNA damage response.The SCF4 complex consists of four components: three constant subunits CUL4, DDB1 and RBX, and a variable subunit which includes substrate-recognition proteins. CUL4 (Cullin) is the core subunit on which the RING-finger protein RBX1 and adaptor protein DDB1 are assembled. RBX1 connects to E2 and DDB1 binds to the substrate-recognition proteins. Each substrate-recognition protein binds to a specific substrate protein. In the CUL4/CRL complex, WDR5, DTL, DDB2 and RFWD2 act as the substrate recognition proteins. DDB1 can bind a substrate directly, and can function as both an adaptor and a substrate-recognition protein._ Signaling description: The core of CUL4/CRL related signaling through specific subset of substrate proteins regulates the cell cycle progression and DNA damage response. Precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: CUL4/CRL targets and degrades the DTL, a protein that controls cell cycle progression, DNA damage and DNA repair via CDKN1A, CDT1 and PCNA. Degradation of DDB2 and RFWD2 leads to control of DNA repair. CUL4/CRL complex degrades WDR5, a protein involved in a variety of cellular processes, including cell cycle progression and chromatin remodeling through the interaction of the HDAC1/2/3. CUL4/CRL can also promote degradation of DET1 required to apoptosis and chromatin remodeling. Animal data: Role of CUL4/CRL in the signaling was revealed partially from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17041588 PS:PMID 17079684 PS:PMID 21212733 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: fibroblast Description: Graves ophthalmopathy (GO) is an autoimmune inflammation of orbits that progresses in Graves disease (GD). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcc6e065-6eac-48ea-9a96-9751e23f6200 NodeType: Pathway Notes: Headnote: Graves ophthalmopathy (GO) is an autoimmune inflammation of orbits that progresses into Graves disease (GD). Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. The disease is caused by an autoimmune response to thyroid antigens. Signaling description: In GO, orbit tissues are infiltrated with lymphocytes and macrophages, while muscle and adipose cells increase in size. Hyaluronic acid is accumulated in the extracellular space. As a result, an inflammatory response is initiated which increases ocular pressure causing pain. GO may occur before, concurrently with, or after the onset of Graves hyperthyroidism. While some degree of ocular involvement such as increased eye muscle thickness can be detected by sensitive imaging techniques including magnetic resonance or computed tomography in almost all patients with GD, clinically apparent ophthalmopathy occurs in 25-50% of patients with GD. A severe form occurs in 3-5% of patients. The immune reaction against TSHR in fibroblast cell membranes leads to fibroblast stimulation and an excess production of collagen and glycosaminoglycans. In addition, several other secondary autoantigens have been detected in affected extraocular muscles such as the flavoprotein subunit of mitochondrial succinate dehydrogenase, G2s, sarcalumenin, and calsequestrin. Antibodies against calsequestrin and collagen XIII have been shown to be very specific and sensitive diagnostic markers for GO. The exact role of genetic factors in the development of GO is unknown, although several susceptibility loci have been proposed. Outcome effects: The presence of autoantibodies for TSHR may activate this receptor on the surface of orbital fibroblasts. TSHR activation causes cell proliferation, secondary activation of immune system cells, and an increase in the expression of enzymes that synthesize hyaluronic acid (HAS1 and HAS2). Additionally, IGF1R exerts similar action and is also overexpressed in patients with GO. Hyaluronic acid synthesis is increased by TGFB1, IL1B, IL1A, IFNG, and IL4 cytokines which are produced by T-cells. The altered function of adhesion molecules such as THY1 and ICAM1 may also participate in the progression of the disorder. Finally, a high level of IL6 may be observed in GO. IL6 can activate adipocyte differentiation, through STAT3 signaling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: eye Organ_System: sensory system PMID: 16365140 PMID: 17521325 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-dcc6e065-6eac-48ea-9a96-9751e23f6200 Graves Ophthalmopathy uuid-dcc6e065-6eac-48ea-9a96-9751e23f6200 PS:CellType fibroblast PS:Description Graves ophthalmopathy (GO) is an autoimmune inflammation of orbits that progresses in Graves disease (GD). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcc6e065-6eac-48ea-9a96-9751e23f6200 PS:NodeType Pathway PS:Notes Headnote: Graves ophthalmopathy (GO) is an autoimmune inflammation of orbits that progresses into Graves disease (GD). Graves disease (GD) is characterized by hyperthyroidism, particular ophthalmopathy, and pretibial myxedema. The disease is caused by an autoimmune response to thyroid antigens. Signaling description: In GO, orbit tissues are infiltrated with lymphocytes and macrophages, while muscle and adipose cells increase in size. Hyaluronic acid is accumulated in the extracellular space. As a result, an inflammatory response is initiated which increases ocular pressure causing pain. GO may occur before, concurrently with, or after the onset of Graves hyperthyroidism. While some degree of ocular involvement such as increased eye muscle thickness can be detected by sensitive imaging techniques including magnetic resonance or computed tomography in almost all patients with GD, clinically apparent ophthalmopathy occurs in 25-50% of patients with GD. A severe form occurs in 3-5% of patients. The immune reaction against TSHR in fibroblast cell membranes leads to fibroblast stimulation and an excess production of collagen and glycosaminoglycans. In addition, several other secondary autoantigens have been detected in affected extraocular muscles such as the flavoprotein subunit of mitochondrial succinate dehydrogenase, G2s, sarcalumenin, and calsequestrin. Antibodies against calsequestrin and collagen XIII have been shown to be very specific and sensitive diagnostic markers for GO. The exact role of genetic factors in the development of GO is unknown, although several susceptibility loci have been proposed. Outcome effects: The presence of autoantibodies for TSHR may activate this receptor on the surface of orbital fibroblasts. TSHR activation causes cell proliferation, secondary activation of immune system cells, and an increase in the expression of enzymes that synthesize hyaluronic acid (HAS1 and HAS2). Additionally, IGF1R exerts similar action and is also overexpressed in patients with GO. Hyaluronic acid synthesis is increased by TGFB1, IL1B, IL1A, IFNG, and IL4 cytokines which are produced by T-cells. The altered function of adhesion molecules such as THY1 and ICAM1 may also participate in the progression of the disorder. Finally, a high level of IL6 may be observed in GO. IL6 can activate adipocyte differentiation, through STAT3 signaling. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ eye PS:Organ_System sensory system PS:PMID 16365140 PS:PMID 17521325 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcda1bbb-f6af-487b-9a0b-d2e8a1dbe48c NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-dcda1bbb-f6af-487b-9a0b-d2e8a1dbe48c TNFRSF5/6 -> RB1/E2F Signaling uuid-dcda1bbb-f6af-487b-9a0b-d2e8a1dbe48c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcda1bbb-f6af-487b-9a0b-d2e8a1dbe48c PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dce3e39e-7247-46a2-92b5-1fe0b894dba8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-dce3e39e-7247-46a2-92b5-1fe0b894dba8 GR-|oxidative stress uuid-dce3e39e-7247-46a2-92b5-1fe0b894dba8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dce3e39e-7247-46a2-92b5-1fe0b894dba8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcfd373d-578e-49a0-b077-24e0dff3af17 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-dcfd373d-578e-49a0-b077-24e0dff3af17 HTR1 -> Membrane Transport uuid-dcfd373d-578e-49a0-b077-24e0dff3af17 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dcfd373d-578e-49a0-b077-24e0dff3af17 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd0cb542-9dbc-477d-a38a-8832b85ea993 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-dd0cb542-9dbc-477d-a38a-8832b85ea993 P2X2/7+>Ca uuid-dd0cb542-9dbc-477d-a38a-8832b85ea993 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd0cb542-9dbc-477d-a38a-8832b85ea993 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd3b6eec-f9a8-47e0-9971-a80005832808 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-dd3b6eec-f9a8-47e0-9971-a80005832808 IL1B -> PGE2 Expression Targets uuid-dd3b6eec-f9a8-47e0-9971-a80005832808 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd3b6eec-f9a8-47e0-9971-a80005832808 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd3fa852-bfe0-42e9-a74f-b3557f197d2e NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-dd3fa852-bfe0-42e9-a74f-b3557f197d2e CHRM1 -> IL2 Production uuid-dd3fa852-bfe0-42e9-a74f-b3557f197d2e PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd3fa852-bfe0-42e9-a74f-b3557f197d2e PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd551047-5f93-40f2-a91a-6c7f0af16bc7 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-dd551047-5f93-40f2-a91a-6c7f0af16bc7 organomercurial reduction template uuid-dd551047-5f93-40f2-a91a-6c7f0af16bc7 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd551047-5f93-40f2-a91a-6c7f0af16bc7 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell CellType: antigen-presenting cell CellType: dendritic cell CellType: macrophage Description: Major histocompatibility complex (MHC) 2 is a cell surface molecule that is responsible for the transmission of exogenous antigens. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd7276df-9e0a-4c89-95cd-556bb02d92dc NodeType: Pathway Notes: Headnote: Major histocompatibility complex (MHC) 2 is a cell surface molecule responsible for the transmission of exogenous antigens. Antigens are protein fragments that invade the cell by endocytosis and then undergo proteolysis. Signaling description: Exogenous antigens are usually presented on MHC2 molecules, which interact with CD4 helper T-cells to activate them. MHC2 is synthesized in the Golgi apparatus. During MHC2 fermentative processing, fragment CLIP (CD74) is separated. HLA-DM binds to MHC2-CD74 complexes, catalyzing the release of CD74 molecule, which then allows binding of the antigenic peptides to the MHC2 groove. HLA-DO may regulate the DM-catalyzed removal of CD74. Exogenous antigens invade the cell by endocytosis and then undergo proteolysis. An endosome fuses with a lysosome, the pH decreases, and acidic proteases digest antigens into peptide fragments. Increased intra-vesicular pH stops the processing. Peptides are then carried to the Golgi apparatus where they bind to MHC2. Outcome effects: Further, MHC2 and the peptide complex migrate through the Golgi vesicles to the outer cell membrane. MHC2 and the peptide complex activate CD4 T-cell differentiation and mediate an immune response. Organ: generic Organ_System: hematological system PMID: 11684289 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-dd7276df-9e0a-4c89-95cd-556bb02d92dc MHC2-Mediated Antigen Presentation uuid-dd7276df-9e0a-4c89-95cd-556bb02d92dc PS:CellType T-cell PS:CellType antigen-presenting cell PS:CellType dendritic cell PS:CellType macrophage PS:Description Major histocompatibility complex (MHC) 2 is a cell surface molecule that is responsible for the transmission of exogenous antigens. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd7276df-9e0a-4c89-95cd-556bb02d92dc PS:NodeType Pathway PS:Notes Headnote: Major histocompatibility complex (MHC) 2 is a cell surface molecule responsible for the transmission of exogenous antigens. Antigens are protein fragments that invade the cell by endocytosis and then undergo proteolysis. Signaling description: Exogenous antigens are usually presented on MHC2 molecules, which interact with CD4 helper T-cells to activate them. MHC2 is synthesized in the Golgi apparatus. During MHC2 fermentative processing, fragment CLIP (CD74) is separated. HLA-DM binds to MHC2-CD74 complexes, catalyzing the release of CD74 molecule, which then allows binding of the antigenic peptides to the MHC2 groove. HLA-DO may regulate the DM-catalyzed removal of CD74. Exogenous antigens invade the cell by endocytosis and then undergo proteolysis. An endosome fuses with a lysosome, the pH decreases, and acidic proteases digest antigens into peptide fragments. Increased intra-vesicular pH stops the processing. Peptides are then carried to the Golgi apparatus where they bind to MHC2. Outcome effects: Further, MHC2 and the peptide complex migrate through the Golgi vesicles to the outer cell membrane. MHC2 and the peptide complex activate CD4 T-cell differentiation and mediate an immune response. PS:Organ generic PS:Organ_System hematological system PS:PMID 11684289 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd872abc-8bc6-4c32-aa88-8fd9db95657c NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-dd872abc-8bc6-4c32-aa88-8fd9db95657c PECAM -> STAT Signaling uuid-dd872abc-8bc6-4c32-aa88-8fd9db95657c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd872abc-8bc6-4c32-aa88-8fd9db95657c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Amyloid plaques, observed in patients with Alzheimer's disease, are composed of aggregated Abeta which is derived from the amyloid precursor protein (APP). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd8d1550-833f-438a-99db-1d5b6895fd65 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: Amyloid plaques are mainly composed of aggregated Abeta, which is derived from the amyloid precursor protein (APP) via a sequential proteolysis by secretases to form a number of peptides. APP is cleaved by beta-secretase (BACE1) with the formation of the C Terminal Fragment (APP-C99), which in turn is cleaved by gamma-secretase resulting in the formation of Abeta. In addition, MME, ACE, IDE, and ECE1 normally cleave Abeta, but become decreased in AD. Outcome effects: The gamma secretase generates a number of isoforms, including Abeta 40 and Abeta 42, with the most common being Abeta 40. However, mutations in the presenilin proteins (PSEN1 and PSEN2) and APP have an effect on gamma-secretase activity resulting in an increased production of the longer form of amyloid beta, Abeta 42, which is the main component of amyloid deposits found in AD brains. Additionally, interactions of SNCA and TGM2 with Abeta result in Abeta plaque formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: nervous system PMID: 10806097 PMID: 16432149 PMID: 21527012 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-dd8d1550-833f-438a-99db-1d5b6895fd65 Amyloid beta Formation in Alzheimer Disease uuid-dd8d1550-833f-438a-99db-1d5b6895fd65 PS:CellType neuron PS:Description Amyloid plaques, observed in patients with Alzheimer's disease, are composed of aggregated Abeta which is derived from the amyloid precursor protein (APP). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd8d1550-833f-438a-99db-1d5b6895fd65 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: Amyloid plaques are mainly composed of aggregated Abeta, which is derived from the amyloid precursor protein (APP) via a sequential proteolysis by secretases to form a number of peptides. APP is cleaved by beta-secretase (BACE1) with the formation of the C Terminal Fragment (APP-C99), which in turn is cleaved by gamma-secretase resulting in the formation of Abeta. In addition, MME, ACE, IDE, and ECE1 normally cleave Abeta, but become decreased in AD. Outcome effects: The gamma secretase generates a number of isoforms, including Abeta 40 and Abeta 42, with the most common being Abeta 40. However, mutations in the presenilin proteins (PSEN1 and PSEN2) and APP have an effect on gamma-secretase activity resulting in an increased production of the longer form of amyloid beta, Abeta 42, which is the main component of amyloid deposits found in AD brains. Additionally, interactions of SNCA and TGM2 with Abeta result in Abeta plaque formation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System nervous system PS:PMID 10806097 PS:PMID 16432149 PS:PMID 21527012 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd9c76a6-8a9a-494a-9d78-3aa7e83afb08 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-dd9c76a6-8a9a-494a-9d78-3aa7e83afb08 TGFb-|Cell cycle uuid-dd9c76a6-8a9a-494a-9d78-3aa7e83afb08 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dd9c76a6-8a9a-494a-9d78-3aa7e83afb08 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ddd6a65f-bfe1-40de-959f-9442386283c6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ddd6a65f-bfe1-40de-959f-9442386283c6 WNT1 Expression Targets uuid-ddd6a65f-bfe1-40de-959f-9442386283c6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ddd6a65f-bfe1-40de-959f-9442386283c6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de1ed3e7-5a2e-4e3c-997c-48549c345272 NodeType: Pathway Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-de1ed3e7-5a2e-4e3c-997c-48549c345272 Proteins Involved in Dilated Cardiomyopathy uuid-de1ed3e7-5a2e-4e3c-997c-48549c345272 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de1ed3e7-5a2e-4e3c-997c-48549c345272 PS:NodeType Pathway PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de440161-7774-4809-a98d-01203310247a NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-de440161-7774-4809-a98d-01203310247a EctodysplasinR -> NF-kB Signaling uuid-de440161-7774-4809-a98d-01203310247a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de440161-7774-4809-a98d-01203310247a PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de4c4216-d49d-4c3b-b83b-e691e7951f81 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-de4c4216-d49d-4c3b-b83b-e691e7951f81 eEF2 diphthamidation template uuid-de4c4216-d49d-4c3b-b83b-e691e7951f81 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de4c4216-d49d-4c3b-b83b-e691e7951f81 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de525fe6-a999-4f8d-9a77-dc5da25ddc97 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-de525fe6-a999-4f8d-9a77-dc5da25ddc97 Dermatan sulfate biosynthesis template uuid-de525fe6-a999-4f8d-9a77-dc5da25ddc97 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de525fe6-a999-4f8d-9a77-dc5da25ddc97 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de588d52-07df-43fe-8760-b1b7a18fae58 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-de588d52-07df-43fe-8760-b1b7a18fae58 Hereditary Breast and Ovarian Cancer Syndrome Clinical Trials uuid-de588d52-07df-43fe-8760-b1b7a18fae58 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de588d52-07df-43fe-8760-b1b7a18fae58 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: General of hypothetical mechanisms that lead to dilation of blood vessels in dura mater in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de5f20c3-3dde-4ab8-bd49-7436275ab4e0 NodeType: Pathway Notes: Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. Signaling description: Nitric oxide (NO) activates signaling pathways that lead to the relaxation of smooth muscles in the blood vessels of meninges. NO activates soluble guanylate cyclase (sGC) leading to the activation of protein kinase G (PKG) through cGMP. PKG phosphorylates myosin light chain phosphatase (MLCP) which can also be phosphorylated by protein kinase A (PKA). PKA is activated by cAMP and cAMP synthesis is mediated by the interaction between histamine and histamine receptor H2 (HRH2) in addition to the activation of Gs alpha (GNAS) and adenylate cyclase (ADCY). Outcome effects: Activated MLCP dephosphorylates light chains of myosin causing muscle relaxation such as vasodilation. The administration of one of the most effective anti-migraine drugs called sumatriptan in the beginning of a migraine seizure can stop an attack. This can be explained by the return of blood vessels to a normal state prior to pain signals since sumatriptan is an agonist of serotonin receptors 1B and 1D. The activation of these receptors triggers calcium/calmodulin-dependent processes that lead to the arrest of MLCP, phosphorylation of myosin light chains, and muscle contraction such as vasoconstriction. Thus, increased amounts of NO and histamine activate pathological vasodilation of blood vessels in dura mater causing headache. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: brain Organ_System: cardiovascular system PMID: 12964492 PMID: 19499287 PMID: 21068832 PMID: 21458376 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-de5f20c3-3dde-4ab8-bd49-7436275ab4e0 NO Effect on Vasodilation and Vasoconstriction uuid-de5f20c3-3dde-4ab8-bd49-7436275ab4e0 PS:CellType vascular smooth muscle cell PS:Description General of hypothetical mechanisms that lead to dilation of blood vessels in dura mater in familial hemiplegic migraine (FHM, G43.105) is presented on the pathway. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de5f20c3-3dde-4ab8-bd49-7436275ab4e0 PS:NodeType Pathway PS:Notes Headnote: Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In FHM, a pattern of neurological symptoms called an aura precedes the headache. There exist three identified forms of FHM known as FHM1, FHM2, and FHM3. Each type of the disease is caused by mutations in a particular gene. Signaling description: Nitric oxide (NO) activates signaling pathways that lead to the relaxation of smooth muscles in the blood vessels of meninges. NO activates soluble guanylate cyclase (sGC) leading to the activation of protein kinase G (PKG) through cGMP. PKG phosphorylates myosin light chain phosphatase (MLCP) which can also be phosphorylated by protein kinase A (PKA). PKA is activated by cAMP and cAMP synthesis is mediated by the interaction between histamine and histamine receptor H2 (HRH2) in addition to the activation of Gs alpha (GNAS) and adenylate cyclase (ADCY). Outcome effects: Activated MLCP dephosphorylates light chains of myosin causing muscle relaxation such as vasodilation. The administration of one of the most effective anti-migraine drugs called sumatriptan in the beginning of a migraine seizure can stop an attack. This can be explained by the return of blood vessels to a normal state prior to pain signals since sumatriptan is an agonist of serotonin receptors 1B and 1D. The activation of these receptors triggers calcium/calmodulin-dependent processes that lead to the arrest of MLCP, phosphorylation of myosin light chains, and muscle contraction such as vasoconstriction. Thus, increased amounts of NO and histamine activate pathological vasodilation of blood vessels in dura mater causing headache. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ brain PS:Organ_System cardiovascular system PS:PMID 12964492 PS:PMID 19499287 PS:PMID 21068832 PS:PMID 21458376 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Ubiquitin-dependent proteolysis plays a central role in cytosolic degradation of short-lived and regulatory proteins important in a variety of basic cellular processes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de6fecfc-771b-49bb-990e-b42739e1ce94 NodeType: Pathway Notes: Headnote: Ubiquitin-dependent proteolysis has a central role in cytosolic degradation of short-lived and regulatory proteins important in a variety of basic cellular processes. Signaling description: The degradation of a protein by this pathway involves two steps including covalent attachment of multiple ubiquitin molecules to the target protein and degradation of the tagged protein by the 26S proteasome complex. Ubiquitin is a small protein of 76 amino acids encoded in mammals by four different genes including UBA52 and RPS27A, which code for a single copy of ubiquitin and UBB and UBC genes, which code for polyubiquitin precursor proteins. Proteins destined for degradation through ubiquitylation are first labeled by ubiquitin by the sequential action of a multi-enzymatic system consisting of ubiquitin-activating enzyme E1, E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligase). E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and target protein. E3s mediate the covalent attachment of multiple ubiquitin moieties to an NH2 group of a lysine residue of the protein substrate to generate an isopeptide bond. Outcome effects: Additional ubiquitin moieties may be transferred to the previously conjugated ubiquitin, resulting in a polyubiquitin chain formation. This chain is recognized by the proteasome and directs the target protein to the 26S proteasome complex for degradation. 26S proteasome is composed of 28 subunits to form a cylindrical structure. The 19S proteasome regulatory particle is cupped at each end of the 20S core proteasome to form the core of the 26S proteasome. Once ubiquitin-tagged, proteins bind to 19S proteasome regulatory particle of the proteasome and then enter the catalytic inner chamber. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-de6fecfc-771b-49bb-990e-b42739e1ce94 Ubiquitin Dependent Protein Degradation uuid-de6fecfc-771b-49bb-990e-b42739e1ce94 PS:CellType generic PS:Description Ubiquitin-dependent proteolysis plays a central role in cytosolic degradation of short-lived and regulatory proteins important in a variety of basic cellular processes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de6fecfc-771b-49bb-990e-b42739e1ce94 PS:NodeType Pathway PS:Notes Headnote: Ubiquitin-dependent proteolysis has a central role in cytosolic degradation of short-lived and regulatory proteins important in a variety of basic cellular processes. Signaling description: The degradation of a protein by this pathway involves two steps including covalent attachment of multiple ubiquitin molecules to the target protein and degradation of the tagged protein by the 26S proteasome complex. Ubiquitin is a small protein of 76 amino acids encoded in mammals by four different genes including UBA52 and RPS27A, which code for a single copy of ubiquitin and UBB and UBC genes, which code for polyubiquitin precursor proteins. Proteins destined for degradation through ubiquitylation are first labeled by ubiquitin by the sequential action of a multi-enzymatic system consisting of ubiquitin-activating enzyme E1, E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligase). E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and target protein. E3s mediate the covalent attachment of multiple ubiquitin moieties to an NH2 group of a lysine residue of the protein substrate to generate an isopeptide bond. Outcome effects: Additional ubiquitin moieties may be transferred to the previously conjugated ubiquitin, resulting in a polyubiquitin chain formation. This chain is recognized by the proteasome and directs the target protein to the 26S proteasome complex for degradation. 26S proteasome is composed of 28 subunits to form a cylindrical structure. The 19S proteasome regulatory particle is cupped at each end of the 20S core proteasome to form the core of the 26S proteasome. Once ubiquitin-tagged, proteins bind to 19S proteasome regulatory particle of the proteasome and then enter the catalytic inner chamber. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:CellType PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: epithelial cell CellType: leukocyte CellType: mast cell CellType: monocyte Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de76f2a6-3884-4f02-8305-a67285a02085 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19748439 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases Tissue: generic urn:agi-pathway:uuid-de76f2a6-3884-4f02-8305-a67285a02085 SARS induces inflamasome uuid-de76f2a6-3884-4f02-8305-a67285a02085 PS:CellType dendritic cell PS:CellType epithelial cell PS:CellType leukocyte PS:CellType mast cell PS:CellType monocyte PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de76f2a6-3884-4f02-8305-a67285a02085 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19748439 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de7acf6e-8dc1-4d6f-93a2-7b60ffa684cf NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-de7acf6e-8dc1-4d6f-93a2-7b60ffa684cf FPR1 -> Cytoskeleton Signaling uuid-de7acf6e-8dc1-4d6f-93a2-7b60ffa684cf PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de7acf6e-8dc1-4d6f-93a2-7b60ffa684cf PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: Macrophages are believed to play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de9325b2-5da2-4f8c-8c07-50a84984db2e NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Macrophages are believed to play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Their numbers are increased (5-10 fold) in the airways, lung parenchyma, bronchoalveolar lavage fluid, and sputum of smokers and patients with COPD. Signaling description: Exposure to tobacco and air pollutants is the key provoking factor of COPD development. Later, bacterial and viral infections add to chronic inflammation maintenance. Cigarette smoke activates innate immune cells including epithelial cells and macrophages by triggering pattern recognition receptors (PRRs), such as toll-like receptors (TLRs). PRRs recognize molecules that are exclusive to microbes called pathogen-associated molecular patterns (PAMPs) and specific endogenous molecules, which are normally intracellular, but are released after cell damage called damage-associated molecular patterns (DAMPs). DAMPs include HMGB1, uric acid, extracellular ATP, heat shock proteins, hyaluronic acid, VCAN, and heparan sulfate. One of the most important PAMPs in COPD is bacterial LPS. Downstream pathways that follow DAMP/PAMP/TLR binding include the activation of MYD88, TIRAP, and TICAM1/2 which leads to the synthesis of inflammatory cytokines (IL6, IL8, IL1A, IL1B, and IL18), chemokines (CXCL1 and CCL2), matrix metalloproteinases (MMP2, MMP9, and MMP12), and elastolytic enzymes (CTSL1, CTSS, and CTSK). Most of the inflammatory proteins that are upregulated in COPD macrophages are regulated by NF-kB which is activated in alveolar macrophages of COPD patients. The activation of TLRs and AGER leads to an increased expression of pro-IL1B and pro-IL18, which are subsequently cleaved into mature interleukins by CASP1, which is a member of NLRP3-inflammasome. The inflammasome may be activated by ATP acting through P2RX7 and P2RY2, as well as by ROS and uric acid. NLRP3 inflammasome assembly is also triggered by low intracellular potassium (K+) levels. Outcome effects: The consequence of sustained macrophage activation in COPD is chronic inflammation and lung destruction by oxygen radicals and proteolytic enzymes. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 18178857 PMID: 18410916 PMID: 19654006 PMID: 20423711 PMID: 20519655 PMID: 21907865 PMID: 23956502 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-de9325b2-5da2-4f8c-8c07-50a84984db2e Alveolar Macrophages Dysfunction in COPD uuid-de9325b2-5da2-4f8c-8c07-50a84984db2e PS:CellType macrophage PS:Description Macrophages are believed to play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de9325b2-5da2-4f8c-8c07-50a84984db2e PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Macrophages are believed to play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Their numbers are increased (5-10 fold) in the airways, lung parenchyma, bronchoalveolar lavage fluid, and sputum of smokers and patients with COPD. Signaling description: Exposure to tobacco and air pollutants is the key provoking factor of COPD development. Later, bacterial and viral infections add to chronic inflammation maintenance. Cigarette smoke activates innate immune cells including epithelial cells and macrophages by triggering pattern recognition receptors (PRRs), such as toll-like receptors (TLRs). PRRs recognize molecules that are exclusive to microbes called pathogen-associated molecular patterns (PAMPs) and specific endogenous molecules, which are normally intracellular, but are released after cell damage called damage-associated molecular patterns (DAMPs). DAMPs include HMGB1, uric acid, extracellular ATP, heat shock proteins, hyaluronic acid, VCAN, and heparan sulfate. One of the most important PAMPs in COPD is bacterial LPS. Downstream pathways that follow DAMP/PAMP/TLR binding include the activation of MYD88, TIRAP, and TICAM1/2 which leads to the synthesis of inflammatory cytokines (IL6, IL8, IL1A, IL1B, and IL18), chemokines (CXCL1 and CCL2), matrix metalloproteinases (MMP2, MMP9, and MMP12), and elastolytic enzymes (CTSL1, CTSS, and CTSK). Most of the inflammatory proteins that are upregulated in COPD macrophages are regulated by NF-kB which is activated in alveolar macrophages of COPD patients. The activation of TLRs and AGER leads to an increased expression of pro-IL1B and pro-IL18, which are subsequently cleaved into mature interleukins by CASP1, which is a member of NLRP3-inflammasome. The inflammasome may be activated by ATP acting through P2RX7 and P2RY2, as well as by ROS and uric acid. NLRP3 inflammasome assembly is also triggered by low intracellular potassium (K+) levels. Outcome effects: The consequence of sustained macrophage activation in COPD is chronic inflammation and lung destruction by oxygen radicals and proteolytic enzymes. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18178857 PS:PMID 18410916 PS:PMID 19654006 PS:PMID 20423711 PS:PMID 20519655 PS:PMID 21907865 PS:PMID 23956502 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de95fed9-41e1-43ec-9d8e-0cee5da7b2c4 NodeType: Pathway Notes: The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. Proteins E4 and E5 of the virus are necessary for maturation of viral particles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-de95fed9-41e1-43ec-9d8e-0cee5da7b2c4 3_Human papilloma virus E4 and E5 proteins in viral reproduction uuid-de95fed9-41e1-43ec-9d8e-0cee5da7b2c4 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-de95fed9-41e1-43ec-9d8e-0cee5da7b2c4 PS:NodeType Pathway PS:Notes The open reading frames of the viral genome are divided into early (E) and late (L) regions. Transcription of viral DNA proceeds sequentially through the E1, E2, E4 and E5, E6, and E7 genes. Proteins E4 and E5 of the virus are necessary for maturation of viral particles. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dea9022e-0e26-496e-b28c-72ba0914371f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-dea9022e-0e26-496e-b28c-72ba0914371f InsulinR -> STAT Signaling uuid-dea9022e-0e26-496e-b28c-72ba0914371f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dea9022e-0e26-496e-b28c-72ba0914371f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: adenohypophysial cell Description: POMC is the source of several important biologically active substances. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-decab122-672b-4490-9344-f90000388598 NodeType: Pathway Notes: Headnote: Pro-opiomelanocortin (POMC) is a prohormone synthesized in the adenohypophysis. POMC is cleaved to give multiple peptide hormones. Signaling description: Adenohypophysial cells respond to corticotropin releasing hormone (CRH) which binds to CRHR1 and mediates ADCY/cAMP/PKA/CREB1 signaling. CREB1 promotes NR4A2/ NR4A1, the essential POMC transcription factors. PCSK2 and PCSK1 cleave POMC into ACTH (adrenocorticotropic hormone), beta-endorphin, beta-lipotropin, alpha-MSH, beta-MSH and gamma-MSH (alpha, beta and gamma melanocyte stimulating hormones). The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: POMC is the source of several important biologically active substances. Organ: pituitary gland Organ_System: nervous system PMID: 12089357 PMID: 26880796 PMID: 27065163 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-decab122-672b-4490-9344-f90000388598 POMC Secretion in adenohypophysis uuid-decab122-672b-4490-9344-f90000388598 PS:CellType adenohypophysial cell PS:Description POMC is the source of several important biologically active substances. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-decab122-672b-4490-9344-f90000388598 PS:NodeType Pathway PS:Notes Headnote: Pro-opiomelanocortin (POMC) is a prohormone synthesized in the adenohypophysis. POMC is cleaved to give multiple peptide hormones. Signaling description: Adenohypophysial cells respond to corticotropin releasing hormone (CRH) which binds to CRHR1 and mediates ADCY/cAMP/PKA/CREB1 signaling. CREB1 promotes NR4A2/ NR4A1, the essential POMC transcription factors. PCSK2 and PCSK1 cleave POMC into ACTH (adrenocorticotropic hormone), beta-endorphin, beta-lipotropin, alpha-MSH, beta-MSH and gamma-MSH (alpha, beta and gamma melanocyte stimulating hormones). The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: POMC is the source of several important biologically active substances. PS:Organ pituitary gland PS:Organ_System nervous system PS:PMID 12089357 PS:PMID 26880796 PS:PMID 27065163 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ded11960-2271-44bf-87b5-b5e013a71b80 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-ded11960-2271-44bf-87b5-b5e013a71b80 MRGX2+>allergic reaction AOP uuid-ded11960-2271-44bf-87b5-b5e013a71b80 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ded11960-2271-44bf-87b5-b5e013a71b80 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Effects of beta-casomorphin on activation of transcription and manifestation of symptoms of autistic disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ded63852-3886-43c5-8eb1-c9a6a7c7bf56 NodeType: Pathway Notes: Beta-casomorphin is involved in transcriptional activation of genes involved in manifestation of autism symptoms (a (Hypothesis)). Organ_System: nervous system PMID: 17520243 PMID: 18337276 PMID: 24621061 PMID: 24657283 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-ded63852-3886-43c5-8eb1-c9a6a7c7bf56 beta-Casomorphins/Opioid Receptors Affect Brain Function (Hypothesis) uuid-ded63852-3886-43c5-8eb1-c9a6a7c7bf56 PS:Description Effects of beta-casomorphin on activation of transcription and manifestation of symptoms of autistic disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ded63852-3886-43c5-8eb1-c9a6a7c7bf56 PS:NodeType Pathway PS:Notes Beta-casomorphin is involved in transcriptional activation of genes involved in manifestation of autism symptoms (a (Hypothesis)). PS:Organ_System nervous system PS:PMID 17520243 PS:PMID 18337276 PS:PMID 24621061 PS:PMID 24657283 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df2069f2-e8a8-4807-a27c-e8ee9de78a77 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-df2069f2-e8a8-4807-a27c-e8ee9de78a77 NSP3 interactions uuid-df2069f2-e8a8-4807-a27c-e8ee9de78a77 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df2069f2-e8a8-4807-a27c-e8ee9de78a77 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df21cdb6-1f02-40f9-94a3-2602ef1e8a21 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the smooth muscle mass within the airway wall is increased in asthma via hypertrophy and/or hyperplasia, with the intrinsic contractile properties of individual muscle cells being unchanged. ASM proliferation is induced by mitogens acting mainly via tyrosine kinase receptors and G protein-coupled receptors. Stimulation of these receptors leads to activation of ERK and phosphoinositide 3-PI3K cascades. Outcome effects: ERK and PI3K-dependent signaling molecules (PDK1, PKB/Akt, p70S6K, Rac1, etc.) cooperate to activate the transcription factors (SP1, CREB, NFkB) required for cyclin D1 gene expression and cell growth. Endothelin-1 is elevated in asthmatic airways and may promote increased ASM mass via its effects on cell growth and apoptosis. ECM components, such as fibronectin, laminin-1 and collagens I and IV, provide strong survival signals to cultured human ASM cells, an effect mediated in part via integrin a5b1. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 17470619 PMID: 19171135 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-df21cdb6-1f02-40f9-94a3-2602ef1e8a21 Airway Smooth Muscle Cell High Rate Proliferation uuid-df21cdb6-1f02-40f9-94a3-2602ef1e8a21 PS:CellType vascular smooth muscle cell PS:Description In asthma, excessive shortening of ASM cells leading to excessive narrowing of the airways contributes significantly to obstruction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df21cdb6-1f02-40f9-94a3-2602ef1e8a21 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: In asthma, excessive shortening of ASM (airway smooth muscle) cells leading to narrowing of the airways contributes significantly to obstruction. This is partially due to the fact that the smooth muscle mass within the airway wall is increased in asthma via hypertrophy and/or hyperplasia, with the intrinsic contractile properties of individual muscle cells being unchanged. ASM proliferation is induced by mitogens acting mainly via tyrosine kinase receptors and G protein-coupled receptors. Stimulation of these receptors leads to activation of ERK and phosphoinositide 3-PI3K cascades. Outcome effects: ERK and PI3K-dependent signaling molecules (PDK1, PKB/Akt, p70S6K, Rac1, etc.) cooperate to activate the transcription factors (SP1, CREB, NFkB) required for cyclin D1 gene expression and cell growth. Endothelin-1 is elevated in asthmatic airways and may promote increased ASM mass via its effects on cell growth and apoptosis. ECM components, such as fibronectin, laminin-1 and collagens I and IV, provide strong survival signals to cultured human ASM cells, an effect mediated in part via integrin a5b1. Highlighted proteins: Proteins with increased expression are highlighted in red, and proteins with decreased expression are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17470619 PS:PMID 19171135 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df476456-216c-4c9e-a523-5bc41d4995e3 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-df476456-216c-4c9e-a523-5bc41d4995e3 L-idonate degradation template uuid-df476456-216c-4c9e-a523-5bc41d4995e3 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df476456-216c-4c9e-a523-5bc41d4995e3 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: I-cell Description: Nutrients and TLRs activate synthesis and secretion of CCK-8 in I-cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df477c7a-a86d-4e01-84e8-6bb4c3a63c62 NodeType: Pathway Notes: Headnote: Intestinal enteroendocrine cells (I-cells) of proximal small intestine can produce CCK-8 in response to various nutrients. The major function of CCK-8 is inhibition of eating behavior and stimulation of satiety. Signaling description: Receptors for fatty acids (FFRA1 and FFRA4), aromatic amino acids (CASR), lysophosphatidic acid (LPAR5), as well as taste receptors type 2 (TAS2R) and toll-like receptors (TLR2, TLR4, TLR5 and TLR9) are expressed on the surface of I-cells. These receptors activate intracellular calcium influx through phospholipase C (PLCB2)/ ITPR1 signaling and activate PKC through cAMP signaling. In turn, PKC activates CREB1. The TLR signaling also leads to phospholipase C (PLCG1)/ ITPR1 induced Ca2+ influx and MAPK1/3 (ERK1/2) dependent CREB1 activation. Transcription factor CREB1 binds to CCK gene promoter and activates preprocholecystokinin transcription. Processing of preprocholecystokinin to CCK-8 is dependent upon PCSK1. Calcium overload via ITPR1 and TRPA1 leads to the secretion of CCK-8 and serotonin. At the mucosal endings of vagal afferent neurons, CCK-8 interacts with CCKAR and through JAKs and STAT3 signaling activates the opening of K+ channel which leads to potassium flow out of the cell, membrane depolarization, and transmission of nerve impulse. Outcome effects: Activation of I-cells by nutrients and TLRs signaling leads to synthesis and secretion of CCK-8. This results in gallbladder contraction, pancreatic juice secretion and stimulation of the sense of satiety. Also, CCK-8 is transferred to the brain by blood flow and, thus inhibits eating behavior and gastric motility. Serotonin also activates gallbladder contraction and pancreatic juice secretion. Organ: colon Organ: intestine Organ: small intestine Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-df477c7a-a86d-4e01-84e8-6bb4c3a63c62 I-cell: CCK-8 Secretion and Regulation of Eating Behavior uuid-df477c7a-a86d-4e01-84e8-6bb4c3a63c62 PS:CellType I-cell PS:Description Nutrients and TLRs activate synthesis and secretion of CCK-8 in I-cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df477c7a-a86d-4e01-84e8-6bb4c3a63c62 PS:NodeType Pathway PS:Notes Headnote: Intestinal enteroendocrine cells (I-cells) of proximal small intestine can produce CCK-8 in response to various nutrients. The major function of CCK-8 is inhibition of eating behavior and stimulation of satiety. Signaling description: Receptors for fatty acids (FFRA1 and FFRA4), aromatic amino acids (CASR), lysophosphatidic acid (LPAR5), as well as taste receptors type 2 (TAS2R) and toll-like receptors (TLR2, TLR4, TLR5 and TLR9) are expressed on the surface of I-cells. These receptors activate intracellular calcium influx through phospholipase C (PLCB2)/ ITPR1 signaling and activate PKC through cAMP signaling. In turn, PKC activates CREB1. The TLR signaling also leads to phospholipase C (PLCG1)/ ITPR1 induced Ca2+ influx and MAPK1/3 (ERK1/2) dependent CREB1 activation. Transcription factor CREB1 binds to CCK gene promoter and activates preprocholecystokinin transcription. Processing of preprocholecystokinin to CCK-8 is dependent upon PCSK1. Calcium overload via ITPR1 and TRPA1 leads to the secretion of CCK-8 and serotonin. At the mucosal endings of vagal afferent neurons, CCK-8 interacts with CCKAR and through JAKs and STAT3 signaling activates the opening of K+ channel which leads to potassium flow out of the cell, membrane depolarization, and transmission of nerve impulse. Outcome effects: Activation of I-cells by nutrients and TLRs signaling leads to synthesis and secretion of CCK-8. This results in gallbladder contraction, pancreatic juice secretion and stimulation of the sense of satiety. Also, CCK-8 is transferred to the brain by blood flow and, thus inhibits eating behavior and gastric motility. Serotonin also activates gallbladder contraction and pancreatic juice secretion. PS:Organ colon PS:Organ intestine PS:Organ small intestine PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Mutant huntingtin causes transcriptional repression of the mitochondrial PPARGC1A. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df4d0d9a-67f0-4d34-9f9a-02110e7c5cfc NodeType: Pathway Notes: Headnote: Mutant huntingtin (HTT) leads to multiple cellular dysfunctions in Huntington disease (HD) via different mechanisms, including transcriptional repression of the mitochondrial master regulator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1alpha, PPARGC1A). Signaling description: PPARGC1A forms complexes with transcription factors, including nuclear respiratory factors, NRF1/2, and the nuclear receptors, PPARalpha/delta/gamma, estrogen related receptor alpha (ERRalpha). These transcription factors, in turn, regulate the expression of many nuclear-encoded mitochondrial genes, such as cytochrome c (CYCS), mitochondrial complexes I-V and the mitochondrial transcription factors TFAM, TFB1M/2M. Deficiency of these factors leads to mitochondrial dysfunction.PPARGC1A plays a role in myelination regulating expression of myelin basic protein (MBP) and myelin-associated oligodendrocyte basic protein (MOBP). PPARGC1A controls enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) taking part in cholesterol metabolism and thereby making impact to myelin synthesis.PPARGC1A plays a role in the suppression of oxidative stress, and it induces antioxidant enzymes superoxide dismutase 1/2 (SOD1/2) and glutathione peroxidase (GPX1). In HD these functions are impaired.Protein with decreased expression or activity is highlighted in blue. Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 21163446 PMID: 21715619 PMID: 23602910 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-df4d0d9a-67f0-4d34-9f9a-02110e7c5cfc PPARGC1A Repression in Huntington Disease uuid-df4d0d9a-67f0-4d34-9f9a-02110e7c5cfc PS:CellType neuron PS:Description Mutant huntingtin causes transcriptional repression of the mitochondrial PPARGC1A. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df4d0d9a-67f0-4d34-9f9a-02110e7c5cfc PS:NodeType Pathway PS:Notes Headnote: Mutant huntingtin (HTT) leads to multiple cellular dysfunctions in Huntington disease (HD) via different mechanisms, including transcriptional repression of the mitochondrial master regulator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1alpha, PPARGC1A). Signaling description: PPARGC1A forms complexes with transcription factors, including nuclear respiratory factors, NRF1/2, and the nuclear receptors, PPARalpha/delta/gamma, estrogen related receptor alpha (ERRalpha). These transcription factors, in turn, regulate the expression of many nuclear-encoded mitochondrial genes, such as cytochrome c (CYCS), mitochondrial complexes I-V and the mitochondrial transcription factors TFAM, TFB1M/2M. Deficiency of these factors leads to mitochondrial dysfunction.PPARGC1A plays a role in myelination regulating expression of myelin basic protein (MBP) and myelin-associated oligodendrocyte basic protein (MOBP). PPARGC1A controls enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) taking part in cholesterol metabolism and thereby making impact to myelin synthesis.PPARGC1A plays a role in the suppression of oxidative stress, and it induces antioxidant enzymes superoxide dismutase 1/2 (SOD1/2) and glutathione peroxidase (GPX1). In HD these functions are impaired.Protein with decreased expression or activity is highlighted in blue. Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 21163446 PS:PMID 21715619 PS:PMID 23602910 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df863640-6260-44ac-99e9-663e45a2ed9b NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-df863640-6260-44ac-99e9-663e45a2ed9b TGFB2-TGFBR2 Expression Targets uuid-df863640-6260-44ac-99e9-663e45a2ed9b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df863640-6260-44ac-99e9-663e45a2ed9b PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df8e1c18-b05e-43c7-8eb7-e5542bb949ab NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-df8e1c18-b05e-43c7-8eb7-e5542bb949ab POMC Expression Targets uuid-df8e1c18-b05e-43c7-8eb7-e5542bb949ab PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df8e1c18-b05e-43c7-8eb7-e5542bb949ab PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: oocyte Description: FOXL2 is involved in sex determination. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df911555-9c89-4c51-8a2a-c27027a85d26 NodeType: Pathway Notes: Headnote: FOXO3 (or PTEN) deletion in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). Animal data: mouse model Mutated proteins: Mutated genes are shown in white-out style. Organ: ovary Organ_System: reproductive system PMID: 16647286 PMID: 17360647 PMID: 18155828 PMID: 20414895 PMID: 21188138 PMID: 21763750 PMID: 24049064 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-df911555-9c89-4c51-8a2a-c27027a85d26 FOXL2 Mutation in Ovarian Dysgenesis uuid-df911555-9c89-4c51-8a2a-c27027a85d26 PS:CellType oocyte PS:Description FOXL2 is involved in sex determination. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df911555-9c89-4c51-8a2a-c27027a85d26 PS:NodeType Pathway PS:Notes Headnote: FOXO3 (or PTEN) deletion in mice oocytes results in inappropriate oocyte activation, premature entry of primordial follicles into the growing pool, oocyte loss and primary ovarian failure (POF). Animal data: mouse model Mutated proteins: Mutated genes are shown in white-out style. PS:Organ ovary PS:Organ_System reproductive system PS:PMID 16647286 PS:PMID 17360647 PS:PMID 18155828 PS:PMID 20414895 PS:PMID 21188138 PS:PMID 21763750 PS:PMID 24049064 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df99f2ed-a571-4375-8709-803410a5ff87 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-df99f2ed-a571-4375-8709-803410a5ff87 EGFR -> Expression Targets in Skin uuid-df99f2ed-a571-4375-8709-803410a5ff87 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-df99f2ed-a571-4375-8709-803410a5ff87 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte Description: Familial Partial Lipodystrophies type 3 (FPL) is resulted from an autosomal dominantly inherited mutation in the PPARG. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfa17016-95b9-4ee5-853a-ef3eb0349c7d NodeType: Pathway Notes: Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. FPL type 3 (FPL3) results from an autosomal dominantly inherited mutation in the PPARG gene. FPL3 is associated with a milder phenotype, with the onset of lipodystrophy beginning in the second decade or later in life. Unlike patients with FPL1, excess fat deposition in areas such as the face, neck, and trunk does not occur. In general, patients with FPL3 develop more severe metabolic derangements compared to FPL2 patients. It is characterized by lipodystrophy associated with skeletal abnormalities including hypoplasia of the mandible and clavicle. Signaling description: PPARG is a member of the peroxisome proliferator-activated receptor subfamily of nuclear receptors which binds to PPARA. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4, thus increasing glucose uptake. PPARA promotes ACOX1 and UCP2 which are involved in lipid metabolism. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ_System: endocrine system Organ_System: integumentary system PMID: 20551664 PMID: 23272513 PMID: 24152769 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: adipose tissue Tissue: connective tissue urn:agi-pathway:uuid-dfa17016-95b9-4ee5-853a-ef3eb0349c7d Familial Partial Lipodystrophy Type 3 Progression (Hypothesis) uuid-dfa17016-95b9-4ee5-853a-ef3eb0349c7d PS:CellType adipocyte PS:Description Familial Partial Lipodystrophies type 3 (FPL) is resulted from an autosomal dominantly inherited mutation in the PPARG. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfa17016-95b9-4ee5-853a-ef3eb0349c7d PS:NodeType Pathway PS:Notes Headnote: Familial partial lipodystrophies (FPL) are a heterogeneous group of disorders with several distinct phenotypes. FPL type 3 (FPL3) results from an autosomal dominantly inherited mutation in the PPARG gene. FPL3 is associated with a milder phenotype, with the onset of lipodystrophy beginning in the second decade or later in life. Unlike patients with FPL1, excess fat deposition in areas such as the face, neck, and trunk does not occur. In general, patients with FPL3 develop more severe metabolic derangements compared to FPL2 patients. It is characterized by lipodystrophy associated with skeletal abnormalities including hypoplasia of the mandible and clavicle. Signaling description: PPARG is a member of the peroxisome proliferator-activated receptor subfamily of nuclear receptors which binds to PPARA. PPARG promotes AGPAT2, LPL, UCP3, RETN, and LEP. AGPAT2, LPL, and UCP3 are involved in adipocyte differentiation while RETN and LEP play an endocrine role. In addition, PPARG promotes SLC2A4, thus increasing glucose uptake. PPARA promotes ACOX1 and UCP2 which are involved in lipid metabolism. The abnormality in glucose uptake and the dysregulation of lipid and protein metabolism causes insulin resistance which ultimately leads to diabetes mellitus. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System endocrine system PS:Organ_System integumentary system PS:PMID 20551664 PS:PMID 23272513 PS:PMID 24152769 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue adipose tissue PS:Tissue connective tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfb10b0f-b001-4fa8-9527-06983178ed50 NodeType: Pathway Notes: Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The majority of pathogenic T-cells in atherosclerosis are of the Th1 profile, which represents the prevailing subtype in atherosclerotic lesions. Th1-cells are thought to posess proinflammatory and pro-atherogenic properties. Outcome effects: The principal Th1 cytokine, IFNG is directly related to atherosclerosis by contributing to all the events that induce the disease progression. In addition, CD40-CD40LG interactions transduce immune and inflammatory signals, which promote the generation of Th1 cytokines. The expression of IL27 is elevated in human atheromas, yet its function in atherosclerosis remains unknown. IL27 promotes early Th1 differentiation. Furthermore, the circulating level of IL27 is strongly correlated with Gensini score, which reflects the severity of coronary artery stenosis, indicating that IL27 may promote the development and progression of coronary artery disease by inducing Th1 differentiation and related cytokine production. Lastly, the proinflammatory cytokine, LTA is thought to contribute to the pathogenesis of atherosclerosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PMID: 17194634 PMID: 20207195 PMID: 21054264 PMID: 22911112 PMID: 23533763 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-dfb10b0f-b001-4fa8-9527-06983178ed50 Th1-Cells Activation and Proliferation in Atherosclerosis uuid-dfb10b0f-b001-4fa8-9527-06983178ed50 PS:CellType T-cell PS:Description Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfb10b0f-b001-4fa8-9527-06983178ed50 PS:NodeType Pathway PS:Notes Headnote: Atherosclerosis is a progressive chronic disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The buildup of fat and cholesterol leads to the formation of plaques in the artery walls which can hamper the blood flow. Signaling description: The majority of pathogenic T-cells in atherosclerosis are of the Th1 profile, which represents the prevailing subtype in atherosclerotic lesions. Th1-cells are thought to posess proinflammatory and pro-atherogenic properties. Outcome effects: The principal Th1 cytokine, IFNG is directly related to atherosclerosis by contributing to all the events that induce the disease progression. In addition, CD40-CD40LG interactions transduce immune and inflammatory signals, which promote the generation of Th1 cytokines. The expression of IL27 is elevated in human atheromas, yet its function in atherosclerosis remains unknown. IL27 promotes early Th1 differentiation. Furthermore, the circulating level of IL27 is strongly correlated with Gensini score, which reflects the severity of coronary artery stenosis, indicating that IL27 may promote the development and progression of coronary artery disease by inducing Th1 differentiation and related cytokine production. Lastly, the proinflammatory cytokine, LTA is thought to contribute to the pathogenesis of atherosclerosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 17194634 PS:PMID 20207195 PS:PMID 21054264 PS:PMID 22911112 PS:PMID 23533763 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue bone marrow PS:CellType PS:Link PS:NodeType PS:PMID PS:Pathway_Author CellType: cancer stem cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfb7666f-cf30-4fd1-8b46-d862efc721f7 NodeType: Pathway PMID: 17392272 PMID: 18490190 PMID: 22847005 PMID: 23888049 PMID: 25081533 PMID: 25954275 PMID: 27070574 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-dfb7666f-cf30-4fd1-8b46-d862efc721f7 Hyaluronic Acid, CD44 and HMMR in Cancer Cells Motility, Invasion, Proliferation and Survival uuid-dfb7666f-cf30-4fd1-8b46-d862efc721f7 PS:CellType cancer stem cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfb7666f-cf30-4fd1-8b46-d862efc721f7 PS:NodeType Pathway PS:PMID 17392272 PS:PMID 18490190 PS:PMID 22847005 PS:PMID 23888049 PS:PMID 25081533 PS:PMID 25954275 PS:PMID 27070574 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfc7d06a-ce42-4e1b-9d9c-76e5a51835ba NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-dfc7d06a-ce42-4e1b-9d9c-76e5a51835ba CYP450 induction by drugs uuid-dfc7d06a-ce42-4e1b-9d9c-76e5a51835ba PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfc7d06a-ce42-4e1b-9d9c-76e5a51835ba PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfc8877c-5b7c-4159-8942-669cd7516a8c NodeType: Pathway Organ: generic Organ_System: generic PMID: 21102635 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-dfc8877c-5b7c-4159-8942-669cd7516a8c Ras-GAP Regulation Signaling uuid-dfc8877c-5b7c-4159-8942-669cd7516a8c PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfc8877c-5b7c-4159-8942-669cd7516a8c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21102635 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfd044ee-18ec-4b02-b642-9f56bba62b8a NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-dfd044ee-18ec-4b02-b642-9f56bba62b8a Fatty Acid Oxidation uuid-dfd044ee-18ec-4b02-b642-9f56bba62b8a PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-dfd044ee-18ec-4b02-b642-9f56bba62b8a PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e029c3ae-8b47-4f42-b549-0917cd7c5fab NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-e029c3ae-8b47-4f42-b549-0917cd7c5fab Proteins with Altered Expression in Cystic Kidney Disease uuid-e029c3ae-8b47-4f42-b549-0917cd7c5fab PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e029c3ae-8b47-4f42-b549-0917cd7c5fab PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0568127-10e2-4698-a494-c1e3ffc5efd6 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e0568127-10e2-4698-a494-c1e3ffc5efd6 AVP/Gs -> CREB/ELK/SRF/AP-1/EGR Expression Targets uuid-e0568127-10e2-4698-a494-c1e3ffc5efd6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0568127-10e2-4698-a494-c1e3ffc5efd6 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e063c340-6f70-414f-8849-f2a2e1d0fc2a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-e063c340-6f70-414f-8849-f2a2e1d0fc2a Complement Component GPCRs Signaling uuid-e063c340-6f70-414f-8849-f2a2e1d0fc2a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e063c340-6f70-414f-8849-f2a2e1d0fc2a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e065a692-9cab-47e8-8677-d66806a10354 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e065a692-9cab-47e8-8677-d66806a10354 Rubisco methylation template uuid-e065a692-9cab-47e8-8677-d66806a10354 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e065a692-9cab-47e8-8677-d66806a10354 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: plasma cell Description: Interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) are all major regulators implicated in multiple myeloma (MM) pathogenesis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e077450a-4b24-43e2-b9ff-7eb44df79291 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: Interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) are all major regulators implicated in multiple myeloma (MM) pathogenesis. These proteins are produced by bone marrow stromal cells and by MM cells. IL6 effects are mediated by JAK/STAT, PI3K/Akt, and RAS/MAPK signaling pathways. IGF1 and VEGFA activate PI3K/Akt and RAS/MAPK pathways. Outcome effects: The activated pathways lead to the expression of many downstream target genes, which triggers the inhibition of apoptosis as well as the activation of MM cell proliferation and migration, angiogenesis (vascularization), tumor expansion, and invasion. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: skeletal system PMID: 15471951 PMID: 16094421 PMID: 16239913 PMID: 17351339 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-e077450a-4b24-43e2-b9ff-7eb44df79291 IL6/IGF1/VEGFA Signaling in Multiple Myeloma uuid-e077450a-4b24-43e2-b9ff-7eb44df79291 PS:CellType cancer cell PS:CellType plasma cell PS:Description Interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) are all major regulators implicated in multiple myeloma (MM) pathogenesis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e077450a-4b24-43e2-b9ff-7eb44df79291 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. Signaling description: Interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) are all major regulators implicated in multiple myeloma (MM) pathogenesis. These proteins are produced by bone marrow stromal cells and by MM cells. IL6 effects are mediated by JAK/STAT, PI3K/Akt, and RAS/MAPK signaling pathways. IGF1 and VEGFA activate PI3K/Akt and RAS/MAPK pathways. Outcome effects: The activated pathways lead to the expression of many downstream target genes, which triggers the inhibition of apoptosis as well as the activation of MM cell proliferation and migration, angiogenesis (vascularization), tumor expansion, and invasion. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System skeletal system PS:PMID 15471951 PS:PMID 16094421 PS:PMID 16239913 PS:PMID 17351339 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: Altered bone remodeling is a key feature of psoriatic arthritis but can present with varying degrees in the individual patient. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0d14dce-dd35-4aa2-9ff9-17fd8b358901 NodeType: Pathway Notes: Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Altered bone remodeling is a key feature of PsA and can be present at varying degrees in an individual patient. Altered bone remodeling is a combination of altered bone formation and bone resorption, represented by the extent of bone erosions. Those erosions result from bone resorption by osteoclasts. In PsA, diverse manifestations of dynamic bone involvement including large eccentric erosions, tuft resorption, periostitis, ankylosis and acro-osteolysis are observed. Signaling description: Two striking features of peripheral involvement in PsA are subchondral perientheseal edema and diffuse bone edema, which are not present in rheumatoid arthritis (RA). The osteoclast formation in PsA patients is supported by data showing the production of osteoclastogenic cytokines, such as RANKL (also known as TNFSF11), which initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. The signaling involves TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 proteins and affects NF-kB and promotes osteoclast differentiation and cell survival. In addition, TNFSF11 promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. In addition, IL6 initiates NF-kB activation and the previously mentioned processes in osteoclasts through ther JAK-STAT pathway. IL1B also affects NF-kB pathway through the MYD88/IRAK4/IRAK1/TRAF6 axis. Outcome effects: Elevated levels of IL6, IL1B, and TNFSF11 in PsA promote osteoclast proliferation, differentiation, and their decreased apoptosis via a number of signaling routes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 12639988 PMID: 15972960 PMID: 17370327 PMID: 23436579 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-e0d14dce-dd35-4aa2-9ff9-17fd8b358901 Osteoclast Activation in Psoriatic Arthritis uuid-e0d14dce-dd35-4aa2-9ff9-17fd8b358901 PS:CellType osteoclast PS:Description Altered bone remodeling is a key feature of psoriatic arthritis but can present with varying degrees in the individual patient. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0d14dce-dd35-4aa2-9ff9-17fd8b358901 PS:NodeType Pathway PS:Notes Headnote: Psoriatic arthritis (PsA) refers to a form of arthritis that affects people with psoriasis. Symptoms include joint pain, stiffness and swelling. Altered bone remodeling is a key feature of PsA and can be present at varying degrees in an individual patient. Altered bone remodeling is a combination of altered bone formation and bone resorption, represented by the extent of bone erosions. Those erosions result from bone resorption by osteoclasts. In PsA, diverse manifestations of dynamic bone involvement including large eccentric erosions, tuft resorption, periostitis, ankylosis and acro-osteolysis are observed. Signaling description: Two striking features of peripheral involvement in PsA are subchondral perientheseal edema and diffuse bone edema, which are not present in rheumatoid arthritis (RA). The osteoclast formation in PsA patients is supported by data showing the production of osteoclastogenic cytokines, such as RANKL (also known as TNFSF11), which initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. The signaling involves TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 proteins and affects NF-kB and promotes osteoclast differentiation and cell survival. In addition, TNFSF11 promotes osteoclast proliferation through the AKT1 pathway. In mature osteoclasts, the same signaling leads to bone resorption. In addition, IL6 initiates NF-kB activation and the previously mentioned processes in osteoclasts through ther JAK-STAT pathway. IL1B also affects NF-kB pathway through the MYD88/IRAK4/IRAK1/TRAF6 axis. Outcome effects: Elevated levels of IL6, IL1B, and TNFSF11 in PsA promote osteoclast proliferation, differentiation, and their decreased apoptosis via a number of signaling routes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 12639988 PS:PMID 15972960 PS:PMID 17370327 PS:PMID 23436579 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0d5ab1d-d8ac-45bd-939f-f44300f6f613 NodeType: Pathway Organ: generic Organ_System: generic PMID: 15450248 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-e0d5ab1d-d8ac-45bd-939f-f44300f6f613 VEGF Signaling uuid-e0d5ab1d-d8ac-45bd-939f-f44300f6f613 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e0d5ab1d-d8ac-45bd-939f-f44300f6f613 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 15450248 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e102e4db-8d24-432b-b19a-1bdcb92bf588 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e102e4db-8d24-432b-b19a-1bdcb92bf588 Cellulose degradation template uuid-e102e4db-8d24-432b-b19a-1bdcb92bf588 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e102e4db-8d24-432b-b19a-1bdcb92bf588 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e130bca2-12f5-4844-8080-6701ee4c8fc9 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-e130bca2-12f5-4844-8080-6701ee4c8fc9 EGFR/ERBB3 -> MEF/MYOD/NFATC/MYOG Signaling uuid-e130bca2-12f5-4844-8080-6701ee4c8fc9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e130bca2-12f5-4844-8080-6701ee4c8fc9 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e14005fd-c6b1-40e8-a467-e09acf6b154b NodeType: Pathway Notes: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: stomach Organ_System: digestive system PMID: 14755326 PMID: 20938460 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-e14005fd-c6b1-40e8-a467-e09acf6b154b OipA Signaling in Helicobacter Pylori Infection uuid-e14005fd-c6b1-40e8-a467-e09acf6b154b PS:CellType epithelial cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e14005fd-c6b1-40e8-a467-e09acf6b154b PS:NodeType Pathway PS:Notes Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ stomach PS:Organ_System digestive system PS:PMID 14755326 PS:PMID 20938460 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: enterocyte Description: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH that controls CA2 metabolism through its effects on intestine. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e15f7bd4-e110-4643-981c-6436b8138d5d NodeType: Pathway Notes: Headnote: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of parathormone. PTH controls calcium metabolism through its effects on intestine. Signaling description: Hypersecretion of PTH is associated with hypercalcemia. Precise mechanisms of the molecular signalings of these processes in intestine are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. CREB1 promotes VDR, which regulates expression of TRPV5/6 and ATP2B1 involved in calcium reabsorption in intestine. Highlighted proteins: PTH with red highlight has increased expression. Ca2+ with red highlight has increased level in blood serum. Organ: colon Organ: intestine Organ_System: digestive system PMID: 12520535 PMID: 22536764 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-e15f7bd4-e110-4643-981c-6436b8138d5d Ca2+ Reabsorption Decline in Intestine uuid-e15f7bd4-e110-4643-981c-6436b8138d5d PS:CellType enterocyte PS:Description Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH that controls CA2 metabolism through its effects on intestine. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e15f7bd4-e110-4643-981c-6436b8138d5d PS:NodeType Pathway PS:Notes Headnote: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of parathormone. PTH controls calcium metabolism through its effects on intestine. Signaling description: Hypersecretion of PTH is associated with hypercalcemia. Precise mechanisms of the molecular signalings of these processes in intestine are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. CREB1 promotes VDR, which regulates expression of TRPV5/6 and ATP2B1 involved in calcium reabsorption in intestine. Highlighted proteins: PTH with red highlight has increased expression. Ca2+ with red highlight has increased level in blood serum. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 12520535 PS:PMID 22536764 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: In secondary glioblastoma TP53 and IDH1/2 mutation are early events. Other mechanisms include PDGFR, MDM2, and CDK4 amplifications, CDKN2A and RB1 deletions, as well as PTEN mutation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e16cd52b-d10d-40b7-af8f-f3006414d625 NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Secondary GBM develops from astrocytoma, oligodendroglioma, or ependymoma. Signaling description: The most important signaling systems deregulated in GBM are receptor tyrosine kinase (RTK), TP53, and RB1 pathways. Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are early and frequent genetic alterations in secondary GBMs, as well as in oligodendroglial tumors. Loss of IDH1 function induces HIF1A, which is implicated in tumor growth. IDH1 proteins also exhibit a gain-of-function phenotype by generating 2-hydroxyglutarate, a toxic metabolite associated with an increased risk of malignant brain tumors in patients. TP53 inactivation due to mutation is also an early event in secondary GBM development. Other mechanisms include PDGFR, MDM2, and CDK4 amplifications, CDKN2A and RB1 deletions, as well as PTEN and IDH2 mutations. In addition, mutations in neurofibromin 2 (NF2) are the major cause of ependymomas, which in the long term develop into secondary GBMs. Outcome effects: Ultimately, these genetic events lead to the activation of proliferation and block of apoptosis resulting in carcinogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 17974913 PMID: 20414201 PMID: 23183634 PMID: 24212955 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-e16cd52b-d10d-40b7-af8f-f3006414d625 Glioblastoma, Secondary uuid-e16cd52b-d10d-40b7-af8f-f3006414d625 PS:CellType cancer cell PS:CellType glial precursor cell PS:Description In secondary glioblastoma TP53 and IDH1/2 mutation are early events. Other mechanisms include PDGFR, MDM2, and CDK4 amplifications, CDKN2A and RB1 deletions, as well as PTEN mutation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e16cd52b-d10d-40b7-af8f-f3006414d625 PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Secondary GBM develops from astrocytoma, oligodendroglioma, or ependymoma. Signaling description: The most important signaling systems deregulated in GBM are receptor tyrosine kinase (RTK), TP53, and RB1 pathways. Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are early and frequent genetic alterations in secondary GBMs, as well as in oligodendroglial tumors. Loss of IDH1 function induces HIF1A, which is implicated in tumor growth. IDH1 proteins also exhibit a gain-of-function phenotype by generating 2-hydroxyglutarate, a toxic metabolite associated with an increased risk of malignant brain tumors in patients. TP53 inactivation due to mutation is also an early event in secondary GBM development. Other mechanisms include PDGFR, MDM2, and CDK4 amplifications, CDKN2A and RB1 deletions, as well as PTEN and IDH2 mutations. In addition, mutations in neurofibromin 2 (NF2) are the major cause of ependymomas, which in the long term develop into secondary GBMs. Outcome effects: Ultimately, these genetic events lead to the activation of proliferation and block of apoptosis resulting in carcinogenesis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 17974913 PS:PMID 20414201 PS:PMID 23183634 PS:PMID 24212955 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: mast cell Description: The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1b56cf3-2449-4a8b-8441-373af9e0c7a2 NodeType: Pathway Notes: Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: IL1A and bacterial lipopolysaccharide (LPS) result in selective release of IL6, TNF, and IL8 without degranulation through vesicles (40-80 nm) much smaller than the secretory granules (800-1000 nm). TLR activation on mast cells causes the release of several cytokines including IL6, IL8, TNF, and IL13. Affected by infection-derived triggers, mast cells also synthesize nitric oxide (NO) through TLR pathway. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-e1b56cf3-2449-4a8b-8441-373af9e0c7a2 Mast-Cell Activation without Degranulation through IL1R1 and TLR Signaling uuid-e1b56cf3-2449-4a8b-8441-373af9e0c7a2 PS:CellType mast cell PS:Description The activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1b56cf3-2449-4a8b-8441-373af9e0c7a2 PS:NodeType Pathway PS:Notes Headnote: Mast cells are dissipated in connective tissue and stored in the spleen and bone marrow and contain large amounts of cytoplasmic granules including proteoglycans (heparin), histamine, interleukins, and neutral proteases. Signaling description: Upon activation, mast cells release the contents of granules into surrounding tissue by a process known as degranulation. At the same time, the activation of mast cells can lead to the synthesis of large amounts of mediators without degranulation. In inflammation, mast cells rarely release the entire contents of granules and synthesize de novo large amounts of molecules that control immune system activation and inflammatory response at the site of injury. It has been shown that specific stimuli (or their combinations) can selectively trigger the expression of specific mediators. The issue of selective synthesis of mediators in mast cells requires further research. Outcome effects: IL1A and bacterial lipopolysaccharide (LPS) result in selective release of IL6, TNF, and IL8 without degranulation through vesicles (40-80 nm) much smaller than the secretory granules (800-1000 nm). TLR activation on mast cells causes the release of several cytokines including IL6, IL8, TNF, and IL13. Affected by infection-derived triggers, mast cells also synthesize nitric oxide (NO) through TLR pathway. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1cab210-5f1d-4102-9952-4b0e2f30908d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e1cab210-5f1d-4102-9952-4b0e2f30908d Serotonin/Gs Expression Targets uuid-e1cab210-5f1d-4102-9952-4b0e2f30908d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1cab210-5f1d-4102-9952-4b0e2f30908d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1ee754d-9fbc-42bb-88db-f5aad2c2a913 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e1ee754d-9fbc-42bb-88db-f5aad2c2a913 TNFSF13B Expression Targets uuid-e1ee754d-9fbc-42bb-88db-f5aad2c2a913 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1ee754d-9fbc-42bb-88db-f5aad2c2a913 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1ff5751-11bf-442e-8f18-8afd545c2c93 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e1ff5751-11bf-442e-8f18-8afd545c2c93 Proteins Involved in T-Cell Acute Lymphoblastic Leukemia uuid-e1ff5751-11bf-442e-8f18-8afd545c2c93 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e1ff5751-11bf-442e-8f18-8afd545c2c93 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e20d0b92-1e4f-4835-b839-aedb5eda887b NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-e20d0b92-1e4f-4835-b839-aedb5eda887b Proteins Involved in Migraine uuid-e20d0b92-1e4f-4835-b839-aedb5eda887b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e20d0b92-1e4f-4835-b839-aedb5eda887b PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2138e4c-56c4-4e0c-978f-28508c20edc5 NodeType: Pathway PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-e2138e4c-56c4-4e0c-978f-28508c20edc5 Cervical Cancer Anatomy and Molecular Biomarkers uuid-e2138e4c-56c4-4e0c-978f-28508c20edc5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2138e4c-56c4-4e0c-978f-28508c20edc5 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: The imbalance of calcium (Ca2) homeostasis which includes Ca2 overload and Ca2 exitotoxicity is observed in Alzheimer's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2538b51-3cfe-4832-a613-616ae849d0fc NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The imbalance of calcium (Ca2+) homeostasis which includes Ca2+ overload and Ca2+ exitotoxicity is observed in Alzheimer's disease (AD). Signaling description: Normally, Ca2+ plays an important role in signal transduction and neuron excitation. Ca2+ overload results from the opening of specific ion channels when Abeta binds to them. These are the voltage-gated calcium channels (VGCCs) and several ligand-gated ion channels (N-methyl-D-aspartate selective glutamate receptor or NMDAR, CHRM1, and CHRNA7). These channels promote Ca2+ influx. In addition, the blockage of Ca2+ ATPase due to lipid peroxidation caused by H2O2 synthesis prevents Ca2+ efflux. Oligomeric Abeta can also form a pore for Ca2+ influx. Furthermore, APP intracellular domain (AICD) is translocated by APBB1 to the nucleus and modifies gene transcription in ways that upset Ca2+ homeostasis. Ca2+ is released into the cytosol from endoplasmic reticulum (ER) via the activation of ITPR1 and RYR3. Basal cytosolic Ca2+ levels are in part maintained by the active uptake by the sarco/endoplasmic reticulum calcium-ATPase (SERCA) at the ER membrane, which is normally regulated by presenilin protein, and mutations in this protein lead to an abnormal increase in the size of ER Ca2+ stores. Outcome effects: Ca2+ overload leads to various consequences: Ca2+ activates NOS1 in neurons leading to NO generation and initiating pathological processes such as mitochondrial depolarization, DNA damage, and others. Specifically, Ca2+ enters the mitochondria via MCU channel and disturbs the respiratory chain. The released electrons are accepted by O2 and superoxide radicals are generated. These events lead to ATP depletion the generation of ROS. Superoxide anion also causes lipid peroxidation. Ca2+ also promotes CYCS release by activating BAD through calmodulin. Increased cytosolic Ca2+ concentration initiates the activation of MAPK signaling cascades leading to CREB activation, a process critical for protein synthesis-dependent synaptic plasticity and long-term potentiation (LTP). Ca2+ also triggers neurofibrillary tangle (NFT) formation through calpain/CDK5/MAPT axis and increases beta-secretase (BACE1) activity. Finally, the affected processes including DNA damage, NFT formation, and CYCS release eventually lead to neuron death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 15975072 PMID: 19221414 PMID: 19402778 PMID: 22453989 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-e2538b51-3cfe-4832-a613-616ae849d0fc Ca2+ Toxicity in Neurons uuid-e2538b51-3cfe-4832-a613-616ae849d0fc PS:CellType neuron PS:Description The imbalance of calcium (Ca2) homeostasis which includes Ca2 overload and Ca2 exitotoxicity is observed in Alzheimer's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2538b51-3cfe-4832-a613-616ae849d0fc PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). The imbalance of calcium (Ca2+) homeostasis which includes Ca2+ overload and Ca2+ exitotoxicity is observed in Alzheimer's disease (AD). Signaling description: Normally, Ca2+ plays an important role in signal transduction and neuron excitation. Ca2+ overload results from the opening of specific ion channels when Abeta binds to them. These are the voltage-gated calcium channels (VGCCs) and several ligand-gated ion channels (N-methyl-D-aspartate selective glutamate receptor or NMDAR, CHRM1, and CHRNA7). These channels promote Ca2+ influx. In addition, the blockage of Ca2+ ATPase due to lipid peroxidation caused by H2O2 synthesis prevents Ca2+ efflux. Oligomeric Abeta can also form a pore for Ca2+ influx. Furthermore, APP intracellular domain (AICD) is translocated by APBB1 to the nucleus and modifies gene transcription in ways that upset Ca2+ homeostasis. Ca2+ is released into the cytosol from endoplasmic reticulum (ER) via the activation of ITPR1 and RYR3. Basal cytosolic Ca2+ levels are in part maintained by the active uptake by the sarco/endoplasmic reticulum calcium-ATPase (SERCA) at the ER membrane, which is normally regulated by presenilin protein, and mutations in this protein lead to an abnormal increase in the size of ER Ca2+ stores. Outcome effects: Ca2+ overload leads to various consequences: Ca2+ activates NOS1 in neurons leading to NO generation and initiating pathological processes such as mitochondrial depolarization, DNA damage, and others. Specifically, Ca2+ enters the mitochondria via MCU channel and disturbs the respiratory chain. The released electrons are accepted by O2 and superoxide radicals are generated. These events lead to ATP depletion the generation of ROS. Superoxide anion also causes lipid peroxidation. Ca2+ also promotes CYCS release by activating BAD through calmodulin. Increased cytosolic Ca2+ concentration initiates the activation of MAPK signaling cascades leading to CREB activation, a process critical for protein synthesis-dependent synaptic plasticity and long-term potentiation (LTP). Ca2+ also triggers neurofibrillary tangle (NFT) formation through calpain/CDK5/MAPT axis and increases beta-secretase (BACE1) activity. Finally, the affected processes including DNA damage, NFT formation, and CYCS release eventually lead to neuron death. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 15975072 PS:PMID 19221414 PS:PMID 19402778 PS:PMID 22453989 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e263f746-c55c-43ce-9507-6d8e6fd60de2 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-e263f746-c55c-43ce-9507-6d8e6fd60de2 Elevated Receptors -> Expression Targets in Respiratory System uuid-e263f746-c55c-43ce-9507-6d8e6fd60de2 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e263f746-c55c-43ce-9507-6d8e6fd60de2 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e26e7c20-5e6a-4f60-bff7-042685ab7a9a NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-e26e7c20-5e6a-4f60-bff7-042685ab7a9a TNFR -> CREB/ELK-SRF Signaling uuid-e26e7c20-5e6a-4f60-bff7-042685ab7a9a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e26e7c20-5e6a-4f60-bff7-042685ab7a9a PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e278708a-7977-4621-a4c4-05af717a03b2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e278708a-7977-4621-a4c4-05af717a03b2 Ubiquinone-6 biosynthesis (eukaryotic) template uuid-e278708a-7977-4621-a4c4-05af717a03b2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e278708a-7977-4621-a4c4-05af717a03b2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e281d49d-c247-47b5-aa78-c9f0692bb277 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-e281d49d-c247-47b5-aa78-c9f0692bb277 B-Cell Receptor -> AP-1 Signaling uuid-e281d49d-c247-47b5-aa78-c9f0692bb277 PS:CellType B-cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e281d49d-c247-47b5-aa78-c9f0692bb277 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Dysregulation of RAS/RAF/MAPK signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e29dc750-8176-4002-bd09-a4f4065b1383 NodeType: Pathway Notes: Headnote: RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation. RASSF family proteins are the effectors of RAS and function as tumor suppressors by regulating the cell cycle and apoptosis. Signaling description: The inactivation of natural inhibitors of RAS signaling - NF1/2 - by mutations leads to its constant activation. Silencing of RASSF proteins by promoter methylation promotes cancer progression. Outcome effects: RAS signaling is constantly activated leading to uncontrolled cell proliferation and apoptosis of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17692468 PMID: 19344752 PMID: 23373991 PMID: 25893302 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e29dc750-8176-4002-bd09-a4f4065b1383 RAS/RAF/MAPK Signaling Activation by Blocking of Tumor Suppressors uuid-e29dc750-8176-4002-bd09-a4f4065b1383 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Dysregulation of RAS/RAF/MAPK signaling pathway contributes to uncontrolled cell proliferation and inhibition of apoptosis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e29dc750-8176-4002-bd09-a4f4065b1383 PS:NodeType Pathway PS:Notes Headnote: RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation. RASSF family proteins are the effectors of RAS and function as tumor suppressors by regulating the cell cycle and apoptosis. Signaling description: The inactivation of natural inhibitors of RAS signaling - NF1/2 - by mutations leads to its constant activation. Silencing of RASSF proteins by promoter methylation promotes cancer progression. Outcome effects: RAS signaling is constantly activated leading to uncontrolled cell proliferation and apoptosis of apoptosis. Animal data: Some of the data were obtained from animal experiments or human cancer lines. Highlighted proteins: Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Evading of Growth Suppressors" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Evading of Growth Suppressors" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17692468 PS:PMID 19344752 PS:PMID 23373991 PS:PMID 25893302 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: osteoblast Description: Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2b771e5-cdfa-4f48-a973-d1be39ea616f NodeType: Pathway Notes: Headnote: Hyperparathyroidism is a common endocrine disorder defined by hypersecretion of parathyroid hormone (PTH). Bone disease in hyperparathyroidism is characterized by decreased bone resorption and low bone mineral density. Pathological fractures, bone pain and deformities are features of osteitis fibrosa cystica which occur in hyperparathyroidism. In this condition, bone mineral density is usually extremely low. Signaling description: Hypersecretion of PTH is associated with osteoclast activation and bone resorption. Precise mechanisms of the molecular signalings of these processes are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. BMP2 binds to BMPR1A/2 and through SMADs activates RUNX2. WNT3A signaling in osteoblast leads to E2F1 activation. CREB1, E2F1 and RUNX2 promote TNFSF11 that initiates osteoclast differentiation. Highlighted proteins: PTH with red highlight has increased expression. Organ: bone Organ_System: skeletal system PMID: 11814673 PMID: 21695250 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: bone tissue urn:agi-pathway:uuid-e2b771e5-cdfa-4f48-a973-d1be39ea616f Bone Resorption in Hyperparathyroidism uuid-e2b771e5-cdfa-4f48-a973-d1be39ea616f PS:CellType osteoblast PS:Description Hyperparathyroidism is one of the most common endocrine disorders, defined by hypersecretion of PTH. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2b771e5-cdfa-4f48-a973-d1be39ea616f PS:NodeType Pathway PS:Notes Headnote: Hyperparathyroidism is a common endocrine disorder defined by hypersecretion of parathyroid hormone (PTH). Bone disease in hyperparathyroidism is characterized by decreased bone resorption and low bone mineral density. Pathological fractures, bone pain and deformities are features of osteitis fibrosa cystica which occur in hyperparathyroidism. In this condition, bone mineral density is usually extremely low. Signaling description: Hypersecretion of PTH is associated with osteoclast activation and bone resorption. Precise mechanisms of the molecular signalings of these processes are well known. Outcome effects: The PTH1R is activated by PTH and mediates GNAS, which stimulates ADCY/PKA/CREB1 cascade. BMP2 binds to BMPR1A/2 and through SMADs activates RUNX2. WNT3A signaling in osteoblast leads to E2F1 activation. CREB1, E2F1 and RUNX2 promote TNFSF11 that initiates osteoclast differentiation. Highlighted proteins: PTH with red highlight has increased expression. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11814673 PS:PMID 21695250 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue bone tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The vesicle fusion is a process of merging the vesicle membrane with the target one resulting in release of biomolecules in the extracellular space (or in the synaptic cleft). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2bf8bdb-32b5-4d43-8a2f-3b3bb6450278 NodeType: Pathway Notes: Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. The process of vesicle fusion involves merging the vesicle membrane with the target membrane resulting in release of large biomolecules in the extracellular space (or in the synaptic cleft). Signaling description: There are several models that explain the formation of the fusion pore, but the exact nature of these processes remains debated. SNARE proteins (syntaxin (STX1A), SNAP-25 and synaptobrevin (VAMP2) form an incredibly stable SNARE complex via a four alpha helical bundle that provides energy for the membranes to fuse. SNARE complex assembly brings the vesicle membrane into close opposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. Complexin (CPLX1) and synaptotagmin (SYT1 ) regulate vesicle release. The post-fusion SNARE complex must be mechanically disassembled. SNARE disassembly can be induced by a single round of ATP hydrolysis supplied by two proteins, ATPase N-ethylmaleimide sensitive factor (NSF) and soluble NSF-attachment protein (NAPA). The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SNARE complex formation drives membrane fusion and NAPA/NSF disassemble SNAREs by inducing shearing/rotation with ATP hydrolysis. Animal data: Some of the data was revealed from animal model experiments. Organ: generic Organ_System: generic PMID: 17397838 PMID: 21936774 PMID: 26498108 PMID: 28163686 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-e2bf8bdb-32b5-4d43-8a2f-3b3bb6450278 Exocytosis: Vesicle Fusion uuid-e2bf8bdb-32b5-4d43-8a2f-3b3bb6450278 PS:CellType generic PS:Description The vesicle fusion is a process of merging the vesicle membrane with the target one resulting in release of biomolecules in the extracellular space (or in the synaptic cleft). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2bf8bdb-32b5-4d43-8a2f-3b3bb6450278 PS:NodeType Pathway PS:Notes Headnote: Exocytosis is the process of secretory vesicle transport to the cell membrane. These membrane-bound vesicles contain proteins to be secreted to the extracellular environment, and membrane proteins and lipids that are sent to become components of the cell membrane. There are two types of exocytosis: Ca2+ triggered non-constitutive exocytosis and non Ca2+ triggered constitutive exocytosis. The process of exocytosis is includes five major stages: vesicle trafficking, vesicle tethering, vesicle docking, vesicle priming (in neuronal exocytosis) and vesicle fusion. The process of vesicle fusion involves merging the vesicle membrane with the target membrane resulting in release of large biomolecules in the extracellular space (or in the synaptic cleft). Signaling description: There are several models that explain the formation of the fusion pore, but the exact nature of these processes remains debated. SNARE proteins (syntaxin (STX1A), SNAP-25 and synaptobrevin (VAMP2) form an incredibly stable SNARE complex via a four alpha helical bundle that provides energy for the membranes to fuse. SNARE complex assembly brings the vesicle membrane into close opposition with the plasma membrane promoting lipid mixing leading to vesicle fusion. Complexin (CPLX1) and synaptotagmin (SYT1 ) regulate vesicle release. The post-fusion SNARE complex must be mechanically disassembled. SNARE disassembly can be induced by a single round of ATP hydrolysis supplied by two proteins, ATPase N-ethylmaleimide sensitive factor (NSF) and soluble NSF-attachment protein (NAPA). The precise mechanism of this is poorly understood. One of hypotheses is described on the pathway. Outcome effects: SNARE complex formation drives membrane fusion and NAPA/NSF disassemble SNAREs by inducing shearing/rotation with ATP hydrolysis. Animal data: Some of the data was revealed from animal model experiments. PS:Organ generic PS:Organ_System generic PS:PMID 17397838 PS:PMID 21936774 PS:PMID 26498108 PS:PMID 28163686 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2db8529-e2ff-45a5-9037-8cfbbc2e4e4d NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-e2db8529-e2ff-45a5-9037-8cfbbc2e4e4d Overview. Diseases of the genitourinary system (chapter 13) uuid-e2db8529-e2ff-45a5-9037-8cfbbc2e4e4d PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2db8529-e2ff-45a5-9037-8cfbbc2e4e4d PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2e3ad74-e03b-47a7-b706-e9721217bc67 NodeType: Pathway Organ: oncogenic Organ_System: oncogenic PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e2e3ad74-e03b-47a7-b706-e9721217bc67 Proteins with Altered Expression in Cancer Metabolic Reprogramming uuid-e2e3ad74-e03b-47a7-b706-e9721217bc67 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e2e3ad74-e03b-47a7-b706-e9721217bc67 PS:NodeType Pathway PS:Organ oncogenic PS:Organ_System oncogenic PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Source CellType: epithelial cell Description: Cataract that is caused by steroid administration is a common side effect from the therapy used to treat different pathologies. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e32b13f6-0d4a-4e74-906c-fdb8055a4fd5 NodeType: Pathway Notes: Headnote: Cataract is clouding of the eye's lens that affects vision. Cataract caused by steroid administration is a common side effect of the therapy used to treat various pathologies. The characteristic features of steroid-induced cataract (SIC) are aberrant lens epithelial cell migration, proliferation, and a central posterior location. Signaling description: Normally, lens epithelial cells continuously proliferate and differentiate into fiber cells via the synthesis of specific proteins such as crystallins, MIP, BFSP1, and BFSP2 in addition to the elimination of organelles and cell migration to the lens nucleus. The process of cell proliferation, differentiation, and migration is upregulated by FGF2 in a dose-dependent manner. A low cytokine concentration initiates epithelial cell proliferation, while moderate cytokine levels lead to migration, and higher concentrations cause differentiation. FGF2, (through MAP2K1/MAP2K2/MAPK1/MAPK3) promotes cell proliferation via the activation of RPS6KB1 and CREBBP transcription factors. At higher concentrations of FGF2, MAF is involved through the same pathway and initiates the transcription of lens specific proteins including crystallins, MIP, BFSP1, and BFSP2. Outcome effects: Steroids can indicrectly influence cataract development by moderately decreasing FGF2 expression, which leads to block of cell differentiation, but the level of FGF2 is still sufficient to promote cell proliferation. In the direct mechanism of steroid-induced cataractogenesis, steroids (glucocorticoids) bind to their intracellular receptor, NR3C1 and initiate the expression of TSC22D3, which is a repressor of cell differentiation. NR3C1 inhibits CDH1 through CTNNB1 and results in the disruption of cell adhesion processes. Lastly, elevated levels of MMP2 and MMP9 are also observed in SIC. The expression of metalloproteinases is initiated by TGFB1. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: eye Organ_System: sensory system PMID: 11952401 PMID: 17900234 PMID: 22259225 PathwayType: signaling Source: Diseases urn:agi-pathway:uuid-e32b13f6-0d4a-4e74-906c-fdb8055a4fd5 Steroids Induced Cataract uuid-e32b13f6-0d4a-4e74-906c-fdb8055a4fd5 PS:CellType epithelial cell PS:Description Cataract that is caused by steroid administration is a common side effect from the therapy used to treat different pathologies. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e32b13f6-0d4a-4e74-906c-fdb8055a4fd5 PS:NodeType Pathway PS:Notes Headnote: Cataract is clouding of the eye's lens that affects vision. Cataract caused by steroid administration is a common side effect of the therapy used to treat various pathologies. The characteristic features of steroid-induced cataract (SIC) are aberrant lens epithelial cell migration, proliferation, and a central posterior location. Signaling description: Normally, lens epithelial cells continuously proliferate and differentiate into fiber cells via the synthesis of specific proteins such as crystallins, MIP, BFSP1, and BFSP2 in addition to the elimination of organelles and cell migration to the lens nucleus. The process of cell proliferation, differentiation, and migration is upregulated by FGF2 in a dose-dependent manner. A low cytokine concentration initiates epithelial cell proliferation, while moderate cytokine levels lead to migration, and higher concentrations cause differentiation. FGF2, (through MAP2K1/MAP2K2/MAPK1/MAPK3) promotes cell proliferation via the activation of RPS6KB1 and CREBBP transcription factors. At higher concentrations of FGF2, MAF is involved through the same pathway and initiates the transcription of lens specific proteins including crystallins, MIP, BFSP1, and BFSP2. Outcome effects: Steroids can indicrectly influence cataract development by moderately decreasing FGF2 expression, which leads to block of cell differentiation, but the level of FGF2 is still sufficient to promote cell proliferation. In the direct mechanism of steroid-induced cataractogenesis, steroids (glucocorticoids) bind to their intracellular receptor, NR3C1 and initiate the expression of TSC22D3, which is a repressor of cell differentiation. NR3C1 inhibits CDH1 through CTNNB1 and results in the disruption of cell adhesion processes. Lastly, elevated levels of MMP2 and MMP9 are also observed in SIC. The expression of metalloproteinases is initiated by TGFB1. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ eye PS:Organ_System sensory system PS:PMID 11952401 PS:PMID 17900234 PS:PMID 22259225 PS:PathwayType signaling PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e350a8fc-4370-4f0b-950a-6a9fbf5f84d6 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e350a8fc-4370-4f0b-950a-6a9fbf5f84d6 Sitosterol biosynthesis template uuid-e350a8fc-4370-4f0b-950a-6a9fbf5f84d6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e350a8fc-4370-4f0b-950a-6a9fbf5f84d6 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e358389b-8d65-4936-acec-7867a4c8dc30 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-e358389b-8d65-4936-acec-7867a4c8dc30 GFs/TNF Influence on Ion Channels in Nociception uuid-e358389b-8d65-4936-acec-7867a4c8dc30 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e358389b-8d65-4936-acec-7867a4c8dc30 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: fibroblast Description: There is an increase in synovial fibroblast proliferation in rheumatoid arthritis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e365b6d9-2ac1-4516-b2f2-b616e512b277 NodeType: Pathway Notes: Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: There is an increase in synovial fibroblast proliferation in RA. The proliferation is triggered by growth factors and cytokines including PDGF, IGF1, FGF2, TGFB1, INHBA, IL6, IL1B, and MIF. IL6 and PDGF are elevated in the disease and interact with the JAK-STAT pathway. IGF1 is also increased in RA and affects the MAPK3/1 pathway. Integrins also play an important role in the process. A high expression of ITGB1, ITGAV, ITGA5, and ITGA1 is observed in RA synovial fibroblasts. Integrins bind to extracellular matrix proteins such as FN1, VTN, collagen, and laminin and activate JUN and FOS transcription factors. Lastly, cytoskeleton is implicated in the process. Outcome effects: STAT transcription factors induce MYC expression which is a positive regulator of cell proliferation. JUN and FOS directly regulate cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: bone Organ_System: skeletal system PMID: 11759230 PMID: 13130463 PMID: 15353290 PMID: 16824621 PMID: 22077951 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: Cartilage Tissue: bone tissue urn:agi-pathway:uuid-e365b6d9-2ac1-4516-b2f2-b616e512b277 Synovial Fibroblast Proliferation in Rheumatoid Arthritis uuid-e365b6d9-2ac1-4516-b2f2-b616e512b277 PS:CellType fibroblast PS:Description There is an increase in synovial fibroblast proliferation in rheumatoid arthritis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e365b6d9-2ac1-4516-b2f2-b616e512b277 PS:NodeType Pathway PS:Notes Headnote: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and causes inflammation and painful swelling. Other symptoms include fatigue, loss of appetite and a low-grade fever. Advanced RA can lead to bone erosion and joint deformity. Signaling description: There is an increase in synovial fibroblast proliferation in RA. The proliferation is triggered by growth factors and cytokines including PDGF, IGF1, FGF2, TGFB1, INHBA, IL6, IL1B, and MIF. IL6 and PDGF are elevated in the disease and interact with the JAK-STAT pathway. IGF1 is also increased in RA and affects the MAPK3/1 pathway. Integrins also play an important role in the process. A high expression of ITGB1, ITGAV, ITGA5, and ITGA1 is observed in RA synovial fibroblasts. Integrins bind to extracellular matrix proteins such as FN1, VTN, collagen, and laminin and activate JUN and FOS transcription factors. Lastly, cytoskeleton is implicated in the process. Outcome effects: STAT transcription factors induce MYC expression which is a positive regulator of cell proliferation. JUN and FOS directly regulate cell proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11759230 PS:PMID 13130463 PS:PMID 15353290 PS:PMID 16824621 PS:PMID 22077951 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue Cartilage PS:Tissue bone tissue PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e36a7f3d-2cf1-4ef1-b12e-5fe73dcd964e NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e36a7f3d-2cf1-4ef1-b12e-5fe73dcd964e Genes with Mutations Associated with Osteopetrosis uuid-e36a7f3d-2cf1-4ef1-b12e-5fe73dcd964e PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e36a7f3d-2cf1-4ef1-b12e-5fe73dcd964e PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: retina cell Description: NF-kB activity is elevated in the cells of trabecular meshwork obtained from the eyes of glaucoma patients of diverse etiology. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e37f5b3c-a8e5-4cf0-a42d-7bd307da442d NodeType: Pathway Notes: Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: NF-kB activity is elevated in the cells of trabecular meshwork obtained from the eyes of glaucoma patients of diverse etiology. The binding of TNF to its receptors leads to receptor trimerization, which promotes the assembly of a multimolecular complex on the TNF receptor, in which ubiquitination of RIPK1 takes place. At that point, IKBKG is recruited to ubiquitinated RIPK1, which leads to the activation of IKBKB and CHUK. Outcome effects: Active IKBKB phosphorylates NFKBIA, which acts as a trigger for ubiquitination and degradation of NFKBIA. This leads to NF-kB activation and recruitment to the nucleus, which causes activation of transcription. OPTN regulates this process by acting as a competitive inhibitor of IKBKG and binds to ubiquitinated RIPK1 by displacing IKBKG. OPTN then recruits CYLD (a deubiquitinase) to the molecular complex thus facilitating deubiquitination of polyubiquitinated RIPK1 by CYLD leading to the down regulation of downstream pathways causing cell apoptosis. Mutated OPTN also triggers the release of cytochrome c (CYCS), loss of mitochondrial membrane potential, and activation of the mitochondrial pathway in neuronal cell apoptosis. Mutated proteins: Mutated gene is shown in white-out style. Organ: eye Organ_System: sensory system PMID: 17702576 PMID: 18929124 PMID: 22155051 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e37f5b3c-a8e5-4cf0-a42d-7bd307da442d OPTN Effects on NF-kB Signaling in Glaucoma uuid-e37f5b3c-a8e5-4cf0-a42d-7bd307da442d PS:CellType retina cell PS:Description NF-kB activity is elevated in the cells of trabecular meshwork obtained from the eyes of glaucoma patients of diverse etiology. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e37f5b3c-a8e5-4cf0-a42d-7bd307da442d PS:NodeType Pathway PS:Notes Headnote: Glaucoma refers to a group of eye disoders in which ocular hypertension damages the optic nerve eventually leading to vision loss. Signaling description: NF-kB activity is elevated in the cells of trabecular meshwork obtained from the eyes of glaucoma patients of diverse etiology. The binding of TNF to its receptors leads to receptor trimerization, which promotes the assembly of a multimolecular complex on the TNF receptor, in which ubiquitination of RIPK1 takes place. At that point, IKBKG is recruited to ubiquitinated RIPK1, which leads to the activation of IKBKB and CHUK. Outcome effects: Active IKBKB phosphorylates NFKBIA, which acts as a trigger for ubiquitination and degradation of NFKBIA. This leads to NF-kB activation and recruitment to the nucleus, which causes activation of transcription. OPTN regulates this process by acting as a competitive inhibitor of IKBKG and binds to ubiquitinated RIPK1 by displacing IKBKG. OPTN then recruits CYLD (a deubiquitinase) to the molecular complex thus facilitating deubiquitination of polyubiquitinated RIPK1 by CYLD leading to the down regulation of downstream pathways causing cell apoptosis. Mutated OPTN also triggers the release of cytochrome c (CYCS), loss of mitochondrial membrane potential, and activation of the mitochondrial pathway in neuronal cell apoptosis. Mutated proteins: Mutated gene is shown in white-out style. PS:Organ eye PS:Organ_System sensory system PS:PMID 17702576 PS:PMID 18929124 PS:PMID 22155051 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: prostate glandular cell Description: AHR serves not only as a transcription factor but also as part of a ligand-dependent E3-type ubiquitin ligase complex to regulate selective protein degradation. Pathway is built using manually curated ResNet data. Pathway is built using manually-curate.. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e389aa71-f513-4e7b-8754-05967f47e799 NodeType: Pathway Notes: Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. In assition, AHR serves as part of a ligand-dependent E3-type ubiquitin ligase complex to regulate selective protein degradation. Signaling description: Protein ubiquitination involves ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin protein ligase (E3), which acts as a bridge between E2 and the substrate. Ligand-bound AHR assembles into the CUL4B-based atypical E3 ubiquitin ligase complex CUL4B-AHR, which includes CUL4B, DNA-binding protein 1 (DDB1), RBX1, subunits of the 19S regulatory particle of the 26S proteasome, ARNT and transducin beta-like 3 (TBL3). Outcome effects: AHR activation by such ligands as 3-methylcholanthrene and beta-naphthoflavone decreased the levels of endogenous estrogen receptors (ESR1/2) and androgen receptor (AR). Organ: prostate Organ_System: reproductive system PMID: 17392787 PMID: 18838062 PMID: 21397018 PMID: 23580432 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-e389aa71-f513-4e7b-8754-05967f47e799 Ubiquitin Ligase Complex in Prostata Cell uuid-e389aa71-f513-4e7b-8754-05967f47e799 PS:CellType prostate glandular cell PS:Description AHR serves not only as a transcription factor but also as part of a ligand-dependent E3-type ubiquitin ligase complex to regulate selective protein degradation. Pathway is built using manually curated ResNet data. Pathway is built using manually-curate.. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e389aa71-f513-4e7b-8754-05967f47e799 PS:NodeType Pathway PS:Notes Headnote: The aryl hydrocarbon receptor (AHR) is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. In assition, AHR serves as part of a ligand-dependent E3-type ubiquitin ligase complex to regulate selective protein degradation. Signaling description: Protein ubiquitination involves ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin protein ligase (E3), which acts as a bridge between E2 and the substrate. Ligand-bound AHR assembles into the CUL4B-based atypical E3 ubiquitin ligase complex CUL4B-AHR, which includes CUL4B, DNA-binding protein 1 (DDB1), RBX1, subunits of the 19S regulatory particle of the 26S proteasome, ARNT and transducin beta-like 3 (TBL3). Outcome effects: AHR activation by such ligands as 3-methylcholanthrene and beta-naphthoflavone decreased the levels of endogenous estrogen receptors (ESR1/2) and androgen receptor (AR). PS:Organ prostate PS:Organ_System reproductive system PS:PMID 17392787 PS:PMID 18838062 PS:PMID 21397018 PS:PMID 23580432 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: Preconditioning ischemia (PI) is a phenomenon that limits myocardial damage. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e397ab10-3eb0-40a6-9e35-b6d1f2319715 NodeType: Pathway Notes: Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Preconditioning ischemia (PI) is a process that limits myocardial damage by a subsequent ischemic attack. Signaling description: In PI, brief periods of ischemia are separated by periods of reperfusion, making the heart muscle more resistant to oxygen deficiency caused by a following ischemic event. Brief periods of ischemia confer protection against a subsequent prolonged and injurious period of ischemia. The mechanism by which PI protects the myocardium is still unknown. PI causes the release of agonists such as adenosine, bradykinin, and opioids, which bind to GPCR and to their receptors and activate the cardioprotective signaling cascades.Ouctome effects: The activation of GPCR leads to the activation of PI3K pathway, which via PDPK1, results in the activation of downstream targets such as AKT1, RPS6KB1, and PRKCE. AKT1 phosphorylates GSK3B, NOS3, and MTOR. The phosphorylation and inhibition of GSK3B leads to the increased activity of GYS1 and ACACA, which participate in glucose metabolism. AKT1 phosphorylates and activates NOS3, which generates nitric oxide (NO). NO activates guanylate cyclase, and, via PKG, activates HK2, which catalyzes a key step in glucose metabolism. In addition, NO induces vasodilation of coronary vessels. Activated MTOR phosphorylates and inactivates eukaryotic translation initiation factor (EIF4E), which forms a complex with EIF4G1, EIF4A1, and PABPC1. This EIF4F complex facilitates the recruitment of mRNA to the ribosome resulting in an increase in protein synthesis. Intracellular Ca2+ activates PKC to induce the expression of STAT1/STAT3, which is involved in cell survival and growth. Organ: heart Organ_System: cardiovascular system PMID: 15539639 PMID: 18391174 PMID: 24224132 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: myocardium urn:agi-pathway:uuid-e397ab10-3eb0-40a6-9e35-b6d1f2319715 Preconditioning Ischemia uuid-e397ab10-3eb0-40a6-9e35-b6d1f2319715 PS:CellType cardiac myocyte PS:Description Preconditioning ischemia (PI) is a phenomenon that limits myocardial damage. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e397ab10-3eb0-40a6-9e35-b6d1f2319715 PS:NodeType Pathway PS:Notes Headnote: Myocardial ischemia is a restriction of the blood supply to myocardium, which occurs due to a coronary artery obstruction and causes oxygen shortage and myocardial damage. Preconditioning ischemia (PI) is a process that limits myocardial damage by a subsequent ischemic attack. Signaling description: In PI, brief periods of ischemia are separated by periods of reperfusion, making the heart muscle more resistant to oxygen deficiency caused by a following ischemic event. Brief periods of ischemia confer protection against a subsequent prolonged and injurious period of ischemia. The mechanism by which PI protects the myocardium is still unknown. PI causes the release of agonists such as adenosine, bradykinin, and opioids, which bind to GPCR and to their receptors and activate the cardioprotective signaling cascades.Ouctome effects: The activation of GPCR leads to the activation of PI3K pathway, which via PDPK1, results in the activation of downstream targets such as AKT1, RPS6KB1, and PRKCE. AKT1 phosphorylates GSK3B, NOS3, and MTOR. The phosphorylation and inhibition of GSK3B leads to the increased activity of GYS1 and ACACA, which participate in glucose metabolism. AKT1 phosphorylates and activates NOS3, which generates nitric oxide (NO). NO activates guanylate cyclase, and, via PKG, activates HK2, which catalyzes a key step in glucose metabolism. In addition, NO induces vasodilation of coronary vessels. Activated MTOR phosphorylates and inactivates eukaryotic translation initiation factor (EIF4E), which forms a complex with EIF4G1, EIF4A1, and PABPC1. This EIF4F complex facilitates the recruitment of mRNA to the ribosome resulting in an increase in protein synthesis. Intracellular Ca2+ activates PKC to induce the expression of STAT1/STAT3, which is involved in cell survival and growth. PS:Organ heart PS:Organ_System cardiovascular system PS:PMID 15539639 PS:PMID 18391174 PS:PMID 24224132 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e3b439dc-8a44-4a44-904c-2d6b1f02b6f7 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-e3b439dc-8a44-4a44-904c-2d6b1f02b6f7 Leptin -> CD25/IL6/IL10 Production uuid-e3b439dc-8a44-4a44-904c-2d6b1f02b6f7 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e3b439dc-8a44-4a44-904c-2d6b1f02b6f7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e3eeeb21-d7a8-43f7-b46b-5a12f908b900 NodeType: Pathway PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e3eeeb21-d7a8-43f7-b46b-5a12f908b900 Endometrial Cancer Anatomy and Molecular Biomarkers uuid-e3eeeb21-d7a8-43f7-b46b-5a12f908b900 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e3eeeb21-d7a8-43f7-b46b-5a12f908b900 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell CellType: macrophage Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e40bdc89-dd15-4faa-b3d4-bc9387f3c785 NodeType: Pathway Notes: Several factors play a role in the development of the endometriosis. Estrogens drive endometriosis lesion development. However, there is also the connection between inflammation and expansion of the disease. The influence of estrogens is not a necessary condition for the implantation of endometrial fragments. However, the presence of estrogens is required for the proliferation and growth of endometriotic cells. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: uterus Organ_System: reproductive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-e40bdc89-dd15-4faa-b3d4-bc9387f3c785 1_Local estrogen production stimulates ectopic endometrium proliferation uuid-e40bdc89-dd15-4faa-b3d4-bc9387f3c785 PS:CellType endometrium cell PS:CellType macrophage PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e40bdc89-dd15-4faa-b3d4-bc9387f3c785 PS:NodeType Pathway PS:Notes Several factors play a role in the development of the endometriosis. Estrogens drive endometriosis lesion development. However, there is also the connection between inflammation and expansion of the disease. The influence of estrogens is not a necessary condition for the implantation of endometrial fragments. However, the presence of estrogens is required for the proliferation and growth of endometriotic cells. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: This pathway illustrates the processes that occur in endothelial cells on first stages of vasospasm (1-7 days). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e40eb10d-6ca7-4116-ae68-fbefabbf06aa NodeType: Pathway Notes: Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. The pathway illustrates the processes that occur in endothelial cells during the first stages of vasospasm (1-7 days). The products of erythrocyte and thrombocyte decay, mainly Ca2+, histamine, and prostaglandins, initiate the events whih lead to the activation of protein kinase C (PKC), either through an increase of intracellular Ca2+ levels or directly via diacylglycerol. In addition, G-proteins activate adenylate cyclase (ADCY) resulting in cAMP synthesis and the activation of protein kinase A (PKA). G-proteins also activate PIP3 synthesis, which in turn result in the activation of AKT1. Furthermore, PKC and PKA phosphorylate and in turn, activate AKT1. In addition, endothelial nitric oxide synthase (NOS3) may be activated through its phosphorylation by several kinases including PKC, PKA, and AKT1. Activated calmodulin is required for the activation of both NOS3 and inducible NO synthase (NOS2). Their synthesis is triggered through an NF-kB-dependent pathway via the activation of AKT1. Outcome effects: The extensive synthesis of nitric oxide (NO) is needed to provide vasodilation at the site of injury. However, the overproduction of NO and the presence of free radicals in adjacent tissues result in the formation of peroxynitrite, which triggers a number of pathological processes such as vasoconstriction, oxidative stress, disruption of Na+ homeostasis and export, intracellular Ca2+ overload, apoptosis, and necrotic cell death. Additionally, the presence of peroxynitrite with free radicals and free oxyhemoglobin lead to lipid peroxidation in membranes, which also promotes cell death. The role of bilirubin oxidation products currently remains unclear; however, it has been shown that these substances are necessary for vasospasm. The activation of DDAH2 by NO and arginine occurs during vasospasm. This enzyme participates in signaling pathways of oxidative stress and apoptosis. Protein arginine methyltransferase 3 (PRMT3) is another enzyme that is activated by NO and displays altered activity in vasospasm. It activates mRNA processing and arrests translation, which disrupts the normal functioning of endothelial cells. Thus, endothelial cell death occurs in early vasospasm, which upsets the normal function of blood vessels and leads to further pathological processes. Highlighted proteins: Entities with increased levels are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PMID: 15795160 PMID: 16265315 PMID: 18173899 PMID: 23050638 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-e40eb10d-6ca7-4116-ae68-fbefabbf06aa NO Synthesis in Early Vasospasm uuid-e40eb10d-6ca7-4116-ae68-fbefabbf06aa PS:CellType endothelial cell PS:Description This pathway illustrates the processes that occur in endothelial cells on first stages of vasospasm (1-7 days). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e40eb10d-6ca7-4116-ae68-fbefabbf06aa PS:NodeType Pathway PS:Notes Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm can be triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and neuronal death. The pathway illustrates the processes that occur in endothelial cells during the first stages of vasospasm (1-7 days). The products of erythrocyte and thrombocyte decay, mainly Ca2+, histamine, and prostaglandins, initiate the events whih lead to the activation of protein kinase C (PKC), either through an increase of intracellular Ca2+ levels or directly via diacylglycerol. In addition, G-proteins activate adenylate cyclase (ADCY) resulting in cAMP synthesis and the activation of protein kinase A (PKA). G-proteins also activate PIP3 synthesis, which in turn result in the activation of AKT1. Furthermore, PKC and PKA phosphorylate and in turn, activate AKT1. In addition, endothelial nitric oxide synthase (NOS3) may be activated through its phosphorylation by several kinases including PKC, PKA, and AKT1. Activated calmodulin is required for the activation of both NOS3 and inducible NO synthase (NOS2). Their synthesis is triggered through an NF-kB-dependent pathway via the activation of AKT1. Outcome effects: The extensive synthesis of nitric oxide (NO) is needed to provide vasodilation at the site of injury. However, the overproduction of NO and the presence of free radicals in adjacent tissues result in the formation of peroxynitrite, which triggers a number of pathological processes such as vasoconstriction, oxidative stress, disruption of Na+ homeostasis and export, intracellular Ca2+ overload, apoptosis, and necrotic cell death. Additionally, the presence of peroxynitrite with free radicals and free oxyhemoglobin lead to lipid peroxidation in membranes, which also promotes cell death. The role of bilirubin oxidation products currently remains unclear; however, it has been shown that these substances are necessary for vasospasm. The activation of DDAH2 by NO and arginine occurs during vasospasm. This enzyme participates in signaling pathways of oxidative stress and apoptosis. Protein arginine methyltransferase 3 (PRMT3) is another enzyme that is activated by NO and displays altered activity in vasospasm. It activates mRNA processing and arrests translation, which disrupts the normal functioning of endothelial cells. Thus, endothelial cell death occurs in early vasospasm, which upsets the normal function of blood vessels and leads to further pathological processes. Highlighted proteins: Entities with increased levels are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 15795160 PS:PMID 16265315 PS:PMID 18173899 PS:PMID 23050638 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e41e1c64-ba51-4399-a158-88a28dfe8b79 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: adipose tissue urn:agi-pathway:uuid-e41e1c64-ba51-4399-a158-88a28dfe8b79 GPCR Family -> Expression Targets in Adipose Tissue uuid-e41e1c64-ba51-4399-a158-88a28dfe8b79 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e41e1c64-ba51-4399-a158-88a28dfe8b79 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue adipose tissue PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e434f45b-8ad4-487c-bf7e-67dfb35247a9 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-e434f45b-8ad4-487c-bf7e-67dfb35247a9 Wnt ->EMT uuid-e434f45b-8ad4-487c-bf7e-67dfb35247a9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e434f45b-8ad4-487c-bf7e-67dfb35247a9 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: odontoblast Description: Dentin is a calcified tissue, is one of the four major components of teeth. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e43660bd-40a3-4a34-ba55-080eb3a4cb59 NodeType: Pathway Notes: Dentin is a calcified tissue, and is one of the four major components of teeth. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with increased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: Tooth Organ: mouth Organ_System: digestive system PMID: 19913215 PMID: 21196346 PMID: 23539364 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: dental enamel Tissue: dentin urn:agi-pathway:uuid-e43660bd-40a3-4a34-ba55-080eb3a4cb59 Dentin Formation Disruption uuid-e43660bd-40a3-4a34-ba55-080eb3a4cb59 PS:CellType odontoblast PS:Description Dentin is a calcified tissue, is one of the four major components of teeth. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e43660bd-40a3-4a34-ba55-080eb3a4cb59 PS:NodeType Pathway PS:Notes Dentin is a calcified tissue, and is one of the four major components of teeth. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with increased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ Tooth PS:Organ mouth PS:Organ_System digestive system PS:PMID 19913215 PS:PMID 21196346 PS:PMID 23539364 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue dental enamel PS:Tissue dentin PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neutrophil Description: Neutrophils are one of the main effector cells in chronic obstructive pulmonary disease. Activated neutrophils lead to tissue damage by the release of neutrophil elastase (ELANE), MMPs, and ROS. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4476a04-e85d-4c9a-a8a4-da2f70f85f67 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Neutrophils are important effector cells in COPD. The number of neutrophils is increased in sputum and bronchoalveolar lavage fluid of patients with COPD. Outcome effects: Activated neutrophils cause tissue damage by the release of neutrophil elastase (ELANE), MMPs, and ROS. Neutrophils also release other serine proteases including cathepsin G and B (CTSG and CTSB) and proteinase 3 (PRTN3). Organ: lung Organ_System: respiratory system PMID: 18410916 PMID: 23956502 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e4476a04-e85d-4c9a-a8a4-da2f70f85f67 Neutrophil Associated Lung Damage in Chronic Obstructive Pulmonary Disease uuid-e4476a04-e85d-4c9a-a8a4-da2f70f85f67 PS:CellType neutrophil PS:Description Neutrophils are one of the main effector cells in chronic obstructive pulmonary disease. Activated neutrophils lead to tissue damage by the release of neutrophil elastase (ELANE), MMPs, and ROS. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4476a04-e85d-4c9a-a8a4-da2f70f85f67 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Neutrophils are important effector cells in COPD. The number of neutrophils is increased in sputum and bronchoalveolar lavage fluid of patients with COPD. Outcome effects: Activated neutrophils cause tissue damage by the release of neutrophil elastase (ELANE), MMPs, and ROS. Neutrophils also release other serine proteases including cathepsin G and B (CTSG and CTSB) and proteinase 3 (PRTN3). PS:Organ lung PS:Organ_System respiratory system PS:PMID 18410916 PS:PMID 23956502 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: mesenchymal stem cell Description: MicroRNAs (MIRs) are tightly involved in regulation of epithelial-to-mesenchymal transition, a transformation process of non-mobile epithelial-like cells into mobile, promoting metastatic dissemination. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e45dff1a-1379-41e2-93ff-1899ce9420ca NodeType: Pathway Notes: Headnote: Small non-coding RNAs or microRNAs (MIRs) are commonly known as potent modifiers of gene expression and are involved in the regulation of epithelial-to-mesenchymal transition (EMT), a transformation process in which non-mobile epithelial-like cells become mobile promoting metastatic dissemination. Signaling description: MIRs and transcription factors involved in EMT (ZEB1/2, SNAI1/2,EZH2) regulate each other in a double-negative feedback manner thereby regulating the EMT process. MIRs were also shown to negatively regulate CDH1 and BMI1. Outcome effects: MIRs may positively or negatively regulate EMT. The effect depends on the particular type of cancer. Animal data: not shown Highlighted proteins: Not shownThe expression of MIRs may differ between different types of cancer. Mutated proteins: not shown Organ: oncogenic Organ_System: oncogenic PMID: 23344542 PMID: 24053443 PMID: 24556840 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e45dff1a-1379-41e2-93ff-1899ce9420ca MicroRNAs in Epithelial to Mesenchymal Transition in Cancer uuid-e45dff1a-1379-41e2-93ff-1899ce9420ca PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType mesenchymal stem cell PS:Description MicroRNAs (MIRs) are tightly involved in regulation of epithelial-to-mesenchymal transition, a transformation process of non-mobile epithelial-like cells into mobile, promoting metastatic dissemination. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e45dff1a-1379-41e2-93ff-1899ce9420ca PS:NodeType Pathway PS:Notes Headnote: Small non-coding RNAs or microRNAs (MIRs) are commonly known as potent modifiers of gene expression and are involved in the regulation of epithelial-to-mesenchymal transition (EMT), a transformation process in which non-mobile epithelial-like cells become mobile promoting metastatic dissemination. Signaling description: MIRs and transcription factors involved in EMT (ZEB1/2, SNAI1/2,EZH2) regulate each other in a double-negative feedback manner thereby regulating the EMT process. MIRs were also shown to negatively regulate CDH1 and BMI1. Outcome effects: MIRs may positively or negatively regulate EMT. The effect depends on the particular type of cancer. Animal data: not shown Highlighted proteins: Not shownThe expression of MIRs may differ between different types of cancer. Mutated proteins: not shown PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 23344542 PS:PMID 24053443 PS:PMID 24556840 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: EZH2 regulates multiple cell functions. Mutations or overexpression of EZH2 has been linked to many forms of cancer. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e45ea795-2451-489c-bef7-07df229c4733 NodeType: Pathway Notes: Headnote: The expression of EZH2 is regulated by HIF1A, E2F1, RAF1/MAPK/ELK1 and other regulators whose pathways can be activated in cancer. Mutation or over-expression of EZH2 has been implicated in many forms of cancer. Signaling description: EZH2 is a methyltransferase that participates in histone methylation and, consequently, transcriptional repression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) involved in embryonic differentiation. The increased levels of EZH2 have been linked to H3K27 (histone H3 family member) trimethylation on promoter regions of several genes. Specifically, EZH1 inhibits the transcription of RAD51, RUNX3, CDKN1C, FOXC1, CDH1, IRF4, PRDM1. Among these, RAD51 controls DNA repair, and, therefore, EZH1 suppresses DNA repair through RAD51 inhibition. Further, RUNX3 controls the expression of CDKN1A, an inhibitor of CCNE1 and CDK2. CDKN1C also inhibits CCNE1. EZH1 activates cell cycle progression through the suppression of RUNX3 and CDKN1C. FOXC1 and CDH1 control cell invasion and metastasis. RUNX3 may influence these processes through FOXC1 and CDH1 inhibition. IRF4 and PRDM1 control B-cell differentiation. EZH1 may block B-cell differentiation through inhibition of these genes in B-cell neoplasms. Elevated concentrations of EZH2 block the phosphorylation of BRCA1 (EZH acts on BRCA1 through PI3K/AKT1). As the negative effect of BRCA1 on CDC25C is eliminated, it can activate CDK1 and thereby trigger mitosis. EZH2 may also directly activate CTNNB1, RELA, STAT3, AR and thus stimulate cell proliferation. Outcome effects: The activation and overexpression of EZH2 in cancer leads to cell cycle activation, inhibition of DNA repair, activation of cell invasion and inhibition of B-cell differentiation. A large number of EZH2 inhibitors are tested in clinical trials, e.g. 3-deazaneplanocin A. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Mutated proteins: Mutated proteins are shown in white-out style. Organ: oncogenic Organ_System: oncogenic PMID: 18723033 PMID: 22211105 PMID: 25038756 PMID: 26027790 PMID: 26845405 PMID: 28665819 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e45ea795-2451-489c-bef7-07df229c4733 EZH2 Methyltransferase Role in Cancer uuid-e45ea795-2451-489c-bef7-07df229c4733 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description EZH2 regulates multiple cell functions. Mutations or overexpression of EZH2 has been linked to many forms of cancer. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e45ea795-2451-489c-bef7-07df229c4733 PS:NodeType Pathway PS:Notes Headnote: The expression of EZH2 is regulated by HIF1A, E2F1, RAF1/MAPK/ELK1 and other regulators whose pathways can be activated in cancer. Mutation or over-expression of EZH2 has been implicated in many forms of cancer. Signaling description: EZH2 is a methyltransferase that participates in histone methylation and, consequently, transcriptional repression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) involved in embryonic differentiation. The increased levels of EZH2 have been linked to H3K27 (histone H3 family member) trimethylation on promoter regions of several genes. Specifically, EZH1 inhibits the transcription of RAD51, RUNX3, CDKN1C, FOXC1, CDH1, IRF4, PRDM1. Among these, RAD51 controls DNA repair, and, therefore, EZH1 suppresses DNA repair through RAD51 inhibition. Further, RUNX3 controls the expression of CDKN1A, an inhibitor of CCNE1 and CDK2. CDKN1C also inhibits CCNE1. EZH1 activates cell cycle progression through the suppression of RUNX3 and CDKN1C. FOXC1 and CDH1 control cell invasion and metastasis. RUNX3 may influence these processes through FOXC1 and CDH1 inhibition. IRF4 and PRDM1 control B-cell differentiation. EZH1 may block B-cell differentiation through inhibition of these genes in B-cell neoplasms. Elevated concentrations of EZH2 block the phosphorylation of BRCA1 (EZH acts on BRCA1 through PI3K/AKT1). As the negative effect of BRCA1 on CDC25C is eliminated, it can activate CDK1 and thereby trigger mitosis. EZH2 may also directly activate CTNNB1, RELA, STAT3, AR and thus stimulate cell proliferation. Outcome effects: The activation and overexpression of EZH2 in cancer leads to cell cycle activation, inhibition of DNA repair, activation of cell invasion and inhibition of B-cell differentiation. A large number of EZH2 inhibitors are tested in clinical trials, e.g. 3-deazaneplanocin A. Animal data: not shown Highlighted proteins: Proteins with red highlights have increased expression/activity. Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18723033 PS:PMID 22211105 PS:PMID 25038756 PS:PMID 26027790 PS:PMID 26845405 PS:PMID 28665819 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4715a21-2d35-4d84-bb71-d462310671bb NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Cell Process urn:agi-pathway:uuid-e4715a21-2d35-4d84-bb71-d462310671bb Retrograde vesicle transport in the Golgi uuid-e4715a21-2d35-4d84-bb71-d462310671bb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4715a21-2d35-4d84-bb71-d462310671bb PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: Homozygous inactivating mutations in SLC4A4 cause proximal renal tubular acidosis and ocular abnormalities invariably associated with short stature. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e479a785-ce6b-4a45-8078-63084e403653 NodeType: Pathway Notes: Homozygous inactivating mutations in SLC4A4 cause proximal renal tubular acidosis and ocular abnormalities invariably associated with short stature. The mutation in SLC4A4 associated with Hemiplegic migraine was found in two sisters. Organ: brain Organ_System: nervous system PMID: 17691981 PMID: 19499287 PMID: 21458376 PMID: 3686049 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-e479a785-ce6b-4a45-8078-63084e403653 Glutamate Overdose and Aura Effect Overiew uuid-e479a785-ce6b-4a45-8078-63084e403653 PS:CellType astrocyte PS:CellType neuron PS:Description Homozygous inactivating mutations in SLC4A4 cause proximal renal tubular acidosis and ocular abnormalities invariably associated with short stature. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e479a785-ce6b-4a45-8078-63084e403653 PS:NodeType Pathway PS:Notes Homozygous inactivating mutations in SLC4A4 cause proximal renal tubular acidosis and ocular abnormalities invariably associated with short stature. The mutation in SLC4A4 associated with Hemiplegic migraine was found in two sisters. PS:Organ brain PS:Organ_System nervous system PS:PMID 17691981 PS:PMID 19499287 PS:PMID 21458376 PS:PMID 3686049 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e47ddf0d-bc6b-44b1-a4b8-cb9c1a51eb1f NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-e47ddf0d-bc6b-44b1-a4b8-cb9c1a51eb1f CD8 -> NFATC Expression Targets uuid-e47ddf0d-bc6b-44b1-a4b8-cb9c1a51eb1f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e47ddf0d-bc6b-44b1-a4b8-cb9c1a51eb1f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4a1cb9a-8a4b-4661-ae02-f8e3ecc6eafb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e4a1cb9a-8a4b-4661-ae02-f8e3ecc6eafb Valine degradation template uuid-e4a1cb9a-8a4b-4661-ae02-f8e3ecc6eafb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4a1cb9a-8a4b-4661-ae02-f8e3ecc6eafb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4a701ec-2ec5-4326-8905-01185bdc470a NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process urn:agi-pathway:uuid-e4a701ec-2ec5-4326-8905-01185bdc470a Epithelial to Mesenchymal Transition in Cancer uuid-e4a701ec-2ec5-4326-8905-01185bdc470a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4a701ec-2ec5-4326-8905-01185bdc470a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4b6afa5-5824-444b-8a6f-1a027cc4a972 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-e4b6afa5-5824-444b-8a6f-1a027cc4a972 Paracrine-|IR uuid-e4b6afa5-5824-444b-8a6f-1a027cc4a972 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4b6afa5-5824-444b-8a6f-1a027cc4a972 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4bf6ef7-84ca-446f-a356-dccfb3a4bbc7 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-e4bf6ef7-84ca-446f-a356-dccfb3a4bbc7 NOTCH -> SMAD3 Signaling uuid-e4bf6ef7-84ca-446f-a356-dccfb3a4bbc7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4bf6ef7-84ca-446f-a356-dccfb3a4bbc7 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4ec1b3e-bf24-4a9e-900b-24b0b1c7964a NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-e4ec1b3e-bf24-4a9e-900b-24b0b1c7964a TNF Receptors -> Expression Targets in Lymphoid System and Blood uuid-e4ec1b3e-bf24-4a9e-900b-24b0b1c7964a PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4ec1b3e-bf24-4a9e-900b-24b0b1c7964a PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Monocytes differentiate into macrophages in injured tissues under the influence of CSF2. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4f42f52-31b7-4df6-857f-13575a8741d4 NodeType: Pathway Notes: Headnote: Monocytes differentiate into macrophages in injured tissues under the influence of CSF2. Macrophages are a heterogeneous cell population. The activation of macrophages in response to pathogenic stimuli, endogenous danger signals, and/or type 1 cytokines (IFNG and TNF) is termed classical activation. The resulting macrophages, identified as M1 macrophages, exhibit potent microbicidal activity and promote strong Th1 immune responses. Signaling description: CSF2 induces monocyte-macrophage M1 lineage differentiation. When CSF2-differentiated human macrophages are engaged with bacterial products and Th1- cytokines such as IFNG and TNF, they are polarized to classically activated M1 macrophages. M1 macrophages are also activated following the recognition of pathogen-associated molecular patterns or PAMPs such as lipopolysaccharide (LPS) and endogenous danger signals such as HMGB1. Additionally, IRF5-mediated cytokine activation is specific for M1 activation. Outcome effects: IRF3 and NF-kB are responsible for the expression of chemokines specific for M1. Furthermore, M1 population is thought to contribute to macrophage-mediated tissue injury. M1 exerts anti-proliferative and cytotoxic activities, which is due in part to the release of reactive oxygen and nitrogen species and proinflammatory cytokines including TNF, IL1, IL6, and IL12. Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-e4f42f52-31b7-4df6-857f-13575a8741d4 Macrophage M1 Lineage uuid-e4f42f52-31b7-4df6-857f-13575a8741d4 PS:CellType macrophage PS:Description Monocytes differentiate into macrophages in injured tissues under the influence of CSF2. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4f42f52-31b7-4df6-857f-13575a8741d4 PS:NodeType Pathway PS:Notes Headnote: Monocytes differentiate into macrophages in injured tissues under the influence of CSF2. Macrophages are a heterogeneous cell population. The activation of macrophages in response to pathogenic stimuli, endogenous danger signals, and/or type 1 cytokines (IFNG and TNF) is termed classical activation. The resulting macrophages, identified as M1 macrophages, exhibit potent microbicidal activity and promote strong Th1 immune responses. Signaling description: CSF2 induces monocyte-macrophage M1 lineage differentiation. When CSF2-differentiated human macrophages are engaged with bacterial products and Th1- cytokines such as IFNG and TNF, they are polarized to classically activated M1 macrophages. M1 macrophages are also activated following the recognition of pathogen-associated molecular patterns or PAMPs such as lipopolysaccharide (LPS) and endogenous danger signals such as HMGB1. Additionally, IRF5-mediated cytokine activation is specific for M1 activation. Outcome effects: IRF3 and NF-kB are responsible for the expression of chemokines specific for M1. Furthermore, M1 population is thought to contribute to macrophage-mediated tissue injury. M1 exerts anti-proliferative and cytotoxic activities, which is due in part to the release of reactive oxygen and nitrogen species and proinflammatory cytokines including TNF, IL1, IL6, and IL12. PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4fcb935-5378-4ccf-944a-5453417f5c17 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e4fcb935-5378-4ccf-944a-5453417f5c17 BMP2/BMPR2 Expression Targets uuid-e4fcb935-5378-4ccf-944a-5453417f5c17 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e4fcb935-5378-4ccf-944a-5453417f5c17 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e50e49ba-40a7-4f25-9e10-b8687a287f8f NodeType: Pathway Organ: pancreas Organ_System: digestive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-e50e49ba-40a7-4f25-9e10-b8687a287f8f Proteins Involved in Peutz-Jeghers Syndrome uuid-e50e49ba-40a7-4f25-9e10-b8687a287f8f PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e50e49ba-40a7-4f25-9e10-b8687a287f8f PS:NodeType Pathway PS:Organ pancreas PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e533d3ee-ae6c-4720-8cb9-3ff9381920e4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-e533d3ee-ae6c-4720-8cb9-3ff9381920e4 COVID19+>HA-hydrogel uuid-e533d3ee-ae6c-4720-8cb9-3ff9381920e4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e533d3ee-ae6c-4720-8cb9-3ff9381920e4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e53a9cf1-79af-422c-86bc-9bd9777dda95 NodeType: Pathway Organ_System: lymphatic system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-e53a9cf1-79af-422c-86bc-9bd9777dda95 Proteins Involved in Marginal Zone Lymphoma uuid-e53a9cf1-79af-422c-86bc-9bd9777dda95 PS:CellType cancer cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e53a9cf1-79af-422c-86bc-9bd9777dda95 PS:NodeType Pathway PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5582a21-f8b0-4380-b40d-12ba2106681c NodeType: Pathway Notes: The mammalian target of rapamycin (mTOR) signaling pathway merges different input signals in the cell to play central role in regulation of cell metabolism, growth, proliferation and survival. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: generic PMID: 23296649 PMID: 26280535 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-e5582a21-f8b0-4380-b40d-12ba2106681c mTOR Signaling Hyperfunction uuid-e5582a21-f8b0-4380-b40d-12ba2106681c PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5582a21-f8b0-4380-b40d-12ba2106681c PS:NodeType Pathway PS:Notes The mammalian target of rapamycin (mTOR) signaling pathway merges different input signals in the cell to play central role in regulation of cell metabolism, growth, proliferation and survival. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System generic PS:PMID 23296649 PS:PMID 26280535 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: adrenal cortex cell Description: Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e562fadb-ef36-4db5-a774-595fb8cd9df8 NodeType: Pathway Notes: Headnote: Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Signaling description: The SNS is responsible for the acute stress response, which requires energy mobilization from the body stores and diverts the blood flow to skeletal muscles. SNS effects are due to the release of noradrenaline (also known as norepinephrine) from sympathetic nerve terminals and the subsequent secretion of epinephrine (also known as adrenaline) and noradrenaline from chromaffin cells of the adrenal medulla. Chromaffin cells are similar to postsynaptic sympathetic neurons and release catecholamines (80% epinephrine and 20% noradrenaline) into the circulation. Acetylcholine, the key neurotransmitter in chromaffin cells, binds to postsynaptic nAChR and mAChR on chromaffin cells. nAChR and mAChR are differentially expressed in two separate populations of chromaffin cells (adrenergic and noradrenergic, respectively), which release different substances (epinephrine and noradrenaline). The cells with nAChR are more abundant. The activation of nAChR quickly leads to chromaffin cell depolarization, which in turn triggers electrical activity and calcium (Ca2+) influx from voltage-gated Ca2+ channels. Outcome effects: Increases in cytosolic Ca2+ lead to the fusion of secretory granules and exocytosis of epinephrine/noradrenaline into the bloodstream. mAChR causes a slow release of Ca2+ from intracellular storage. ADCYAP1 causes persistent catecholamine release by the adrenal medulla. ADCYAP1 response includes PLC and PKC activation and Na+/Ca2+ exchange-mediated depolarization in chromaffin cells allowing LVACC Ca2+ channels to release catecholamine. In addition, angiotensin II is a potent regulator of catecholamine synthesis and release. Angiotensinogen (AGT), which is produced by the liver, does not appear to be an acute-phase protein. However, some forms of acute inflammation, such as an injection of lipopolysaccharide/cellulite or partial hepatectomy, increases the hepatic synthesis of AGT. AGT is converted to the active form, angiotensin II, by renin (REN) and ACE. The synthesis of catecholamine occurs in advance and NGF serves as a mitogen for chromaffin cells which may be involved in this process. Catecholamines, such as noradrenaline and epinephrine, mediate adaptive cardiovascular and metabolic effects through interactions with adrenergic receptors. Alpha adrenergic receptors generally produce excitatory responses of smooth muscle in which they are located. Beta-adrenergic receptors generally produce inhibitory responses of smooth muscle in response to bronchodilation, vasodilation, and uterine relaxation. ADRB1 produces cardiac positive responses and produces lipolysis in adipose tissue. Organ: adrenal gland Organ: brain Organ_System: endocrine system Organ_System: nervous system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-e562fadb-ef36-4db5-a774-595fb8cd9df8 SNS Related Adrenal Cortex Response uuid-e562fadb-ef36-4db5-a774-595fb8cd9df8 PS:CellType adrenal cortex cell PS:Description Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e562fadb-ef36-4db5-a774-595fb8cd9df8 PS:NodeType Pathway PS:Notes Headnote: Physiological responses to stressors such as inflammation are primarily mediated by two neuroendocrine systems: sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Signaling description: The SNS is responsible for the acute stress response, which requires energy mobilization from the body stores and diverts the blood flow to skeletal muscles. SNS effects are due to the release of noradrenaline (also known as norepinephrine) from sympathetic nerve terminals and the subsequent secretion of epinephrine (also known as adrenaline) and noradrenaline from chromaffin cells of the adrenal medulla. Chromaffin cells are similar to postsynaptic sympathetic neurons and release catecholamines (80% epinephrine and 20% noradrenaline) into the circulation. Acetylcholine, the key neurotransmitter in chromaffin cells, binds to postsynaptic nAChR and mAChR on chromaffin cells. nAChR and mAChR are differentially expressed in two separate populations of chromaffin cells (adrenergic and noradrenergic, respectively), which release different substances (epinephrine and noradrenaline). The cells with nAChR are more abundant. The activation of nAChR quickly leads to chromaffin cell depolarization, which in turn triggers electrical activity and calcium (Ca2+) influx from voltage-gated Ca2+ channels. Outcome effects: Increases in cytosolic Ca2+ lead to the fusion of secretory granules and exocytosis of epinephrine/noradrenaline into the bloodstream. mAChR causes a slow release of Ca2+ from intracellular storage. ADCYAP1 causes persistent catecholamine release by the adrenal medulla. ADCYAP1 response includes PLC and PKC activation and Na+/Ca2+ exchange-mediated depolarization in chromaffin cells allowing LVACC Ca2+ channels to release catecholamine. In addition, angiotensin II is a potent regulator of catecholamine synthesis and release. Angiotensinogen (AGT), which is produced by the liver, does not appear to be an acute-phase protein. However, some forms of acute inflammation, such as an injection of lipopolysaccharide/cellulite or partial hepatectomy, increases the hepatic synthesis of AGT. AGT is converted to the active form, angiotensin II, by renin (REN) and ACE. The synthesis of catecholamine occurs in advance and NGF serves as a mitogen for chromaffin cells which may be involved in this process. Catecholamines, such as noradrenaline and epinephrine, mediate adaptive cardiovascular and metabolic effects through interactions with adrenergic receptors. Alpha adrenergic receptors generally produce excitatory responses of smooth muscle in which they are located. Beta-adrenergic receptors generally produce inhibitory responses of smooth muscle in response to bronchodilation, vasodilation, and uterine relaxation. ADRB1 produces cardiac positive responses and produces lipolysis in adipose tissue. PS:Organ adrenal gland PS:Organ brain PS:Organ_System endocrine system PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5c9abbd-1048-477e-8351-597745e14a76 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-e5c9abbd-1048-477e-8351-597745e14a76 EphrinB -> Cytoskeleton Signaling uuid-e5c9abbd-1048-477e-8351-597745e14a76 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5c9abbd-1048-477e-8351-597745e14a76 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell CellType: hepatocyte Description: Hepatocellular carcinoma (HCC) is one of the most vascular solid tumors with angiogenesis playing an important role in its development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5e574df-acda-4034-8f72-077db35bf496 NodeType: Pathway Notes: Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: The formation of new blood vessels, which is initiated by hypoxic or ischemic conditions, is a key mechanism in the pathogenesis of chronic liver diseases (CLDs). Low physiological oxygen levels lead to an accumulation of hypoxia inducible factors (HIFs) that stimulate the expression of angiogenic growth factors. HCC is one of the most vascular solid tumors with angiogenesis playing an important role in its development, progression, and metastasis. HCC cells display rapid growth and thus are in need of a high oxygen and nutrient supply. HCC lesions are characterized by arterial hypervascularity to provide the tumor with highly oxygenated blood. However, these new vessels are marked by a disorganized vasculature which consists of leaky, hemorrhagic, and torturous vessels. The irregularity of tumor vessels results in chaotic blood flow with poorly oxygenated blood. Blood vessel formation is a multifactorial process with the first step being destabilization through ANG and hyperpermeability of the vessel wall. HCC cells secrete a number of angiogenic growth factors such as VEGFs, PDGFs, and TGFs. Outcome effects: The growth factors activate endothelial cells (ECs) and basement membranes. VEGFA and TGFA induce EC proliferation and migration and cell-to-cell contact is established through cadherins and integrins. Tube formation is completed via TGFB1 and PDGFA while vessel formation is completed following stabilization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. Organ: liver Organ_System: digestive system PMID: 21073649 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-e5e574df-acda-4034-8f72-077db35bf496 Vascularization in Hepatocellular Carcinoma uuid-e5e574df-acda-4034-8f72-077db35bf496 PS:CellType cancer cell PS:CellType cancer stem cell PS:CellType hepatocyte PS:Description Hepatocellular carcinoma (HCC) is one of the most vascular solid tumors with angiogenesis playing an important role in its development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e5e574df-acda-4034-8f72-077db35bf496 PS:NodeType Pathway PS:Notes Headnote: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and is most prevalent in Asia and Africa. In more than 80% of cases, HCC is associated with cirrhosis or advanced fibrosis. Cirrhosis typically results from chronic infection with HBV or HCV, alcohol abuse, or metabolic disorders such as hemochromatosis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Signaling description: The formation of new blood vessels, which is initiated by hypoxic or ischemic conditions, is a key mechanism in the pathogenesis of chronic liver diseases (CLDs). Low physiological oxygen levels lead to an accumulation of hypoxia inducible factors (HIFs) that stimulate the expression of angiogenic growth factors. HCC is one of the most vascular solid tumors with angiogenesis playing an important role in its development, progression, and metastasis. HCC cells display rapid growth and thus are in need of a high oxygen and nutrient supply. HCC lesions are characterized by arterial hypervascularity to provide the tumor with highly oxygenated blood. However, these new vessels are marked by a disorganized vasculature which consists of leaky, hemorrhagic, and torturous vessels. The irregularity of tumor vessels results in chaotic blood flow with poorly oxygenated blood. Blood vessel formation is a multifactorial process with the first step being destabilization through ANG and hyperpermeability of the vessel wall. HCC cells secrete a number of angiogenic growth factors such as VEGFs, PDGFs, and TGFs. Outcome effects: The growth factors activate endothelial cells (ECs) and basement membranes. VEGFA and TGFA induce EC proliferation and migration and cell-to-cell contact is established through cadherins and integrins. Tube formation is completed via TGFB1 and PDGFA while vessel formation is completed following stabilization. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated gene is shown in white-out style. PS:Organ liver PS:Organ_System digestive system PS:PMID 21073649 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e603dec2-3613-45f0-9826-932b6de56dba NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-e603dec2-3613-45f0-9826-932b6de56dba AAT Deficiency Biomarkers uuid-e603dec2-3613-45f0-9826-932b6de56dba PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e603dec2-3613-45f0-9826-932b6de56dba PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6251ec8-03f8-46f9-b91b-da9442f31779 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-e6251ec8-03f8-46f9-b91b-da9442f31779 Collagen biosynthesis uuid-e6251ec8-03f8-46f9-b91b-da9442f31779 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6251ec8-03f8-46f9-b91b-da9442f31779 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e62918bf-d6b8-40cc-8289-e1e0ff41362b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e62918bf-d6b8-40cc-8289-e1e0ff41362b Amino sugars synthesis (Eukaryots) template uuid-e62918bf-d6b8-40cc-8289-e1e0ff41362b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e62918bf-d6b8-40cc-8289-e1e0ff41362b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Th17 cells are T-cells producing IL-17A, IL-17F, IL-22, and IL-21. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e650574e-2c87-441e-9450-028949772b8b NodeType: Pathway Notes: Headnote: Th17 cells are T-cells producing IL-17A, IL-17F, IL-22, and IL-21. These cells play an important role in the control of specific pathogens and the development of autoimmune diseases. Signaling description: Th17 cell differentiation is induced by IL-6 and TGFB1. These cytokines trigger STAT3 phosphorylation, which in turns induces the expression of the Th17 cell-specific transcription factors RORA and RORC, followed by IL17 and IL22 expression. AHR is also expressed in response to IL6 and TGFB1 and participates in Th17 cell differentiation. AHR ligands (FICZ and other) can boost the differentiation of Th17 cells. AHR signalling in T-helper type 17 (Th17) cells promotes the expression of IL-21 and IL-22, and it also limits the activation of STAT5, which mediate the inhibitory effects of IL-2 on Th17 cell differentiation, respectively. Outcome effects: IL2 and IL21 are negative regulators of Th17 differentiation. AhR cooperates with STAT3 to induce the expression of the epigenetic modifier Aiolos (IKZF3). IKZF3 modifies the epigenetic status of the IL2 promoter, limiting its accessibility to transcription factors and effectively silencing IL-2 expression. During early stages, AhR might limit the inhibitory effects of IL-2 and promote IL-10 production, whereas in late stages it might contribute to the expression of IL-21 and IL-22. Activation of Ahr by FICZ enhances the Th17 differentiation via upregulating microRNA (miR)-212 / 132 that targets B-cell lymphoma (BCL6), a negative regulator of Th17. Organ: generic Organ_System: lymphatic system PMID: 18053739 PMID: 18607004 PMID: 19100241 PMID: 21266768 PMID: 21278738 PMID: 23021777 PMID: 23190340 PMID: 23580432 PMID: 23818645 PMID: 24527450 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-e650574e-2c87-441e-9450-028949772b8b AHR Signaling in Th17 Cells Function uuid-e650574e-2c87-441e-9450-028949772b8b PS:CellType T-cell PS:Description Th17 cells are T-cells producing IL-17A, IL-17F, IL-22, and IL-21. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e650574e-2c87-441e-9450-028949772b8b PS:NodeType Pathway PS:Notes Headnote: Th17 cells are T-cells producing IL-17A, IL-17F, IL-22, and IL-21. These cells play an important role in the control of specific pathogens and the development of autoimmune diseases. Signaling description: Th17 cell differentiation is induced by IL-6 and TGFB1. These cytokines trigger STAT3 phosphorylation, which in turns induces the expression of the Th17 cell-specific transcription factors RORA and RORC, followed by IL17 and IL22 expression. AHR is also expressed in response to IL6 and TGFB1 and participates in Th17 cell differentiation. AHR ligands (FICZ and other) can boost the differentiation of Th17 cells. AHR signalling in T-helper type 17 (Th17) cells promotes the expression of IL-21 and IL-22, and it also limits the activation of STAT5, which mediate the inhibitory effects of IL-2 on Th17 cell differentiation, respectively. Outcome effects: IL2 and IL21 are negative regulators of Th17 differentiation. AhR cooperates with STAT3 to induce the expression of the epigenetic modifier Aiolos (IKZF3). IKZF3 modifies the epigenetic status of the IL2 promoter, limiting its accessibility to transcription factors and effectively silencing IL-2 expression. During early stages, AhR might limit the inhibitory effects of IL-2 and promote IL-10 production, whereas in late stages it might contribute to the expression of IL-21 and IL-22. Activation of Ahr by FICZ enhances the Th17 differentiation via upregulating microRNA (miR)-212 / 132 that targets B-cell lymphoma (BCL6), a negative regulator of Th17. PS:Organ generic PS:Organ_System lymphatic system PS:PMID 18053739 PS:PMID 18607004 PS:PMID 19100241 PS:PMID 21266768 PS:PMID 21278738 PS:PMID 23021777 PS:PMID 23190340 PS:PMID 23580432 PS:PMID 23818645 PS:PMID 24527450 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The secretion of insulin from pancreatic beta-cells is a complex process. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6534244-8510-4b59-a550-1e92e2fbaba6 NodeType: Pathway Notes: Headnote: The secretion of insulin from pancreatic beta-cells is a complex process. Signaling description: At the first stage insulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum.The following translation factors initiate the process: PDX1, NEUROD1, and CREB1. Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus where it is packaged into secretory granules located close to the cell membrane. Proinsulin is cleaved into equimolar amounts of insulin and C-peptide (not shown) by proprotein convertase subtilisin/kexin type 1 (PCSK1) and carboxypeptidase E (CPE) in the secretory granules. The process of insulin secretion involves fusion of the secretory granules with the cell membrane and exocytosis of insulin, C-peptide, and proinsulin. The primary stimulus for insulin secretion is the beta-cell response to changes in ambient glucose.A widely accepted sequence of events involved in glucose-induced insulin secretion is as follows: glucose is transported into beta cells through facilitated diffusion of GLUT1 or GLUT2 glucose transporters. Intracellular glucose is metabolized in glycolysis to ATP. Elevation in the ATP/ADP ratio induces closure of cell-surface ATP-sensitive K channels (KCNJ11), leading to cell membrane depolarization. Cell-surface voltage-dependent Ca2 channels (VDCC) are opened facilitating extracellular Ca2 influx into the beta cell. Outcome effects: Ca2 activates PLC and the additional Ca2 portion is released from intracellular storage. Arise in free cytosolic Ca2 triggers the exocytosis of insulin. Hormones gastric inhibitory polypeptide (GIP) and glucagon (GCG) through theirs receptors GIPR and GLP1R also promote insulin release. Compounds with elevated level are highlighted in red. Organ: pancreas Organ_System: endocrine system PMID: 11078440 PMID: 12469359 PMID: 16075046 PMID: 21595263 PMID: 22660720 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-e6534244-8510-4b59-a550-1e92e2fbaba6 Insulin Secretion uuid-e6534244-8510-4b59-a550-1e92e2fbaba6 PS:CellType insulin-secreting cell PS:Description The secretion of insulin from pancreatic beta-cells is a complex process. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6534244-8510-4b59-a550-1e92e2fbaba6 PS:NodeType Pathway PS:Notes Headnote: The secretion of insulin from pancreatic beta-cells is a complex process. Signaling description: At the first stage insulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum.The following translation factors initiate the process: PDX1, NEUROD1, and CREB1. Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus where it is packaged into secretory granules located close to the cell membrane. Proinsulin is cleaved into equimolar amounts of insulin and C-peptide (not shown) by proprotein convertase subtilisin/kexin type 1 (PCSK1) and carboxypeptidase E (CPE) in the secretory granules. The process of insulin secretion involves fusion of the secretory granules with the cell membrane and exocytosis of insulin, C-peptide, and proinsulin. The primary stimulus for insulin secretion is the beta-cell response to changes in ambient glucose.A widely accepted sequence of events involved in glucose-induced insulin secretion is as follows: glucose is transported into beta cells through facilitated diffusion of GLUT1 or GLUT2 glucose transporters. Intracellular glucose is metabolized in glycolysis to ATP. Elevation in the ATP/ADP ratio induces closure of cell-surface ATP-sensitive K channels (KCNJ11), leading to cell membrane depolarization. Cell-surface voltage-dependent Ca2 channels (VDCC) are opened facilitating extracellular Ca2 influx into the beta cell. Outcome effects: Ca2 activates PLC and the additional Ca2 portion is released from intracellular storage. Arise in free cytosolic Ca2 triggers the exocytosis of insulin. Hormones gastric inhibitory polypeptide (GIP) and glucagon (GCG) through theirs receptors GIPR and GLP1R also promote insulin release. Compounds with elevated level are highlighted in red. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 11078440 PS:PMID 12469359 PS:PMID 16075046 PS:PMID 21595263 PS:PMID 22660720 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e653a894-93f7-4d21-87ec-b4525f642410 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-e653a894-93f7-4d21-87ec-b4525f642410 TMPRSS2 genetic variants uuid-e653a894-93f7-4d21-87ec-b4525f642410 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e653a894-93f7-4d21-87ec-b4525f642410 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: macrophage Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e654f87d-9cbe-48e8-bab2-26e9133b113f NodeType: Pathway Notes: Macrophages are important for innate immune responses, producing pro-inflammatory cytokines, and contribute to TLR-mediated tuning of adaptive immune responses. Organ: generic Organ_System: hematological system PMID: 19244278 PMID: 19703987 PMID: 21930594 PMID: 23580432 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-e654f87d-9cbe-48e8-bab2-26e9133b113f AHR Signaling in M1 Macrophages Function uuid-e654f87d-9cbe-48e8-bab2-26e9133b113f PS:CellType macrophage PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e654f87d-9cbe-48e8-bab2-26e9133b113f PS:NodeType Pathway PS:Notes Macrophages are important for innate immune responses, producing pro-inflammatory cytokines, and contribute to TLR-mediated tuning of adaptive immune responses. PS:Organ generic PS:Organ_System hematological system PS:PMID 19244278 PS:PMID 19703987 PS:PMID 21930594 PS:PMID 23580432 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e663943a-f660-413e-9bcf-63763cff08cd NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-e663943a-f660-413e-9bcf-63763cff08cd TLR -> ARRB2/NF-kB Signaling uuid-e663943a-f660-413e-9bcf-63763cff08cd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e663943a-f660-413e-9bcf-63763cff08cd PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6baf6ba-c096-45fb-ac53-4a9aa03b50ae NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e6baf6ba-c096-45fb-ac53-4a9aa03b50ae Dronabinol/Anandamide Expression Targets uuid-e6baf6ba-c096-45fb-ac53-4a9aa03b50ae PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e6baf6ba-c096-45fb-ac53-4a9aa03b50ae PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Unidentified antigens are recognized by antigen presenting cells (APCs) and subsequently presented to and activate CD4 T cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e701088c-cafb-4254-8d3e-de9c160f0af8 NodeType: Pathway Notes: Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Signaling description: Unidentified antigens are recognized by antigen presenting cells (APCs) and subsequently presented to and activate CD4 T-cells. T-cells that are activated through interactions between T-cell receptor (TCR) and CD40 interact with B-lymphocytes, leading to B-cell proliferation and differentiation into plasma cells. Th2 lymphocytes mainly produce IL4, IL13, IL5, and IL10 cytokines which contribute to B-cell proliferation and differentiation. Outcome effects: Activated T-helper lymphocytes then secrete profibrotic cytokines including IL4, IL13, and TGFB1 which act on circulating fibroblasts and ultimately lead to collagen deposition. IL4 and IL13 are able to stimulate collagen production and inhibit collagenase synthesis which favors fibrosis. IL10, similar to IL4 and IL13, inhibits Th1 differentiation and reduces the inflammation process. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: skin Organ_System: integumentary system PMID: 18221988 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-e701088c-cafb-4254-8d3e-de9c160f0af8 Th2-Cells Function in Systemic Scleroderma uuid-e701088c-cafb-4254-8d3e-de9c160f0af8 PS:CellType T-cell PS:Description Unidentified antigens are recognized by antigen presenting cells (APCs) and subsequently presented to and activate CD4 T cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e701088c-cafb-4254-8d3e-de9c160f0af8 PS:NodeType Pathway PS:Notes Headnote: Systemic scleroderma, also known as systemic sclerosis (SSc) is a rare chronic autoimmune disease of undetermined cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints and visceral organs. Death usually occurs due to lung, heart, and kidney involvement. Signaling description: Unidentified antigens are recognized by antigen presenting cells (APCs) and subsequently presented to and activate CD4 T-cells. T-cells that are activated through interactions between T-cell receptor (TCR) and CD40 interact with B-lymphocytes, leading to B-cell proliferation and differentiation into plasma cells. Th2 lymphocytes mainly produce IL4, IL13, IL5, and IL10 cytokines which contribute to B-cell proliferation and differentiation. Outcome effects: Activated T-helper lymphocytes then secrete profibrotic cytokines including IL4, IL13, and TGFB1 which act on circulating fibroblasts and ultimately lead to collagen deposition. IL4 and IL13 are able to stimulate collagen production and inhibit collagenase synthesis which favors fibrosis. IL10, similar to IL4 and IL13, inhibits Th1 differentiation and reduces the inflammation process. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18221988 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e702a605-aeeb-49b4-ac1e-53feca34bd40 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-e702a605-aeeb-49b4-ac1e-53feca34bd40 Capecitabine and Fluorafur Metabolism uuid-e702a605-aeeb-49b4-ac1e-53feca34bd40 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e702a605-aeeb-49b4-ac1e-53feca34bd40 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:NodeType PS:Notes PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Notes: Read the description in the book: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Source: Atlas urn:agi-pathway:uuid-e730ab71-14fb-48fb-a43d-0ab6a78aeb63 3_mixed network of dexamethasone targets uuid-e730ab71-14fb-48fb-a43d-0ab6a78aeb63 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Notes Read the description in the book: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS; MIM 260920) is an autosomal recessive autoinflammatory disease caused by mutations of the MVK gene. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e74716a0-88da-4e29-a893-b7334f667895 NodeType: Pathway Notes: Headnote: Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) is an autosomal recessive autoinflammatory disease caused by mutations of the MVK gene, which encodes mevalonate kinase, an enzyme involved in cholesterol and isoprene biosynthesis. The clinical spectrum of MKD ranges from mild forms of disease to lethal forms of mevalonic aciduria based on the level of residual MVK activity. Signaling description: Although it has been suggested that inflammation in MKD is related to elevated mevalonic acid levels, a shortage of nonsterol isoprenoid end products has also been shown to result in a caspase-mediated increase in IL1B production. Outcome effects: As a result of increased IL1B production, most MKD patients have increased levels of IgD (over three times the upper limit of the normal range) both during the fever episodes and under basal conditions; at the same time, 20% of patients show no increase in IgD levels and IgD levels are normal in very young infants with MKD/HIDS. Moreover, the level of IgD is not related to the severity of the disease. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ_System: hematological system PMID: 21760510 PMID: 23110805 PMID: 24247370 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-e74716a0-88da-4e29-a893-b7334f667895 Mevalonate Kinase Deficiency uuid-e74716a0-88da-4e29-a893-b7334f667895 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS; MIM 260920) is an autosomal recessive autoinflammatory disease caused by mutations of the MVK gene. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e74716a0-88da-4e29-a893-b7334f667895 PS:NodeType Pathway PS:Notes Headnote: Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) is an autosomal recessive autoinflammatory disease caused by mutations of the MVK gene, which encodes mevalonate kinase, an enzyme involved in cholesterol and isoprene biosynthesis. The clinical spectrum of MKD ranges from mild forms of disease to lethal forms of mevalonic aciduria based on the level of residual MVK activity. Signaling description: Although it has been suggested that inflammation in MKD is related to elevated mevalonic acid levels, a shortage of nonsterol isoprenoid end products has also been shown to result in a caspase-mediated increase in IL1B production. Outcome effects: As a result of increased IL1B production, most MKD patients have increased levels of IgD (over three times the upper limit of the normal range) both during the fever episodes and under basal conditions; at the same time, 20% of patients show no increase in IgD levels and IgD levels are normal in very young infants with MKD/HIDS. Moreover, the level of IgD is not related to the severity of the disease. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ_System hematological system PS:PMID 21760510 PS:PMID 23110805 PS:PMID 24247370 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: keratinocyte Description: MIF expression in human cholesteatomas is related to the levels of biologic aggressiveness reflected in their recurrence status and MMP expression. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e747ca75-d231-4418-9a76-4eebe5453679 NodeType: Pathway Notes: Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: MIF expression in human cholesteatomas is related to the level of their biologic aggressiveness estimated by the recurrence status and the level of MMP expression; as well as the cholesteatoma differentiation status reflected in galactin and RARbeta expressions. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 11568623 PMID: 16513304 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-e747ca75-d231-4418-9a76-4eebe5453679 MIF Role in Cholesteatoma uuid-e747ca75-d231-4418-9a76-4eebe5453679 PS:CellType cancer cell PS:CellType keratinocyte PS:Description MIF expression in human cholesteatomas is related to the levels of biologic aggressiveness reflected in their recurrence status and MMP expression. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e747ca75-d231-4418-9a76-4eebe5453679 PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: MIF expression in human cholesteatomas is related to the level of their biologic aggressiveness estimated by the recurrence status and the level of MMP expression; as well as the cholesteatoma differentiation status reflected in galactin and RARbeta expressions. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 11568623 PS:PMID 16513304 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e75c7b4c-0836-4618-91c5-c423f3349188 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-e75c7b4c-0836-4618-91c5-c423f3349188 Proteins Involved in Endometrioid Ovarian Carcinoma uuid-e75c7b4c-0836-4618-91c5-c423f3349188 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e75c7b4c-0836-4618-91c5-c423f3349188 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease associated with enhanced innate immune responsiveness. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e76bbaf7-cda3-419e-af15-e363936ef639 NodeType: Pathway Notes: Headnote: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease associated with enhanced innate immune responsiveness. TRAPS is characterized clinically by recurrent fevers, abdominal pain, migratory rash, myalgia, arthralgia, and systemic amyloidosis. TRAPS is caused by mutations in the extracellular domain of the gene encoding TNFRSF1A. Signaling description: In TRAPS, mutant TNFRSF1A leads to enhanced inflammation through the increased activation of MAPKs, independent of TNF. Cells harboring TRAPS-associated TNFRSF1A mutations display spontaneous MAPK activation, as well as enhanced and prolonged MAPK activation following LPS stimulation. Reactive oxygen species (ROS) can potentiate MAPK activation by inactivation of MAPK phosphatases through the oxidation of their catalytic cysteine residues. TNF is a major cytokine involved in systemic inflammation. It is now proposed that abnormal oligomerization or misfolding of TNFRSF1A leads to retention in the endoplasmic reticulum (ER), decreased binding to TNF, ligand-independent signaling, and a reduction in TNF-induced apoptosis which underlies the pathogenesis of the disease. The increased activation of proinflammatory MAPKs secondary to stress-induced overproduction of mitochondrial oxygen species has also been demonstrated. The failure of mutant TNFRSF1A to be localized at the plasma membrane is associated with TNFRSF1A accumulation and aggregation in the ER. As autophagy is suggested to be the only mechanism effective in the clearance of TNFRSF1A aggregates, it has been proposed that the resulting autophagy defect may underlie TRAPS-associated induction of NF-kB. Outcome effects: In TRAPS, heterozygous TNFRSF1A mutant cells produce higher levels of several inflammatory cytokines including IL1B, TNF, and IL6 in response to LPS stimulation when compared to wild-type cells. TRAPS-associated induction of NF-kB triggers innate immune responses and excessive IL1B secretion which leads to chronic inflammation. In addition, increased levels of the ER stress response and XBP1 together with high ROS generation may contribute to the proinflammatory state associated with TRAPS. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: generic Organ_System: generic Organ_System: hematological system PMID: 24247370 PMID: 24282415 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: generic urn:agi-pathway:uuid-e76bbaf7-cda3-419e-af15-e363936ef639 TNF Receptor Associated Periodic Syndrome uuid-e76bbaf7-cda3-419e-af15-e363936ef639 PS:CellType generic PS:Description Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease associated with enhanced innate immune responsiveness. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e76bbaf7-cda3-419e-af15-e363936ef639 PS:NodeType Pathway PS:Notes Headnote: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease associated with enhanced innate immune responsiveness. TRAPS is characterized clinically by recurrent fevers, abdominal pain, migratory rash, myalgia, arthralgia, and systemic amyloidosis. TRAPS is caused by mutations in the extracellular domain of the gene encoding TNFRSF1A. Signaling description: In TRAPS, mutant TNFRSF1A leads to enhanced inflammation through the increased activation of MAPKs, independent of TNF. Cells harboring TRAPS-associated TNFRSF1A mutations display spontaneous MAPK activation, as well as enhanced and prolonged MAPK activation following LPS stimulation. Reactive oxygen species (ROS) can potentiate MAPK activation by inactivation of MAPK phosphatases through the oxidation of their catalytic cysteine residues. TNF is a major cytokine involved in systemic inflammation. It is now proposed that abnormal oligomerization or misfolding of TNFRSF1A leads to retention in the endoplasmic reticulum (ER), decreased binding to TNF, ligand-independent signaling, and a reduction in TNF-induced apoptosis which underlies the pathogenesis of the disease. The increased activation of proinflammatory MAPKs secondary to stress-induced overproduction of mitochondrial oxygen species has also been demonstrated. The failure of mutant TNFRSF1A to be localized at the plasma membrane is associated with TNFRSF1A accumulation and aggregation in the ER. As autophagy is suggested to be the only mechanism effective in the clearance of TNFRSF1A aggregates, it has been proposed that the resulting autophagy defect may underlie TRAPS-associated induction of NF-kB. Outcome effects: In TRAPS, heterozygous TNFRSF1A mutant cells produce higher levels of several inflammatory cytokines including IL1B, TNF, and IL6 in response to LPS stimulation when compared to wild-type cells. TRAPS-associated induction of NF-kB triggers innate immune responses and excessive IL1B secretion which leads to chronic inflammation. In addition, increased levels of the ER stress response and XBP1 together with high ROS generation may contribute to the proinflammatory state associated with TRAPS. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ generic PS:Organ_System generic PS:Organ_System hematological system PS:PMID 24247370 PS:PMID 24282415 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Pancreatic endoderm develops from endoderm following the expression of PDX1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7727c14-a8da-4e8b-882e-6bf0dc5b9396 NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Pancreatic beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: Pancreatic endoderm develops from endoderm following the expression of PDX1. Pancreatic endoderm differentiates into pancreatic ductal, acinar or endocrine cells. All islet endocrine cell types derive from NEUROG3-positive cells. NEUROG3 expression levels are regulated by NOTCH signaling, which represses NEUROG3 expression and maintains the progenitor phenotype. Outcome effects: Several days following the appearance of NEUROG3-positive cells, endocrine cells expressing insulin or glucagon (or both) appear in these cultures. Studies directly measuring neogenesis have never been performed in humans. Animal data: rodent model. Organ: pancreas Organ_System: endocrine system PMID: 23715541 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-e7727c14-a8da-4e8b-882e-6bf0dc5b9396 Transcription Factors in beta-Cell Neogenesis (Rodent Model) uuid-e7727c14-a8da-4e8b-882e-6bf0dc5b9396 PS:CellType insulin-secreting cell PS:Description Pancreatic endoderm develops from endoderm following the expression of PDX1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7727c14-a8da-4e8b-882e-6bf0dc5b9396 PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Pancreatic beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: Pancreatic endoderm develops from endoderm following the expression of PDX1. Pancreatic endoderm differentiates into pancreatic ductal, acinar or endocrine cells. All islet endocrine cell types derive from NEUROG3-positive cells. NEUROG3 expression levels are regulated by NOTCH signaling, which represses NEUROG3 expression and maintains the progenitor phenotype. Outcome effects: Several days following the appearance of NEUROG3-positive cells, endocrine cells expressing insulin or glucagon (or both) appear in these cultures. Studies directly measuring neogenesis have never been performed in humans. Animal data: rodent model. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 23715541 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e795098d-1bf2-4432-9f13-d7f9ac6ceed1 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-e795098d-1bf2-4432-9f13-d7f9ac6ceed1 GR decouples glucose intake from INS uuid-e795098d-1bf2-4432-9f13-d7f9ac6ceed1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e795098d-1bf2-4432-9f13-d7f9ac6ceed1 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7a553d8-cc54-41ae-b83a-bc3920968ff6 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-e7a553d8-cc54-41ae-b83a-bc3920968ff6 CHRNA7 -> CREB Signaling uuid-e7a553d8-cc54-41ae-b83a-bc3920968ff6 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7a553d8-cc54-41ae-b83a-bc3920968ff6 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: DNA damage checkpoint machinery is impaired in cancers allowing cell with damaged DNA to proliferate. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7cb2465-07aa-4431-8266-57b4ef1e8ba0 NodeType: Pathway Notes: Headnote: Cell cycle checkpoints are control mechanisms in eukaryotic cells which ensure proper cell division. There exist three major checkpoints: the G1 checkpoint, also known as the restriction or start checkpoint, the G2/M checkpoint, and the metaphase checkpoint. DNA damage response activates the cell cycle checkpoint. Cell cycle progression is controlled by CDKs activated by CDC25A/B/C phosphatases. The induction of double strand breaks in DNA activates the ATM/CHEK2 pathway, while exposed ssDNA initiates the ATR/CHEK1 pathway. Both pathways inactivate CDC25A/B/C leading to a temporal cell cycle arrest. Activation of TP53/ CDKN1A pathway is crucial for the G1 checkpoint. The activation of the MAPKAPK2 pathway contributes to the checkpoint activation and maintenance. Signaling description: ATR, ATM, BRCA1/2, CHEK1/2 and other proteins critical for DNA damage checkpoint are mutated or downregulated in many types of cancer. CDKs are often mutated or overexpressed, CDC25A/B are often overexpressed in cancers. Outcome effects: Despite DNA damage, cell cycle is not stopped and apoptosis is not induced allowing the cancer cell to proliferate. Animal data: The data were obtained both from animal models and human cancer cell lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. Organ: oncogenic Organ_System: oncogenic PMID: 16928813 PMID: 19075565 PMID: 22914294 PMID: 25914721 PMID: 26295265 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e7cb2465-07aa-4431-8266-57b4ef1e8ba0 DNA Damage Checkpoint Impairment in Cancer uuid-e7cb2465-07aa-4431-8266-57b4ef1e8ba0 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description DNA damage checkpoint machinery is impaired in cancers allowing cell with damaged DNA to proliferate. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7cb2465-07aa-4431-8266-57b4ef1e8ba0 PS:NodeType Pathway PS:Notes Headnote: Cell cycle checkpoints are control mechanisms in eukaryotic cells which ensure proper cell division. There exist three major checkpoints: the G1 checkpoint, also known as the restriction or start checkpoint, the G2/M checkpoint, and the metaphase checkpoint. DNA damage response activates the cell cycle checkpoint. Cell cycle progression is controlled by CDKs activated by CDC25A/B/C phosphatases. The induction of double strand breaks in DNA activates the ATM/CHEK2 pathway, while exposed ssDNA initiates the ATR/CHEK1 pathway. Both pathways inactivate CDC25A/B/C leading to a temporal cell cycle arrest. Activation of TP53/ CDKN1A pathway is crucial for the G1 checkpoint. The activation of the MAPKAPK2 pathway contributes to the checkpoint activation and maintenance. Signaling description: ATR, ATM, BRCA1/2, CHEK1/2 and other proteins critical for DNA damage checkpoint are mutated or downregulated in many types of cancer. CDKs are often mutated or overexpressed, CDC25A/B are often overexpressed in cancers. Outcome effects: Despite DNA damage, cell cycle is not stopped and apoptosis is not induced allowing the cancer cell to proliferate. Animal data: The data were obtained both from animal models and human cancer cell lines. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Sustaining of Proliferative Signaling" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Sustaining of Proliferative Signaling" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 16928813 PS:PMID 19075565 PS:PMID 22914294 PS:PMID 25914721 PS:PMID 26295265 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: EPCAM is a transmembrane glycoprotein mediating cell-cell adhesion in epithelia, it is involved in cell signaling, migration, proliferation and has oncogenic potential. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7cded2e-9f55-4dd1-84db-f5ff5e8db682 NodeType: Pathway Notes: Headnote: EPCAM is a transmembrane glycoprotein which mediates intercellular adhesion in epithelia, is involved in cell signaling, migration, proliferation, and differentiation and has oncogenic potential. EPCAM is expressed exclusively in epithelia and epithelial-derived neoplasms. Signaling description: EPCAM is cleaved by PSEN2 (which is a part of the gamma-secretase complex), ADAM17 and BACE1. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with FHL2, CTNNB1, and LEF1 proteins inside the nucleus. This complex then binds to DNA and positively regulates the transcription of various genes including MYC CCND1 and CCNE1, which promotes tumor growth. CTNNB1 is involved in the activation of NANOG, POU5F1 and SOX2, thus, mediating epithelial to mesenchymal transition (EMT). EPCAM can inhibit CDH1-dependent cell-to-cell adhesion by disrupting the link between CTNNA1 and F-actin. EPCAM potentiates EMT and cell migration through inhibition of CDH1. EPCAM directly binds to KREMLEN1 and disrupts the KREMLEN1-DKK2 interaction, which prevents KREMLEN1-DKK2-mediated removal of LRP6 from the cell surface. In this way, EPCAM mediates WNT signaling activation. EPCAM directly regulates CD44, BSG (CD147), CD9, TSPAN8 and some other proteins implicated in cancer metastatic progression. Outcome effects: EPCAM potentiates cancer cell migration and proliferation. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Organ: oncogenic Organ_System: oncogenic PMID: 17211480 PMID: 18508627 PMID: 19584271 PMID: 22647938 PMID: 23618806 PMID: 24008668 PMID: 25477371 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-e7cded2e-9f55-4dd1-84db-f5ff5e8db682 EPCAM in Cancer Cell Motility and Proliferation uuid-e7cded2e-9f55-4dd1-84db-f5ff5e8db682 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description EPCAM is a transmembrane glycoprotein mediating cell-cell adhesion in epithelia, it is involved in cell signaling, migration, proliferation and has oncogenic potential. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7cded2e-9f55-4dd1-84db-f5ff5e8db682 PS:NodeType Pathway PS:Notes Headnote: EPCAM is a transmembrane glycoprotein which mediates intercellular adhesion in epithelia, is involved in cell signaling, migration, proliferation, and differentiation and has oncogenic potential. EPCAM is expressed exclusively in epithelia and epithelial-derived neoplasms. Signaling description: EPCAM is cleaved by PSEN2 (which is a part of the gamma-secretase complex), ADAM17 and BACE1. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with FHL2, CTNNB1, and LEF1 proteins inside the nucleus. This complex then binds to DNA and positively regulates the transcription of various genes including MYC CCND1 and CCNE1, which promotes tumor growth. CTNNB1 is involved in the activation of NANOG, POU5F1 and SOX2, thus, mediating epithelial to mesenchymal transition (EMT). EPCAM can inhibit CDH1-dependent cell-to-cell adhesion by disrupting the link between CTNNA1 and F-actin. EPCAM potentiates EMT and cell migration through inhibition of CDH1. EPCAM directly binds to KREMLEN1 and disrupts the KREMLEN1-DKK2 interaction, which prevents KREMLEN1-DKK2-mediated removal of LRP6 from the cell surface. In this way, EPCAM mediates WNT signaling activation. EPCAM directly regulates CD44, BSG (CD147), CD9, TSPAN8 and some other proteins implicated in cancer metastatic progression. Outcome effects: EPCAM potentiates cancer cell migration and proliferation. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 17211480 PS:PMID 18508627 PS:PMID 19584271 PS:PMID 22647938 PS:PMID 23618806 PS:PMID 24008668 PS:PMID 25477371 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7eabb13-3729-4cfe-b7ac-79fc8259e4f2 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: generic urn:agi-pathway:uuid-e7eabb13-3729-4cfe-b7ac-79fc8259e4f2 BDKRB1/2 -> Prostaglandin Generation uuid-e7eabb13-3729-4cfe-b7ac-79fc8259e4f2 PS:CellType generic PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e7eabb13-3729-4cfe-b7ac-79fc8259e4f2 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8164858-4625-4255-b43d-0a7ac2dc5da4 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-e8164858-4625-4255-b43d-0a7ac2dc5da4 Lipoyl-Protein Complex Biosynthesis II uuid-e8164858-4625-4255-b43d-0a7ac2dc5da4 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8164858-4625-4255-b43d-0a7ac2dc5da4 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: Arterial Hypertension (AH) is a chronic increase in blood pressure. AH is related to vasoconstriction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e81a18db-ac03-4704-a5b9-6b139251fb6c NodeType: Pathway Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction, which is believed to be an early component of the arterial hypertensive process. Signaling description: Excessive vasoconstriction is a consequence of smooth muscle cell proliferation and dysfunction. Abundant levels of angiotensin II, noradrenaline, AVP, and EDN1 have a central role in smooth muscle cell dysfunction. They function as growth factors influencing smooth muscle cell proliferation, growth, and contraction. Angiotensin II acts through AGTR1, while noradrenaline binds ADRA1A. The receptor for AVP is AVPR1A, whereas EDN1 binds EDNRA/B. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLC and phosphatidyl-inositol-calcium second messenger system. PLC mediates the cleavage of PIP2 to diacylglycerol and IP3. Further, diacylglycerol activates PRKCD, and IP3 binds ITPR1 on the endoplasmic reticulum (ER), releasing Ca2+ and raising cytosolic Ca2+ concentrations. In addition, Ca2+ enters through the voltage-dependent, L-type calcium channels such as CACNB2, CACNA1C, and CACNA2D1 and is released via RYR3 into the sarcoplasmic reticulum. Outcome effects: Ca2+ is a highly versatile, intracellular signal that regulates many different cellular processes and proteins such as RASGRP1 and RASGRF1, which activate the MAPK cascade. PRKCD activates the MAPK pathway via PTK2B/SRC, which are involved in smooth muscle cell proliferation and growth. MAPK1 and MAPK3 activate MYLK that phosphorylates MYL12B to facilitate myosin interaction with actin filaments to produce the contractile activity. GNAQ stimulates the activation of RHOA, which, through ROCK1, decreases MYOCD expression. MYOCD is a smooth muscle and cardiac cell specific transcriptional factor that acts as a cofactor of SRF and TAGLN and is involved in smooth muscle cell contraction. Highlighted proteins: Entities with increased level or activity are highlighted in red. Organ: blood vessel Organ_System: cardiovascular system PMID: 21248162 PMID: 24685403 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-e81a18db-ac03-4704-a5b9-6b139251fb6c Smooth Muscle Cell Dysfunction in Arterial Hypertension uuid-e81a18db-ac03-4704-a5b9-6b139251fb6c PS:CellType vascular smooth muscle cell PS:Description Arterial Hypertension (AH) is a chronic increase in blood pressure. AH is related to vasoconstriction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e81a18db-ac03-4704-a5b9-6b139251fb6c PS:NodeType Pathway PS:Notes Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. The pathogenesis of arterial hypertension is associated with mechanisms of vasoconstriction, which is believed to be an early component of the arterial hypertensive process. Signaling description: Excessive vasoconstriction is a consequence of smooth muscle cell proliferation and dysfunction. Abundant levels of angiotensin II, noradrenaline, AVP, and EDN1 have a central role in smooth muscle cell dysfunction. They function as growth factors influencing smooth muscle cell proliferation, growth, and contraction. Angiotensin II acts through AGTR1, while noradrenaline binds ADRA1A. The receptor for AVP is AVPR1A, whereas EDN1 binds EDNRA/B. The activity of these receptors is mediated by G proteins such as GNA11 and GNAQ, which activate PLC and phosphatidyl-inositol-calcium second messenger system. PLC mediates the cleavage of PIP2 to diacylglycerol and IP3. Further, diacylglycerol activates PRKCD, and IP3 binds ITPR1 on the endoplasmic reticulum (ER), releasing Ca2+ and raising cytosolic Ca2+ concentrations. In addition, Ca2+ enters through the voltage-dependent, L-type calcium channels such as CACNB2, CACNA1C, and CACNA2D1 and is released via RYR3 into the sarcoplasmic reticulum. Outcome effects: Ca2+ is a highly versatile, intracellular signal that regulates many different cellular processes and proteins such as RASGRP1 and RASGRF1, which activate the MAPK cascade. PRKCD activates the MAPK pathway via PTK2B/SRC, which are involved in smooth muscle cell proliferation and growth. MAPK1 and MAPK3 activate MYLK that phosphorylates MYL12B to facilitate myosin interaction with actin filaments to produce the contractile activity. GNAQ stimulates the activation of RHOA, which, through ROCK1, decreases MYOCD expression. MYOCD is a smooth muscle and cardiac cell specific transcriptional factor that acts as a cofactor of SRF and TAGLN and is involved in smooth muscle cell contraction. Highlighted proteins: Entities with increased level or activity are highlighted in red. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 21248162 PS:PMID 24685403 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Agomelatine (Valdoxan) is a novel antidepressant drug that simultaneously acts as a melatonin receptor (MTNR1A) agonist and as a serotonin receptor (HTR2C) antagonist. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e820398d-62c1-49c3-8321-7a6ee8540359 NodeType: Pathway Notes: Headnote: Agomelatine (Valdoxan) is a novel antidepressant drug that simultaneously acts as a melatonin receptor (MTNR1A) agonist and as a serotonin receptor (HTR2C) antagonist. Signaling description: Agomelatine`s dual mechanism of action is unique and is the basis of efficacy in treating both depressive symptoms and sleep-wakefulness rhythm disorders. Both melatonin and serotonin receptors are present in the suprachiasmatic nucleus (SCN). Outcome effects: Melatonin receptor signaling leads to the resynchronization of circadian and sleep rhythms. In SCN, as in the frontal cortex, excitatory HTR2C receptors are localized on GABAergic interneurons. Therefore, their blockade disinhibits fronto-cortical dopaminergic and adrenergic transmission, the activity of which may be compromised in depression. Organ: brain Organ_System: nervous system PMID: 18342269 PMID: 20577266 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-e820398d-62c1-49c3-8321-7a6ee8540359 Agomelatine Antidepressant Action uuid-e820398d-62c1-49c3-8321-7a6ee8540359 PS:CellType neuron PS:Description Agomelatine (Valdoxan) is a novel antidepressant drug that simultaneously acts as a melatonin receptor (MTNR1A) agonist and as a serotonin receptor (HTR2C) antagonist. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e820398d-62c1-49c3-8321-7a6ee8540359 PS:NodeType Pathway PS:Notes Headnote: Agomelatine (Valdoxan) is a novel antidepressant drug that simultaneously acts as a melatonin receptor (MTNR1A) agonist and as a serotonin receptor (HTR2C) antagonist. Signaling description: Agomelatine`s dual mechanism of action is unique and is the basis of efficacy in treating both depressive symptoms and sleep-wakefulness rhythm disorders. Both melatonin and serotonin receptors are present in the suprachiasmatic nucleus (SCN). Outcome effects: Melatonin receptor signaling leads to the resynchronization of circadian and sleep rhythms. In SCN, as in the frontal cortex, excitatory HTR2C receptors are localized on GABAergic interneurons. Therefore, their blockade disinhibits fronto-cortical dopaminergic and adrenergic transmission, the activity of which may be compromised in depression. PS:Organ brain PS:Organ_System nervous system PS:PMID 18342269 PS:PMID 20577266 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: ameloblast CellType: odontoblast Description: Rothmund-Thomson syndrome is an autosomal recessive condition characterized by poikiloderma, skeletal and dental anomalies, and a predisposition to osteosarcoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8311b72-5d14-4914-8a35-373ba5dce8fc NodeType: Pathway Notes: Rothmund-Thomson syndrome (RTS, Poikiloderma atrophicans congenitale) is an autosomal recessive condition characterized by poikiloderma, skeletal and dental anomalies, and a predisposition to osteosarcoma. RTS results from mutations in RECQL4. Mutated genes: Mutated genes are shown in white-out style. Organ: Tooth Organ: mouth Organ_System: digestive system PMID: 20113479 PMID: 27320928 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: dental enamel Tissue: dentin urn:agi-pathway:uuid-e8311b72-5d14-4914-8a35-373ba5dce8fc Dentin Formation in Rothmund-Thomson Syndrome uuid-e8311b72-5d14-4914-8a35-373ba5dce8fc PS:CellType ameloblast PS:CellType odontoblast PS:Description Rothmund-Thomson syndrome is an autosomal recessive condition characterized by poikiloderma, skeletal and dental anomalies, and a predisposition to osteosarcoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8311b72-5d14-4914-8a35-373ba5dce8fc PS:NodeType Pathway PS:Notes Rothmund-Thomson syndrome (RTS, Poikiloderma atrophicans congenitale) is an autosomal recessive condition characterized by poikiloderma, skeletal and dental anomalies, and a predisposition to osteosarcoma. RTS results from mutations in RECQL4. Mutated genes: Mutated genes are shown in white-out style. PS:Organ Tooth PS:Organ mouth PS:Organ_System digestive system PS:PMID 20113479 PS:PMID 27320928 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue dental enamel PS:Tissue dentin PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e843cdf5-d344-4c79-bce7-52f8f9938a48 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-e843cdf5-d344-4c79-bce7-52f8f9938a48 Overview. Diseases of the digestive system (chapter 10) uuid-e843cdf5-d344-4c79-bce7-52f8f9938a48 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e843cdf5-d344-4c79-bce7-52f8f9938a48 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: thyroid cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e88f97cc-5ac8-481d-9c08-730f6409882b NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-e88f97cc-5ac8-481d-9c08-730f6409882b Proteins Involved in Thyroid Dysgenesis uuid-e88f97cc-5ac8-481d-9c08-730f6409882b PS:CellType thyroid cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e88f97cc-5ac8-481d-9c08-730f6409882b PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: astrocyte CellType: neuron Description: The central protein involved in Alzheimer's disease (AD) is amyloid precursor protein (APP). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8aaec44-26cb-4a8f-a17c-9f8b10f3fef9 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The central protein involved in the pathogenesis of AD is amyloid precursor protein (APP). The APP gene encodes the precursor protein of Abeta. SorL1, a protein genetically linked to AD, regulates the APP translocation inside the cell. Further, there are polymorphisms in several genes encoding the retromer complex (RC) or RC-associated proteins that are genetically associated with AD. In addition, LPR1, a lipoprotein receptor, also plays an important role in AD. Generally, it affects the metabolism of cholesterol and apolipoprotein E, the major risk factors for spontaneous AD. Human apolipoprotein E (APOE) has three common isoforms (ApoE2, ApoE3, and ApoE4) with different effects on lipid and neuronal homeostasis. ApoE4 is the major known genetic risk factor for AD. This allele is over-represented in all late-onset familial AD patients. Brain ApoE4 is synthesized and secreted primarily by astrocytes. Finally, mutations and altered function of proteins involved in endocytosis in neurons are also implicated in AD. Outcome effects: SorL1 associates with APP in the Golgi apparatus. In the absence or diminished function of SorL1, APP is delivered to a late-endosome where it can be cleaved to produce Abeta peptides. Further, the obstruction of the RC by inhibiting RC proteins such as VPS26A or VPS35 also increases Abeta production. Then, LPR1 also stimulates the formation of Abeta through binding to the APP. Additionally, one of the potential roles for ApoE4 is an enhanced Abeta production. Finally, proteins involved in endocytosis in neurons may also enhance Abeta synthesis in the cell. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 16567625 PMID: 16957580 PMID: 18045146 PMID: 19064752 PMID: 20079752 PMID: 23264752 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-e8aaec44-26cb-4a8f-a17c-9f8b10f3fef9 Amyloid beta and APP Intracellular Transport in Alzheimer Disease uuid-e8aaec44-26cb-4a8f-a17c-9f8b10f3fef9 PS:CellType astrocyte PS:CellType neuron PS:Description The central protein involved in Alzheimer's disease (AD) is amyloid precursor protein (APP). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8aaec44-26cb-4a8f-a17c-9f8b10f3fef9 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The central protein involved in the pathogenesis of AD is amyloid precursor protein (APP). The APP gene encodes the precursor protein of Abeta. SorL1, a protein genetically linked to AD, regulates the APP translocation inside the cell. Further, there are polymorphisms in several genes encoding the retromer complex (RC) or RC-associated proteins that are genetically associated with AD. In addition, LPR1, a lipoprotein receptor, also plays an important role in AD. Generally, it affects the metabolism of cholesterol and apolipoprotein E, the major risk factors for spontaneous AD. Human apolipoprotein E (APOE) has three common isoforms (ApoE2, ApoE3, and ApoE4) with different effects on lipid and neuronal homeostasis. ApoE4 is the major known genetic risk factor for AD. This allele is over-represented in all late-onset familial AD patients. Brain ApoE4 is synthesized and secreted primarily by astrocytes. Finally, mutations and altered function of proteins involved in endocytosis in neurons are also implicated in AD. Outcome effects: SorL1 associates with APP in the Golgi apparatus. In the absence or diminished function of SorL1, APP is delivered to a late-endosome where it can be cleaved to produce Abeta peptides. Further, the obstruction of the RC by inhibiting RC proteins such as VPS26A or VPS35 also increases Abeta production. Then, LPR1 also stimulates the formation of Abeta through binding to the APP. Additionally, one of the potential roles for ApoE4 is an enhanced Abeta production. Finally, proteins involved in endocytosis in neurons may also enhance Abeta synthesis in the cell. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 16567625 PS:PMID 16957580 PS:PMID 18045146 PS:PMID 19064752 PS:PMID 20079752 PS:PMID 23264752 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8bf3c23-3dff-477d-abd2-aee3cad57f17 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-e8bf3c23-3dff-477d-abd2-aee3cad57f17 oxLDL->endothelial cells proliferation uuid-e8bf3c23-3dff-477d-abd2-aee3cad57f17 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8bf3c23-3dff-477d-abd2-aee3cad57f17 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8bfc2d1-8183-462b-a485-40314b50ae82 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-e8bfc2d1-8183-462b-a485-40314b50ae82 COVID19->NK cells uuid-e8bfc2d1-8183-462b-a485-40314b50ae82 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8bfc2d1-8183-462b-a485-40314b50ae82 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8ef6901-acb0-471f-9ff6-5bafd1b9e2e0 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: colon Organ_System: digestive system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-e8ef6901-acb0-471f-9ff6-5bafd1b9e2e0 NOTCH1 -> Expression Targets in Colon uuid-e8ef6901-acb0-471f-9ff6-5bafd1b9e2e0 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8ef6901-acb0-471f-9ff6-5bafd1b9e2e0 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ colon PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8f8a18f-9eb9-4280-b17a-961a40a87fbd NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: appendix Organ: colon Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-e8f8a18f-9eb9-4280-b17a-961a40a87fbd Elevated Receptors -> Expression Targets in Appendix uuid-e8f8a18f-9eb9-4280-b17a-961a40a87fbd PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e8f8a18f-9eb9-4280-b17a-961a40a87fbd PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ appendix PS:Organ colon PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e901329f-25b8-45dd-b290-8830906550c4 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-e901329f-25b8-45dd-b290-8830906550c4 Integrins in Myofibroblast differentiation uuid-e901329f-25b8-45dd-b290-8830906550c4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e901329f-25b8-45dd-b290-8830906550c4 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e98ed934-ea10-4970-8860-09347edcf035 NodeType: Pathway Organ: ovary Organ_System: reproductive system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-e98ed934-ea10-4970-8860-09347edcf035 Proteins with Altered Expression in Ovarian Cancer uuid-e98ed934-ea10-4970-8860-09347edcf035 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e98ed934-ea10-4970-8860-09347edcf035 PS:NodeType Pathway PS:Organ ovary PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e99220ad-b57e-4d4e-9e3b-979aec3f34f2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-e99220ad-b57e-4d4e-9e3b-979aec3f34f2 InsR signaling -|feedback uuid-e99220ad-b57e-4d4e-9e3b-979aec3f34f2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e99220ad-b57e-4d4e-9e3b-979aec3f34f2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e997b52d-f358-43a6-9937-263ec5e00dc6 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Cell Process urn:agi-pathway:uuid-e997b52d-f358-43a6-9937-263ec5e00dc6 Glycosylation Quality Control and ERAD in Viral Stress Response uuid-e997b52d-f358-43a6-9937-263ec5e00dc6 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e997b52d-f358-43a6-9937-263ec5e00dc6 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Cell Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9b42385-481a-41c3-924c-e6b2b4493b2c NodeType: Pathway Notes: Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in the nephron. Those channels are responsible for Na+ and Cl- reabsorption into the blood and K+ excretion in the distal renal tubules. Excessive Na+ levels in plasma are the reason for increased blood volume and high blood pressure. So the maintenance of Na+/Cl-/K+ homeostasis by the kidney system is necessary for the maintenance of normal concentrations of ions and healthy blood pressure regulation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: kidney Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epithelium urn:agi-pathway:uuid-e9b42385-481a-41c3-924c-e6b2b4493b2c 2_The role of aldosterone in the regulation of Na+/Cl-/K+ homeostasis uuid-e9b42385-481a-41c3-924c-e6b2b4493b2c PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9b42385-481a-41c3-924c-e6b2b4493b2c PS:NodeType Pathway PS:Notes Aldosterone regulates the activity of ion channels that control electrolyte transport across epithelia in the nephron. Those channels are responsible for Na+ and Cl- reabsorption into the blood and K+ excretion in the distal renal tubules. Excessive Na+ levels in plasma are the reason for increased blood volume and high blood pressure. So the maintenance of Na+/Cl-/K+ homeostasis by the kidney system is necessary for the maintenance of normal concentrations of ions and healthy blood pressure regulation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9c9f15f-f511-4598-b264-755e9788f365 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-e9c9f15f-f511-4598-b264-755e9788f365 Glutamate Release in Nociception uuid-e9c9f15f-f511-4598-b264-755e9788f365 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9c9f15f-f511-4598-b264-755e9788f365 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: The principal function of most T cells is to respond to specific foreign antigens while maintaining self-tolerance. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9d54b7f-58d4-4474-938b-b2f67dabbcbb NodeType: Pathway Notes: Headnote: The principal function of most T-cells is to respond to specific foreign antigens while maintaining self-tolerance. Signaling description: T-cell receptor (TCR) signaling in naive T-cells is important to this process, which is initiated by TCR binding to antigen-MHC protein complex on the surface of antigen presenting cells. This leads to a succession of intracellular signaling events that lead to the generation of a T-cell response. Namely, LCK, a member of the Src family protein tyrosine kinases is activated which leads to the phosphorylation of CD3 coreceptor cytoplasmic domains, specifically at immunoreceptor tyrosine-based activation (ITAM) motifs. These phosphorylated ITAMs serve as binding sites for ZAP70. ZAP70 is activated by LCK-mediated phosphorylation and subsequent autophosphorylation. Activated ZAP70 then phosphorylates a variety of linker/adapter proteins such as LAT and LCP2. Further signaling proteins are then recruited which results in calcium mobilization, actin cytoskeleton reorganization, and activation of Ras. In addition, a sequential three-part protein kinase cascade is initiated which consists of MAP3K, MAP2K, and MAPK. Enzymatically active transducers such as PI3K and PLCG1 help relay the signal downstream. Outcome effects: These signals lead to the activation of transcription factors such as NF-AT and NF-kB, which ultimately result in cellular proliferation, differentiation, cytokine production, and activation-induced cell death. These signaling cascades regulate T-cell development, activation, and effector function. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-e9d54b7f-58d4-4474-938b-b2f67dabbcbb T-Cell Receptor Signaling uuid-e9d54b7f-58d4-4474-938b-b2f67dabbcbb PS:CellType T-cell PS:Description The principal function of most T cells is to respond to specific foreign antigens while maintaining self-tolerance. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9d54b7f-58d4-4474-938b-b2f67dabbcbb PS:NodeType Pathway PS:Notes Headnote: The principal function of most T-cells is to respond to specific foreign antigens while maintaining self-tolerance. Signaling description: T-cell receptor (TCR) signaling in naive T-cells is important to this process, which is initiated by TCR binding to antigen-MHC protein complex on the surface of antigen presenting cells. This leads to a succession of intracellular signaling events that lead to the generation of a T-cell response. Namely, LCK, a member of the Src family protein tyrosine kinases is activated which leads to the phosphorylation of CD3 coreceptor cytoplasmic domains, specifically at immunoreceptor tyrosine-based activation (ITAM) motifs. These phosphorylated ITAMs serve as binding sites for ZAP70. ZAP70 is activated by LCK-mediated phosphorylation and subsequent autophosphorylation. Activated ZAP70 then phosphorylates a variety of linker/adapter proteins such as LAT and LCP2. Further signaling proteins are then recruited which results in calcium mobilization, actin cytoskeleton reorganization, and activation of Ras. In addition, a sequential three-part protein kinase cascade is initiated which consists of MAP3K, MAP2K, and MAPK. Enzymatically active transducers such as PI3K and PLCG1 help relay the signal downstream. Outcome effects: These signals lead to the activation of transcription factors such as NF-AT and NF-kB, which ultimately result in cellular proliferation, differentiation, cytokine production, and activation-induced cell death. These signaling cascades regulate T-cell development, activation, and effector function. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9ded0f3-a142-4f39-8b07-13d7dae22874 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e9ded0f3-a142-4f39-8b07-13d7dae22874 TGFB1-TGFBR1/AP-1 Expression Targets uuid-e9ded0f3-a142-4f39-8b07-13d7dae22874 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9ded0f3-a142-4f39-8b07-13d7dae22874 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9e2934b-3c1a-456e-8928-16ad806c41f9 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e9e2934b-3c1a-456e-8928-16ad806c41f9 Xylogalacturonan biosynthesis template uuid-e9e2934b-3c1a-456e-8928-16ad806c41f9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9e2934b-3c1a-456e-8928-16ad806c41f9 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9ea060b-41ec-40ec-bfed-941f6cd6a90b NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-e9ea060b-41ec-40ec-bfed-941f6cd6a90b Pyridoxal 5'-phosphate biosynthesis template uuid-e9ea060b-41ec-40ec-bfed-941f6cd6a90b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9ea060b-41ec-40ec-bfed-941f6cd6a90b PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9f32b81-2d3c-4d39-b9e7-e7bacf90a344 NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-e9f32b81-2d3c-4d39-b9e7-e7bacf90a344 Achondroplasia Clinical Trials uuid-e9f32b81-2d3c-4d39-b9e7-e7bacf90a344 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9f32b81-2d3c-4d39-b9e7-e7bacf90a344 PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9f9d411-6bc8-4971-84d6-d9296856fcb7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-e9f9d411-6bc8-4971-84d6-d9296856fcb7 EDA Expression Targets uuid-e9f9d411-6bc8-4971-84d6-d9296856fcb7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-e9f9d411-6bc8-4971-84d6-d9296856fcb7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea23d13b-2468-4a5d-bea0-7dd9c0b12587 NodeType: Pathway Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-ea23d13b-2468-4a5d-bea0-7dd9c0b12587 Proteins Involved in Myocarditis uuid-ea23d13b-2468-4a5d-bea0-7dd9c0b12587 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea23d13b-2468-4a5d-bea0-7dd9c0b12587 PS:NodeType Pathway PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea3a187f-8bf7-455e-bc63-fb59955f7e09 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ea3a187f-8bf7-455e-bc63-fb59955f7e09 Proteins with Altered Expression in Age-Related Macular Degeneration uuid-ea3a187f-8bf7-455e-bc63-fb59955f7e09 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea3a187f-8bf7-455e-bc63-fb59955f7e09 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea3d730e-5bb0-4b2c-8462-b175a2ed1367 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ea3d730e-5bb0-4b2c-8462-b175a2ed1367 PLG -> STAT1/NF-kB Expression Targets uuid-ea3d730e-5bb0-4b2c-8462-b175a2ed1367 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea3d730e-5bb0-4b2c-8462-b175a2ed1367 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Activated inhibitors of apoptosis inhibit caspases and block programmed cell death in cancer cells. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea407473-7ff2-4513-9ed4-3937e3546bd7 NodeType: Pathway Notes: Headnote: Inhibitor of apoptosis proteins (IAPs) are endogenous inhibitors of caspases which can inhibit caspase activity by binding to their active sites, promoting degradation of active caspases or by keeping the caspases away from their substrates. Activated inhibitors of apoptosis inhibit caspases and block programmed cell death in cancer cells. Signaling description: BIRC2/3 may be activated due to mutations. Other factors leading to hyperexpression of IAPs include activation by HIF1A, STAT3, NFKB1, CTNNB1, ARHGEF3 and loss of suppression from TP53, XAF1 and DIABLO. Outcome effects: IAPS inactivate caspases 3 and 9 resulting in block of apoptosis. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. Organ: oncogenic Organ_System: oncogenic PMID: 18931692 PMID: 21453675 PMID: 21943236 PMID: 25328816 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-ea407473-7ff2-4513-9ed4-3937e3546bd7 Apoptosis Block by Inhibitor of Apoptosis Proteins (IAPs) in Cancer uuid-ea407473-7ff2-4513-9ed4-3937e3546bd7 PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Activated inhibitors of apoptosis inhibit caspases and block programmed cell death in cancer cells. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea407473-7ff2-4513-9ed4-3937e3546bd7 PS:NodeType Pathway PS:Notes Headnote: Inhibitor of apoptosis proteins (IAPs) are endogenous inhibitors of caspases which can inhibit caspase activity by binding to their active sites, promoting degradation of active caspases or by keeping the caspases away from their substrates. Activated inhibitors of apoptosis inhibit caspases and block programmed cell death in cancer cells. Signaling description: BIRC2/3 may be activated due to mutations. Other factors leading to hyperexpression of IAPs include activation by HIF1A, STAT3, NFKB1, CTNNB1, ARHGEF3 and loss of suppression from TP53, XAF1 and DIABLO. Outcome effects: IAPS inactivate caspases 3 and 9 resulting in block of apoptosis. Animal data: Some of the data were obtained from animal experiments. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer-Associated Resisting to Cell Death" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer-Associated Resisting to Cell Death" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 18931692 PS:PMID 21453675 PS:PMID 21943236 PS:PMID 25328816 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: Several enzymes of the Krebs cycle have been found mutated in both sporadic and hereditary forms of cancer. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea41e3dc-beea-4956-b6d3-93828773b1df NodeType: Pathway Notes: Headnote: Several enzymes of the Krebs cycle (tricarboxylic acid cycle, TCA) have been found to be mutated in both sporadic and hereditary forms of cancer. These include IDH1/2, SDHA, SDHB, SDHC, SDHD, SDHAF2 and FH. Signaling description: The mutated isocitrate dehydrogenase 1/2 (IDH1/2) produces an oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG), thus, depleting a-KG. The decreased level of a-KG depletes the rest of the cycle (succinate, fumarate, malate). The accumulation of 2HG leads to inhibition of TET1/2/3 enzymes and a decrease of 5-hydroxymethylcytosine (5hmC) level influences DNA methylation and changes gene expression. The decreased level of a-KG impedes ALKBH2/3 activation and disrupts DNA repair. 2-HG also inhibits collagen prolylhydroxylases involved in collagen maturation thereby promoting cancer cell migration and invasion. The SDH complex is a heterotetramer of SDHA, SDHB, SDHC and SDHD subunits converting succinate to fumarate. SDH5 (SDHAF2) is a factor required for the flavination of SDHA and assembly of the tetramer. FH is an enzyme of the TCA cycle that catalyzes the hydration of fumarate into malate. Loss of SDH leads to an accumulation of succinate, and loss of FH leads to an accumulation of fumarate. Succinate and fumarate at high concentrations are regarded as oncometabolites and inhibit the prolyl hydroxylases EGLN1/3, leading to pseudo-hypoxia and activation if HIF1A and HIF2A (EPAS1). HIF activation provokes multiple events including activation of glycolysis. Succinate, fumarate and 2-HG also inhibit KDM4A leading to the impairment of chromatin remodeling. 2-HG activates MTOR signaling via the KDM4A/DEPTOR/MTOR axis. Fumarate regulates the level of oxidative stress through KEAP1/ NFE2L2. Outcome effects: The outcome is gene- and mutation-dependent. The effects may include impairment of DNA repair, methylation and chromatin remodeling, induction of pseudo-hypoxia, inhibition of apoptosis, activation of cell motility and invasion and changes in the oxidative stress level. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Organ: oncogenic Organ_System: oncogenic PMID: 21764377 PMID: 21771581 PMID: 23071355 PMID: 23999438 PMID: 25057353 PMID: 25124653 PMID: 27386546 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-ea41e3dc-beea-4956-b6d3-93828773b1df Mutations in Krebs Cycle Enzymes in Cancer uuid-ea41e3dc-beea-4956-b6d3-93828773b1df PS:CellType cancer cell PS:CellType cancer stem cell PS:Description Several enzymes of the Krebs cycle have been found mutated in both sporadic and hereditary forms of cancer. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea41e3dc-beea-4956-b6d3-93828773b1df PS:NodeType Pathway PS:Notes Headnote: Several enzymes of the Krebs cycle (tricarboxylic acid cycle, TCA) have been found to be mutated in both sporadic and hereditary forms of cancer. These include IDH1/2, SDHA, SDHB, SDHC, SDHD, SDHAF2 and FH. Signaling description: The mutated isocitrate dehydrogenase 1/2 (IDH1/2) produces an oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG), thus, depleting a-KG. The decreased level of a-KG depletes the rest of the cycle (succinate, fumarate, malate). The accumulation of 2HG leads to inhibition of TET1/2/3 enzymes and a decrease of 5-hydroxymethylcytosine (5hmC) level influences DNA methylation and changes gene expression. The decreased level of a-KG impedes ALKBH2/3 activation and disrupts DNA repair. 2-HG also inhibits collagen prolylhydroxylases involved in collagen maturation thereby promoting cancer cell migration and invasion. The SDH complex is a heterotetramer of SDHA, SDHB, SDHC and SDHD subunits converting succinate to fumarate. SDH5 (SDHAF2) is a factor required for the flavination of SDHA and assembly of the tetramer. FH is an enzyme of the TCA cycle that catalyzes the hydration of fumarate into malate. Loss of SDH leads to an accumulation of succinate, and loss of FH leads to an accumulation of fumarate. Succinate and fumarate at high concentrations are regarded as oncometabolites and inhibit the prolyl hydroxylases EGLN1/3, leading to pseudo-hypoxia and activation if HIF1A and HIF2A (EPAS1). HIF activation provokes multiple events including activation of glycolysis. Succinate, fumarate and 2-HG also inhibit KDM4A leading to the impairment of chromatin remodeling. 2-HG activates MTOR signaling via the KDM4A/DEPTOR/MTOR axis. Fumarate regulates the level of oxidative stress through KEAP1/ NFE2L2. Outcome effects: The outcome is gene- and mutation-dependent. The effects may include impairment of DNA repair, methylation and chromatin remodeling, induction of pseudo-hypoxia, inhibition of apoptosis, activation of cell motility and invasion and changes in the oxidative stress level. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metabolic Reprogramming (Krebs Cycle)" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 21764377 PS:PMID 21771581 PS:PMID 23071355 PS:PMID 23999438 PS:PMID 25057353 PS:PMID 25124653 PS:PMID 27386546 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6beb83-5ddc-46cf-93c0-6e6206d1ed46 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ea6beb83-5ddc-46cf-93c0-6e6206d1ed46 VEGFR -> CTNNB Signaling uuid-ea6beb83-5ddc-46cf-93c0-6e6206d1ed46 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6beb83-5ddc-46cf-93c0-6e6206d1ed46 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6d74a4-a5e9-4d10-9ca2-aa5e8e81a9e4 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: generic urn:agi-pathway:uuid-ea6d74a4-a5e9-4d10-9ca2-aa5e8e81a9e4 Werner Syndrome (Adult Progeria) uuid-ea6d74a4-a5e9-4d10-9ca2-aa5e8e81a9e4 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6d74a4-a5e9-4d10-9ca2-aa5e8e81a9e4 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6da540-4af7-4924-aa3f-b68349799dfb NodeType: Pathway PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Receptor Signaling urn:agi-pathway:uuid-ea6da540-4af7-4924-aa3f-b68349799dfb INSR -> ARRB2/AKT/SRC Signaling uuid-ea6da540-4af7-4924-aa3f-b68349799dfb PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea6da540-4af7-4924-aa3f-b68349799dfb PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Source PS:Tissue CellType: monocyte Description: Gout is a monosodium urate (MSU) crystal deposition disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea757da4-9c86-4901-a25f-a6c51263fe91 NodeType: Pathway Notes: Headnote: Gout is a crystal deposition disease with clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment due to monosodium urate (MSU) crystal deposition. Low pH/temperature and local dehydration contribute to the crystal formation. Monocytes among other cell types are the first to react to the process of urate crystal deposition in the joints. Signaling description: MSU crystals may activate monocytes via the toll-like receptor (TLR) pathway and the inflammasome. The recognition of extracellular MSU crystals by TLR2 and TLR4 expressed by monocytes induce IL1B transcription. TLR2 and TLR4 signal transduction relies on MYD88, TICAM2, TIRAP and the adaptor proteins. Then, CD14, a phagocyte-expressed pattern recognition receptor functionally interacts with both TLR2 and TLR4 which could bind crystals and promote urate-induced inflammation. This signal transduction causes NF-kB and JUN activation which results in IL1B, TNF, IL6, and IL8 expression. In addition, obesity contributes to the pathology. Specifically, free fatty acids bind to TLR2 and accelerate the activation of monocytes. Lastly, the inflammasome activation depends on the NLRP3 complex assembly promoting CASP1-induced IL1B cleavage to generate the mature cytokine form. Outcome effects: The cytokines promote the recruitment of neutrophils to the inflamed joint through the activation of endothelial cells. IL1B is the source of pain and inflammation and along with IL6 and PGE2 (synthesized as a result of CD14 signaling) contribute to osteoclast differentiation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ_System: lymphatic system PMID: 23087690 PathwayType: signaling Source: Diseases Tissue: blood urn:agi-pathway:uuid-ea757da4-9c86-4901-a25f-a6c51263fe91 Monocytes Function in Gout uuid-ea757da4-9c86-4901-a25f-a6c51263fe91 PS:CellType monocyte PS:Description Gout is a monosodium urate (MSU) crystal deposition disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea757da4-9c86-4901-a25f-a6c51263fe91 PS:NodeType Pathway PS:Notes Headnote: Gout is a crystal deposition disease with clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment due to monosodium urate (MSU) crystal deposition. Low pH/temperature and local dehydration contribute to the crystal formation. Monocytes among other cell types are the first to react to the process of urate crystal deposition in the joints. Signaling description: MSU crystals may activate monocytes via the toll-like receptor (TLR) pathway and the inflammasome. The recognition of extracellular MSU crystals by TLR2 and TLR4 expressed by monocytes induce IL1B transcription. TLR2 and TLR4 signal transduction relies on MYD88, TICAM2, TIRAP and the adaptor proteins. Then, CD14, a phagocyte-expressed pattern recognition receptor functionally interacts with both TLR2 and TLR4 which could bind crystals and promote urate-induced inflammation. This signal transduction causes NF-kB and JUN activation which results in IL1B, TNF, IL6, and IL8 expression. In addition, obesity contributes to the pathology. Specifically, free fatty acids bind to TLR2 and accelerate the activation of monocytes. Lastly, the inflammasome activation depends on the NLRP3 complex assembly promoting CASP1-induced IL1B cleavage to generate the mature cytokine form. Outcome effects: The cytokines promote the recruitment of neutrophils to the inflamed joint through the activation of endothelial cells. IL1B is the source of pain and inflammation and along with IL6 and PGE2 (synthesized as a result of CD14 signaling) contribute to osteoclast differentiation. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ_System lymphatic system PS:PMID 23087690 PS:PathwayType signaling PS:Source Diseases PS:Tissue blood PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea75f340-10ce-49cd-a71c-d6ea76916dcb NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ea75f340-10ce-49cd-a71c-d6ea76916dcb Folate biosynthesis and SAM cycle template uuid-ea75f340-10ce-49cd-a71c-d6ea76916dcb PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea75f340-10ce-49cd-a71c-d6ea76916dcb PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell Description: BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea7ba171-9338-4e25-8f4c-3b305441e115 NodeType: Pathway Notes: Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 protein is involved in PAH as it regulates pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. BMP2 can act through the non-canonical WNT-pathway. Namely, BMP2 is responsible for SMAD1 phosphorylation, or with the loss of BMPR2 (as in some cases of familial and idiopathic pulmonary arterial hypertension), ACVR2A/SMAD3-dependent recruitment of DVL1 to promote RHOA/RAC1 signaling necessary for actin cytoskeleton rearrangement, cell contraction, and motility. Outcome effects: BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. Organ: lung Organ_System: cardiovascular system PMID: 19029018 PMID: 19139264 PMID: 19329555 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ea7ba171-9338-4e25-8f4c-3b305441e115 BMP2 and Non-Canonical WNT Signaling in Pulmonary Artery Endothelial Cells uuid-ea7ba171-9338-4e25-8f4c-3b305441e115 PS:CellType endothelial cell PS:Description BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea7ba171-9338-4e25-8f4c-3b305441e115 PS:NodeType Pathway PS:Notes Headnote: Pulmonary arterial hypertension (PAH) is increased blood pressure in the pulmonary artery. Signaling description: BMP2 protein is involved in PAH as it regulates pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. BMP2 can act through the non-canonical WNT-pathway. Namely, BMP2 is responsible for SMAD1 phosphorylation, or with the loss of BMPR2 (as in some cases of familial and idiopathic pulmonary arterial hypertension), ACVR2A/SMAD3-dependent recruitment of DVL1 to promote RHOA/RAC1 signaling necessary for actin cytoskeleton rearrangement, cell contraction, and motility. Outcome effects: BMP2 recruits both canonical and non-canonical WNT signaling pathways to promote pulmonary artery endothelial cell (PAEC) proliferation, survival, and motility. PS:Organ lung PS:Organ_System cardiovascular system PS:PMID 19029018 PS:PMID 19139264 PS:PMID 19329555 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: basophil Description: The role of basophils in the pathophysiology of allergic asthma is still incompletely understood. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea7bc821-0786-4357-998a-7e108c6ec570 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The role of basophils in the pathophysiology of allergic asthma is still poorly understood. Human basophils are a major source of IL4 and IL13, the key cytokines implicated in stimulating and amplifying the TH2 response and asthma progress. Activation of basophils, similarly to that of mast cells, is characterized primarily by degranulation and release of heparin, histamine, and leukotrienes from granules, and leads to immediate hypersensitivity reactions. Unlike mast cells, basophils are introduced into blood in an already mature state, thus their effects are faster than those of mast cells. Unlike mast cells, basophils express MHC class II and co-stimulatory molecules which can transmit peptide antigens to Th2-cells and therefore stimulate their differentiation. Similarly to mast cells, which also express the high-affinity IgE receptor FceRI, basophils release inflammatory mediators such as histamine and LTC4 in response to IgE-mediated activation. FceRI is expressed on mast cells and basophils in the form of tetramers (FCER1A / MS4A2/2 of FCER1G). Antigen binding to IgE cross-links two FceRI leading to Lyn phosphorylation. In addition to the well-characterized ability of basophils to be activated by antigen-IgE complexes, basophils have also been shown to be activated by the IgD antibody class molecules. IL-3 is the key cytokine that activate maturation of basophils. IL-3 seems to have a prominent pro-survival effect on basophils that depends on the kinase PIM1. IL-3 also enhances the production of IL-4 and IL-13 from basophils in response to IgE-mediated activation. In basophils, IL-4 and IL-13 production also induced by TLR2 related signaling. IL-33 is also specific to the process of basophil activation. IL-33 is expressed by dermal fibroblasts, airway epithelial cells and bronchial smooth muscle cells and is associated with IL-4, IL-13 and IL-6. Outcome effects: Basophils are known to contribute to allergic responses by inducing smooth muscle contraction once they migrate to the area of inflammation during the late phase response. Leukotrienes (LT) C4, LTD4, and LTE4, are smooth muscle constrictors. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 22918559 PMID: 8609103 PMID: 9753516 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ea7bc821-0786-4357-998a-7e108c6ec570 Basophil Activation in Asthma uuid-ea7bc821-0786-4357-998a-7e108c6ec570 PS:CellType basophil PS:Description The role of basophils in the pathophysiology of allergic asthma is still incompletely understood. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea7bc821-0786-4357-998a-7e108c6ec570 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The role of basophils in the pathophysiology of allergic asthma is still poorly understood. Human basophils are a major source of IL4 and IL13, the key cytokines implicated in stimulating and amplifying the TH2 response and asthma progress. Activation of basophils, similarly to that of mast cells, is characterized primarily by degranulation and release of heparin, histamine, and leukotrienes from granules, and leads to immediate hypersensitivity reactions. Unlike mast cells, basophils are introduced into blood in an already mature state, thus their effects are faster than those of mast cells. Unlike mast cells, basophils express MHC class II and co-stimulatory molecules which can transmit peptide antigens to Th2-cells and therefore stimulate their differentiation. Similarly to mast cells, which also express the high-affinity IgE receptor FceRI, basophils release inflammatory mediators such as histamine and LTC4 in response to IgE-mediated activation. FceRI is expressed on mast cells and basophils in the form of tetramers (FCER1A / MS4A2/2 of FCER1G). Antigen binding to IgE cross-links two FceRI leading to Lyn phosphorylation. In addition to the well-characterized ability of basophils to be activated by antigen-IgE complexes, basophils have also been shown to be activated by the IgD antibody class molecules. IL-3 is the key cytokine that activate maturation of basophils. IL-3 seems to have a prominent pro-survival effect on basophils that depends on the kinase PIM1. IL-3 also enhances the production of IL-4 and IL-13 from basophils in response to IgE-mediated activation. In basophils, IL-4 and IL-13 production also induced by TLR2 related signaling. IL-33 is also specific to the process of basophil activation. IL-33 is expressed by dermal fibroblasts, airway epithelial cells and bronchial smooth muscle cells and is associated with IL-4, IL-13 and IL-6. Outcome effects: Basophils are known to contribute to allergic responses by inducing smooth muscle contraction once they migrate to the area of inflammation during the late phase response. Leukotrienes (LT) C4, LTD4, and LTE4, are smooth muscle constrictors. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 22918559 PS:PMID 8609103 PS:PMID 9753516 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea98f6eb-9553-4bad-b13b-956069310c49 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ea98f6eb-9553-4bad-b13b-956069310c49 IL1B -> NO Expression Targets uuid-ea98f6eb-9553-4bad-b13b-956069310c49 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ea98f6eb-9553-4bad-b13b-956069310c49 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Hyperhomocysteinemia (HHcy) is characterized by abnormally high level of homocysteine in the blood. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eab5eab0-11b9-4eb5-b24d-3fe288020703 NodeType: Pathway Notes: Headnote: Hyperhomocysteinemia (HHcy) is a condition characterized by an abnormally high level of homocysteine in the blood. Severe homozygous forms of hyperhomocysteinemia cause homocystinuria, which is characterized by mental retardation, ectopia lentis, and skeletal abnormalities, although premature death is typically a consequence of thromboembolic events. Deficiencies of vitamin B6, folic acid (vitamin B9), and vitamin B12 can lead to HHcy. Chronic consumption of alcohol may also result in increased plasma levels of homocysteine due to disruption of folate metabolism. HHcy is strongly associated with end-stage renal disease due to impaired homocysteine excretion. HHcy was shown to cause cypercoagulation conditions. Signaling description: Homocysteine, a sulfur-containing amino acid, absent in natural diets, synthesized from methionine and either recycled back into methionine or converted into cysteine with the aid of the B-group vitamins. About 50% of homocysteine is converted back to methionine by remethylation. This requires active folate and vitamin B12, in order to donate a methyl group. The remaining homocysteine is transsulfurated to cysteine, with vitamin B6 as the co-factor. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in HHcy. Outcome effects: Homocysteine inhibits the expression of thrombomodulin (THBD), the thrombin cofactor responsible for PROC activation, and inhibits antithrombin III (SERPINC1) binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of SERPINC1. Homocysteine also increases F3 expression.Homocysteine impairs endothelial cell surface plasminogen activation by posttranslationally modifying annexin A2 (ANXA2), the coreceptor for plasminogen (PLG) and tissue plasminogen activator (PLAT). HHcy is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease.Mutated genes are shown in white-out style. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: generic Organ_System: hematological system PMID: 17550314 PMID: 18729731 PMID: 19841539 PMID: 21105837 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: blood urn:agi-pathway:uuid-eab5eab0-11b9-4eb5-b24d-3fe288020703 Hyperhomocysteinemia Induced Thrombophilia uuid-eab5eab0-11b9-4eb5-b24d-3fe288020703 PS:CellType generic PS:Description Hyperhomocysteinemia (HHcy) is characterized by abnormally high level of homocysteine in the blood. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eab5eab0-11b9-4eb5-b24d-3fe288020703 PS:NodeType Pathway PS:Notes Headnote: Hyperhomocysteinemia (HHcy) is a condition characterized by an abnormally high level of homocysteine in the blood. Severe homozygous forms of hyperhomocysteinemia cause homocystinuria, which is characterized by mental retardation, ectopia lentis, and skeletal abnormalities, although premature death is typically a consequence of thromboembolic events. Deficiencies of vitamin B6, folic acid (vitamin B9), and vitamin B12 can lead to HHcy. Chronic consumption of alcohol may also result in increased plasma levels of homocysteine due to disruption of folate metabolism. HHcy is strongly associated with end-stage renal disease due to impaired homocysteine excretion. HHcy was shown to cause cypercoagulation conditions. Signaling description: Homocysteine, a sulfur-containing amino acid, absent in natural diets, synthesized from methionine and either recycled back into methionine or converted into cysteine with the aid of the B-group vitamins. About 50% of homocysteine is converted back to methionine by remethylation. This requires active folate and vitamin B12, in order to donate a methyl group. The remaining homocysteine is transsulfurated to cysteine, with vitamin B6 as the co-factor. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in HHcy. Outcome effects: Homocysteine inhibits the expression of thrombomodulin (THBD), the thrombin cofactor responsible for PROC activation, and inhibits antithrombin III (SERPINC1) binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of SERPINC1. Homocysteine also increases F3 expression.Homocysteine impairs endothelial cell surface plasminogen activation by posttranslationally modifying annexin A2 (ANXA2), the coreceptor for plasminogen (PLG) and tissue plasminogen activator (PLAT). HHcy is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease.Mutated genes are shown in white-out style. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ generic PS:Organ_System hematological system PS:PMID 17550314 PS:PMID 18729731 PS:PMID 19841539 PS:PMID 21105837 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuroglia Description: Amyloid beta (Abeta) clearance dysfunction will lead to an accumulation of misfolded proteins and aggregates in neurons. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eabe8191-8438-4931-88ba-c39d2c66cec5 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: Protein clearance is critical for the maintenance of neuronal cell integrity and a disruption of this process will lead to the accumulation of misfolded proteins and aggregates. Defective removal of Abeta from the brain may be a decisive event in the pathogenesis of AD. Amyloid precursor protein (APP) cleavage creates mainly the amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42). This cleavage is localized to different subcellular compartments. The Abeta peptides are released to the extracellular space where they can form cytotoxic oligomers and aggregate into amyloid deposits. In the extracellular space, Abeta aggregates are partly removed by the surrounding cells including astrocytes and microglia cells. Abeta binds to A2M, APOE, and CLU which are the ligands of the LRP1 and LRP2 receptors. LRP binds to clathrin adaptor AP-2 which interacts with the clathrin coat. Outcome effects: The activation of clathrin coat proteins promotes endocytosis of the receptor-ligand complex with Abeta. Organ: brain Organ_System: nervous system PMID: 15974929 PMID: 20704558 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-eabe8191-8438-4931-88ba-c39d2c66cec5 Amyloid beta Clearance in Alzheimer Disease uuid-eabe8191-8438-4931-88ba-c39d2c66cec5 PS:CellType neuroglia PS:Description Amyloid beta (Abeta) clearance dysfunction will lead to an accumulation of misfolded proteins and aggregates in neurons. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eabe8191-8438-4931-88ba-c39d2c66cec5 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: Protein clearance is critical for the maintenance of neuronal cell integrity and a disruption of this process will lead to the accumulation of misfolded proteins and aggregates. Defective removal of Abeta from the brain may be a decisive event in the pathogenesis of AD. Amyloid precursor protein (APP) cleavage creates mainly the amyloid peptides of 40 amino acid residues (Abeta 40) and a more amyloidogenic peptide of 42 amino acid residues (Abeta 42). This cleavage is localized to different subcellular compartments. The Abeta peptides are released to the extracellular space where they can form cytotoxic oligomers and aggregate into amyloid deposits. In the extracellular space, Abeta aggregates are partly removed by the surrounding cells including astrocytes and microglia cells. Abeta binds to A2M, APOE, and CLU which are the ligands of the LRP1 and LRP2 receptors. LRP binds to clathrin adaptor AP-2 which interacts with the clathrin coat. Outcome effects: The activation of clathrin coat proteins promotes endocytosis of the receptor-ligand complex with Abeta. PS:Organ brain PS:Organ_System nervous system PS:PMID 15974929 PS:PMID 20704558 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eadee6be-277a-46d6-b906-378d164639dc NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-eadee6be-277a-46d6-b906-378d164639dc OSM/IL6ST/LIFR Expression Targets uuid-eadee6be-277a-46d6-b906-378d164639dc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eadee6be-277a-46d6-b906-378d164639dc PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eadfb747-6ef5-4cb4-857b-a77eaea97a58 NodeType: Pathway Notes: Headnote: The adherens junctions initiate cell-cell contacts and mediate maturation and maintenance of the contact. They consist of nectin and cadherin family cell adhesion molecules linked to the actin cytoskeleton through their binding proteins. Signaling description: The cytoplasmic regions of classical cadherins such as CDH1, CDH2, CDH3, and CDH12 bind catenins including CTNNA1, CTNNB1, JUP, and CTNND1, which in turn bind vinculin (VCL), EPB41, MAGI1, MAGI2, MLLT4, and other proteins to regulate actin polymerization. MAGI2-CTNNB1 interaction at epithelial-cadherin junctions prevents the degradation of PTEN, which significantly decreases cell proliferation activity of AKT1. Similarly, MAGI1-CTNNB1 interaction at neuronal-cadherin junctions activates NOTCH1 on neighboring cells resulting in lateral inhibition of cell differentiation and firm adhesion. IQGAP1 regulates cadherin/catenin-mediated intercellular adhesion both positively and negatively. It captures and stabilizes microtubules/tubulins, leading to the establishment of polarized cell morphology and directional cell migration. Outcome effects: Weak adhesions are formed due to growth factor-induced activation of receptor protein tyrosine kinases such as MET which causes the dissociation of CTNND1 and CTNNB1 from the cadherin/catenin complex, leading to the loss of cell adhesion function. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-eadfb747-6ef5-4cb4-857b-a77eaea97a58 Adherens Junction Assembly (Cadherins) uuid-eadfb747-6ef5-4cb4-857b-a77eaea97a58 PS:CellType generic PS:Description Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eadfb747-6ef5-4cb4-857b-a77eaea97a58 PS:NodeType Pathway PS:Notes Headnote: The adherens junctions initiate cell-cell contacts and mediate maturation and maintenance of the contact. They consist of nectin and cadherin family cell adhesion molecules linked to the actin cytoskeleton through their binding proteins. Signaling description: The cytoplasmic regions of classical cadherins such as CDH1, CDH2, CDH3, and CDH12 bind catenins including CTNNA1, CTNNB1, JUP, and CTNND1, which in turn bind vinculin (VCL), EPB41, MAGI1, MAGI2, MLLT4, and other proteins to regulate actin polymerization. MAGI2-CTNNB1 interaction at epithelial-cadherin junctions prevents the degradation of PTEN, which significantly decreases cell proliferation activity of AKT1. Similarly, MAGI1-CTNNB1 interaction at neuronal-cadherin junctions activates NOTCH1 on neighboring cells resulting in lateral inhibition of cell differentiation and firm adhesion. IQGAP1 regulates cadherin/catenin-mediated intercellular adhesion both positively and negatively. It captures and stabilizes microtubules/tubulins, leading to the establishment of polarized cell morphology and directional cell migration. Outcome effects: Weak adhesions are formed due to growth factor-induced activation of receptor protein tyrosine kinases such as MET which causes the dissociation of CTNND1 and CTNNB1 from the cadherin/catenin complex, leading to the loss of cell adhesion function. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eaf00b67-9d2b-4400-bcd1-83821f16af26 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-eaf00b67-9d2b-4400-bcd1-83821f16af26 FibronectinR -> CTNNB Signaling uuid-eaf00b67-9d2b-4400-bcd1-83821f16af26 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eaf00b67-9d2b-4400-bcd1-83821f16af26 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eafc68bb-8489-471e-b751-a561a13ead44 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-eafc68bb-8489-471e-b751-a561a13ead44 TNFR -> AP-1/ATF/TP53 Signaling uuid-eafc68bb-8489-471e-b751-a561a13ead44 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eafc68bb-8489-471e-b751-a561a13ead44 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb0af87d-5e76-4826-9444-ee515e97051b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-eb0af87d-5e76-4826-9444-ee515e97051b Excitotoxicity Damage of Striatum Medium Spiny Neurons in Huntington Disease uuid-eb0af87d-5e76-4826-9444-ee515e97051b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb0af87d-5e76-4826-9444-ee515e97051b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb0b58ea-9b58-4618-971f-741ac3440b02 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-eb0b58ea-9b58-4618-971f-741ac3440b02 HTR4/6/7 -> Vasodilation uuid-eb0b58ea-9b58-4618-971f-741ac3440b02 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb0b58ea-9b58-4618-971f-741ac3440b02 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb2728d9-4c96-4200-93f3-2155ca681e96 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-eb2728d9-4c96-4200-93f3-2155ca681e96 Fatty acid synthesis template uuid-eb2728d9-4c96-4200-93f3-2155ca681e96 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb2728d9-4c96-4200-93f3-2155ca681e96 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb298173-a61e-46e7-86c5-5d9fe3dd9c29 NodeType: Pathway Organ_System: nervous system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-eb298173-a61e-46e7-86c5-5d9fe3dd9c29 Proteins Involved in Diabetic Neuropathy uuid-eb298173-a61e-46e7-86c5-5d9fe3dd9c29 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb298173-a61e-46e7-86c5-5d9fe3dd9c29 PS:NodeType Pathway PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb54393e-2485-44a2-8ac9-2dfccef34228 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-eb54393e-2485-44a2-8ac9-2dfccef34228 WNT-+>myofibroblats uuid-eb54393e-2485-44a2-8ac9-2dfccef34228 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb54393e-2485-44a2-8ac9-2dfccef34228 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: muscle cell Description: Obesity is one main trigger of insulin resistance in muscle and liver. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb78d195-8a10-4c92-bf3b-9b03fb659cc8 NodeType: Pathway Notes: Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Free fatty acids released from the adipose tissue bind to toll-like receptors, TLR2 and TLR4 and activate MAPK8, MAPK9, and IKBKB via MYD88/IRAK/TRAF6. As a result, IRS is inactivated via phosphorylation. In addition, adipose tissue-derived CXCL5 is a newly discovered cytokine mediating insulin resistance in muscle. CXCL5 is able to inhibit INS action in the muscles by activating the JAK/STAT/SOCS signaling pathway. Furthermore, low adiponectin (ADIPOQ) levels are observed in insulin resistance. Normally, ADIPOQ binds to its receptor, ADIPOR1 and through APPL1/STK11 activates AMPK. AMPK promotes free fatty acid oxidation by downregulation of ACACB and ACLY which participate in the inhibition of CPT1B. Outcome effects: Substances released from the adipose tissue (including CXCL5 and free fatty acids) provoke inhibition of the insulin (INS) signal transduction leading to the disruption of glycogen synthesis, as well as the essential protein synthesis. The decreased level of ADIPOQ in insulin resistance leads to the disruption of fatty acid oxidation and storage of triglycerides. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ_System: endocrine system PMID: 11080610 PMID: 15143200 PMID: 18220592 PMID: 20157549 PMID: 22360800 PMID: 23017713 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: muscle urn:agi-pathway:uuid-eb78d195-8a10-4c92-bf3b-9b03fb659cc8 Insulin Resistance in Myocytes Induced by Obesity uuid-eb78d195-8a10-4c92-bf3b-9b03fb659cc8 PS:CellType muscle cell PS:Description Obesity is one main trigger of insulin resistance in muscle and liver. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb78d195-8a10-4c92-bf3b-9b03fb659cc8 PS:NodeType Pathway PS:Notes Headnote: Insulin resistance (IR) is a chronic condition characterized by a decreased ability of the cells to respond to insulin. IR typically coexists with obesity and announces the onset of diabetes mellitus type 2. Several mechanisms lead to insulin resistance in the liver and muscles. Signaling description: Free fatty acids released from the adipose tissue bind to toll-like receptors, TLR2 and TLR4 and activate MAPK8, MAPK9, and IKBKB via MYD88/IRAK/TRAF6. As a result, IRS is inactivated via phosphorylation. In addition, adipose tissue-derived CXCL5 is a newly discovered cytokine mediating insulin resistance in muscle. CXCL5 is able to inhibit INS action in the muscles by activating the JAK/STAT/SOCS signaling pathway. Furthermore, low adiponectin (ADIPOQ) levels are observed in insulin resistance. Normally, ADIPOQ binds to its receptor, ADIPOR1 and through APPL1/STK11 activates AMPK. AMPK promotes free fatty acid oxidation by downregulation of ACACB and ACLY which participate in the inhibition of CPT1B. Outcome effects: Substances released from the adipose tissue (including CXCL5 and free fatty acids) provoke inhibition of the insulin (INS) signal transduction leading to the disruption of glycogen synthesis, as well as the essential protein synthesis. The decreased level of ADIPOQ in insulin resistance leads to the disruption of fatty acid oxidation and storage of triglycerides. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ_System endocrine system PS:PMID 11080610 PS:PMID 15143200 PS:PMID 18220592 PS:PMID 20157549 PS:PMID 22360800 PS:PMID 23017713 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb803dab-48a4-4d94-8694-abe280cb613f NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-eb803dab-48a4-4d94-8694-abe280cb613f AngiopoietinR -> AP-1 Signaling uuid-eb803dab-48a4-4d94-8694-abe280cb613f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb803dab-48a4-4d94-8694-abe280cb613f PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Sonic hedgehog signaling is one of the key pathways in neuroblastoma development. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb986c82-8933-4df7-9e88-4c1344e16360 NodeType: Pathway Notes: Headnote: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and it originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Sonic hedgehog signaling is one of the key pathways in neuroblastoma development. Sonic hedgehog protein ligand (SHH) interacts with PTCH1 and SMO receptors. PTCH1 inhibits the activation of SMO, when SHH signaling is switched off. Canonical Sonic hedgehog signaling acts through the GLI1/2/3 transcription factors, and GLI1 is the agent which induces the expression of many other target genes. GLI2 acts as an activator or repressor of this pathway with its action dependent on the presence of GLI1. GLI3 always acts as repressor and in the absence of SHH signaling, GLI3 enters the nucleus with the help of SUFU and shows reversal as compared to GLI1 on SHH target genes. Outcome effects: The downstream target genes of SHH-GLI include CCND1/2, CCNB1, PAX6, NKX2-2, MYCN, and others. The activation of these genes leads to the enhancement of proliferation and inhibition of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ_System: nervous system PMID: 19622100 PMID: 22350753 PMID: 22949014 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-eb986c82-8933-4df7-9e88-4c1344e16360 Sonic Hedgehog Signaling in Neuroblastoma uuid-eb986c82-8933-4df7-9e88-4c1344e16360 PS:CellType cancer cell PS:CellType neural stem cell PS:Description Sonic hedgehog signaling is one of the key pathways in neuroblastoma development. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb986c82-8933-4df7-9e88-4c1344e16360 PS:NodeType Pathway PS:Notes Headnote: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and it originates from precursor cells of the peripheral (sympathetic) nervous system (neural crest neuroblasts). Tumors are most frequently found in the adrenal medulla and paraspinal ganglia, but can arise anywhere along the sympathetic chain. Signaling description: Sonic hedgehog signaling is one of the key pathways in neuroblastoma development. Sonic hedgehog protein ligand (SHH) interacts with PTCH1 and SMO receptors. PTCH1 inhibits the activation of SMO, when SHH signaling is switched off. Canonical Sonic hedgehog signaling acts through the GLI1/2/3 transcription factors, and GLI1 is the agent which induces the expression of many other target genes. GLI2 acts as an activator or repressor of this pathway with its action dependent on the presence of GLI1. GLI3 always acts as repressor and in the absence of SHH signaling, GLI3 enters the nucleus with the help of SUFU and shows reversal as compared to GLI1 on SHH target genes. Outcome effects: The downstream target genes of SHH-GLI include CCND1/2, CCNB1, PAX6, NKX2-2, MYCN, and others. The activation of these genes leads to the enhancement of proliferation and inhibition of apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ_System nervous system PS:PMID 19622100 PS:PMID 22350753 PS:PMID 22949014 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb9b87ad-3209-4807-8bb0-e65062ad5b04 NodeType: Pathway Notes: The gonadotropic hormones regulate the synthesis of both androgens and estrogens. About 60%–85% of women with PCOS have clinical hyperandrogenism in the form of excessive androgen biosynthesis in the ovaries. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-eb9b87ad-3209-4807-8bb0-e65062ad5b04 2_Impaired steroidogenesis in PCOS uuid-eb9b87ad-3209-4807-8bb0-e65062ad5b04 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eb9b87ad-3209-4807-8bb0-e65062ad5b04 PS:NodeType Pathway PS:Notes The gonadotropic hormones regulate the synthesis of both androgens and estrogens. About 60%–85% of women with PCOS have clinical hyperandrogenism in the form of excessive androgen biosynthesis in the ovaries. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebcdbb56-bef0-497a-af50-6154a963215b NodeType: Pathway Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ebcdbb56-bef0-497a-af50-6154a963215b Proteins Involved in Thyroid Hormone Resistance uuid-ebcdbb56-bef0-497a-af50-6154a963215b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebcdbb56-bef0-497a-af50-6154a963215b PS:NodeType Pathway PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebd0b6cd-d7eb-4373-939c-ef6620112700 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ebd0b6cd-d7eb-4373-939c-ef6620112700 Lipid IVA biosynthesis template uuid-ebd0b6cd-d7eb-4373-939c-ef6620112700 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebd0b6cd-d7eb-4373-939c-ef6620112700 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebe2f356-c760-4e21-8486-0c558b6cafa0 NodeType: Pathway Notes: Loss-of-function mutations in the gene encoding steroid sulfatase (STS) were found in patients with X-linked ichthyosis. STS hydrolyzes several 3-beta-hydroxysteroid sulfates, which are metabolic precursors of estrogens, androgens, and cholesterol. STS is ubiquitously expressed in tissues. Nonfunctional STS reduces the available cholesterol to form the extracellular lamellar bilayers in the skin. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: skin Organ_System: integumentary system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ebe2f356-c760-4e21-8486-0c558b6cafa0 2_Harlequin ichthyosis overview uuid-ebe2f356-c760-4e21-8486-0c558b6cafa0 PS:CellType keratinocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebe2f356-c760-4e21-8486-0c558b6cafa0 PS:NodeType Pathway PS:Notes Loss-of-function mutations in the gene encoding steroid sulfatase (STS) were found in patients with X-linked ichthyosis. STS hydrolyzes several 3-beta-hydroxysteroid sulfates, which are metabolic precursors of estrogens, androgens, and cholesterol. STS is ubiquitously expressed in tissues. Nonfunctional STS reduces the available cholesterol to form the extracellular lamellar bilayers in the skin. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ skin PS:Organ_System integumentary system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Hypoparathyroidism is an endocrine syndrome characterized by hyposecretion of PTH that controls Ca2 and Pi metabolism through its effects on kidney. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebe5f31d-279a-4986-ba53-beb039b2c2b7 NodeType: Pathway Notes: Headnote: Hypoparathyroidism refers to an endocrine syndrome characterized by hyposecretion of parathyroid hormone (PTH), which regulates Ca2+ and Pi metabolism through its effects on the kidney. Hence, hyposecretion of PTH is associated with impaired Renal Ca2+/Pi reabsorption leading to hypocalcemia and hyperphosphatemia. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: kidney Organ_System: urinary tract PMID: 23652552 PMID: 25905252 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-ebe5f31d-279a-4986-ba53-beb039b2c2b7 Ca2+/Pi Reabsorption Decline in Kidney in Hypoparathyroidism uuid-ebe5f31d-279a-4986-ba53-beb039b2c2b7 PS:CellType epithelial cell PS:Description Hypoparathyroidism is an endocrine syndrome characterized by hyposecretion of PTH that controls Ca2 and Pi metabolism through its effects on kidney. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ebe5f31d-279a-4986-ba53-beb039b2c2b7 PS:NodeType Pathway PS:Notes Headnote: Hypoparathyroidism refers to an endocrine syndrome characterized by hyposecretion of parathyroid hormone (PTH), which regulates Ca2+ and Pi metabolism through its effects on the kidney. Hence, hyposecretion of PTH is associated with impaired Renal Ca2+/Pi reabsorption leading to hypocalcemia and hyperphosphatemia. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 23652552 PS:PMID 25905252 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec10aa13-9f79-4a1a-bf55-e02906f84ee7 NodeType: Pathway Notes: Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ_System: hematological system Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers Tissue: blood urn:agi-pathway:uuid-ec10aa13-9f79-4a1a-bf55-e02906f84ee7 GPCRs Family -> Expression Targets in Lymphoid System and Blood uuid-ec10aa13-9f79-4a1a-bf55-e02906f84ee7 PS:Description Overexpressed receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec10aa13-9f79-4a1a-bf55-e02906f84ee7 PS:NodeType Pathway PS:Notes Overexpressed receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Tissue blood PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec1313a0-afd4-4b62-a9f3-29a29bbdaea7 NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ec1313a0-afd4-4b62-a9f3-29a29bbdaea7 Proteins Involved in Osteoarthritis uuid-ec1313a0-afd4-4b62-a9f3-29a29bbdaea7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec1313a0-afd4-4b62-a9f3-29a29bbdaea7 PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec23c154-9524-4642-a1b5-7ef59daaf175 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ec23c154-9524-4642-a1b5-7ef59daaf175 Monolignol biosynthesis template uuid-ec23c154-9524-4642-a1b5-7ef59daaf175 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec23c154-9524-4642-a1b5-7ef59daaf175 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec3a9858-fd1b-4fcd-b9a1-e4774dd8f929 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ec3a9858-fd1b-4fcd-b9a1-e4774dd8f929 EGFR -> CTNND Signaling uuid-ec3a9858-fd1b-4fcd-b9a1-e4774dd8f929 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec3a9858-fd1b-4fcd-b9a1-e4774dd8f929 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: The pro-inflammatory activity of T helper 17 (Th17) cells could be beneficial to the host during an infection in Chron's disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec637721-d9c7-4f3b-9749-af10719494b2 NodeType: Pathway Notes: Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Signaling description: The pro-inflammatory activity of T helper 17 (Th17) cells can be beneficial to the host during an infection. However, uncontrolled or inappropriate Th17 activation has been linked to several autoimmune and autoinflammatory pathologies. Th17 cells are activated mainly through IL-23R, which in turn activates the JAK-STAT-TYK pathway that enhances pro-inflammatory cytokine production. The increased production of IL-12 and IL-23 in Crohn's disease induces the Th17-cell immune responses. It has been demonstrated that anti-IL12/IL23p40 antibody therapy, which targets both Th1-cells and Th17-cells, is an effective treatment for Crohn's disease. Th17 cells from patients with Crohn's disease express high levels of STAT3, a transcription factor required for IL17 expression. In addition, polymorphisms in CCR6, JAK2, TYK2, STAT3, IL23R genes have been associated with Crohn's disease and T17-cell mediated effects. Outcome effects: IL17 is involved in the recruitment, activation and migration of neutrophils. Activated T17cells are involved in maintaining chronic inflammation and ulceration of the gut in patients with Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: lymphatic system PMID: 19592695 PMID: 19958311 PMID: 20169125 PMID: 21436303 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: blood urn:agi-pathway:uuid-ec637721-d9c7-4f3b-9749-af10719494b2 Th17-Cell Activation in Crohn's Disease uuid-ec637721-d9c7-4f3b-9749-af10719494b2 PS:CellType T-cell PS:Description The pro-inflammatory activity of T helper 17 (Th17) cells could be beneficial to the host during an infection in Chron's disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec637721-d9c7-4f3b-9749-af10719494b2 PS:NodeType Pathway PS:Notes Headnote: Crohn's disease is a chronic autoimmune granulomatous inflammation of the gastrointestinal tract. It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Crohn's disease is an inflammatory phenomenon that has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Signaling description: The pro-inflammatory activity of T helper 17 (Th17) cells can be beneficial to the host during an infection. However, uncontrolled or inappropriate Th17 activation has been linked to several autoimmune and autoinflammatory pathologies. Th17 cells are activated mainly through IL-23R, which in turn activates the JAK-STAT-TYK pathway that enhances pro-inflammatory cytokine production. The increased production of IL-12 and IL-23 in Crohn's disease induces the Th17-cell immune responses. It has been demonstrated that anti-IL12/IL23p40 antibody therapy, which targets both Th1-cells and Th17-cells, is an effective treatment for Crohn's disease. Th17 cells from patients with Crohn's disease express high levels of STAT3, a transcription factor required for IL17 expression. In addition, polymorphisms in CCR6, JAK2, TYK2, STAT3, IL23R genes have been associated with Crohn's disease and T17-cell mediated effects. Outcome effects: IL17 is involved in the recruitment, activation and migration of neutrophils. Activated T17cells are involved in maintaining chronic inflammation and ulceration of the gut in patients with Crohn's disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System lymphatic system PS:PMID 19592695 PS:PMID 19958311 PS:PMID 20169125 PS:PMID 21436303 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue blood PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Source PS:Tissue CellType: muscle cell Description: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in muscle function. Plasma levels of IL6 significantly increase after exercise. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec7cea1c-4288-4a2e-aca8-183210aa2e7e NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Plasma levels of IL6 significantly increase after exercise. Several mechanisms may link exercise to IL6 production, although the exact details are yet to be elucidated. During prolonged exercise, IL6 expression can be induced by Ca2+/calcineurin-NFATC1/ Jun/Fos pathway. A more intense contraction with higher Ca2+ amplitudes can activate NF-kB and MAPK8 signaling for IL6 production. Another signal for IL6 induction is a decreased glycogen level, by p38 kinase directly or through activating NF-kB. An epinephrine response is also a likely cause of IL6 up-regulation. Outcome effects: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Acting in a hormone-like fashion, IL6 affects glucose homeostasis and lipolysis in liver and adipose tissue, and decreases inflammation through inhibiting pro-inflammatory cytokines such as TNFA. Organ_System: musculoskeletal system PathwayType: signaling Source: Diseases Tissue: muscle urn:agi-pathway:uuid-ec7cea1c-4288-4a2e-aca8-183210aa2e7e IL6 Overexpression After Contraction in Skeletal Muscles in Muscular Dystrophies uuid-ec7cea1c-4288-4a2e-aca8-183210aa2e7e PS:CellType muscle cell PS:Description Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in muscle function. Plasma levels of IL6 significantly increase after exercise. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ec7cea1c-4288-4a2e-aca8-183210aa2e7e PS:NodeType Pathway PS:Notes Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Signaling description: Plasma levels of IL6 significantly increase after exercise. Several mechanisms may link exercise to IL6 production, although the exact details are yet to be elucidated. During prolonged exercise, IL6 expression can be induced by Ca2+/calcineurin-NFATC1/ Jun/Fos pathway. A more intense contraction with higher Ca2+ amplitudes can activate NF-kB and MAPK8 signaling for IL6 production. Another signal for IL6 induction is a decreased glycogen level, by p38 kinase directly or through activating NF-kB. An epinephrine response is also a likely cause of IL6 up-regulation. Outcome effects: Interleukin 6 (IL6) is a pleiotropic cytokine that plays a key role in a broad range of processes including inflammation, immune response, metabolism, muscle function, and oncogenesis. Acting in a hormone-like fashion, IL6 affects glucose homeostasis and lipolysis in liver and adipose tissue, and decreases inflammation through inhibiting pro-inflammatory cytokines such as TNFA. PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Source Diseases PS:Tissue muscle PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ecc1ae21-691e-4102-8c2f-322e564e70f2 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling urn:agi-pathway:uuid-ecc1ae21-691e-4102-8c2f-322e564e70f2 NPR1/NPR2 -> Fatty Acid Signaling uuid-ecc1ae21-691e-4102-8c2f-322e564e70f2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ecc1ae21-691e-4102-8c2f-322e564e70f2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ece09aa4-48a7-4394-ba3c-3a695d4b4cb8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-ece09aa4-48a7-4394-ba3c-3a695d4b4cb8 Natriuretic hormone-|IR uuid-ece09aa4-48a7-4394-ba3c-3a695d4b4cb8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ece09aa4-48a7-4394-ba3c-3a695d4b4cb8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: GNRH1 release from hypothalamus is regulated by KISS1 and TAC3. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ece5d8a1-df94-40aa-b15b-9a63425e8267 NodeType: Pathway Notes: Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a resultant lack of sex steroids production. Loss-of-function mutations in KISS1, KISS1R, TAC3, TACR3, GNRH1 and PCSK1 in humans cause hypogonadotrophic hypogonadism. Signaling description: Fertility in mammals is initiated at puberty by the pulsatile secretion of gonadotrophin releasing hormone (GNRH1) from a small number of neurons in the hypothalamus. GNRH1 release is regulated by kisspeptin (KISS1). KISS1 binds to its GPR54 (KISS1R) receptor, which is Gq-coupled to activate PLCB. PLC has multiple downstream actions resultant from cleaving PIP2 to InsP3 and diacylglycerol (DAG). Since PIP2 facilitates Kir channels opening, cleavage of this fatty acid attenuates these opening. DAG activates calcium TRPC1,3,4,5,6,7 channels. Once depolarized, Ca2+ entry through high voltage-activated Ca2+ channels can also contribute to facilitating TRPC channel opening. Massive Ca2+ influx stimulates GNRH1 release. Several studies also had shown the presence of TACR3 receptors on hypothalamus neurons. TACR3 and KISS1R both signal via Gq/11, so they may be expected to show synergistic activities. Mutated genes are shown in white-out style. Organ: brain Organ: hypothalamus Organ_System: endocrine system PMID: 18434521 PMID: 19740674 PMID: 22229029 PMID: 23550004 PMID: 25071724 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-ece5d8a1-df94-40aa-b15b-9a63425e8267 GNRH Release Impairment in Hypogonadotrophic Hypogonadism uuid-ece5d8a1-df94-40aa-b15b-9a63425e8267 PS:CellType neuron PS:Description GNRH1 release from hypothalamus is regulated by KISS1 and TAC3. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ece5d8a1-df94-40aa-b15b-9a63425e8267 PS:NodeType Pathway PS:Notes Headnote: Hypogonadotropic hypogonadism (HH) is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins by the pituitary gland and a resultant lack of sex steroids production. Loss-of-function mutations in KISS1, KISS1R, TAC3, TACR3, GNRH1 and PCSK1 in humans cause hypogonadotrophic hypogonadism. Signaling description: Fertility in mammals is initiated at puberty by the pulsatile secretion of gonadotrophin releasing hormone (GNRH1) from a small number of neurons in the hypothalamus. GNRH1 release is regulated by kisspeptin (KISS1). KISS1 binds to its GPR54 (KISS1R) receptor, which is Gq-coupled to activate PLCB. PLC has multiple downstream actions resultant from cleaving PIP2 to InsP3 and diacylglycerol (DAG). Since PIP2 facilitates Kir channels opening, cleavage of this fatty acid attenuates these opening. DAG activates calcium TRPC1,3,4,5,6,7 channels. Once depolarized, Ca2+ entry through high voltage-activated Ca2+ channels can also contribute to facilitating TRPC channel opening. Massive Ca2+ influx stimulates GNRH1 release. Several studies also had shown the presence of TACR3 receptors on hypothalamus neurons. TACR3 and KISS1R both signal via Gq/11, so they may be expected to show synergistic activities. Mutated genes are shown in white-out style. PS:Organ brain PS:Organ hypothalamus PS:Organ_System endocrine system PS:PMID 18434521 PS:PMID 19740674 PS:PMID 22229029 PS:PMID 23550004 PS:PMID 25071724 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Pyelonephritis is a nonspecific inflammation of kidney tubular system. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed038c6b-eeea-47f5-971f-65368f3e0cf0 NodeType: Pathway Notes: Pyelonephritis is a nonspecific inflammation of kidney tubular system. If uropathogens breach the physical barriers of the urothelium they are recognized by TLRs that mobilize the immune responses of the kidney epithelial cells. Organ: kidney Organ_System: urinary tract PMID: 16982918 PMID: 17003836 PMID: 19241891 PMID: 23732397 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-ed038c6b-eeea-47f5-971f-65368f3e0cf0 Toll-like Receptors in Pyelonephritis uuid-ed038c6b-eeea-47f5-971f-65368f3e0cf0 PS:CellType epithelial cell PS:Description Pyelonephritis is a nonspecific inflammation of kidney tubular system. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed038c6b-eeea-47f5-971f-65368f3e0cf0 PS:NodeType Pathway PS:Notes Pyelonephritis is a nonspecific inflammation of kidney tubular system. If uropathogens breach the physical barriers of the urothelium they are recognized by TLRs that mobilize the immune responses of the kidney epithelial cells. PS:Organ kidney PS:Organ_System urinary tract PS:PMID 16982918 PS:PMID 17003836 PS:PMID 19241891 PS:PMID 23732397 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed34f6af-821e-439a-9dfc-b8a10e4b68fd NodeType: Pathway Organ: Parathyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-ed34f6af-821e-439a-9dfc-b8a10e4b68fd Proteins Involved in Hyperparathyroidism uuid-ed34f6af-821e-439a-9dfc-b8a10e4b68fd PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed34f6af-821e-439a-9dfc-b8a10e4b68fd PS:NodeType Pathway PS:Organ Parathyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed3da83c-76d8-40a6-bb4e-b21a9dfb8d8a NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ed3da83c-76d8-40a6-bb4e-b21a9dfb8d8a Levodopa in Parkinson Treatment uuid-ed3da83c-76d8-40a6-bb4e-b21a9dfb8d8a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed3da83c-76d8-40a6-bb4e-b21a9dfb8d8a PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Lesch-Nyhan syndrome is a rare disorder of purine metabolism, inherited is linked to the X chromosome and the resulting lack of hypoxanthine phosphoribosyltransferase 1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed5cfba2-056f-407e-a8bb-3e3cd865cf82 NodeType: Pathway Notes: Headnote: Deficiency of HPRT1 Leads to Lesch-Nyhan Syndrome. Lesch-Nyhan syndrome - a rare disorder of purine metabolism, inherited is linked to the X chromosome and the resulting lack of hypoxanthine phosphoribosyltransferase 1. The frequency of classic Lesch-Nyhan syndrome ranges from 1: 100000-1: 300000; the prevalence of the variant forms of the disease is unknown. Patients with the classic syndrome have a kidney damage and respiratory system and rarely live up to 30 years. Signaling Descriptions: Normally, HPRT1 is present in all cells, in the largest number contained in the brain, particularly in the basal ganglia. Manifestations of the syndrome include hyperuricemia, mental retardation, cerebral palsy, and choreoathetosis with early and later muscle spasticity and dystonia, dysarthria. HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Striatal dopaminergic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation. The link between dopamine and purine synthesis is a nucleotide guanosine triphosphate (GTP). The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency. Also 6-hydroxydopamine (oxidopamine) toxicity in rodents used as animal model for the syndrome. Oxidopamine inhibits BDNF - the major factor for grow and homeostasis of neurons. The hyperuricemia is accompanying Lesch-Nyhan syndrome. The increased uric acid levels in tissue of patients with Lesch-Nyhan disease might be toxic to the developing nervous system.Mutated gene is shown in white-out style. Compounds with elevated level are highlighted in red. Organ: kidney Organ: lung Organ_System: endocrine system PMID: 10852837 PMID: 11773585 PMID: 11882343 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: generic urn:agi-pathway:uuid-ed5cfba2-056f-407e-a8bb-3e3cd865cf82 HPRT1 Deficiency in Lesch-Nyhan Syndrome uuid-ed5cfba2-056f-407e-a8bb-3e3cd865cf82 PS:Description Lesch-Nyhan syndrome is a rare disorder of purine metabolism, inherited is linked to the X chromosome and the resulting lack of hypoxanthine phosphoribosyltransferase 1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed5cfba2-056f-407e-a8bb-3e3cd865cf82 PS:NodeType Pathway PS:Notes Headnote: Deficiency of HPRT1 Leads to Lesch-Nyhan Syndrome. Lesch-Nyhan syndrome - a rare disorder of purine metabolism, inherited is linked to the X chromosome and the resulting lack of hypoxanthine phosphoribosyltransferase 1. The frequency of classic Lesch-Nyhan syndrome ranges from 1: 100000-1: 300000; the prevalence of the variant forms of the disease is unknown. Patients with the classic syndrome have a kidney damage and respiratory system and rarely live up to 30 years. Signaling Descriptions: Normally, HPRT1 is present in all cells, in the largest number contained in the brain, particularly in the basal ganglia. Manifestations of the syndrome include hyperuricemia, mental retardation, cerebral palsy, and choreoathetosis with early and later muscle spasticity and dystonia, dysarthria. HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Striatal dopaminergic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation. The link between dopamine and purine synthesis is a nucleotide guanosine triphosphate (GTP). The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency. Also 6-hydroxydopamine (oxidopamine) toxicity in rodents used as animal model for the syndrome. Oxidopamine inhibits BDNF - the major factor for grow and homeostasis of neurons. The hyperuricemia is accompanying Lesch-Nyhan syndrome. The increased uric acid levels in tissue of patients with Lesch-Nyhan disease might be toxic to the developing nervous system.Mutated gene is shown in white-out style. Compounds with elevated level are highlighted in red. PS:Organ kidney PS:Organ lung PS:Organ_System endocrine system PS:PMID 10852837 PS:PMID 11773585 PS:PMID 11882343 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed90e9a3-150d-424d-b148-0e2a904eaf9b NodeType: Pathway Organ: skin Organ_System: integumentary system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-ed90e9a3-150d-424d-b148-0e2a904eaf9b Genes with Mutations Associated with Psoriasis uuid-ed90e9a3-150d-424d-b148-0e2a904eaf9b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ed90e9a3-150d-424d-b148-0e2a904eaf9b PS:NodeType Pathway PS:Organ skin PS:Organ_System integumentary system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-edbb6411-4d76-41bc-898c-62c81e2e02ab NodeType: Pathway Notes: Polycystic kidney disease results from ciliopathies. The polycystins and fibrocystin are found on the apical membrane of renal tubule epithelial cells, which are located in primary cilia and then spread into the tubule lumen. Presumably the cilia act as sensors. When they are flexed by urine flow, they translate that fluid flow into chemical signals that regulate tubular development and function. The loss of cilia alone is inadequate to cause cyst formation. However, a large body of evidence connects mutations in the genes encoding the polycystins and fibrocystin with the origin of cyst formation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: kidney Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: epithelium urn:agi-pathway:uuid-edbb6411-4d76-41bc-898c-62c81e2e02ab 2_Dysfunction of cilia in polycystic kidney disease uuid-edbb6411-4d76-41bc-898c-62c81e2e02ab PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-edbb6411-4d76-41bc-898c-62c81e2e02ab PS:NodeType Pathway PS:Notes Polycystic kidney disease results from ciliopathies. The polycystins and fibrocystin are found on the apical membrane of renal tubule epithelial cells, which are located in primary cilia and then spread into the tubule lumen. Presumably the cilia act as sensors. When they are flexed by urine flow, they translate that fluid flow into chemical signals that regulate tubular development and function. The loss of cilia alone is inadequate to cause cyst formation. However, a large body of evidence connects mutations in the genes encoding the polycystins and fibrocystin with the origin of cyst formation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-edc165e5-2a1c-4bc0-a96e-3d455cbd1650 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-edc165e5-2a1c-4bc0-a96e-3d455cbd1650 TLR9 Expression Targets uuid-edc165e5-2a1c-4bc0-a96e-3d455cbd1650 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-edc165e5-2a1c-4bc0-a96e-3d455cbd1650 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eddd7343-66f8-47b5-bf9b-574369da9bd8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-eddd7343-66f8-47b5-bf9b-574369da9bd8 Hypoxia->EMT uuid-eddd7343-66f8-47b5-bf9b-574369da9bd8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eddd7343-66f8-47b5-bf9b-574369da9bd8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: The prominent increase in the level of BDNF caused by status epilepticus drives distinct changes in gene expression through the activation of at least three pathways. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee204493-31a4-4e0f-9704-7c4dbbce74c7 NodeType: Pathway Notes: Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: The prominent increase in the level of BDNF caused by status epilepticus drives distinct changes in gene expression through the activation of at least three pathways including PKC/MAPK, Ras/MAPK, and JAK/STAT. Outcome effects: As a result, BDNF modulates the expression of inhibitory GABA-A receptor subunits in the brain and is responsible for the decrease of GABRA1 and the increase of GABRA4 leading to recurrent spontaneous seizures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ: brain Organ_System: nervous system PMID: 16901909 PMID: 18922788 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-ee204493-31a4-4e0f-9704-7c4dbbce74c7 BDNF Upregulation Triggered by Seizures uuid-ee204493-31a4-4e0f-9704-7c4dbbce74c7 PS:CellType neuron PS:Description The prominent increase in the level of BDNF caused by status epilepticus drives distinct changes in gene expression through the activation of at least three pathways. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee204493-31a4-4e0f-9704-7c4dbbce74c7 PS:NodeType Pathway PS:Notes Headnote: Epilepsy is a common neurological condition defined by recurrent, unprovoked seizures and affects 1% of the world's population. Epileptogenesis is common following brain trauma, ischemia, and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Seizures damage the brain and if they are prolonged (status epilepticus) or repeatedly evoked they can cause neuronal death, especially within vulnerable brain regions such as the hippocampus. Signaling description: The prominent increase in the level of BDNF caused by status epilepticus drives distinct changes in gene expression through the activation of at least three pathways including PKC/MAPK, Ras/MAPK, and JAK/STAT. Outcome effects: As a result, BDNF modulates the expression of inhibitory GABA-A receptor subunits in the brain and is responsible for the decrease of GABRA1 and the increase of GABRA4 leading to recurrent spontaneous seizures. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 16901909 PS:PMID 18922788 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee237513-5761-4bbf-9c23-bbfaa50f7f9d NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ee237513-5761-4bbf-9c23-bbfaa50f7f9d AREG -> CREB/CREBBP Expression Targets uuid-ee237513-5761-4bbf-9c23-bbfaa50f7f9d PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee237513-5761-4bbf-9c23-bbfaa50f7f9d PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: cancer stem cell Description: CDH1 is a tumor suppressor gene, loss of CDH1 function contributes to progression of epithelial to mesenchymal transition and cancer cell invasion / metastasis Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee28d5a4-dabd-485d-af97-2bc590be655b NodeType: Pathway Notes: Headnote: CDH1 (cadherin-1, E-cadherin) is a crucial type of cell-cell adhesion molecules and works at adherens junctions to hold epithelial cells tightly together. CDH1 can sequester CTNNB1 to the cell membrane. Signaling description: CDH1 may be down-regulated in different types of cancers due to transcriptional suppression or mutations. Several transcription factors such as SNAI1/2/3, ZEB1/2, TWIST1, KLF8, TCF3, FOXQ1, PRRX1, FOXC1/2, GSC down-regulate CDH1 expression. EPCAM also may down-regulate CDH1. The loss of CDH1 expression results in CTNNB1 release into the cytoplasm. Normally, upon CDH1 loss, liberated CTNNB1 is rapidly phosphorylated by APC/AXIN1/GSK3B complex and subsequently degraded by the ubiquitin-proteasome pathway. If APC or AXIN1 is nonfunctional, as is the case in many cancer cells, or if GSK3B and AXIN1 is repressed by an activated WNT signaling pathway, CTNNB1 accumulates at high levels in the cytoplasm. Subsequently, it translocates to the nucleus, where it binds to TCF4 and LEF1 and modulates the expression of epithelial to mesenchymal transition (EMT)-inducing transcription factors. Cytoplasmic CTNND1 is bound to CDH1 and activates the RHO-family GTPases RAC1 and CDC42 and represses RHOA. PI3K is recruited to the membrane by CDH1 and activates TIAM1 and subsequently activates RAC1 and CDC42. cells. Outcome effects: Taken together, these activities affect the organization of actin cytoskeleton and possibly the migratory behavior of tumour cells, as follows: activated CDC42 and RAC1 promote the formation of filopodia and lamellipodia, respectively. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metastasis" for details. Organ: oncogenic Organ_System: oncogenic PMID: 14964308 PMID: 19029934 PMID: 20457567 PMID: 20460404 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Pathological Process Tissue: oncogenic urn:agi-pathway:uuid-ee28d5a4-dabd-485d-af97-2bc590be655b CDH1 Down regulation Promotes Cancer Cell Migration and Metastases uuid-ee28d5a4-dabd-485d-af97-2bc590be655b PS:CellType cancer cell PS:CellType cancer stem cell PS:Description CDH1 is a tumor suppressor gene, loss of CDH1 function contributes to progression of epithelial to mesenchymal transition and cancer cell invasion / metastasis PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee28d5a4-dabd-485d-af97-2bc590be655b PS:NodeType Pathway PS:Notes Headnote: CDH1 (cadherin-1, E-cadherin) is a crucial type of cell-cell adhesion molecules and works at adherens junctions to hold epithelial cells tightly together. CDH1 can sequester CTNNB1 to the cell membrane. Signaling description: CDH1 may be down-regulated in different types of cancers due to transcriptional suppression or mutations. Several transcription factors such as SNAI1/2/3, ZEB1/2, TWIST1, KLF8, TCF3, FOXQ1, PRRX1, FOXC1/2, GSC down-regulate CDH1 expression. EPCAM also may down-regulate CDH1. The loss of CDH1 expression results in CTNNB1 release into the cytoplasm. Normally, upon CDH1 loss, liberated CTNNB1 is rapidly phosphorylated by APC/AXIN1/GSK3B complex and subsequently degraded by the ubiquitin-proteasome pathway. If APC or AXIN1 is nonfunctional, as is the case in many cancer cells, or if GSK3B and AXIN1 is repressed by an activated WNT signaling pathway, CTNNB1 accumulates at high levels in the cytoplasm. Subsequently, it translocates to the nucleus, where it binds to TCF4 and LEF1 and modulates the expression of epithelial to mesenchymal transition (EMT)-inducing transcription factors. Cytoplasmic CTNND1 is bound to CDH1 and activates the RHO-family GTPases RAC1 and CDC42 and represses RHOA. PI3K is recruited to the membrane by CDH1 and activates TIAM1 and subsequently activates RAC1 and CDC42. cells. Outcome effects: Taken together, these activities affect the organization of actin cytoskeleton and possibly the migratory behavior of tumour cells, as follows: activated CDC42 and RAC1 promote the formation of filopodia and lamellipodia, respectively. Highlighted proteins: Proteins with increased expression/activity are highlighted in red. Proteins with decreased expression/activity are highlighted in blue. See pathway "Proteins with Altered Expression in Cancer Metastases" for details. Mutated genes: Mutated genes are shown in white-out style. See pathway "Genes with Mutations in Cancer Metastasis" for details. PS:Organ oncogenic PS:Organ_System oncogenic PS:PMID 14964308 PS:PMID 19029934 PS:PMID 20457567 PS:PMID 20460404 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Pathological Process PS:Tissue oncogenic PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee2be583-9513-45ea-bd1a-7bcbe55fbc76 NodeType: Pathway Notes: Existing hypotheses suggest several reasons for the observed overreaction including the increased mass or hypercontraction of asthmatic ASM cells and changes in the architecture of the epithelium and the ECM. Increased airway muscle mass and neovascularization result in remodeling of airway tissues. Hyperplasia or an increase in cellular proliferation, of ASM cells, is thought to be a more direct reason than hypertrophy for remodeling. Fibrosis, thickening of the airway basement membrane zone, increased deposition of ECM proteins, and other signs of tissue remodeling provoke further tissue injury. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ee2be583-9513-45ea-bd1a-7bcbe55fbc76 4_2_Airway smooth muscle cells proliferation and airway tissue remodeling uuid-ee2be583-9513-45ea-bd1a-7bcbe55fbc76 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee2be583-9513-45ea-bd1a-7bcbe55fbc76 PS:NodeType Pathway PS:Notes Existing hypotheses suggest several reasons for the observed overreaction including the increased mass or hypercontraction of asthmatic ASM cells and changes in the architecture of the epithelium and the ECM. Increased airway muscle mass and neovascularization result in remodeling of airway tissues. Hyperplasia or an increase in cellular proliferation, of ASM cells, is thought to be a more direct reason than hypertrophy for remodeling. Fibrosis, thickening of the airway basement membrane zone, increased deposition of ECM proteins, and other signs of tissue remodeling provoke further tissue injury. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee41033d-0019-41c9-b4ce-bf91b58fe346 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ee41033d-0019-41c9-b4ce-bf91b58fe346 T-Cell Receptor -> STAT Signaling uuid-ee41033d-0019-41c9-b4ce-bf91b58fe346 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee41033d-0019-41c9-b4ce-bf91b58fe346 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: ADAM33 association with asthma have been replicated in over 33 different population samples worldwide. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee434f7b-e858-42a5-90a9-fd7fc1d02c5d NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: ADAM33 association with asthma has been replicated in over 33 different population samples worldwide. ADAM33 protein expression is increased in epithelium, smooth muscle and mesenchymal cells of asthmatic patients compared to those of nonasthmatic controls. Most likely, ADAM33 acts as a cell surface sheddase to release growth factors and modify cell surface receptor expression. Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface. ADAM33 might be linked to the action of TGF-ß signaling. Outcome effects: TGF-ß signaling increases ADAM33 expression during the differentiation of the fibroblastic progenitors among the components of EMTU (epithelial mesenchymal tropic unit) to myofibroblasts. Mutated proteins: Mutated proteins are shown in white-out style. Organ: lung Organ_System: respiratory system PMID: 17640346 PMID: 22852121 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ee434f7b-e858-42a5-90a9-fd7fc1d02c5d ADAM33 Role in Asthma uuid-ee434f7b-e858-42a5-90a9-fd7fc1d02c5d PS:Description ADAM33 association with asthma have been replicated in over 33 different population samples worldwide. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee434f7b-e858-42a5-90a9-fd7fc1d02c5d PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: ADAM33 association with asthma has been replicated in over 33 different population samples worldwide. ADAM33 protein expression is increased in epithelium, smooth muscle and mesenchymal cells of asthmatic patients compared to those of nonasthmatic controls. Most likely, ADAM33 acts as a cell surface sheddase to release growth factors and modify cell surface receptor expression. Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface. ADAM33 might be linked to the action of TGF-ß signaling. Outcome effects: TGF-ß signaling increases ADAM33 expression during the differentiation of the fibroblastic progenitors among the components of EMTU (epithelial mesenchymal tropic unit) to myofibroblasts. Mutated proteins: Mutated proteins are shown in white-out style. PS:Organ lung PS:Organ_System respiratory system PS:PMID 17640346 PS:PMID 22852121 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee4c82e2-326c-4c80-900e-c2e800d34e99 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ee4c82e2-326c-4c80-900e-c2e800d34e99 phytochelatin biosynthesis template uuid-ee4c82e2-326c-4c80-900e-c2e800d34e99 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee4c82e2-326c-4c80-900e-c2e800d34e99 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee6865c2-971c-4b14-be17-c09a370c38d9 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-ee6865c2-971c-4b14-be17-c09a370c38d9 Sialophorin -> CTNNB/MYC/TP53 Signaling uuid-ee6865c2-971c-4b14-be17-c09a370c38d9 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ee6865c2-971c-4b14-be17-c09a370c38d9 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eea74433-041f-4da8-9ac2-fe448374ce45 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-eea74433-041f-4da8-9ac2-fe448374ce45 PR-toxin biosynthesis uuid-eea74433-041f-4da8-9ac2-fe448374ce45 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eea74433-041f-4da8-9ac2-fe448374ce45 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eedea31a-0dd2-45b9-a877-9962542f40b7 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-eedea31a-0dd2-45b9-a877-9962542f40b7 Selencompound Biosynthesis uuid-eedea31a-0dd2-45b9-a877-9962542f40b7 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eedea31a-0dd2-45b9-a877-9962542f40b7 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eee7e96e-aee9-45d9-83cd-707428827e53 NodeType: Pathway Organ: bronchus Organ: lung Organ_System: respiratory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-eee7e96e-aee9-45d9-83cd-707428827e53 Proteins Involved in Pulmonary Emphysema uuid-eee7e96e-aee9-45d9-83cd-707428827e53 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eee7e96e-aee9-45d9-83cd-707428827e53 PS:NodeType Pathway PS:Organ bronchus PS:Organ lung PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eef2af5b-a6be-4f5a-93c2-4940952285ab NodeType: Pathway Notes: The release of insulin from the pancreas is not continuous, but instead, it oscillates with a period of approximately 3–6 min. Pulsatile insulin secretion from individual beta cells is driven by the oscillation of intracellular Ca2 levels, cyclic pacing of cellular metabolism, and the intracellular ATP/ADP ratio. The process of insulin secretion, like any exocytosis event, involves secretory granule trafficking, tethering, docking, priming, and fusion with the cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-eef2af5b-a6be-4f5a-93c2-4940952285ab 1_2_Insulin synthesis and secretion: insulin secretion uuid-eef2af5b-a6be-4f5a-93c2-4940952285ab PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-eef2af5b-a6be-4f5a-93c2-4940952285ab PS:NodeType Pathway PS:Notes The release of insulin from the pancreas is not continuous, but instead, it oscillates with a period of approximately 3–6 min. Pulsatile insulin secretion from individual beta cells is driven by the oscillation of intracellular Ca2 levels, cyclic pacing of cellular metabolism, and the intracellular ATP/ADP ratio. The process of insulin secretion, like any exocytosis event, involves secretory granule trafficking, tethering, docking, priming, and fusion with the cell membrane. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef130d33-f28b-4e11-b06d-3d8d5d84f504 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ef130d33-f28b-4e11-b06d-3d8d5d84f504 myo-Inositol and glucuronate catabolism template uuid-ef130d33-f28b-4e11-b06d-3d8d5d84f504 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef130d33-f28b-4e11-b06d-3d8d5d84f504 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef2c6904-1389-4b48-a784-22f466986b7c NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-ef2c6904-1389-4b48-a784-22f466986b7c Hemophilia Mutated Genes uuid-ef2c6904-1389-4b48-a784-22f466986b7c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef2c6904-1389-4b48-a784-22f466986b7c PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef32d536-072d-4c57-98ab-dbff84fb7c24 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-ef32d536-072d-4c57-98ab-dbff84fb7c24 TGFB3-TGFBR1 Expression Targets uuid-ef32d536-072d-4c57-98ab-dbff84fb7c24 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef32d536-072d-4c57-98ab-dbff84fb7c24 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: macrophage Description: Cigarette smoke extract induces the premature senescence of lung fibroblasts in a CAV1-dependent manner. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef912730-cb38-4e24-bdb7-005f3f93f6ff NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Fibroblasts have an important role in repair and lung homeostasis. There is a reduced growth rate of lung fibroblasts in patients with COPD. Cigarette smoke extract induces the premature senescence of lung fibroblasts in a CAV1-dependent manner. Following oxidative stress, the CAV1 gene promoter is activated through p38 MAPK-SP1-dependent and NF-kB-dependent pathways. Outcome effects: The upregulation of CAV1 promotes cellular senescence by activating TP53/CDKN1A.The activation of TP53 by CAV1 occurs through different mechanisms: 1) interaction of CAV1 with MDM2 prevents the MDM2-dependent degradation of TP53; 2) inhibition of TXNRD1 through direct interaction with CAV1 activates TP53; 3) sequestration of PPP2CB into caveolar membranes activates ATM, which in turns phosphorylates and activates TP53. The activation of TP53 leads to the upregulation of CDKN1A, inhibition of cell proliferation, and induction of cellular senescence. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 16840774 PMID: 20157570 PMID: 22100852 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-ef912730-cb38-4e24-bdb7-005f3f93f6ff CAV1 Dependent Senescence of Lung Fibroblasts uuid-ef912730-cb38-4e24-bdb7-005f3f93f6ff PS:CellType macrophage PS:Description Cigarette smoke extract induces the premature senescence of lung fibroblasts in a CAV1-dependent manner. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ef912730-cb38-4e24-bdb7-005f3f93f6ff PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Fibroblasts have an important role in repair and lung homeostasis. There is a reduced growth rate of lung fibroblasts in patients with COPD. Cigarette smoke extract induces the premature senescence of lung fibroblasts in a CAV1-dependent manner. Following oxidative stress, the CAV1 gene promoter is activated through p38 MAPK-SP1-dependent and NF-kB-dependent pathways. Outcome effects: The upregulation of CAV1 promotes cellular senescence by activating TP53/CDKN1A.The activation of TP53 by CAV1 occurs through different mechanisms: 1) interaction of CAV1 with MDM2 prevents the MDM2-dependent degradation of TP53; 2) inhibition of TXNRD1 through direct interaction with CAV1 activates TP53; 3) sequestration of PPP2CB into caveolar membranes activates ATM, which in turns phosphorylates and activates TP53. The activation of TP53 leads to the upregulation of CDKN1A, inhibition of cell proliferation, and induction of cellular senescence. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 16840774 PS:PMID 20157570 PS:PMID 22100852 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-efb80e16-d038-418b-a727-ed7bd7e32732 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-efb80e16-d038-418b-a727-ed7bd7e32732 PTPRC -> STAT6 Expression Targets uuid-efb80e16-d038-418b-a727-ed7bd7e32732 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-efb80e16-d038-418b-a727-ed7bd7e32732 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-efcc1206-fd86-4dd3-8597-f26d529a6597 NodeType: Pathway Notes: Headnote: Testosterone acting through the androgen receptor (AR), is a potent inhibitor of AMH production. In the normal fetus and infant the lack of AR expression results in high AMH production by Sertoli cells. During childhood, there is a physiologic hypogonadotrophic state resulting in very low testosterone level; AMH level remains high, but somewhat lower probably due to the lack of FSH stimulus. In normal puberty testosterone prevails over FSH, resulting in AMH inhibition. Signaling description: Follicle-stimulation hormone (FSH) binds to the FSH receptor (FSHR) present on Sertoli cell membrane, and triggers protein G-mediated activation of adenylyl cyclase (ADCY), resulting in an increase of cAMP levels and activation of protein kinase A (PKA). PKA induces Sertoli cell proliferation and also nuclear translocation of transcription factors NFkB, SOX9, NR5A1, GATA4 and WT1 which bind to specific response elements on the AMH promoter, enhancing AMH expression. Organ: testis Organ_System: reproductive system PMID: 18713818 PMID: 21693691 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-efcc1206-fd86-4dd3-8597-f26d529a6597 Testicular AMH Production uuid-efcc1206-fd86-4dd3-8597-f26d529a6597 PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-efcc1206-fd86-4dd3-8597-f26d529a6597 PS:NodeType Pathway PS:Notes Headnote: Testosterone acting through the androgen receptor (AR), is a potent inhibitor of AMH production. In the normal fetus and infant the lack of AR expression results in high AMH production by Sertoli cells. During childhood, there is a physiologic hypogonadotrophic state resulting in very low testosterone level; AMH level remains high, but somewhat lower probably due to the lack of FSH stimulus. In normal puberty testosterone prevails over FSH, resulting in AMH inhibition. Signaling description: Follicle-stimulation hormone (FSH) binds to the FSH receptor (FSHR) present on Sertoli cell membrane, and triggers protein G-mediated activation of adenylyl cyclase (ADCY), resulting in an increase of cAMP levels and activation of protein kinase A (PKA). PKA induces Sertoli cell proliferation and also nuclear translocation of transcription factors NFkB, SOX9, NR5A1, GATA4 and WT1 which bind to specific response elements on the AMH promoter, enhancing AMH expression. PS:Organ testis PS:Organ_System reproductive system PS:PMID 18713818 PS:PMID 21693691 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Link PS:NodeType PS:Pathway_Author CellType: endothelial cell Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f001e5f6-7a18-4b08-a177-b30c187b6290 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-f001e5f6-7a18-4b08-a177-b30c187b6290 GRP,PTGFR+>myofibroblats uuid-f001e5f6-7a18-4b08-a177-b30c187b6290 PS:CellType endothelial cell PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f001e5f6-7a18-4b08-a177-b30c187b6290 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f02994ed-2fed-47fe-8a03-5f4c38ddf6b1 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f02994ed-2fed-47fe-8a03-5f4c38ddf6b1 Pentose transformations template uuid-f02994ed-2fed-47fe-8a03-5f4c38ddf6b1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f02994ed-2fed-47fe-8a03-5f4c38ddf6b1 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neural crest cell Description: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of ganglia in the colon. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f05c9624-8ef9-4f2b-b4a8-7992c8390c8f NodeType: Pathway Notes: Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells.Headnote: Mutations in the RET tyrosine kinase receptor gene are the most frequent genetic abnormities in HSCR. Normally, RET receptor triggers one of the most important signal transduction routes which is crucial for the migration, proliferation, and differentiation of the neural crest stem cells. In addition, GDNF, a ligand of RET, normally exerts a chemoattractive effect on enteric crest-derived precursors which migrate along a GDNF gradient. Furthermore, NRTN is a ligand in the GDNF family, which normally binds GFRA1 and RET to promote the projection and branching of some enteric neuron axons. Endothelin signaling is also usually necessary for normal neural crest stem cell migration. EDN3 is a secreted peptide expressed by gut mesenchyme that binds to the G-protein coupled receptor, EDNRB on migrating cells. ECE1 post-translationally modifies the immature form of EDN3 into the active form. Additionally, NRG1 signals through ERBB2 and ERBB3 receptors to regulate neural crest cell development. The role of modifier genes appears to be significant in HSCR. L1CAM is a modifier of RET and EDN3/EDNRB genes. A mutation of L1CAM in conjunction with a mutation in EDN3 or EDNRB significantly increases the severity of intestinal aganglionosis compared to a loss of EDN3 or EDNRB alone. NRG1 may also act as a modifier gene for RET. Individuals that possess a specific NRG1 haplotype have an increased risk of HSCR conferred by RET. Outcome effects: Mutations of RET, GDNF, NRTN, NRG1/3, EDN3, EDNRB, ECE1, and L1CAM lead to HSCR development. All of these mutations lead to loss of function and impairment of enteric neural crest cells to migrate and proliferate which leads to aganglionosis. Mutated genes: Mutated genes are shown in white-out style. Organ: colon Organ: intestine Organ_System: digestive system PMID: 15660316 PMID: 19215589 PMID: 22174542 PMID: 23043324 PMID: 23528997 PMID: 23639815 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f05c9624-8ef9-4f2b-b4a8-7992c8390c8f EDN, NRG, NRTN, and GDNF/RET Signaling in Hirschsprung Disease uuid-f05c9624-8ef9-4f2b-b4a8-7992c8390c8f PS:CellType neural crest cell PS:Description Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of ganglia in the colon. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f05c9624-8ef9-4f2b-b4a8-7992c8390c8f PS:NodeType Pathway PS:Notes Headnote: Hirschsprung disease (HSCR) is a congenital disorder that is characterized by intestinal dysmotility due to an absence of enteric ganglia along variable lengths of the intestinal tract, preferably in the colon. HSCR results from aberrant migration, proliferation, or differentiation of vagal neural crest cells.Headnote: Mutations in the RET tyrosine kinase receptor gene are the most frequent genetic abnormities in HSCR. Normally, RET receptor triggers one of the most important signal transduction routes which is crucial for the migration, proliferation, and differentiation of the neural crest stem cells. In addition, GDNF, a ligand of RET, normally exerts a chemoattractive effect on enteric crest-derived precursors which migrate along a GDNF gradient. Furthermore, NRTN is a ligand in the GDNF family, which normally binds GFRA1 and RET to promote the projection and branching of some enteric neuron axons. Endothelin signaling is also usually necessary for normal neural crest stem cell migration. EDN3 is a secreted peptide expressed by gut mesenchyme that binds to the G-protein coupled receptor, EDNRB on migrating cells. ECE1 post-translationally modifies the immature form of EDN3 into the active form. Additionally, NRG1 signals through ERBB2 and ERBB3 receptors to regulate neural crest cell development. The role of modifier genes appears to be significant in HSCR. L1CAM is a modifier of RET and EDN3/EDNRB genes. A mutation of L1CAM in conjunction with a mutation in EDN3 or EDNRB significantly increases the severity of intestinal aganglionosis compared to a loss of EDN3 or EDNRB alone. NRG1 may also act as a modifier gene for RET. Individuals that possess a specific NRG1 haplotype have an increased risk of HSCR conferred by RET. Outcome effects: Mutations of RET, GDNF, NRTN, NRG1/3, EDN3, EDNRB, ECE1, and L1CAM lead to HSCR development. All of these mutations lead to loss of function and impairment of enteric neural crest cells to migrate and proliferate which leads to aganglionosis. Mutated genes: Mutated genes are shown in white-out style. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 15660316 PS:PMID 19215589 PS:PMID 22174542 PS:PMID 23043324 PS:PMID 23528997 PS:PMID 23639815 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Hereditary Breast and Ovarian Cancer Syndrome (HBOC) is an autosomal dominant hereditary disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f06f24ba-d98a-47ee-aef1-c610e3ae0f9b NodeType: Pathway Notes: Headnote: Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant hereditary disorder characterized by an increased risk of breast and ovarian cancers, fallopian tube carcinoma, and papillary serous carcinoma of the peritoneum. Other signs include an early onset of cancer, increased chance of bilateral cancers, family history of male breast and prostate cancer, and an increased risk of colorectal, pancreas, and stomach cancer. Signaling description: Approximately 5-10% of breast and ovarian cancers are related to an inherited gene mutation. Of these cases, 84% of hereditary breast cancer and more than 90% of hereditary ovarian cancer are caused by germline mutations in the BRCA1 and/or BRCA2 genes. Rare cases of HBOC are due to a germline mutation in the DNA repair genes. The major pathogenic processes in HBOC include increased cell proliferation, block of apoptosis and chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with the DNA mismatch repair protein complex (MLH1/MSH2/MSH3/MSH6) and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2. Outcome effects: Mutations in these genes lead to block of DNA repair and a dysfunction in the DNA damage response. Furthermore, BRCA1 suppresses ESR1 and its coactivator, EP300, which participate in the formation of the chromatin remodeling complexes, KAT2B/MYSM1 and KAT2A/TADA2A/TADA3 and induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: breast Organ: ovary Organ_System: integumentary system Organ_System: reproductive system PMID: 17901820 PMID: 20494261 PMID: 22434244 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-f06f24ba-d98a-47ee-aef1-c610e3ae0f9b Hereditary Breast and Ovarian Cancer Syndrome uuid-f06f24ba-d98a-47ee-aef1-c610e3ae0f9b PS:CellType epithelial cell PS:Description Hereditary Breast and Ovarian Cancer Syndrome (HBOC) is an autosomal dominant hereditary disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f06f24ba-d98a-47ee-aef1-c610e3ae0f9b PS:NodeType Pathway PS:Notes Headnote: Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant hereditary disorder characterized by an increased risk of breast and ovarian cancers, fallopian tube carcinoma, and papillary serous carcinoma of the peritoneum. Other signs include an early onset of cancer, increased chance of bilateral cancers, family history of male breast and prostate cancer, and an increased risk of colorectal, pancreas, and stomach cancer. Signaling description: Approximately 5-10% of breast and ovarian cancers are related to an inherited gene mutation. Of these cases, 84% of hereditary breast cancer and more than 90% of hereditary ovarian cancer are caused by germline mutations in the BRCA1 and/or BRCA2 genes. Rare cases of HBOC are due to a germline mutation in the DNA repair genes. The major pathogenic processes in HBOC include increased cell proliferation, block of apoptosis and chromatin remodeling, dysfunction of DNA repair, and loss of cell differentiation. Normally, BRCA1 and BRCA2 play a central role in DNA repair, response to DNA damage, prevention of chromosome breaks, and genomic stability. BRCA1 interacts with the DNA mismatch repair protein complex (MLH1/MSH2/MSH3/MSH6) and genes that participate in homologous recombination and double-strand break repair such as BRCA2, RAD51, BRIP1, PALB2, MRN complex (RAD50/MRE11A/NBN), and PARP1/2. Outcome effects: Mutations in these genes lead to block of DNA repair and a dysfunction in the DNA damage response. Furthermore, BRCA1 suppresses ESR1 and its coactivator, EP300, which participate in the formation of the chromatin remodeling complexes, KAT2B/MYSM1 and KAT2A/TADA2A/TADA3 and induce the expression of downstream target genes that are involved in cell proliferation, differentiation, and apoptosis. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ breast PS:Organ ovary PS:Organ_System integumentary system PS:Organ_System reproductive system PS:PMID 17901820 PS:PMID 20494261 PS:PMID 22434244 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f0846fd1-403f-461b-9f9e-98c02dfa4e19 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f0846fd1-403f-461b-9f9e-98c02dfa4e19 CXCL2 Expression Targets uuid-f0846fd1-403f-461b-9f9e-98c02dfa4e19 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f0846fd1-403f-461b-9f9e-98c02dfa4e19 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f08e8487-e7df-44ae-ae0c-2ff2bc5db5d7 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f08e8487-e7df-44ae-ae0c-2ff2bc5db5d7 EphrinR Expression Targets uuid-f08e8487-e7df-44ae-ae0c-2ff2bc5db5d7 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f08e8487-e7df-44ae-ae0c-2ff2bc5db5d7 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f0fc406f-f159-4a69-b60c-ef69b72e8be2 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f0fc406f-f159-4a69-b60c-ef69b72e8be2 phytochromobilin biosynthesis template uuid-f0fc406f-f159-4a69-b60c-ef69b72e8be2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f0fc406f-f159-4a69-b60c-ef69b72e8be2 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: neural stem cell Description: Medulloblastoma arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead NodeType: Pathway Notes: Headnote: Medulloblastoma is a tumor that arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Signaling description: The central pathways involved in medulloblastoma pathogenesis are Sonic hedgehog homolog (SHH), WNT, Notch, ERBB, BMP, and IGF/PI3K signaling. In the SHH pathway, binding of SHH to its receptor (PTCH1) relieves inhibition on the downstream effector SMO and allows the release of GLI from inhibitory protein, SUFU. Inactivating mutations of PTCH1 and SUFU and/or activating mutations of SMO have been found in 15-30% of sporadic medulloblastomas. Additionally, germline mutations in PTCH1 cause Gorlin syndrome (basal cell nevus syndrome). Further, in WNT pathway, WNT3A ligand binds to its receptor (FZD) leading to the release of its downstream effector beta-catenin (CTNNB1) from an inhibitory complex that includes APC and AXIN1/2 proteins. Subsequent nuclear accumulation of CTNNB1 is thought to mediate its tumorigenic functions through the activation of TCF7/LEF1 transcription factors. Approximately 20% of sporadic medulloblastomas have mutations in APC, AXIN1/2, or CTNNB1. APC mutations are found in Turcot syndrome, which has a predisposition to medulloblastoma development. In addition, TP53 may be silenced due to mutations in medulloblastoma. TP53 mutations are typical for Li-Fraumeni syndrome, which has a high incidence of medulloblastoma development. Furthermore, Notch1/2/3 are overexpressed in a subset of medulloblastomas. Also, ERBB is important in regulating the development of the neuronal tissue. ERBB2 and ERBB4 are overexpressed in medulloblastoma and are able to activate the PI3K/AKT1 signaling. ERBB2 is overexpressed in 28% of medulloblastoma cases. Additionally, deletion mutants of ERBB4 have been found in childhood medulloblastomas. The IGF system also plays an important role in neuronal development and is involved in the development of brain tumors. Most medulloblastomas overexpress IGF1, IGF2, and IGF1R proteins. Outcome effects: The downstream targets of SHH are BMI1, CCND1/2, SOX2, NANOG, and others. Further, TCF7/LEF1 transcription factors activate MYC, OTX2, REST, and SOX4/11 target genes, which have established roles in cellular proliferation, block of differentiation, and inhibition of apoptosis (MYC, MYCN, and MNT may be overexpressed in medulloblastoma due to activating mutations/amplifications). Also, the up-regulation of Notch signaling activates the HES1/5 transcription factors, which negatively regulate the differentiation of neural progenitor cells. The, ERBB2 is thought to promote tumorigenesis by promoting the expression of pro-metastatic genes such as S100A4 and CCL5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 16290230 PMID: 18676356 PMID: 20414201 PMID: 20581434 PMID: 21243257 PMID: 22134537 PMID: 22430388 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead Medulloblastoma uuid-f116e34c-a226-42f4-84de-37e046996ead PS:CellType cancer cell PS:CellType neural stem cell PS:Description Medulloblastoma arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead PS:NodeType Pathway PS:Notes Headnote: Medulloblastoma is a tumor that arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Signaling description: The central pathways involved in medulloblastoma pathogenesis are Sonic hedgehog homolog (SHH), WNT, Notch, ERBB, BMP, and IGF/PI3K signaling. In the SHH pathway, binding of SHH to its receptor (PTCH1) relieves inhibition on the downstream effector SMO and allows the release of GLI from inhibitory protein, SUFU. Inactivating mutations of PTCH1 and SUFU and/or activating mutations of SMO have been found in 15-30% of sporadic medulloblastomas. Additionally, germline mutations in PTCH1 cause Gorlin syndrome (basal cell nevus syndrome). Further, in WNT pathway, WNT3A ligand binds to its receptor (FZD) leading to the release of its downstream effector beta-catenin (CTNNB1) from an inhibitory complex that includes APC and AXIN1/2 proteins. Subsequent nuclear accumulation of CTNNB1 is thought to mediate its tumorigenic functions through the activation of TCF7/LEF1 transcription factors. Approximately 20% of sporadic medulloblastomas have mutations in APC, AXIN1/2, or CTNNB1. APC mutations are found in Turcot syndrome, which has a predisposition to medulloblastoma development. In addition, TP53 may be silenced due to mutations in medulloblastoma. TP53 mutations are typical for Li-Fraumeni syndrome, which has a high incidence of medulloblastoma development. Furthermore, Notch1/2/3 are overexpressed in a subset of medulloblastomas. Also, ERBB is important in regulating the development of the neuronal tissue. ERBB2 and ERBB4 are overexpressed in medulloblastoma and are able to activate the PI3K/AKT1 signaling. ERBB2 is overexpressed in 28% of medulloblastoma cases. Additionally, deletion mutants of ERBB4 have been found in childhood medulloblastomas. The IGF system also plays an important role in neuronal development and is involved in the development of brain tumors. Most medulloblastomas overexpress IGF1, IGF2, and IGF1R proteins. Outcome effects: The downstream targets of SHH are BMI1, CCND1/2, SOX2, NANOG, and others. Further, TCF7/LEF1 transcription factors activate MYC, OTX2, REST, and SOX4/11 target genes, which have established roles in cellular proliferation, block of differentiation, and inhibition of apoptosis (MYC, MYCN, and MNT may be overexpressed in medulloblastoma due to activating mutations/amplifications). Also, the up-regulation of Notch signaling activates the HES1/5 transcription factors, which negatively regulate the differentiation of neural progenitor cells. The, ERBB2 is thought to promote tumorigenesis by promoting the expression of pro-metastatic genes such as S100A4 and CCL5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 16290230 PS:PMID 18676356 PS:PMID 20414201 PS:PMID 20581434 PS:PMID 21243257 PS:PMID 22134537 PS:PMID 22430388 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f11edfc4-376c-4817-bf5f-5d2fd236f059 NodeType: Pathway Organ_System: musculoskeletal system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-f11edfc4-376c-4817-bf5f-5d2fd236f059 Muscular Facioscapulohumeral Dystrophy Biomarkers uuid-f11edfc4-376c-4817-bf5f-5d2fd236f059 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f11edfc4-376c-4817-bf5f-5d2fd236f059 PS:NodeType Pathway PS:Organ_System musculoskeletal system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: One of the main epigenetic feature of the centenarian sample is its low DNA methylation density at CpG-poor promoters and tissue-specific genes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f17b76c2-03b9-4a8a-ac21-c09d8ab44e2c NodeType: Pathway Notes: Headnote: One of the main epigenetic feature of the centenarian sample is its low DNA methylation density at CpG-poor promoters and tissue-specific genes. DNA methylation age lies in the Horvath's epigenetic clock method which allows comparing the ages of different areas of the human body using the same aging clock. Non-LTR type retrotransposons (which includes LINEs (long interspersed elements) and SINEs (short interspersed elements)) are sequences of DNA that can move within the genome. Retrotransposons that inserts itself into genome can disable genes and destabilize the genome. Outcome effects: Methylated genes and histones and mobile elements alter normal transcription, lead to mutations accumulation and in the whole trigger cell senescence. Organ: generic Organ_System: generic PMID: 22771540 PMID: 26378584 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-f17b76c2-03b9-4a8a-ac21-c09d8ab44e2c Epigenetic Alterations Triggers Genomic Instability uuid-f17b76c2-03b9-4a8a-ac21-c09d8ab44e2c PS:CellType generic PS:Description One of the main epigenetic feature of the centenarian sample is its low DNA methylation density at CpG-poor promoters and tissue-specific genes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f17b76c2-03b9-4a8a-ac21-c09d8ab44e2c PS:NodeType Pathway PS:Notes Headnote: One of the main epigenetic feature of the centenarian sample is its low DNA methylation density at CpG-poor promoters and tissue-specific genes. DNA methylation age lies in the Horvath's epigenetic clock method which allows comparing the ages of different areas of the human body using the same aging clock. Non-LTR type retrotransposons (which includes LINEs (long interspersed elements) and SINEs (short interspersed elements)) are sequences of DNA that can move within the genome. Retrotransposons that inserts itself into genome can disable genes and destabilize the genome. Outcome effects: Methylated genes and histones and mobile elements alter normal transcription, lead to mutations accumulation and in the whole trigger cell senescence. PS:Organ generic PS:Organ_System generic PS:PMID 22771540 PS:PMID 26378584 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1810da8-aa15-453b-9fe1-215875507a63 NodeType: Pathway Organ: bone Organ: joint Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-f1810da8-aa15-453b-9fe1-215875507a63 Genes with Mutations Associated with Psoriatic Arthritis uuid-f1810da8-aa15-453b-9fe1-215875507a63 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1810da8-aa15-453b-9fe1-215875507a63 PS:NodeType Pathway PS:Organ bone PS:Organ joint PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1847cc8-f93c-4c5c-9b6a-01918d69eff4 NodeType: Pathway Notes: Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). RHO activates molecules of the G-protein transducin by catalyzing GDP/GTP exchange on the transducin alpha-subunit, G-alpha-t. Further, G-alpha-t-GTP separates from the transducing beta/gamma-subunits and binds to the gamma-subunit of its effector, cGMP phosphodiesterase 6 (PDE6), which releases the subunit's inhibitory effect on the catalytic alpha- and beta-subunits of PDE6. Activated PDE6 rapidly hydrolyzes cGMP, thereby reducing its concentration in the cytoplasm and causes closure of cGMP-gated cation channels (CNGA1 and CNGB1) in the plasma membrane. The level of Ca2+ decreases in light because its influx is reduced when cGMP-gated channels close, whereas Ca2+ efflux via the Ca2+/K+/Na+ exchanger continues. Outcome effects: The resulting closure of the cGMP-sensitive cation channels blocks the dark current and hyperpolarizes the photoreceptor membrane. The rate of glutamate release from the synapses is reduced, thus converting and relaying the light signal to the postsynaptic neurons as electrical signal. The reduction of intracellular Ca2+ is sensed by several different Ca2+-binding proteins including guanylate cyclase activators 1A/B (GUCA1A and GUCA1B), which stimulate cGMP synthesis by GUCY2D and GUCY2F when Ca2+ decreases. The reduction in intracellular Ca2+ also affects other Ca+-binding proteins including recoverin (RCVRN). Normally, RCVRN inhibits the ability of G protein-coupled receptor kinase (GRK1) to phosphorylate and inactivate RHO. When the level of Ca2+ decreases, this inhibition fails to occur and RHO is inactivated. Highlighted proteins: Entities with decreased level are highlighted in blue. Organ: Retina Organ: eye Organ_System: sensory system PMID: 12596926 PMID: 22074925 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Biological Process urn:agi-pathway:uuid-f1847cc8-f93c-4c5c-9b6a-01918d69eff4 RHO Signaling (Light) uuid-f1847cc8-f93c-4c5c-9b6a-01918d69eff4 PS:Description Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1847cc8-f93c-4c5c-9b6a-01918d69eff4 PS:NodeType Pathway PS:Notes Headnote: Phototransduction is the conversion of light to electrical nerve signals in the outer segments of photoreceptors. Signaling description: Phototransduction begins when a photon causes isomerization of the chromophore 11-cis-retinal into all-trans-retinal, which induces a rapid conformational change and activation of rhodopsin (RHO). RHO activates molecules of the G-protein transducin by catalyzing GDP/GTP exchange on the transducin alpha-subunit, G-alpha-t. Further, G-alpha-t-GTP separates from the transducing beta/gamma-subunits and binds to the gamma-subunit of its effector, cGMP phosphodiesterase 6 (PDE6), which releases the subunit's inhibitory effect on the catalytic alpha- and beta-subunits of PDE6. Activated PDE6 rapidly hydrolyzes cGMP, thereby reducing its concentration in the cytoplasm and causes closure of cGMP-gated cation channels (CNGA1 and CNGB1) in the plasma membrane. The level of Ca2+ decreases in light because its influx is reduced when cGMP-gated channels close, whereas Ca2+ efflux via the Ca2+/K+/Na+ exchanger continues. Outcome effects: The resulting closure of the cGMP-sensitive cation channels blocks the dark current and hyperpolarizes the photoreceptor membrane. The rate of glutamate release from the synapses is reduced, thus converting and relaying the light signal to the postsynaptic neurons as electrical signal. The reduction of intracellular Ca2+ is sensed by several different Ca2+-binding proteins including guanylate cyclase activators 1A/B (GUCA1A and GUCA1B), which stimulate cGMP synthesis by GUCY2D and GUCY2F when Ca2+ decreases. The reduction in intracellular Ca2+ also affects other Ca+-binding proteins including recoverin (RCVRN). Normally, RCVRN inhibits the ability of G protein-coupled receptor kinase (GRK1) to phosphorylate and inactivate RHO. When the level of Ca2+ decreases, this inhibition fails to occur and RHO is inactivated. Highlighted proteins: Entities with decreased level are highlighted in blue. PS:Organ Retina PS:Organ eye PS:Organ_System sensory system PS:PMID 12596926 PS:PMID 22074925 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neutrophil Description: Neutrophils can move towards a chemoattractant gradient both in the bloodstream and by transmigration through the blood vessel wall. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f193b4ee-1b19-4421-8168-981c5ffd9757 NodeType: Pathway Notes: Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Neutrophils can move towards a chemoattractant gradient both in the bloodstream and by transmigration through the blood vessel wall. Chemoattractants are soluble molecules that guide cell movement; moving in the direction of increasing their concentration in a process called chemotaxis. CXCL12 is the chemoattractant that facilitates the exit of neutrophils to the blood marrow niche and their entrance into the bloodstream. It is possible that CXCL12-related signaling leads to changes in the binding affinity state of ITGA4 and significantly increases VCAM1 binding by ITGA4, although the details of this mechanism are poorly understood. Chemoattractants for neutrophils in the bloodstream are proinflammatory cytokines and molecules associated with cell degradation in the focus of inflammation. Non-specific chemoattractants for all leukocytes are fMLP, polypeptides (C5a), lipids (LTB4), and PF4. IL8 is the principal factor in neutrophil delivery. Other chemokines that are specific for neutrophils include PPBP, CXCL5, CXCL2, and CXCL6. Outcome effects: Chemoattractant receptors mediate the process of chemotaxis mainly through the signaling of G-protein related actin reorganization. G-protein related signaling activates Rho family GTPases including RAC1, RAC2, RHOA, and CDC42, which cause the actin related protein 2/3 complex to promote actin polymerization. Actin cytoskeleton remodeling is required for the first phase of exocytosis, which is the binding of granules to the plasma membrane. RAC1 and RAC2 differentially regulate actin polymerization in neutrophils through uncapping and actin related protein 2/3 complex/CFL1, respectively. An increase in the level of calcium ions is also required for cytoskeleton activation during chemotaxis. The synthesis of arachidonic acid derivatives, as well as the modulation of myosin proteins, stimulates the motility of membranes and cellular migration. The general mechanism of neutrophil degranulation is also associated with cytoskeleton reorganization. However, degranulation does not occur spontaneously during chemotaxis, but is dependent on the combination, pattern of interactions, and concentrations of regulating factors. This also applies to another function of neutrophils, which is the synthesis of reactive oxygen species (ROS). Organ: generic Organ_System: hematological system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-f193b4ee-1b19-4421-8168-981c5ffd9757 Neutrophil Chemotaxis uuid-f193b4ee-1b19-4421-8168-981c5ffd9757 PS:CellType neutrophil PS:Description Neutrophils can move towards a chemoattractant gradient both in the bloodstream and by transmigration through the blood vessel wall. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f193b4ee-1b19-4421-8168-981c5ffd9757 PS:NodeType Pathway PS:Notes Headnote: Neutrophils belong to a subtype of leukocytes that contain granules known as granulocytes. Neutrophils, the largest class of granulocytes, are major antibacterial cellular agents in inflammation since they combine the functions of granulocytes and phagocytes. Neutrophils comprise more than 50% of circulating leukocytes and more than 90% of circulating phagocytes. Signaling description: Neutrophils can move towards a chemoattractant gradient both in the bloodstream and by transmigration through the blood vessel wall. Chemoattractants are soluble molecules that guide cell movement; moving in the direction of increasing their concentration in a process called chemotaxis. CXCL12 is the chemoattractant that facilitates the exit of neutrophils to the blood marrow niche and their entrance into the bloodstream. It is possible that CXCL12-related signaling leads to changes in the binding affinity state of ITGA4 and significantly increases VCAM1 binding by ITGA4, although the details of this mechanism are poorly understood. Chemoattractants for neutrophils in the bloodstream are proinflammatory cytokines and molecules associated with cell degradation in the focus of inflammation. Non-specific chemoattractants for all leukocytes are fMLP, polypeptides (C5a), lipids (LTB4), and PF4. IL8 is the principal factor in neutrophil delivery. Other chemokines that are specific for neutrophils include PPBP, CXCL5, CXCL2, and CXCL6. Outcome effects: Chemoattractant receptors mediate the process of chemotaxis mainly through the signaling of G-protein related actin reorganization. G-protein related signaling activates Rho family GTPases including RAC1, RAC2, RHOA, and CDC42, which cause the actin related protein 2/3 complex to promote actin polymerization. Actin cytoskeleton remodeling is required for the first phase of exocytosis, which is the binding of granules to the plasma membrane. RAC1 and RAC2 differentially regulate actin polymerization in neutrophils through uncapping and actin related protein 2/3 complex/CFL1, respectively. An increase in the level of calcium ions is also required for cytoskeleton activation during chemotaxis. The synthesis of arachidonic acid derivatives, as well as the modulation of myosin proteins, stimulates the motility of membranes and cellular migration. The general mechanism of neutrophil degranulation is also associated with cytoskeleton reorganization. However, degranulation does not occur spontaneously during chemotaxis, but is dependent on the combination, pattern of interactions, and concentrations of regulating factors. This also applies to another function of neutrophils, which is the synthesis of reactive oxygen species (ROS). PS:Organ generic PS:Organ_System hematological system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f197628e-3e89-4080-b2bf-02600c22d752 NodeType: Pathway Organ: kidney Organ: lung Organ: skin Organ_System: respiratory system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f197628e-3e89-4080-b2bf-02600c22d752 Proteins with Altered Expression in Cystic Fibrosis uuid-f197628e-3e89-4080-b2bf-02600c22d752 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f197628e-3e89-4080-b2bf-02600c22d752 PS:NodeType Pathway PS:Organ kidney PS:Organ lung PS:Organ skin PS:Organ_System respiratory system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell Description: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder, is characterized by mucocutaneous pigmentations, gastrointestinal polyposis, and an increased risk of cancers. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1a35eca-5871-4446-9029-c42475ab0e8e NodeType: Pathway Notes: Headnote: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder which is characterized by mucocutaneous pigmentations, gastrointestinal polyposis, and an increased risk of cancers. PJS is caused by germline mutations in STK11 tumor suppressor gene which results in the development of hamartomatous polyps at an early age which may cause various complications including abdominal pain, anemia, and acute intestinal obstruction. In addition, patients have an increased risk of developing various cancers including gastrointestinal, pancreatic, lung, breast, uterine, ovarian, and testicular. The pathogenesis of hamartomas and carcinomas is unclear. Signaling description: STK11 is a master kinase involved in the regulation of multiple signaling pathways. STK11 forms a heterotrimeric complex with psuedokinase STRADA and scaffold protein CAB39. These proteins regulate STK11 stability, kinase activity, and subcellular localization. The physiological function of this protein complex is to regulate multiple biological pathways involving TP53-dependent and independent apoptosis, cell cycle and proliferation, chromatin remodeling, angiogenesis, energy metabolism, and control of cell polarity. Normally, STK11 phosphorylates and activates PTEN, AMPK, TP53, and SMAD4. PTEN negatively regulates intracellular levels of PIP3 and functions as a tumor suppressor by negatively regulating AKT1 signaling pathway. AMPK is a heterotrimer consisting of an alpha catalytic subunit (PRKAA1), two non-catalytic beta (PRKAB1), and gamma (PRKAG1) subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. Outcome effects: Activated AKT1 phosphorylates and activates MTOR which is a central regulator of cellular glucose and lipid metabolism, growth, and survival. In addition, AKT1 inhibits FOXO1 and FOXO3 which are involved in cell differentiation and apoptosis. AKT1 directly phosphorylates TSC1 and TSC2 to inactivate TSC1/2 tumor suppressor complex. TSC1/2 complex inactivates the small GTPase RHEB which activates MTOR via RPTOR. TSC2 interacts with SMAD2 and SMAD3 which bind to SMAD4 and forms a heterotrimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in cell functions. At the same time, activated AMPK stimulates TSC1/2 complex, through AMPK-mediated TSC2 phosphorylation, and thus inhibits MTOR signaling. Further, STK11 suppresses tumor growth by inhibiting STAT3 which acts as a transcription activator and plays a key role in many cellular processes such as cell proliferation, differentiation, cell cycle, apoptosis, and vascularization. STK11 interacts with SMARCA4, an essential component of chromatin remodeling complex. Germline mutations of STK11 lead to disruption of cell cycle, differentiation, and metabolism in addition to redundant cell proliferation, block of apoptosis, and chromatin remodeling which result in tumorigenesis. Mutated genes: Mutated gene is shown in white-out style. Organ: pancreas Organ_System: digestive system Organ_System: integumentary system Organ_System: reproductive system PMID: 19916169 PMID: 21272562 PMID: 23287572 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-f1a35eca-5871-4446-9029-c42475ab0e8e Peutz-Jeghers Syndrome uuid-f1a35eca-5871-4446-9029-c42475ab0e8e PS:CellType epithelial cell PS:Description Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder, is characterized by mucocutaneous pigmentations, gastrointestinal polyposis, and an increased risk of cancers. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1a35eca-5871-4446-9029-c42475ab0e8e PS:NodeType Pathway PS:Notes Headnote: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder which is characterized by mucocutaneous pigmentations, gastrointestinal polyposis, and an increased risk of cancers. PJS is caused by germline mutations in STK11 tumor suppressor gene which results in the development of hamartomatous polyps at an early age which may cause various complications including abdominal pain, anemia, and acute intestinal obstruction. In addition, patients have an increased risk of developing various cancers including gastrointestinal, pancreatic, lung, breast, uterine, ovarian, and testicular. The pathogenesis of hamartomas and carcinomas is unclear. Signaling description: STK11 is a master kinase involved in the regulation of multiple signaling pathways. STK11 forms a heterotrimeric complex with psuedokinase STRADA and scaffold protein CAB39. These proteins regulate STK11 stability, kinase activity, and subcellular localization. The physiological function of this protein complex is to regulate multiple biological pathways involving TP53-dependent and independent apoptosis, cell cycle and proliferation, chromatin remodeling, angiogenesis, energy metabolism, and control of cell polarity. Normally, STK11 phosphorylates and activates PTEN, AMPK, TP53, and SMAD4. PTEN negatively regulates intracellular levels of PIP3 and functions as a tumor suppressor by negatively regulating AKT1 signaling pathway. AMPK is a heterotrimer consisting of an alpha catalytic subunit (PRKAA1), two non-catalytic beta (PRKAB1), and gamma (PRKAG1) subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. Outcome effects: Activated AKT1 phosphorylates and activates MTOR which is a central regulator of cellular glucose and lipid metabolism, growth, and survival. In addition, AKT1 inhibits FOXO1 and FOXO3 which are involved in cell differentiation and apoptosis. AKT1 directly phosphorylates TSC1 and TSC2 to inactivate TSC1/2 tumor suppressor complex. TSC1/2 complex inactivates the small GTPase RHEB which activates MTOR via RPTOR. TSC2 interacts with SMAD2 and SMAD3 which bind to SMAD4 and forms a heterotrimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in cell functions. At the same time, activated AMPK stimulates TSC1/2 complex, through AMPK-mediated TSC2 phosphorylation, and thus inhibits MTOR signaling. Further, STK11 suppresses tumor growth by inhibiting STAT3 which acts as a transcription activator and plays a key role in many cellular processes such as cell proliferation, differentiation, cell cycle, apoptosis, and vascularization. STK11 interacts with SMARCA4, an essential component of chromatin remodeling complex. Germline mutations of STK11 lead to disruption of cell cycle, differentiation, and metabolism in addition to redundant cell proliferation, block of apoptosis, and chromatin remodeling which result in tumorigenesis. Mutated genes: Mutated gene is shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:Organ_System integumentary system PS:Organ_System reproductive system PS:PMID 19916169 PS:PMID 21272562 PS:PMID 23287572 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1a79d86-24fc-4642-80f4-107fbaf63091 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f1a79d86-24fc-4642-80f4-107fbaf63091 CCL8 Expression Targets uuid-f1a79d86-24fc-4642-80f4-107fbaf63091 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1a79d86-24fc-4642-80f4-107fbaf63091 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: Prostate cancer (PC) is the most common cancer in men. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1b03225-52d0-4eff-8c11-063df8d05611 NodeType: Pathway Notes: Prostate cancer (PC) is the most common cancer in men. TRPM8 mediates Ca2 and Na2 influx. TRPM8 expression in PC tissue was significantly greater than that in nonmalignant tissue. Organ: prostate Organ_System: reproductive system PMID: 17510704 PMID: 19339216 PMID: 20730379 PMID: 21052713 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-f1b03225-52d0-4eff-8c11-063df8d05611 TRPM8 Effects in Prostate Cancer (Hypothesis) uuid-f1b03225-52d0-4eff-8c11-063df8d05611 PS:CellType cancer cell PS:CellType epithelial cell PS:Description Prostate cancer (PC) is the most common cancer in men. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1b03225-52d0-4eff-8c11-063df8d05611 PS:NodeType Pathway PS:Notes Prostate cancer (PC) is the most common cancer in men. TRPM8 mediates Ca2 and Na2 influx. TRPM8 expression in PC tissue was significantly greater than that in nonmalignant tissue. PS:Organ prostate PS:Organ_System reproductive system PS:PMID 17510704 PS:PMID 19339216 PS:PMID 20730379 PS:PMID 21052713 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue epithelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1ef4c29-883d-4fea-b5bb-ab01242a98ed NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-f1ef4c29-883d-4fea-b5bb-ab01242a98ed IL13R -> STAT Signaling uuid-f1ef4c29-883d-4fea-b5bb-ab01242a98ed PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1ef4c29-883d-4fea-b5bb-ab01242a98ed PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1fb3d35-5a5a-44d4-8f1d-65f98f9eac1e NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f1fb3d35-5a5a-44d4-8f1d-65f98f9eac1e SARS non-canonical replicase (NSP7) inhibitors uuid-f1fb3d35-5a5a-44d4-8f1d-65f98f9eac1e PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f1fb3d35-5a5a-44d4-8f1d-65f98f9eac1e PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: kidney tubule cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f204eb29-e3ef-409b-a2dd-e2d995f4f310 NodeType: Pathway Notes: Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis, renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications. It is caused by mutations in the carbonic anhydrase II (CA2) gene. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: kidney Organ_System: urinary tract PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-f204eb29-e3ef-409b-a2dd-e2d995f4f310 3_Renal tubular acidosis associated with carbonic anhydrase II mutation and osteopetrosis uuid-f204eb29-e3ef-409b-a2dd-e2d995f4f310 PS:CellType kidney tubule cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f204eb29-e3ef-409b-a2dd-e2d995f4f310 PS:NodeType Pathway PS:Notes Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis, renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications. It is caused by mutations in the carbonic anhydrase II (CA2) gene. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: keratinocyte Description: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays an important role in a variety of cellular events including inflammatory reaction, immune response and cellular proliferation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2056c7a-8b1b-4a63-b97c-2624c8a82fa2 NodeType: Pathway Notes: Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Interleukin-6 (IL-6) is a pleiotropic cytokine that has an important role in a variety of cellular events including inflammatory reaction, immune response and cellular proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ: ear Organ_System: sensory system PMID: 24321752 PMID: 24551293 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-f2056c7a-8b1b-4a63-b97c-2624c8a82fa2 IL6/JAK/STAT3 Signaling in Cholesteatoma uuid-f2056c7a-8b1b-4a63-b97c-2624c8a82fa2 PS:CellType cancer cell PS:CellType keratinocyte PS:Description Interleukin-6 (IL-6) is a pleiotropic cytokine that plays an important role in a variety of cellular events including inflammatory reaction, immune response and cellular proliferation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2056c7a-8b1b-4a63-b97c-2624c8a82fa2 PS:NodeType Pathway PS:Notes Headnote: Cholesteatoma is a destructive disease characterized by the progressive expansion of keratinizing squamous epithelium in the middle ear and mastoid and chronic inflammatory reaction of the subepithelial connective tissue, which gradually expands and causes serious complications due to destruction of nearby bony structures. Signaling description: Interleukin-6 (IL-6) is a pleiotropic cytokine that has an important role in a variety of cellular events including inflammatory reaction, immune response and cellular proliferation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ ear PS:Organ_System sensory system PS:PMID 24321752 PS:PMID 24551293 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f214cba8-0a46-4101-b0fe-210ecb026651 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f214cba8-0a46-4101-b0fe-210ecb026651 Xylan biosynthesis template uuid-f214cba8-0a46-4101-b0fe-210ecb026651 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f214cba8-0a46-4101-b0fe-210ecb026651 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: Osteoclast activation occurs in postmenopausal osteoporosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f22609c6-f93e-4594-ac08-cab691f19d62 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Following the menopause, risk of bone loss is increased due to lower levels of estrogen. Postmenopausal osteoporosis is characterized by osteoclast activation. Signaling description: In postmenopause, the deficiency of estrogens leads to insufficient TNFRSF11B expression. Normally, estrogens prevent bone loss by blocking the production of proinflammatory cytokines such as TNF by bone marrow and bone cells. Therefore, the lack of estrogens in postmenopausal women promotes a decrease of TNFRSF11B, and increase of the TNFSF11/TNFRSF11B ratio. TNFSF11 also known as RANKL, initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. TNF affects the same pathways through its receptors (TNFRSF1A and TNFRSF1B). In mature osteoclasts, the signaling causes CTSK and MMP13 expression. Outcome effects: The signaling from TNFSF11 involves TRAF6, TRAF2, and TRAF5 proteins, affects NF-kB and MAPK pathways and eventually triggers osteoclast activation (bone resorption). In addition, TNFSF11 promotes osteoclast survival through the AKT1 pathway. Activation of CTSK and MMP13 expression leads to bone resorption by osteoclasts. Normally, calcitonins inhibit osteoclast-mediated bone resorption through calcitonin receptors (CALCR). Polymorphisms in CALCR may contribute to the pathology. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 11086020 PMID: 16322775 PMID: 20890027 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f22609c6-f93e-4594-ac08-cab691f19d62 Osteoclast Activation in Postmenopause uuid-f22609c6-f93e-4594-ac08-cab691f19d62 PS:CellType osteoclast PS:Description Osteoclast activation occurs in postmenopausal osteoporosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f22609c6-f93e-4594-ac08-cab691f19d62 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Following the menopause, risk of bone loss is increased due to lower levels of estrogen. Postmenopausal osteoporosis is characterized by osteoclast activation. Signaling description: In postmenopause, the deficiency of estrogens leads to insufficient TNFRSF11B expression. Normally, estrogens prevent bone loss by blocking the production of proinflammatory cytokines such as TNF by bone marrow and bone cells. Therefore, the lack of estrogens in postmenopausal women promotes a decrease of TNFRSF11B, and increase of the TNFSF11/TNFRSF11B ratio. TNFSF11 also known as RANKL, initiates osteoclast differentiation by binding to TNFRSF11A receptor on the osteoclast surface. TNF affects the same pathways through its receptors (TNFRSF1A and TNFRSF1B). In mature osteoclasts, the signaling causes CTSK and MMP13 expression. Outcome effects: The signaling from TNFSF11 involves TRAF6, TRAF2, and TRAF5 proteins, affects NF-kB and MAPK pathways and eventually triggers osteoclast activation (bone resorption). In addition, TNFSF11 promotes osteoclast survival through the AKT1 pathway. Activation of CTSK and MMP13 expression leads to bone resorption by osteoclasts. Normally, calcitonins inhibit osteoclast-mediated bone resorption through calcitonin receptors (CALCR). Polymorphisms in CALCR may contribute to the pathology. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11086020 PS:PMID 16322775 PS:PMID 20890027 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: melanocyte Description: Vitiligo is a common skin disorder characterized by the acquired loss of constitutional pigmentation manifesting as white macules caused by a loss of functioning epidermal melanocytes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f22883b8-99d8-481a-9712-459b9e293ec5 NodeType: Pathway Notes: Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: The actual mechanism of autoimmune-mediated melanocyte apoptosis in vitiligo has not been definitively determined. Vitiligo develops as result of interplay between genetic and environmental factors. Outcome effects: Dysregulation of the immune response in vitiligo makes the melanocyte an autoimmune target. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with decreased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 11121127 PMID: 11886510 PMID: 18548110 PMID: 20958268 PMID: 23226069 PMID: 23425123 PMID: 23539007 PMID: 23668538 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-f22883b8-99d8-481a-9712-459b9e293ec5 Vitiligo uuid-f22883b8-99d8-481a-9712-459b9e293ec5 PS:CellType melanocyte PS:Description Vitiligo is a common skin disorder characterized by the acquired loss of constitutional pigmentation manifesting as white macules caused by a loss of functioning epidermal melanocytes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f22883b8-99d8-481a-9712-459b9e293ec5 PS:NodeType Pathway PS:Notes Headnote: Vitiligo is a chronic pigmentary skin disorder in which patches of skin lose their pigmentation. The disease may also involve mucous membranes and normally affects both sides of the body. Vitiligo is thought to be a disease with autoimmune origin that occurs due to a genetic predisposition. The autoimmune process in vitiligo leads to the destruction of melanocytes in the skin which creates the hypopigmented lesions. Signaling description: The actual mechanism of autoimmune-mediated melanocyte apoptosis in vitiligo has not been definitively determined. Vitiligo develops as result of interplay between genetic and environmental factors. Outcome effects: Dysregulation of the immune response in vitiligo makes the melanocyte an autoimmune target. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with decreased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 11121127 PS:PMID 11886510 PS:PMID 18548110 PS:PMID 20958268 PS:PMID 23226069 PS:PMID 23425123 PS:PMID 23539007 PS:PMID 23668538 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f23a418a-5b08-4355-ad18-ada2a00af45c NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f23a418a-5b08-4355-ad18-ada2a00af45c Genes with Mutations Associated with Glaucoma uuid-f23a418a-5b08-4355-ad18-ada2a00af45c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f23a418a-5b08-4355-ad18-ada2a00af45c PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f244f343-bbf0-46c7-97f8-0d72c112f897 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: thyroid gland Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-f244f343-bbf0-46c7-97f8-0d72c112f897 Elevated Receptors -> Expression Targets in Thyroid Gland uuid-f244f343-bbf0-46c7-97f8-0d72c112f897 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f244f343-bbf0-46c7-97f8-0d72c112f897 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ thyroid gland PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f25d5df1-9b62-4758-9566-bd2e48d82f9a NodeType: Pathway Organ_System: hematological system Organ_System: lymphatic system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-f25d5df1-9b62-4758-9566-bd2e48d82f9a Genes with Mutations Associated with Systemic Scleroderma uuid-f25d5df1-9b62-4758-9566-bd2e48d82f9a PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f25d5df1-9b62-4758-9566-bd2e48d82f9a PS:NodeType Pathway PS:Organ_System hematological system PS:Organ_System lymphatic system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f28e9ee5-fe34-41dc-b00c-1dc470b5e9da NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f28e9ee5-fe34-41dc-b00c-1dc470b5e9da Fatty acid elongation (yeast cytoplasm) template uuid-f28e9ee5-fe34-41dc-b00c-1dc470b5e9da PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f28e9ee5-fe34-41dc-b00c-1dc470b5e9da PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f29b312b-67cf-4298-9c49-4f99c863f79b NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-f29b312b-67cf-4298-9c49-4f99c863f79b HTR3A -> Cation Transport uuid-f29b312b-67cf-4298-9c49-4f99c863f79b PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f29b312b-67cf-4298-9c49-4f99c863f79b PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2c4c2e2-a89a-460a-8752-0cce795db5f9 NodeType: Pathway PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Protein Modification urn:agi-pathway:uuid-f2c4c2e2-a89a-460a-8752-0cce795db5f9 H2AT120, H2AK119 and H3K4 Interplay in Epigenetic Regulation uuid-f2c4c2e2-a89a-460a-8752-0cce795db5f9 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2c4c2e2-a89a-460a-8752-0cce795db5f9 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Protein Modification PS:Description PS:Link PS:NodeType PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2d01af1-7bc9-4d30-8bf2-d146967f0a09 NodeType: Pathway Organ_System: endocrine system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f2d01af1-7bc9-4d30-8bf2-d146967f0a09 Proteins Involved in Diabetes Mellitus Type 1 uuid-f2d01af1-7bc9-4d30-8bf2-d146967f0a09 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2d01af1-7bc9-4d30-8bf2-d146967f0a09 PS:NodeType Pathway PS:Organ_System endocrine system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2e5c254-fb66-459e-b7a2-3f4029368c03 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f2e5c254-fb66-459e-b7a2-3f4029368c03 PAF (plasmanyl, alkyl) phospholipid biosynthesis template uuid-f2e5c254-fb66-459e-b7a2-3f4029368c03 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2e5c254-fb66-459e-b7a2-3f4029368c03 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2ed38d4-bfdf-4375-9d80-7835582d1009 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-f2ed38d4-bfdf-4375-9d80-7835582d1009 ADCY-PKA-|Myofibroblasts in corneal stroma uuid-f2ed38d4-bfdf-4375-9d80-7835582d1009 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2ed38d4-bfdf-4375-9d80-7835582d1009 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: The airway and alveoli are lined with epithelial cells that not only provide a barrier between the host and the environment but are also an important source for the production of mediators. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2fd4361-fd14-432b-a19d-0474f641d467 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: Cigarette smoke can activate epithelial cells to secrete a variety of inflammatory mediators and proteases including TNF, TGFB1, IL1B, IL8, MMP1, MMP2, and MMP14. Cigarette smoke has been shown to induce intracellular signaling via the TLR4 and AGER receptors. Cigarette smoke extract exposure leads to EGR1 elevation by activating the MAPK1/3 pathway. The upregulated EGR1 can activate transcription of its target gene GGPS1, which is responsible for the reactivation of the MAPK1/3 pathway via Ras forming a vicious circle. EGR1 is a genetic susceptibility factor that can control the production of MMP2 and MMP14 to overwhelm the anti-protease systems and lead to the destruction of alveolar septal architecture. In addition, the expression of AGER receptor, which binds HMGB1, is elevated in airway epithelium in COPD patients. Extracellular ATP causes the release of IL8 and IL6 via activation of P2YR-subtypes from airway epithelial cells. SIRT1 is downregulated in lung cells from COPD patients as a result of post-translational oxidative modification by cigarette smoke-derived components. Outcome effects: SIRT1 plays an important role in the inflammatory response, regulation of aging, DNA repair, and telomere maintenance which are implicated in the pathogenesis of COPD. The reduction of SIRT1 results in the deacetylation of DNA repair proteins such as FOXO3, TP53, and histone H3 leading to premature lung aging. Normally, pro-inflammatory cytokine release is reduced by SIRT1 via deacetylating RELA, the p65 subunit of NF-kB. When SIRT1 is downregulated, the production of cytokines is elevated. SIRT1 can deacetylate NFE2L2, a master regulator of the cellular redox state, thereby disrupting the antioxidant response. In addition, the levels of CDKN1A and CDKN2A are significantly increased in COPD lung tissue making an impact on cell aging. Cigarette smoke causes DNA damage and impairs double-strand break (DSB) repair, which is aggravated in patients with COPD and emphysema. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: lung Organ_System: respiratory system PMID: 18410916 PMID: 19136405 PMID: 19614601 PMID: 21224049 PMID: 21730072 PMID: 21907865 PMID: 22178470 PMID: 22978694 PMID: 23977698 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f2fd4361-fd14-432b-a19d-0474f641d467 Alveolar Epithelial Cell Dysfunction in COPD uuid-f2fd4361-fd14-432b-a19d-0474f641d467 PS:CellType epithelial cell PS:Description The airway and alveoli are lined with epithelial cells that not only provide a barrier between the host and the environment but are also an important source for the production of mediators. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f2fd4361-fd14-432b-a19d-0474f641d467 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. The airway and alveoli are lined with epithelial cells, which provide a barrier between the host and the environment, and are also an important source of mediator molecules. The alveolar epithelial cells have an important role in the pathogenesis COPD. Signaling description: Cigarette smoke can activate epithelial cells to secrete a variety of inflammatory mediators and proteases including TNF, TGFB1, IL1B, IL8, MMP1, MMP2, and MMP14. Cigarette smoke has been shown to induce intracellular signaling via the TLR4 and AGER receptors. Cigarette smoke extract exposure leads to EGR1 elevation by activating the MAPK1/3 pathway. The upregulated EGR1 can activate transcription of its target gene GGPS1, which is responsible for the reactivation of the MAPK1/3 pathway via Ras forming a vicious circle. EGR1 is a genetic susceptibility factor that can control the production of MMP2 and MMP14 to overwhelm the anti-protease systems and lead to the destruction of alveolar septal architecture. In addition, the expression of AGER receptor, which binds HMGB1, is elevated in airway epithelium in COPD patients. Extracellular ATP causes the release of IL8 and IL6 via activation of P2YR-subtypes from airway epithelial cells. SIRT1 is downregulated in lung cells from COPD patients as a result of post-translational oxidative modification by cigarette smoke-derived components. Outcome effects: SIRT1 plays an important role in the inflammatory response, regulation of aging, DNA repair, and telomere maintenance which are implicated in the pathogenesis of COPD. The reduction of SIRT1 results in the deacetylation of DNA repair proteins such as FOXO3, TP53, and histone H3 leading to premature lung aging. Normally, pro-inflammatory cytokine release is reduced by SIRT1 via deacetylating RELA, the p65 subunit of NF-kB. When SIRT1 is downregulated, the production of cytokines is elevated. SIRT1 can deacetylate NFE2L2, a master regulator of the cellular redox state, thereby disrupting the antioxidant response. In addition, the levels of CDKN1A and CDKN2A are significantly increased in COPD lung tissue making an impact on cell aging. Cigarette smoke causes DNA damage and impairs double-strand break (DSB) repair, which is aggravated in patients with COPD and emphysema. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ lung PS:Organ_System respiratory system PS:PMID 18410916 PS:PMID 19136405 PS:PMID 19614601 PS:PMID 21224049 PS:PMID 21730072 PS:PMID 21907865 PS:PMID 22178470 PS:PMID 22978694 PS:PMID 23977698 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: lactotroph Description: Prolactin (PRL) is a protein enabling female mammals to produce milk. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f34034a9-b1fc-4f85-a4d5-8df3b6ddc09d NodeType: Pathway Notes: Headnote: Prolactin (PRL) is a protein enabling female mammals to produce milk. Estrogens stimulate PRL expression via ESR1. Signaling description: The classical dopaminergic inhibition of PRL release from the anterior pituitary is mediated through DRD2 receptor, G-proteins and adenylate cyclase (ADCY). Action of dopamine induces a rapid change in cytosolic Ca2+ concentration, due to the coupling of DRD2 receptor to voltage-gated calcium channels or via indirect action on GIRK and resulting in a marked decline in intracellular Ca2+. Estrogen effects on lactotroph cell growth are mediated through estrogen-induced stimulatory or inhibitory action of TGFs and other growth factors. Increasing estrogen concentrations reduce the intrapituitary production of TGFB1 and stimulate the synthesis of TGFB3. These two factors have opposite effects on lactotroph cell growth, since TGFB1 inhibits and TGFB3 stimulates the proliferation of these cells. Interestingly, these estradiol-induced changes are dependent on the presence of folliculostellate cells (FS). In particular, in FS cells estradiol-induced TGFB3 stimulates the production of FGF2, which is a potent stimulator of PRL production and lactotroph cell proliferation. Alternatively, estrogens may affect lactotroph growth and function through altering the dopaminergic control. It is well known that estradiol downregulates hypothalamic DA production and suppresses the activity of DRD2 in lactotrophs by uncoupling the receptors from G proteins. Whereas estrogens predominantly stimulate PRL synthesis and release, this hormone was shown to differently affect lactotroph cell growth by acting either proliferatively or apoptotically. Regarding apoptosis, it has been demonstrated that estrogens upregulate the Fas/FasL apoptotic pathway in lactotrophs and induce the intrapituitary production of TNF, which acts apoptotically through the TNF receptor 1 (TNFR1) expressed on lactotrophs. Whether lactotrophs undergo proliferation or apoptosis will then depend on the actual dominance of a specific factor during the cycle. Outcome effects: PRL stimulates lactation, has a role in many other processes and regulates fertility. Organ: pituitary gland Organ_System: endocrine system PMID: 17307904 PMID: 20371569 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-f34034a9-b1fc-4f85-a4d5-8df3b6ddc09d Estrogens in Prolactin Production uuid-f34034a9-b1fc-4f85-a4d5-8df3b6ddc09d PS:CellType lactotroph PS:Description Prolactin (PRL) is a protein enabling female mammals to produce milk. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f34034a9-b1fc-4f85-a4d5-8df3b6ddc09d PS:NodeType Pathway PS:Notes Headnote: Prolactin (PRL) is a protein enabling female mammals to produce milk. Estrogens stimulate PRL expression via ESR1. Signaling description: The classical dopaminergic inhibition of PRL release from the anterior pituitary is mediated through DRD2 receptor, G-proteins and adenylate cyclase (ADCY). Action of dopamine induces a rapid change in cytosolic Ca2+ concentration, due to the coupling of DRD2 receptor to voltage-gated calcium channels or via indirect action on GIRK and resulting in a marked decline in intracellular Ca2+. Estrogen effects on lactotroph cell growth are mediated through estrogen-induced stimulatory or inhibitory action of TGFs and other growth factors. Increasing estrogen concentrations reduce the intrapituitary production of TGFB1 and stimulate the synthesis of TGFB3. These two factors have opposite effects on lactotroph cell growth, since TGFB1 inhibits and TGFB3 stimulates the proliferation of these cells. Interestingly, these estradiol-induced changes are dependent on the presence of folliculostellate cells (FS). In particular, in FS cells estradiol-induced TGFB3 stimulates the production of FGF2, which is a potent stimulator of PRL production and lactotroph cell proliferation. Alternatively, estrogens may affect lactotroph growth and function through altering the dopaminergic control. It is well known that estradiol downregulates hypothalamic DA production and suppresses the activity of DRD2 in lactotrophs by uncoupling the receptors from G proteins. Whereas estrogens predominantly stimulate PRL synthesis and release, this hormone was shown to differently affect lactotroph cell growth by acting either proliferatively or apoptotically. Regarding apoptosis, it has been demonstrated that estrogens upregulate the Fas/FasL apoptotic pathway in lactotrophs and induce the intrapituitary production of TNF, which acts apoptotically through the TNF receptor 1 (TNFR1) expressed on lactotrophs. Whether lactotrophs undergo proliferation or apoptosis will then depend on the actual dominance of a specific factor during the cycle. Outcome effects: PRL stimulates lactation, has a role in many other processes and regulates fertility. PS:Organ pituitary gland PS:Organ_System endocrine system PS:PMID 17307904 PS:PMID 20371569 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f37105c5-3cfa-4aef-bc7c-b75270a6f0c0 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: gallbladder Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-f37105c5-3cfa-4aef-bc7c-b75270a6f0c0 Elevated Receptors -> Expression Targets in Gallbladder uuid-f37105c5-3cfa-4aef-bc7c-b75270a6f0c0 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f37105c5-3cfa-4aef-bc7c-b75270a6f0c0 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ gallbladder PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuroglia CellType: neuron Description: Vascular dementia is caused by the death of neurons (and glial cells), caused by the loss of nutrition. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f385ad64-3d6a-4138-a2df-2529b428fc5d NodeType: Pathway Notes: Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm is triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and death of neurons. Chronic vasoconstriction which lasts several days after SAH causes energy and oxygen (O2) starvation which leads to lack of adenosine triphosphate (ATP), which in turn leads to the arrest of ion pumps, primarily Na+/K+-exchanging ATPase. Outcome effects: The misbalance between K+ and Na+ ions results in uncontrolled neuronal necrosis. Other significant processes activated by O2 starvation in cells include the appearance of H2O2 and a decrease in ATP synthesis. The products of neuronal death cause vasoconstriction of adjacent blood vessels which extends the injury. Thus, in the late stages of vasospasm necrosis of neurons adjacent to the SAH lesions occurs. The extent of necrosis is directly correlated to the severity of SAH. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: brain Organ_System: nervous system PMID: 24294978 PMID: 25987538 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-f385ad64-3d6a-4138-a2df-2529b428fc5d Brain Cell Necrosis in Vascular Dementia uuid-f385ad64-3d6a-4138-a2df-2529b428fc5d PS:CellType neuroglia PS:CellType neuron PS:Description Vascular dementia is caused by the death of neurons (and glial cells), caused by the loss of nutrition. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f385ad64-3d6a-4138-a2df-2529b428fc5d PS:NodeType Pathway PS:Notes Headnote: Intracranial vasospasm is a severe complication of subarachnoid hemorrhage (SAH). SAH may occur spontaneously, however it generally results from a ruptured cerebral aneurysm or head injury. Neuronal death is the cause of high mortality and disability rate in patients with vasospasm. Signaling description: Vasospasm is triggered by products of cellular decay such as serotonin, histamine, norepinephrine, prostaglandins, thromboxanes, endothelin, hemoglobin, nitric oxide, and free radicals. The major pathological processes involved in the development of vasospasm are vasoconstriction, endothelial dysfunction, and death of neurons. Chronic vasoconstriction which lasts several days after SAH causes energy and oxygen (O2) starvation which leads to lack of adenosine triphosphate (ATP), which in turn leads to the arrest of ion pumps, primarily Na+/K+-exchanging ATPase. Outcome effects: The misbalance between K+ and Na+ ions results in uncontrolled neuronal necrosis. Other significant processes activated by O2 starvation in cells include the appearance of H2O2 and a decrease in ATP synthesis. The products of neuronal death cause vasoconstriction of adjacent blood vessels which extends the injury. Thus, in the late stages of vasospasm necrosis of neurons adjacent to the SAH lesions occurs. The extent of necrosis is directly correlated to the severity of SAH. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ brain PS:Organ_System nervous system PS:PMID 24294978 PS:PMID 25987538 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3ab12fb-9ebb-489c-acdf-9409de63e830 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-f3ab12fb-9ebb-489c-acdf-9409de63e830 ALK -> STAT Signaling uuid-f3ab12fb-9ebb-489c-acdf-9409de63e830 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3ab12fb-9ebb-489c-acdf-9409de63e830 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:NodeType PS:Organ_System PS:Source CellType: dendritic cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 NodeType: Pathway Organ_System: hematological system Source: Atlas Source: Diabetes, type 1 urn:agi-pathway:uuid-f3b062f3-d914-4994-93af-cbb55537dfa5 4_diabetes mellitus type 1: conventional dendritic cell uuid-f3b062f3-d914-4994-93af-cbb55537dfa5 PS:CellType dendritic cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:NodeType Pathway PS:Organ_System hematological system PS:Source Atlas PS:Source Diabetes, type 1 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3b86d8c-4ef3-4b6e-94cf-353bdd477696 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-f3b86d8c-4ef3-4b6e-94cf-353bdd477696 Proteins Involved in Sleep Initiation and Maintenance Disorders uuid-f3b86d8c-4ef3-4b6e-94cf-353bdd477696 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3b86d8c-4ef3-4b6e-94cf-353bdd477696 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: Angiogenesis is a key factor for the successful establishment and growth of endometriotic lesions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3d5b985-1bd3-47f4-80b6-194c6ae3a6a2 NodeType: Pathway Notes: Headnote: Angiogenesis is a key factor for the successful establishment and growth of endometriotic lesions. The two main regulators of angiogenesis are vascular endothelial growth factors (VEGF) and angiopoietins (ANGPT). Signaling description: VEGFA and VEGFC its principal receptor VEGFR2 (KDR) are strongly up-regulated in endometriotic lesions. VEGFA specifically acts as endothelial cells (EC) mitogen, enhances EC migration, and increases vascular permeability. Inhibition of VEGF leads to a significant decrease in the number of endometriotic lesions. Levels of Angiopoeitin-1 and -2 (ANGPT1/2) are both increased in the endometrium of patients with endometriosis. The shift of the ANGPT1/2 balance in favor of ANGPT2 destabilizes pre-existing vessels and makes them prone to sprout. Organ: uterus Organ_System: reproductive system PMID: 16723371 PMID: 19755482 PMID: 22718320 PMID: 23766765 PMID: 24927773 PMID: 25203958 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f3d5b985-1bd3-47f4-80b6-194c6ae3a6a2 Angiogenesis in Endometriosis uuid-f3d5b985-1bd3-47f4-80b6-194c6ae3a6a2 PS:CellType endometrium cell PS:Description Angiogenesis is a key factor for the successful establishment and growth of endometriotic lesions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3d5b985-1bd3-47f4-80b6-194c6ae3a6a2 PS:NodeType Pathway PS:Notes Headnote: Angiogenesis is a key factor for the successful establishment and growth of endometriotic lesions. The two main regulators of angiogenesis are vascular endothelial growth factors (VEGF) and angiopoietins (ANGPT). Signaling description: VEGFA and VEGFC its principal receptor VEGFR2 (KDR) are strongly up-regulated in endometriotic lesions. VEGFA specifically acts as endothelial cells (EC) mitogen, enhances EC migration, and increases vascular permeability. Inhibition of VEGF leads to a significant decrease in the number of endometriotic lesions. Levels of Angiopoeitin-1 and -2 (ANGPT1/2) are both increased in the endometrium of patients with endometriosis. The shift of the ANGPT1/2 balance in favor of ANGPT2 destabilizes pre-existing vessels and makes them prone to sprout. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 16723371 PS:PMID 19755482 PS:PMID 22718320 PS:PMID 23766765 PS:PMID 24927773 PS:PMID 25203958 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The interaction of PTPRN/STAT5 in beta cells is involved in the mechanism of coordination in the amount of insulin stored and secreted. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3f2b3cd-7452-479e-9e22-71f17486d79c NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: The interaction of PTPRN/STAT5 in beta-cells is involved in the mechanism regulation of the amount of insulin stored and secreted. Prior to their linkage to the cytoskeleton, insulin granules are anchored to the actin cortex via PTPRN. Upon activation, beta-cells elevate calcium (Ca2+) levels and activate CAPN1 which cleaves off a cytosolic fragment from PTPRN. Outcome effects: The free PTPRN cytosolic fragment then moves to the nucleus and binds to STAT5 to prevent STAT5 from dephosphorylation, which in turns upregulates insulin transcription. The sumoylation of PTPRN by PIAS4 reverses the binding of PTPRN to STAT5. Animal data: rodent model. Organ: pancreas Organ_System: endocrine system PMID: 22974359 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f3f2b3cd-7452-479e-9e22-71f17486d79c PTPRN/STAT5 in Insulin Synthesis in beta-Cell (Rodent Model) uuid-f3f2b3cd-7452-479e-9e22-71f17486d79c PS:CellType insulin-secreting cell PS:Description The interaction of PTPRN/STAT5 in beta cells is involved in the mechanism of coordination in the amount of insulin stored and secreted. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f3f2b3cd-7452-479e-9e22-71f17486d79c PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are the insulin-secreting cells in the islets of Langerhans. Beta-cell dysfunction is central in the pathogenesis of diabetes mellitus. Signaling description: The interaction of PTPRN/STAT5 in beta-cells is involved in the mechanism regulation of the amount of insulin stored and secreted. Prior to their linkage to the cytoskeleton, insulin granules are anchored to the actin cortex via PTPRN. Upon activation, beta-cells elevate calcium (Ca2+) levels and activate CAPN1 which cleaves off a cytosolic fragment from PTPRN. Outcome effects: The free PTPRN cytosolic fragment then moves to the nucleus and binds to STAT5 to prevent STAT5 from dephosphorylation, which in turns upregulates insulin transcription. The sumoylation of PTPRN by PIAS4 reverses the binding of PTPRN to STAT5. Animal data: rodent model. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22974359 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f40f5eaf-4dd1-41b8-a822-256da8b18309 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f40f5eaf-4dd1-41b8-a822-256da8b18309 IL16 -> AP-1 Expression Targets uuid-f40f5eaf-4dd1-41b8-a822-256da8b18309 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f40f5eaf-4dd1-41b8-a822-256da8b18309 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron Description: Cholesterol and estrogen play a dual role regarding the functioning of mitochondria in Alzheimer's Disease. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f436c9f8-fd7d-4699-8023-dcab12ab6b43 NodeType: Pathway Notes: Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The elevated expression of mitochondrial Abeta-binding alcohol dehydrogenase and the translocation protein (TSPO), shown in AD, may affect the mechanisms of neuroprotective action of estrogen and cholesterol. Normally estrogen and cholesterol act as neuroprotectors restricting the release of reactive oxygen species (ROS) from mitochondria and decreasing cytotoxic effects of Abeta. At the same time, estrogens can themselves produce cytotoxic effects since they participate in the control of mitochondrial fusion and production of ROS during the catechol - quinone redox cycling. In neurons of patients with AD, Abeta in the mitochondrial matrix decreases the activity of antioxidant enzymes such as SOD1 and SOD2, while cholesterol and estrogens enhance their expression. Outcome effects: Reduced activity of SOD1 and SOD2 leads to the increased synthesis of ROS. Therefore, cholesterol and estrogens have a neuroprotective in AD role not only through the inhibition of Abeta, but also through the enhanced expression of SOD1 and SOD2. Mutated genes: Mutated gene is shown in white-out style. Organ: brain Organ_System: nervous system PMID: 12437582 PMID: 12607822 PMID: 17261779 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f436c9f8-fd7d-4699-8023-dcab12ab6b43 Estrogen Effects in Mitochondria in Alzheimer Disease uuid-f436c9f8-fd7d-4699-8023-dcab12ab6b43 PS:CellType neuron PS:Description Cholesterol and estrogen play a dual role regarding the functioning of mitochondria in Alzheimer's Disease. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f436c9f8-fd7d-4699-8023-dcab12ab6b43 PS:NodeType Pathway PS:Notes Headnote: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with symptoms including short-term memory loss, disorientation, problems with self care, mood swings, and behavioural issues. AD is characterized by the formation of amyloid plaques (deposits of amyloid beta peptide (Abeta) outside the cells) and neurofibrillary tangles (aggregates of hyperphosphorylated microtubule-associated protein tau (MAPT) inside the neurons). Signaling description: The elevated expression of mitochondrial Abeta-binding alcohol dehydrogenase and the translocation protein (TSPO), shown in AD, may affect the mechanisms of neuroprotective action of estrogen and cholesterol. Normally estrogen and cholesterol act as neuroprotectors restricting the release of reactive oxygen species (ROS) from mitochondria and decreasing cytotoxic effects of Abeta. At the same time, estrogens can themselves produce cytotoxic effects since they participate in the control of mitochondrial fusion and production of ROS during the catechol - quinone redox cycling. In neurons of patients with AD, Abeta in the mitochondrial matrix decreases the activity of antioxidant enzymes such as SOD1 and SOD2, while cholesterol and estrogens enhance their expression. Outcome effects: Reduced activity of SOD1 and SOD2 leads to the increased synthesis of ROS. Therefore, cholesterol and estrogens have a neuroprotective in AD role not only through the inhibition of Abeta, but also through the enhanced expression of SOD1 and SOD2. Mutated genes: Mutated gene is shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 12437582 PS:PMID 12607822 PS:PMID 17261779 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f445e1af-645b-4667-a4c2-615ca21fe102 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f445e1af-645b-4667-a4c2-615ca21fe102 Erythropoietin -> NF-kB Expression Targets uuid-f445e1af-645b-4667-a4c2-615ca21fe102 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f445e1af-645b-4667-a4c2-615ca21fe102 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is build using HIstome database Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4947841-d79d-4a82-a11c-19a2e84aba8f NodeType: Pathway Notes: Please, see http://www.iiserpune.ac.in/~coee/histome/ Organ_System: generic PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-f4947841-d79d-4a82-a11c-19a2e84aba8f H3 Lysine Modification Sites uuid-f4947841-d79d-4a82-a11c-19a2e84aba8f PS:Description Pathway is build using HIstome database PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4947841-d79d-4a82-a11c-19a2e84aba8f PS:NodeType Pathway PS:Notes Please, see http://www.iiserpune.ac.in/~coee/histome/ PS:Organ_System generic PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f49b9ea4-0b81-4b76-9dae-3aa167c7f6f4 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-f49b9ea4-0b81-4b76-9dae-3aa167c7f6f4 Sodium Flux Regulation uuid-f49b9ea4-0b81-4b76-9dae-3aa167c7f6f4 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f49b9ea4-0b81-4b76-9dae-3aa167c7f6f4 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4d26f71-2947-4f6b-ae2b-afdffb5e0fea NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-f4d26f71-2947-4f6b-ae2b-afdffb5e0fea AGER -> NF-kB Signaling uuid-f4d26f71-2947-4f6b-ae2b-afdffb5e0fea PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4d26f71-2947-4f6b-ae2b-afdffb5e0fea PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4ea7cc6-5344-4944-bf57-314df42ecef8 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f4ea7cc6-5344-4944-bf57-314df42ecef8 Leptin -> ELK/SRF Expression Targets uuid-f4ea7cc6-5344-4944-bf57-314df42ecef8 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f4ea7cc6-5344-4944-bf57-314df42ecef8 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: osteoclast Description: TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction play a key role in osteoclast activation in multiple myeloma (MM). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5122733-1979-4cb3-bb46-fbd91a0e3f41 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. More than 80% of MM patients develop bone disease with severe bone pain and pathologic fractures. Signaling description: TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction play a key role in osteoclast activation in multiple myeloma (MM). Normally, the balance between bone synthesis and resorption is regulated by TNFSF11 and its decoy receptor, TNFRSF11B. In MM bone disease, there is a remarkable imbalance between them with the highly overexpressed TNFSF11 and suppressed TNFRSF11B. TNFSF11 interacts with TNFRSF11A and activates NF-kB, MAPK/FOS-JUN, and calcineurin/NFATC1 pathways. TRAF6 is one of the main regulators in all of these pathways. The activation of Notch by the overexpression of JAG1 and JAG2 results in PI3K/Akt and NF-kB pathway activation. In addition, overexpressed CCL3/20 activates CCR family members leading to signaling via G-proteins/PKC/MAPK and PI3K/Akt. Outcome effects: The described events result in osteoclast adhesion, activation, and fusion as well as bone resorption and osteoclast apoptosis inhibition leading to the initiation and progression of MM bone disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. Organ_System: skeletal system PMID: 16917004 PMID: 17634140 PMID: 19286761 PMID: 20392262 PMID: 21411443 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-f5122733-1979-4cb3-bb46-fbd91a0e3f41 Osteoclast Activation in Multiple Myeloma uuid-f5122733-1979-4cb3-bb46-fbd91a0e3f41 PS:CellType cancer cell PS:CellType osteoclast PS:Description TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction play a key role in osteoclast activation in multiple myeloma (MM). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5122733-1979-4cb3-bb46-fbd91a0e3f41 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a form of hematologic malignancy in which normal plasma cells transform into malignant myeloma cells and accumulate in the bone marrow. MM is characterized by the presence of monoclonal immunoglobulin in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency, and is mainly a disease of old patients. More than 80% of MM patients develop bone disease with severe bone pain and pathologic fractures. Signaling description: TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction play a key role in osteoclast activation in multiple myeloma (MM). Normally, the balance between bone synthesis and resorption is regulated by TNFSF11 and its decoy receptor, TNFRSF11B. In MM bone disease, there is a remarkable imbalance between them with the highly overexpressed TNFSF11 and suppressed TNFRSF11B. TNFSF11 interacts with TNFRSF11A and activates NF-kB, MAPK/FOS-JUN, and calcineurin/NFATC1 pathways. TRAF6 is one of the main regulators in all of these pathways. The activation of Notch by the overexpression of JAG1 and JAG2 results in PI3K/Akt and NF-kB pathway activation. In addition, overexpressed CCL3/20 activates CCR family members leading to signaling via G-proteins/PKC/MAPK and PI3K/Akt. Outcome effects: The described events result in osteoclast adhesion, activation, and fusion as well as bone resorption and osteoclast apoptosis inhibition leading to the initiation and progression of MM bone disease. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and protein with decreased expression or activity is highlighted in blue. PS:Organ_System skeletal system PS:PMID 16917004 PS:PMID 17634140 PS:PMID 19286761 PS:PMID 20392262 PS:PMID 21411443 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Age-related hearing loss (ARHL) is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f51fc0b0-cd9c-488e-8ae8-6e6dae7a8a34 NodeType: Pathway Notes: Headnote: Age-related hearing loss (ARHL) is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Signaling description: ARHL is associated with an age-dependent loss of sensory hair cells. An example of a predisposing allele is cadherin 23 (CDH23) Cdh23ahl. Signaling description: The Cdh23ahl allele encodes a protein present in the tip links of the outer hair cells and is associated with a rapid progression of ARHL. Polymorphisms in PCDH15, also present in stereocilia tip links, are similarly associated with ARHL. Myosin 15A (MYO15A) and myosin 6 (MYO6) polymorphisms also predispose to ARHL. Organ: ear Organ_System: sensory system PMID: 20624897 PMID: 21782914 PMID: 22581638 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f51fc0b0-cd9c-488e-8ae8-6e6dae7a8a34 Cochlear Hair Cell Stereocilia Proteins Mutations (Age-Related) uuid-f51fc0b0-cd9c-488e-8ae8-6e6dae7a8a34 PS:CellType sensory hair cell PS:Description Age-related hearing loss (ARHL) is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f51fc0b0-cd9c-488e-8ae8-6e6dae7a8a34 PS:NodeType Pathway PS:Notes Headnote: Age-related hearing loss (ARHL) is the result of genetic predispositions combined with various insults to the inner ear accumulated during a lifetime. Signaling description: ARHL is associated with an age-dependent loss of sensory hair cells. An example of a predisposing allele is cadherin 23 (CDH23) Cdh23ahl. Signaling description: The Cdh23ahl allele encodes a protein present in the tip links of the outer hair cells and is associated with a rapid progression of ARHL. Polymorphisms in PCDH15, also present in stereocilia tip links, are similarly associated with ARHL. Myosin 15A (MYO15A) and myosin 6 (MYO6) polymorphisms also predispose to ARHL. PS:Organ ear PS:Organ_System sensory system PS:PMID 20624897 PS:PMID 21782914 PS:PMID 22581638 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5262c00-82dc-4066-b053-40999c0af7fa NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-f5262c00-82dc-4066-b053-40999c0af7fa Genes with Mutations Associated with Vascular Dementia uuid-f5262c00-82dc-4066-b053-40999c0af7fa PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5262c00-82dc-4066-b053-40999c0af7fa PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5561958-67c8-45de-8ca8-f92cd686b958 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-f5561958-67c8-45de-8ca8-f92cd686b958 Bradykinin+>myofibroblasts (hypothesis) uuid-f5561958-67c8-45de-8ca8-f92cd686b958 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5561958-67c8-45de-8ca8-f92cd686b958 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ba69f3-e2a4-42a2-b037-e242e3e35def NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-f5ba69f3-e2a4-42a2-b037-e242e3e35def Genes with Mutations Associated with Frontotemporal Dementia uuid-f5ba69f3-e2a4-42a2-b037-e242e3e35def PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ba69f3-e2a4-42a2-b037-e242e3e35def PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell CellType: goblet cell Description: Up-regulation of mucin production represents an important host innate defense response against invading microbes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5d9af72-a4c9-410a-b91d-58d76b1be891 NodeType: Pathway Notes: Up-regulation of mucin production represents an important host innate defense response against invading microbes. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: ear Organ_System: sensory system PMID: 18037371 PMID: 18782768 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: middle ear mucosa urn:agi-pathway:uuid-f5d9af72-a4c9-410a-b91d-58d76b1be891 MUC5AC Expression by NTHi and S. Pneumoniae uuid-f5d9af72-a4c9-410a-b91d-58d76b1be891 PS:CellType epithelial cell PS:CellType goblet cell PS:Description Up-regulation of mucin production represents an important host innate defense response against invading microbes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5d9af72-a4c9-410a-b91d-58d76b1be891 PS:NodeType Pathway PS:Notes Up-regulation of mucin production represents an important host innate defense response against invading microbes. Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ ear PS:Organ_System sensory system PS:PMID 18037371 PS:PMID 18782768 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue middle ear mucosa PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5eb3ce5-ff1a-4c4e-b9ee-77b0f6e469f9 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-f5eb3ce5-ff1a-4c4e-b9ee-77b0f6e469f9 L-Sugars Oxidation uuid-f5eb3ce5-ff1a-4c4e-b9ee-77b0f6e469f9 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5eb3ce5-ff1a-4c4e-b9ee-77b0f6e469f9 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ebb917-aa57-4df6-89e6-7ed95b2db11f NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f5ebb917-aa57-4df6-89e6-7ed95b2db11f EGF -> STAT Expression Targets uuid-f5ebb917-aa57-4df6-89e6-7ed95b2db11f PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ebb917-aa57-4df6-89e6-7ed95b2db11f PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ed2f1d-87f2-41e4-95b0-420d3f08a980 NodeType: Pathway Organ: colon Organ: intestine Organ_System: digestive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f5ed2f1d-87f2-41e4-95b0-420d3f08a980 Proteins Involved in Inflammatory Bowel Diseases uuid-f5ed2f1d-87f2-41e4-95b0-420d3f08a980 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ed2f1d-87f2-41e4-95b0-420d3f08a980 PS:NodeType Pathway PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ee87a3-387f-412f-8a84-d7b734d02e61 NodeType: Pathway Notes: Headnote: The adherens junctions initiate cell-cell contacts and mediate maturation and maintenance of the contact. They consist of nectin and cadherin family cell adhesion molecules linked to the actin cytoskeleton through their binding proteins. Nectin and nectin-like molecules are cellular adhesion molecules involved in calcium-independent cellular adhesion. Signaling description: Generally, all nectins have one intracellular domain, a single transmembrane helix, and three extracellular domains. The binding of MLLT4 and F-actin at nectin-nectin junctions induces major cytoskeletal regulators such as TJP1, LMO7, SSX2IP, ACTN1, CTNNA1, ZYX, SORBS1, vinculin (VCL), KEAP1, epsin (EPN1), tubulins, and myosins to modulate cytoskeletal reorganization and actin polymerization. Nectin recruits and activates SRC, which then phosphorylates CDC42 and VAV2 through the CRK-RAPGEF1 complex. Nectin-induced activation of CDC42 and RAC1 signaling pathway leads to the formation of filopodia and lamellipodia, respectively. Outcome effects: Activated CDC42 and RAC1 bind to and specifically activate their downstream effectors which include scaffolding proteins such as BAIAP2, WAS, WASL, IQGAP1, and WASFs. This allows signals to flow through the actin related protein 2/3 complex to coordinate the initiation of new filaments. Nectin-induced activation of PARD3 and CDC42 enhance cell adhesion through the regulation of tight junctions in a highly-controlled manner. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-f5ee87a3-387f-412f-8a84-d7b734d02e61 Adherens Junction Assembly (Nectin) uuid-f5ee87a3-387f-412f-8a84-d7b734d02e61 PS:CellType generic PS:Description Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f5ee87a3-387f-412f-8a84-d7b734d02e61 PS:NodeType Pathway PS:Notes Headnote: The adherens junctions initiate cell-cell contacts and mediate maturation and maintenance of the contact. They consist of nectin and cadherin family cell adhesion molecules linked to the actin cytoskeleton through their binding proteins. Nectin and nectin-like molecules are cellular adhesion molecules involved in calcium-independent cellular adhesion. Signaling description: Generally, all nectins have one intracellular domain, a single transmembrane helix, and three extracellular domains. The binding of MLLT4 and F-actin at nectin-nectin junctions induces major cytoskeletal regulators such as TJP1, LMO7, SSX2IP, ACTN1, CTNNA1, ZYX, SORBS1, vinculin (VCL), KEAP1, epsin (EPN1), tubulins, and myosins to modulate cytoskeletal reorganization and actin polymerization. Nectin recruits and activates SRC, which then phosphorylates CDC42 and VAV2 through the CRK-RAPGEF1 complex. Nectin-induced activation of CDC42 and RAC1 signaling pathway leads to the formation of filopodia and lamellipodia, respectively. Outcome effects: Activated CDC42 and RAC1 bind to and specifically activate their downstream effectors which include scaffolding proteins such as BAIAP2, WAS, WASL, IQGAP1, and WASFs. This allows signals to flow through the actin related protein 2/3 complex to coordinate the initiation of new filaments. Nectin-induced activation of PARD3 and CDC42 enhance cell adhesion through the regulation of tight junctions in a highly-controlled manner. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f60a18c1-eb6e-48c0-aa47-823dc246b089 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f60a18c1-eb6e-48c0-aa47-823dc246b089 Plastoquinone biosynthesis template uuid-f60a18c1-eb6e-48c0-aa47-823dc246b089 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f60a18c1-eb6e-48c0-aa47-823dc246b089 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f67d572f-8465-4d2c-9492-302aefec058c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f67d572f-8465-4d2c-9492-302aefec058c SMN1->actin uuid-f67d572f-8465-4d2c-9492-302aefec058c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f67d572f-8465-4d2c-9492-302aefec058c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f69c1559-ead8-4d18-b24f-423c10316396 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Protein Modification urn:agi-pathway:uuid-f69c1559-ead8-4d18-b24f-423c10316396 BMI1-mediated Epigenetic Regulation and Expression Targets uuid-f69c1559-ead8-4d18-b24f-423c10316396 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f69c1559-ead8-4d18-b24f-423c10316396 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Protein Modification PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell CellType: macrophage Description: Normally after the function of alveolar macrophages is complete, they are negatively regulated, mainly by interactions with bronchial and alveolar epithelial cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6a8d482-bd28-4c27-985b-88cd4bfde951 NodeType: Pathway Notes: Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Normally, as soon as the function of alveolar macrophages is complete, they are negatively regulated by soluble mediators and by cell-cell interactions, primarily by interactions with bronchial and alveolar epithelial cells. CD200 receptor (CD200R1) interacts with CD200 on the respiratory epithelium, recruiting DOK2 and Ras GTPase-activating protein RASA2, which inhibits Ras/MAPK/JUN-FOS inflammatory pathways. This inhibitory mechanism is impaired due to the death of bronchial and alveolar epithelial cells in COPD and pulmonary emphysema. IL10 is abundant in the lungs and restricts inflammation by triggering JAK1 signaling and activating the STAT3 pathway to induce the expression of negative regulators such as SOCS3 and MIR146B. Outcome effects: SOCS3 blocks the expression of pro-inflammatory cytokines, whereas MIR146B directly inhibits TLR4 expression and signaling. The mannose receptor (MRC1) blocks the recognition of TLR4 ligands and restricts phagocytosis of pathogens such as Pseudomonas aeruginosa. SFTPA1 and SFTPD are abundant in the airways and block TLR2 and TLR4 interactions with their respective ligands, as well as their interactions with the TLR coreceptors LY96 and CD14, which prevents the activation of NF-kB and the initiation of the inflammatory response. The binding of surfactant proteins to SIRPA recruits PTPN6 and activates RHOA, which inhibits phagocytosis. Organ: lung Organ_System: respiratory system PMID: 24445666 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f6a8d482-bd28-4c27-985b-88cd4bfde951 Alveolar Macrophage Negative Regulation Declined in COPD uuid-f6a8d482-bd28-4c27-985b-88cd4bfde951 PS:CellType epithelial cell PS:CellType macrophage PS:Description Normally after the function of alveolar macrophages is complete, they are negatively regulated, mainly by interactions with bronchial and alveolar epithelial cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6a8d482-bd28-4c27-985b-88cd4bfde951 PS:NodeType Pathway PS:Notes Headnote: Chronic obstructive pulmonary disease (COPD) refers to a group of progressive lung diseases characterized by a long-term worsening airway obstruction. Signaling description: Normally, as soon as the function of alveolar macrophages is complete, they are negatively regulated by soluble mediators and by cell-cell interactions, primarily by interactions with bronchial and alveolar epithelial cells. CD200 receptor (CD200R1) interacts with CD200 on the respiratory epithelium, recruiting DOK2 and Ras GTPase-activating protein RASA2, which inhibits Ras/MAPK/JUN-FOS inflammatory pathways. This inhibitory mechanism is impaired due to the death of bronchial and alveolar epithelial cells in COPD and pulmonary emphysema. IL10 is abundant in the lungs and restricts inflammation by triggering JAK1 signaling and activating the STAT3 pathway to induce the expression of negative regulators such as SOCS3 and MIR146B. Outcome effects: SOCS3 blocks the expression of pro-inflammatory cytokines, whereas MIR146B directly inhibits TLR4 expression and signaling. The mannose receptor (MRC1) blocks the recognition of TLR4 ligands and restricts phagocytosis of pathogens such as Pseudomonas aeruginosa. SFTPA1 and SFTPD are abundant in the airways and block TLR2 and TLR4 interactions with their respective ligands, as well as their interactions with the TLR coreceptors LY96 and CD14, which prevents the activation of NF-kB and the initiation of the inflammatory response. The binding of surfactant proteins to SIRPA recruits PTPN6 and activates RHOA, which inhibits phagocytosis. PS:Organ lung PS:Organ_System respiratory system PS:PMID 24445666 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6cfebf6-ef2a-4724-b80c-34284d85e37c NodeType: Pathway Organ: mouth Organ_System: digestive system PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-f6cfebf6-ef2a-4724-b80c-34284d85e37c Salivary Proteins Role in Periodontitis uuid-f6cfebf6-ef2a-4724-b80c-34284d85e37c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6cfebf6-ef2a-4724-b80c-34284d85e37c PS:NodeType Pathway PS:Organ mouth PS:Organ_System digestive system PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6d0553c-3a22-4381-bdc7-4cca605ec802 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f6d0553c-3a22-4381-bdc7-4cca605ec802 GH2/GHR Expression Target uuid-f6d0553c-3a22-4381-bdc7-4cca605ec802 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6d0553c-3a22-4381-bdc7-4cca605ec802 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6f275d9-59d0-4d2c-aaa9-83f3712127d4 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f6f275d9-59d0-4d2c-aaa9-83f3712127d4 Tyrosine byosynthesis template uuid-f6f275d9-59d0-4d2c-aaa9-83f3712127d4 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6f275d9-59d0-4d2c-aaa9-83f3712127d4 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: cancer cell CellType: melanocyte Description: Dysregulated expression of microRNA genes is involved in melanoma development and progression. MIR137, MIR221, MIR222, MIR34B, MIR34C, MIR199A1 and others possess an oncogenic role in melanoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6f48362-71f7-4aeb-b69d-600a30be6df5 NodeType: Pathway Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Studies have shown that dysregulation of the expression of microRNA (miRNA) genes contribute to melanoma development and progression. Signaling description: MiRNAs are a set of small (ca 22 nucleotides) single-stranded non-protein-coding RNA molecules, which can recognize and bind 3'-untranslated regions of mRNA and block translation of the gene or induce cleavage of the mRNA. Relatively few studies have focused on the role of miRNAs in the pathogenesis and development of melanoma. MIR137 has been identified as a trigger for micropthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and survival of significant functional importance in melanoma. In addition, MIR221 and MIR222 possess an oncogenic role in melanoma and other cancers when their expression is deregulated. Furthermore, it is likely that MIR34B, MIR34C, and MIR199A1 have the capacity to impair MET-mediated invasive growth. Outcome effects: MIR137, MIR221, MIR222, MIR34B, MIR34C, MIR199A1 and others possess an oncogenic role in melanoma. MiRNAs interact with melanoma related-signaling hubs including the key regulator of melanocyte development MITF, and thus contribute to the biology and progression of melanoma. Highlighted proteins: MiRNAs with increased expression are highlighted in red, and miRNAs with decreased expression are highlighted in blue. Double highlighted miRNAs can be either over- or underexpressed. Organ: skin Organ_System: integumentary system PMID: 18316599 PMID: 18983236 PMID: 19074879 PMID: 20644734 PMID: 22004179 PMID: 22503822 PMID: 22958787 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f6f48362-71f7-4aeb-b69d-600a30be6df5 MicroRNAs Role in Melanoma uuid-f6f48362-71f7-4aeb-b69d-600a30be6df5 PS:CellType cancer cell PS:CellType melanocyte PS:Description Dysregulated expression of microRNA genes is involved in melanoma development and progression. MIR137, MIR221, MIR222, MIR34B, MIR34C, MIR199A1 and others possess an oncogenic role in melanoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f6f48362-71f7-4aeb-b69d-600a30be6df5 PS:NodeType Pathway PS:Notes Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma. Studies have shown that dysregulation of the expression of microRNA (miRNA) genes contribute to melanoma development and progression. Signaling description: MiRNAs are a set of small (ca 22 nucleotides) single-stranded non-protein-coding RNA molecules, which can recognize and bind 3'-untranslated regions of mRNA and block translation of the gene or induce cleavage of the mRNA. Relatively few studies have focused on the role of miRNAs in the pathogenesis and development of melanoma. MIR137 has been identified as a trigger for micropthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and survival of significant functional importance in melanoma. In addition, MIR221 and MIR222 possess an oncogenic role in melanoma and other cancers when their expression is deregulated. Furthermore, it is likely that MIR34B, MIR34C, and MIR199A1 have the capacity to impair MET-mediated invasive growth. Outcome effects: MIR137, MIR221, MIR222, MIR34B, MIR34C, MIR199A1 and others possess an oncogenic role in melanoma. MiRNAs interact with melanoma related-signaling hubs including the key regulator of melanocyte development MITF, and thus contribute to the biology and progression of melanoma. Highlighted proteins: MiRNAs with increased expression are highlighted in red, and miRNAs with decreased expression are highlighted in blue. Double highlighted miRNAs can be either over- or underexpressed. PS:Organ skin PS:Organ_System integumentary system PS:PMID 18316599 PS:PMID 18983236 PS:PMID 19074879 PS:PMID 20644734 PS:PMID 22004179 PS:PMID 22503822 PS:PMID 22958787 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f75d8c4f-7c68-46a4-860a-e66bd3d7c059 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f75d8c4f-7c68-46a4-860a-e66bd3d7c059 Pentose phosphate shunt template uuid-f75d8c4f-7c68-46a4-860a-e66bd3d7c059 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f75d8c4f-7c68-46a4-860a-e66bd3d7c059 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f76a049f-b5ea-4040-8816-785f589c3d91 NodeType: Pathway PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-f76a049f-b5ea-4040-8816-785f589c3d91 CD80 -> STAT Expression Targets uuid-f76a049f-b5ea-4040-8816-785f589c3d91 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f76a049f-b5ea-4040-8816-785f589c3d91 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: endometrium cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f76a3859-fdfc-4e97-953d-28cc2890550a NodeType: Pathway Notes: Headnote: Environmental toxicants can act as endocrine disrupters on the female reproductive system. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is resistant to degradation and due to its lipophilic nature, accumulates in the fat tissue and in the food chain. Human and animal exposure to TCDD affects levels of the steroid receptors and steroid-responsive gene expression and has an impact on metabolism and serum transport of steroids. Signaling description: The effects of dioxin exposure are mediated by binding to the cytosolic aryl hydrocarbon receptor (AHR). Upon ligand binding, the receptor translocates to the nucleus and heterodimerizes with aryl hydrocarbon nuclear translocator (ARNT). AHR can affect cellular signaling through interactions with various regulatory and signaling proteins, including those mediated by the estrogen receptors (ESR1/2) and NF-kB. Activated AHR complexes associate directly with ESR1 and ESR2 in the absence of estrogen resulting in transcriptional activation of canonically estrogen-dependent genes. The ligand-dependent transcriptional activity of ESR1 has been found to be stimulated by g-synuclein (SNCG); furthermore, human ESR1 requires SNCG for efficient transcriptional activity. AHR also interacts with nuclear factor kappa-B (NF-kB) signaling pathways. The pleiotropic transcription factor, NF-kB has been identified to protect cells from apoptosis. B-cell lymphoma/ leukemia-2 (BCL2) is a well-known anti-apoptotic signaling protein. In normal endometrium, BCL2 demonstrates cyclical expression decreasing during the menstrual and late proliferative phases, indicating hormonal regulation. However, this regulation is lost in endometriosis.Dioxins via AHR induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Glycodelin (PAEP) is an endometrium-derived protein known for its angiogenic, immunosuppressive, and contraceptive effects. It is up-regulated by AHR and impairs binding sperm to the egg making impact into dioxin - and endometriosis- associated infertility. Organ: uterus Organ_System: reproductive system PMID: 18849443 PMID: 20104429 PMID: 24927773 PMID: 25920525 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-f76a3859-fdfc-4e97-953d-28cc2890550a Dioxin Role in Endometriosis uuid-f76a3859-fdfc-4e97-953d-28cc2890550a PS:CellType endometrium cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f76a3859-fdfc-4e97-953d-28cc2890550a PS:NodeType Pathway PS:Notes Headnote: Environmental toxicants can act as endocrine disrupters on the female reproductive system. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is resistant to degradation and due to its lipophilic nature, accumulates in the fat tissue and in the food chain. Human and animal exposure to TCDD affects levels of the steroid receptors and steroid-responsive gene expression and has an impact on metabolism and serum transport of steroids. Signaling description: The effects of dioxin exposure are mediated by binding to the cytosolic aryl hydrocarbon receptor (AHR). Upon ligand binding, the receptor translocates to the nucleus and heterodimerizes with aryl hydrocarbon nuclear translocator (ARNT). AHR can affect cellular signaling through interactions with various regulatory and signaling proteins, including those mediated by the estrogen receptors (ESR1/2) and NF-kB. Activated AHR complexes associate directly with ESR1 and ESR2 in the absence of estrogen resulting in transcriptional activation of canonically estrogen-dependent genes. The ligand-dependent transcriptional activity of ESR1 has been found to be stimulated by g-synuclein (SNCG); furthermore, human ESR1 requires SNCG for efficient transcriptional activity. AHR also interacts with nuclear factor kappa-B (NF-kB) signaling pathways. The pleiotropic transcription factor, NF-kB has been identified to protect cells from apoptosis. B-cell lymphoma/ leukemia-2 (BCL2) is a well-known anti-apoptotic signaling protein. In normal endometrium, BCL2 demonstrates cyclical expression decreasing during the menstrual and late proliferative phases, indicating hormonal regulation. However, this regulation is lost in endometriosis.Dioxins via AHR induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Glycodelin (PAEP) is an endometrium-derived protein known for its angiogenic, immunosuppressive, and contraceptive effects. It is up-regulated by AHR and impairs binding sperm to the egg making impact into dioxin - and endometriosis- associated infertility. PS:Organ uterus PS:Organ_System reproductive system PS:PMID 18849443 PS:PMID 20104429 PS:PMID 24927773 PS:PMID 25920525 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: endothelial cell Description: Reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in normal cardiovascular function. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7736c37-87c8-4ac8-bfa3-b6fd0ec16bb0 NodeType: Pathway Notes: Headnote: Reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in normal cardiovascular function. However, being highly active chemicals, ROS play a crucial role in the development of cardiovascular pathology. Signaling description: The major source of ROS in the cardiovascular system is NAD(P)H oxidase complex, which is efficiently activated by vasoactive agent AGT, acting through the G-protein-coupled AT1 receptor (AGTR1). The activation of NAD(P)H oxidase complex requires a concerted effort of protein kinase C (PKC), RAC1, and ceramides. The highly reactive and short-living superoxide radical, produced by NAD(P)H oxidase, is rapidly metabolized to H2O2 by Cu2+/Zn2+ superoxide dismutase (SOD1). H2O2 is a stable oxidant which can diffuse through membranes and act at long distances as a modulator of redox-sensitive cellular factors. AGT-induced activation of proinflammatory molecule expression requires NAD(P)H oxidase activity and is mediated through the activation of redox-regulated transcription factor NF-kB. Outcome effects: NAD(P)H oxidase-derived H2O2 activates IKBK which phosphorylates NFKBIA and releases active NF-kB, which then translocates to the nucleus where it activates target promoters which trigger the transcription of a range of proinflammatory factors. Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-f7736c37-87c8-4ac8-bfa3-b6fd0ec16bb0 ROS in Triggering Vascular Inflammation uuid-f7736c37-87c8-4ac8-bfa3-b6fd0ec16bb0 PS:CellType endothelial cell PS:Description Reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in normal cardiovascular function. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7736c37-87c8-4ac8-bfa3-b6fd0ec16bb0 PS:NodeType Pathway PS:Notes Headnote: Reactive oxygen species (ROS), such as superoxide radical and hydrogen peroxide (H2O2), are important signaling molecules in normal cardiovascular function. However, being highly active chemicals, ROS play a crucial role in the development of cardiovascular pathology. Signaling description: The major source of ROS in the cardiovascular system is NAD(P)H oxidase complex, which is efficiently activated by vasoactive agent AGT, acting through the G-protein-coupled AT1 receptor (AGTR1). The activation of NAD(P)H oxidase complex requires a concerted effort of protein kinase C (PKC), RAC1, and ceramides. The highly reactive and short-living superoxide radical, produced by NAD(P)H oxidase, is rapidly metabolized to H2O2 by Cu2+/Zn2+ superoxide dismutase (SOD1). H2O2 is a stable oxidant which can diffuse through membranes and act at long distances as a modulator of redox-sensitive cellular factors. AGT-induced activation of proinflammatory molecule expression requires NAD(P)H oxidase activity and is mediated through the activation of redox-regulated transcription factor NF-kB. Outcome effects: NAD(P)H oxidase-derived H2O2 activates IKBK which phosphorylates NFKBIA and releases active NF-kB, which then translocates to the nucleus where it activates target promoters which trigger the transcription of a range of proinflammatory factors. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source Description: Chloracne is the typical toxic response of the skin to TCDD (dioxin). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7aec14b-b915-4ab4-bd76-c7a125b299e1 NodeType: Pathway Notes: Headnote: Chloracne is the typical toxic response of the skin to TCDD (dioxin). The key feature of chloracne is non-inflammatory alteration of keratinization of the pilosebaceous unit that results in the formation of comedones, straw-coloured cysts, pustules and noninfectious abscesses that may scar. Signaling description: Chloracne is characterized by atrophy of the sebaceous glands, keratinocyte hyperpigmentation, and epidermal hyperplasia. Recently, the skin lesions were recognized as hamartomas and, in the case of TCDD poisoning, represent a TCDD metabolizing compartment. Outcome effects: TCDD promotes terminal differentiation of keratinocytes, possibly mediated by changes in the expression of transforming growth factor alpha (TGFA) and epidermal growth factor (EGF). NFE2L2 was reported to be upregulated in chloracne and controls the expression of growth factor epigen (EPGN), secretory leukocyte peptidase inhibitor (SLPI), and small proline-rich protein 2d (SPRR2D). In hair follicles, the latter three were identified as the likely causes of infundibular acanthosis, hyperkeratosis, and cyst formation. TCDD also enhances filaggrin (FLG), involucrin (IVL), and IL1B expression. Organ: skin Organ_System: integumentary system PMID: 16881967 PMID: 21998131 PMID: 24966027 PMID: 25733915 PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process urn:agi-pathway:uuid-f7aec14b-b915-4ab4-bd76-c7a125b299e1 Dioxin Induced Chloracne (Hypothesis) uuid-f7aec14b-b915-4ab4-bd76-c7a125b299e1 PS:Description Chloracne is the typical toxic response of the skin to TCDD (dioxin). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7aec14b-b915-4ab4-bd76-c7a125b299e1 PS:NodeType Pathway PS:Notes Headnote: Chloracne is the typical toxic response of the skin to TCDD (dioxin). The key feature of chloracne is non-inflammatory alteration of keratinization of the pilosebaceous unit that results in the formation of comedones, straw-coloured cysts, pustules and noninfectious abscesses that may scar. Signaling description: Chloracne is characterized by atrophy of the sebaceous glands, keratinocyte hyperpigmentation, and epidermal hyperplasia. Recently, the skin lesions were recognized as hamartomas and, in the case of TCDD poisoning, represent a TCDD metabolizing compartment. Outcome effects: TCDD promotes terminal differentiation of keratinocytes, possibly mediated by changes in the expression of transforming growth factor alpha (TGFA) and epidermal growth factor (EGF). NFE2L2 was reported to be upregulated in chloracne and controls the expression of growth factor epigen (EPGN), secretory leukocyte peptidase inhibitor (SLPI), and small proline-rich protein 2d (SPRR2D). In hair follicles, the latter three were identified as the likely causes of infundibular acanthosis, hyperkeratosis, and cyst formation. TCDD also enhances filaggrin (FLG), involucrin (IVL), and IL1B expression. PS:Organ skin PS:Organ_System integumentary system PS:PMID 16881967 PS:PMID 21998131 PS:PMID 24966027 PS:PMID 25733915 PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7b1b53d-9d8f-4220-8f89-0c217967857b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f7b1b53d-9d8f-4220-8f89-0c217967857b ACE2 tanscription factors uuid-f7b1b53d-9d8f-4220-8f89-0c217967857b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7b1b53d-9d8f-4220-8f89-0c217967857b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7b337eb-bbc3-433c-a4b7-e418dd211bc2 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-f7b337eb-bbc3-433c-a4b7-e418dd211bc2 Lacto- and Neolacto-Type Glycosphingolipid Biosynthesis uuid-f7b337eb-bbc3-433c-a4b7-e418dd211bc2 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7b337eb-bbc3-433c-a4b7-e418dd211bc2 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7cb4fa8-60ff-4504-ad32-cb4762d38163 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-f7cb4fa8-60ff-4504-ad32-cb4762d38163 Vascular Motility uuid-f7cb4fa8-60ff-4504-ad32-cb4762d38163 PS:CellType vascular smooth muscle cell PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f7cb4fa8-60ff-4504-ad32-cb4762d38163 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Link PS:NodeType PS:PMID PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f804c942-a75e-48c9-8e75-4c028b5f6e5f NodeType: Pathway PMID: 18313409 Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-f804c942-a75e-48c9-8e75-4c028b5f6e5f TGFB1-+>COL/SMA in cornea uuid-f804c942-a75e-48c9-8e75-4c028b5f6e5f PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f804c942-a75e-48c9-8e75-4c028b5f6e5f PS:NodeType Pathway PS:PMID 18313409 PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f809ce38-e5bd-434f-a0fa-08939aa5059a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f809ce38-e5bd-434f-a0fa-08939aa5059a Similar immunological disorders - Cells uuid-f809ce38-e5bd-434f-a0fa-08939aa5059a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f809ce38-e5bd-434f-a0fa-08939aa5059a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: epithelial cell Description: STK11 is somatic mutated in most cases of pancreatic ductal carcinoma. Germline mutations of STK11 have also been detected in many known cases of familial pancreatic cancer. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f80e94e3-337d-4996-9df2-54a40f9f9464 NodeType: Pathway Notes: Headnote: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. PDAC has a very poor prognosis due to the inability to diagnose the disease at an early and localized stage. Approximately 90% of all pancreatic tumors metastasize beyond the pancreas. Epidemiological and experimental studies have suggested a link between pancreatic cancer to smoking, diabetes, and a high-fat diet. However, it is not clear how these factors influence pancreatic cancer. It is generally believed that PDAC and cancers of exocrine pancreas originate from ductal cells. Somatic mutations in STK11 are observed in most cases of PDAC. Germline mutations of STK11 have also been detected in many known cases of familial pancreatic cancer. Signaling description: STK11 is a master kinase which is involved in the regulation of multiple signaling pathways. STK11 forms a heterotrimeric complex with psuedokinase STRADA and the scaffold protein CAB39. These proteins regulate STK11 stability, kinase activity, and subcellular localization. The physiological function of this protein complex is to regulate multiple biological pathways involving TP53-dependent and independent apoptosis, cell cycle and proliferation, chromatin remodeling, angiogenesis, energy metabolism, and control of cell polarity. Normally, STK11 phosphorylates and activates PTEN, AMPK, TP53, and SMAD4. PTEN negatively regulates intracellular levels of PIP3 and functions as a tumor suppressor by negatively regulating AKT1 signaling pathway. Activated AKT1 phosphorylates and activates MTOR which is a central regulator of cellular glucose and lipid metabolism, growth, and survival. In addition, AKT1 inhibits FOXO1 and FOXO3 which are involved in cell differentiation and apoptosis. AKT1 directly phosphorylates TSC1 and TSC2 to inactivate TSC1/2 tumor suppressor complex. In turn, TSC1/2 complex inactivates the small GTPase RHEB, which activates MTOR via RPTOR. TSC2 interacts with SMAD2 and SMAD3 which bind to SMAD4 and forms a heterotrimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in a variety of cell functions. AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1), which in turn phosphorylates and activates TSC2. AMPK is a heterotrimer consisting of an alpha catalytic subunit (PRKAA1), two non-catalytic beta (PRKAB1) and gamma (PRKAG1) subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. Activated AMPK stimulates TSC1/2 complex through AMPK-mediated TSC2 phosphorylation, and consequently inhibits MTOR signaling. STK11 suppresses tumor growth by inhibiting STAT3, which acts as a transcription activator and plays a key role in many cellular processes such as cell proliferation, differentiation, cell cycle, apoptosis, and vascularization. STK11 interacts with SMARCA4, an essential component of chromatin remodeling complex. Outcome effects: Germline and somatic mutations of STK11 lead to disruption of the cell cycle, differentiation and metabolism, redundant cell proliferation, block of apoptosis and chromatin remodeling resulting in tumorigenesis. Mutated genes: Mutated genes are shown in white-out style. Organ: pancreas Organ_System: digestive system PMID: 16702400 PMID: 22806689 PMID: 23135763 PMID: 23287572 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-f80e94e3-337d-4996-9df2-54a40f9f9464 STK11 Signaling in Pancreatic Neoplasms uuid-f80e94e3-337d-4996-9df2-54a40f9f9464 PS:CellType cancer cell PS:CellType epithelial cell PS:Description STK11 is somatic mutated in most cases of pancreatic ductal carcinoma. Germline mutations of STK11 have also been detected in many known cases of familial pancreatic cancer. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f80e94e3-337d-4996-9df2-54a40f9f9464 PS:NodeType Pathway PS:Notes Headnote: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer related deaths. PDAC has a very poor prognosis due to the inability to diagnose the disease at an early and localized stage. Approximately 90% of all pancreatic tumors metastasize beyond the pancreas. Epidemiological and experimental studies have suggested a link between pancreatic cancer to smoking, diabetes, and a high-fat diet. However, it is not clear how these factors influence pancreatic cancer. It is generally believed that PDAC and cancers of exocrine pancreas originate from ductal cells. Somatic mutations in STK11 are observed in most cases of PDAC. Germline mutations of STK11 have also been detected in many known cases of familial pancreatic cancer. Signaling description: STK11 is a master kinase which is involved in the regulation of multiple signaling pathways. STK11 forms a heterotrimeric complex with psuedokinase STRADA and the scaffold protein CAB39. These proteins regulate STK11 stability, kinase activity, and subcellular localization. The physiological function of this protein complex is to regulate multiple biological pathways involving TP53-dependent and independent apoptosis, cell cycle and proliferation, chromatin remodeling, angiogenesis, energy metabolism, and control of cell polarity. Normally, STK11 phosphorylates and activates PTEN, AMPK, TP53, and SMAD4. PTEN negatively regulates intracellular levels of PIP3 and functions as a tumor suppressor by negatively regulating AKT1 signaling pathway. Activated AKT1 phosphorylates and activates MTOR which is a central regulator of cellular glucose and lipid metabolism, growth, and survival. In addition, AKT1 inhibits FOXO1 and FOXO3 which are involved in cell differentiation and apoptosis. AKT1 directly phosphorylates TSC1 and TSC2 to inactivate TSC1/2 tumor suppressor complex. In turn, TSC1/2 complex inactivates the small GTPase RHEB, which activates MTOR via RPTOR. TSC2 interacts with SMAD2 and SMAD3 which bind to SMAD4 and forms a heterotrimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes involved in a variety of cell functions. AKT1 inhibits GSK3B which leads to the stabilization of cytosolic beta-catenin (CTNNB1), which in turn phosphorylates and activates TSC2. AMPK is a heterotrimer consisting of an alpha catalytic subunit (PRKAA1), two non-catalytic beta (PRKAB1) and gamma (PRKAG1) subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. Activated AMPK stimulates TSC1/2 complex through AMPK-mediated TSC2 phosphorylation, and consequently inhibits MTOR signaling. STK11 suppresses tumor growth by inhibiting STAT3, which acts as a transcription activator and plays a key role in many cellular processes such as cell proliferation, differentiation, cell cycle, apoptosis, and vascularization. STK11 interacts with SMARCA4, an essential component of chromatin remodeling complex. Outcome effects: Germline and somatic mutations of STK11 lead to disruption of the cell cycle, differentiation and metabolism, redundant cell proliferation, block of apoptosis and chromatin remodeling resulting in tumorigenesis. Mutated genes: Mutated genes are shown in white-out style. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 16702400 PS:PMID 22806689 PS:PMID 23135763 PS:PMID 23287572 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: adipocyte CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f80f7234-e117-4064-a1cc-164e5802f097 NodeType: Pathway Notes: Headnote: Majeed syndrome is an autoinflammatory disorder with chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. Majeed syndrome is typically more severe compared to sporadic CRMO (Chronic Recurrent Multifocal Osteomyelitis) and may be accompanied by recurrent fevers. Majeed syndrome has an autosomal-recessive mode of inheritance and is linked to mutations in the LPIN2 gene, which encodes the lipin 2 protein, expressed in the liver, kidneys, gastrointestinal system, lymphoid tissues, and the bone marrow. Signaling description: Lipin 2 is a phosphatidate phosphatase which plays a role in lipid metabolism, and its role in the control of inflammatory responses is not completely established. Based on findings in the field of obesity-induced chronic inflammation, it has been suggested that fatty acids induce a pro-inflammatory phenotype through the toll-like receptors (TLR) 2 and 4 stimulation which results in the activation of MAPKs, particularly MAPK8, and the induction of the NLRP3 inflammasome. Outcome effects: Cells with increased lipin 2 expression fail to produce pro-inflammatory cytokines, whereas reduced lipin 2 expression mediates increased expression of TNF, IL6, and CCL2. The phosphatase activity of lipin 2 is completely abolished in Majeed patients carrying the LPIN2 mutation, which leads to increased inflammatory responses. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ: skin Organ_System: skeletal system PMID: 22334674 PMID: 23087183 PMID: 24359092 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: adipose tissue Tissue: bone tissue Tissue: epidermis urn:agi-pathway:uuid-f80f7234-e117-4064-a1cc-164e5802f097 Majeed Syndrome uuid-f80f7234-e117-4064-a1cc-164e5802f097 PS:CellType adipocyte PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f80f7234-e117-4064-a1cc-164e5802f097 PS:NodeType Pathway PS:Notes Headnote: Majeed syndrome is an autoinflammatory disorder with chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. Majeed syndrome is typically more severe compared to sporadic CRMO (Chronic Recurrent Multifocal Osteomyelitis) and may be accompanied by recurrent fevers. Majeed syndrome has an autosomal-recessive mode of inheritance and is linked to mutations in the LPIN2 gene, which encodes the lipin 2 protein, expressed in the liver, kidneys, gastrointestinal system, lymphoid tissues, and the bone marrow. Signaling description: Lipin 2 is a phosphatidate phosphatase which plays a role in lipid metabolism, and its role in the control of inflammatory responses is not completely established. Based on findings in the field of obesity-induced chronic inflammation, it has been suggested that fatty acids induce a pro-inflammatory phenotype through the toll-like receptors (TLR) 2 and 4 stimulation which results in the activation of MAPKs, particularly MAPK8, and the induction of the NLRP3 inflammasome. Outcome effects: Cells with increased lipin 2 expression fail to produce pro-inflammatory cytokines, whereas reduced lipin 2 expression mediates increased expression of TNF, IL6, and CCL2. The phosphatase activity of lipin 2 is completely abolished in Majeed patients carrying the LPIN2 mutation, which leads to increased inflammatory responses. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ skin PS:Organ_System skeletal system PS:PMID 22334674 PS:PMID 23087183 PS:PMID 24359092 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue adipose tissue PS:Tissue bone tissue PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: dendritic cell CellType: leukocyte Description: TLR4 is a member of the Toll-like receptor (TLR) family. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f816533d-ef61-426e-adeb-add226dd8c1c NodeType: Pathway Notes: Headnote: TLR4 is a member of the Toll-like receptor (TLR) family. TLRs recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. TLR4 is the primary receptor for LPS on gram-negative bacteria. TLR4 can cause autoimmune disease, when it becomes a receptor for fragments of native DNA/RNA and molecules released by apoptotic cells. The specific signaling cascade activated by TLRs depends on the type of cytoplasmic adaptor molecules. TLR4 acts through both MYD88 and TICAM2-dependent pathways. The MYD88-dependent pathway leads to the activation of NF-kB, MAPK1, MAPK8, IRF5, and p38 MAPK (MAPK14) in addition to the transcription of proinflammatory genes. Activated by TLR4, TICAM2 participates in MYD88-dependent pathway by recruiting TRAF6. The TLR4-TICAM2 association also triggers the activation of IRF3 and IRF7, and thereby the expression of IFNs. Outcome effects: Finally, TLR4 activation results in strong expression of cytokines and proinflammatory proteins by leukocytes. Organ: generic Organ_System: lymphatic system PMID: 20680345 PMID: 23414417 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process Tissue: generic urn:agi-pathway:uuid-f816533d-ef61-426e-adeb-add226dd8c1c TLR4 Signaling in Leukocytes uuid-f816533d-ef61-426e-adeb-add226dd8c1c PS:CellType dendritic cell PS:CellType leukocyte PS:Description TLR4 is a member of the Toll-like receptor (TLR) family. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f816533d-ef61-426e-adeb-add226dd8c1c PS:NodeType Pathway PS:Notes Headnote: TLR4 is a member of the Toll-like receptor (TLR) family. TLRs recognize pathogen-associated molecular patterns (PAMPs) which are small molecular motifs found on pathogens and activate innate immune responses, thereby protecting the organism from infection. Signaling description: Typical PAMPs are bacterial lipopolysaccharide (LPS), bacterial flagellin, lipoteichoic acid from gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses such as dsRNA or unmethylated CpG motifs. TLR4 is the primary receptor for LPS on gram-negative bacteria. TLR4 can cause autoimmune disease, when it becomes a receptor for fragments of native DNA/RNA and molecules released by apoptotic cells. The specific signaling cascade activated by TLRs depends on the type of cytoplasmic adaptor molecules. TLR4 acts through both MYD88 and TICAM2-dependent pathways. The MYD88-dependent pathway leads to the activation of NF-kB, MAPK1, MAPK8, IRF5, and p38 MAPK (MAPK14) in addition to the transcription of proinflammatory genes. Activated by TLR4, TICAM2 participates in MYD88-dependent pathway by recruiting TRAF6. The TLR4-TICAM2 association also triggers the activation of IRF3 and IRF7, and thereby the expression of IFNs. Outcome effects: Finally, TLR4 activation results in strong expression of cytokines and proinflammatory proteins by leukocytes. PS:Organ generic PS:Organ_System lymphatic system PS:PMID 20680345 PS:PMID 23414417 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8610c14-7f9d-44d5-a921-aa5684f882a4 NodeType: Pathway Organ: kidney Organ_System: urinary tract PathwayType: network Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Diseases urn:agi-pathway:uuid-f8610c14-7f9d-44d5-a921-aa5684f882a4 Genes with Mutations Associated with Urea Cycle Disorders uuid-f8610c14-7f9d-44d5-a921-aa5684f882a4 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8610c14-7f9d-44d5-a921-aa5684f882a4 PS:NodeType Pathway PS:Organ kidney PS:Organ_System urinary tract PS:PathwayType network PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cancer cell CellType: glial precursor cell Description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of glioblastoma (GBM). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f890e7d4-f03f-4e14-baa4-e72665a341ae NodeType: Pathway Notes: Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The classical subtype is described by genetic alterations in EGFR, RB1, CDK4, and CCND2 genes with a distinct lack of TP53 mutations. There is also an overexpression of NES in addition to Notch (NOTCH3, JAG1, and LFNG) and Sonic hedgehog (SMO, GAS1, and GLI2) proteins. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: brain Organ_System: nervous system PMID: 20129251 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: nerve tissue urn:agi-pathway:uuid-f890e7d4-f03f-4e14-baa4-e72665a341ae Glioblastoma, Classical Subtype uuid-f890e7d4-f03f-4e14-baa4-e72665a341ae PS:CellType cancer cell PS:CellType glial precursor cell PS:Description The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of glioblastoma (GBM). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f890e7d4-f03f-4e14-baa4-e72665a341ae PS:NodeType Pathway PS:Notes Headnote: Glioblastoma multiforme (GBM) is the most frequent and malignant subtype of glioma. It is subdivided into primary and secondary GBM with distinct disease subtypes that affect patients of different age and develop through different genetic pathways. Signaling description: The Cancer Genome Atlas (TCGA) Research Network recently provided a new molecular classification of GBM. Genomic profiling resulted in a gene-expression-based molecular classification of GBM into 4 distinct subtypes including proneural, neural, classical, and mesenchymal. These subtypes were shown to have divergent clinical courses, prognoses, and treatment responses. The classical subtype is described by genetic alterations in EGFR, RB1, CDK4, and CCND2 genes with a distinct lack of TP53 mutations. There is also an overexpression of NES in addition to Notch (NOTCH3, JAG1, and LFNG) and Sonic hedgehog (SMO, GAS1, and GLI2) proteins. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ brain PS:Organ_System nervous system PS:PMID 20129251 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8a5834e-4d4a-4d04-84cb-0c77e27439e5 NodeType: Pathway Notes: Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. Organ: uterus Organ_System: reproductive system PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biomarkers urn:agi-pathway:uuid-f8a5834e-4d4a-4d04-84cb-0c77e27439e5 Elevated Receptors -> Expression Targets in Uterus uuid-f8a5834e-4d4a-4d04-84cb-0c77e27439e5 PS:Description Elevated receptors were selected from proteins with elevated expression level in normal tissues, from HPA (https://www.proteinatlas.org). Receptor expression targets were selected from the Pathway Studio database. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8a5834e-4d4a-4d04-84cb-0c77e27439e5 PS:NodeType Pathway PS:Notes Elevated receptors are proteins in cell membrane with some level of elevated expression in one of the analyzed tissues according to Human Protein Atlas, 2017 (https://www.proteinatlas.org). Receptor targets are proteins which expression level is regulated by the receptor signaling in the described anatomical part. PS:Organ uterus PS:Organ_System reproductive system PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biomarkers PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8d934be-6af1-4292-a7a2-bd1f8d22e56c NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f8d934be-6af1-4292-a7a2-bd1f8d22e56c Inflammaging+>COVID19 uuid-f8d934be-6af1-4292-a7a2-bd1f8d22e56c PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f8d934be-6af1-4292-a7a2-bd1f8d22e56c PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Regulatory T cells (Tregs) play a central role in T-cell-mediated immune responses and the development of type 1A and fulminant type 1 diabetes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f90d9649-50e4-426d-9351-ad1310503d9e NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Regulatory T-cells (Tregs) play a central role in T-cell-mediated immune responses and the development of type 1A and fulminant type 1 diabetes.CD4 FOXP3 T-cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA FOXP3 low resting Tregs (r-Tregs), CD45RA-FOXP3 high activated Tregs (a-Tregs) and CD45RA-FOXP3 low non-suppressive T cells (non-Tregs). Several islet-related autoantibodies, such as anti-GAD2 antibodies, INS autoantibodies, anti-PTPRN antibodies, and anti-SLC30A8 antibodies have been recognized as markers for type 1A diabetes; however, these antibodies are not cytotoxic. Type 1A diabetes is a T cell-mediated disease with autoimmune response against beta-cells; and T-cells are central players in the development of the autoimmune process. Outcome effects: Tregs play a vital role in suppressing the T cell-mediated immune response. Their dysfunction can cause T cell-mediated autoimmune disease. Several markers for Tregs, including FOXP3, CTLA4, CD25 high (CD25 is the alpha chain of the IL2 receptor), and CD127 low (CD127 is the alpha subunit of the IL7 receptor), have been identified. Among these molecules, CTLA4 may functionally be crucial for Tregs as they suppress the immune response. r-Tregs are able to convert to a-Tregs after and/or during T-cell receptor (TCR) stimulation and suppress the proliferation of responder cells and themselves in a negative feedback manner. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PMID: 15699487 PMID: 21980171 PMID: 23607886 PMID: 9686693 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f90d9649-50e4-426d-9351-ad1310503d9e Treg-Cell Function in Diabetes Mellitus Type 1 uuid-f90d9649-50e4-426d-9351-ad1310503d9e PS:CellType T-cell PS:Description Regulatory T cells (Tregs) play a central role in T-cell-mediated immune responses and the development of type 1A and fulminant type 1 diabetes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f90d9649-50e4-426d-9351-ad1310503d9e PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Signaling description: Regulatory T-cells (Tregs) play a central role in T-cell-mediated immune responses and the development of type 1A and fulminant type 1 diabetes.CD4 FOXP3 T-cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA FOXP3 low resting Tregs (r-Tregs), CD45RA-FOXP3 high activated Tregs (a-Tregs) and CD45RA-FOXP3 low non-suppressive T cells (non-Tregs). Several islet-related autoantibodies, such as anti-GAD2 antibodies, INS autoantibodies, anti-PTPRN antibodies, and anti-SLC30A8 antibodies have been recognized as markers for type 1A diabetes; however, these antibodies are not cytotoxic. Type 1A diabetes is a T cell-mediated disease with autoimmune response against beta-cells; and T-cells are central players in the development of the autoimmune process. Outcome effects: Tregs play a vital role in suppressing the T cell-mediated immune response. Their dysfunction can cause T cell-mediated autoimmune disease. Several markers for Tregs, including FOXP3, CTLA4, CD25 high (CD25 is the alpha chain of the IL2 receptor), and CD127 low (CD127 is the alpha subunit of the IL7 receptor), have been identified. Among these molecules, CTLA4 may functionally be crucial for Tregs as they suppress the immune response. r-Tregs are able to convert to a-Tregs after and/or during T-cell receptor (TCR) stimulation and suppress the proliferation of responder cells and themselves in a negative feedback manner. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:PMID 15699487 PS:PMID 21980171 PS:PMID 23607886 PS:PMID 9686693 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: endothelial cell CellType: smooth muscle myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f915dca1-d4c6-478d-89da-af9ea05da6f5 NodeType: Pathway Organ: blood vessel Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process urn:agi-pathway:uuid-f915dca1-d4c6-478d-89da-af9ea05da6f5 EDNRA/B -> Vascular Motility uuid-f915dca1-d4c6-478d-89da-af9ea05da6f5 PS:CellType endothelial cell PS:CellType smooth muscle myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f915dca1-d4c6-478d-89da-af9ea05da6f5 PS:NodeType Pathway PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9209b75-a81e-4cfa-a4e2-da08f00709d6 NodeType: Pathway Notes: LIPF is the enzyme that is secreted by the chief cells in the stomach. LIPF is important for lipid digestion in duodenal lumen. PNLIP is the enzyme hydrolyzing dietary triglycerides in the adult. Absence of PNLIP results in malabsorption of dietary fat. Organ: pancreas Organ_System: digestive system PMID: 11099794 PMID: 27663184 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process urn:agi-pathway:uuid-f9209b75-a81e-4cfa-a4e2-da08f00709d6 Gastric and Pancreatic Lipase Function uuid-f9209b75-a81e-4cfa-a4e2-da08f00709d6 PS:CellType insulin-secreting cell PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9209b75-a81e-4cfa-a4e2-da08f00709d6 PS:NodeType Pathway PS:Notes LIPF is the enzyme that is secreted by the chief cells in the stomach. LIPF is important for lipid digestion in duodenal lumen. PNLIP is the enzyme hydrolyzing dietary triglycerides in the adult. Absence of PNLIP results in malabsorption of dietary fat. PS:Organ pancreas PS:Organ_System digestive system PS:PMID 11099794 PS:PMID 27663184 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f94022f7-be3c-4e71-839e-a258b2a1cb93 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-f94022f7-be3c-4e71-839e-a258b2a1cb93 Serotonin/Gq Expression Targets uuid-f94022f7-be3c-4e71-839e-a258b2a1cb93 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f94022f7-be3c-4e71-839e-a258b2a1cb93 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Hyperglycemia in beta cells increases glucose oxidation and oxidative stress. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f95f525b-3213-4842-ad37-6e20e3f4647c NodeType: Pathway Notes: Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Signaling description: In beta cells, hyperglycemia increases glucose oxidation and oxidative stress. The major source of oxidative stress is most likely the mitochondrial electron transport chain. Pancreatic islets are known for the extremely low level of expression of H2O2-inactivating enzymes such as catalase and glutathione peroxidase and their unusual susceptibility to reactive oxygen species (ROS). Hyperglycemia has been shown to increase the production of LDHA, UCP2, and CREM in rodent beta-cells. The overexpression of CREM in insulin-secreting rat cells directly suppresses the transcriptional activation of the INS promoter. Chronic exposure to long-chain saturated fatty acids (FFA) is another risk factor for the destruction of beta-cells. When fatty acids are esterified to oleate and palmitate in the ER, the ER stress markers such as XBP1 and ATF6 are induced. ER stress is caused by an accumulation of irreversible misfolded or unfolded protein which leads to beta-cell death. Oleate and palmitate also trigger ER stress through the ER calcium depletion. Palmitate induces a rapid degradation of CPE and this may contribute to ER stress due to an accumulation of unprocessed proinsulin. FFA induces apoptosis in beta cell lines, but the mechanisms are not well understood. The specific toxic effects of FFA may be related to ceramide formation. Ceramide was shown to be implicated in cell apoptosis. PPARD attenuates palmitate-induced ER stress by promoting fatty acid oxidation. In addition, pancreatic beta cells that are chronically exposed to fatty acids show higher CPT1A levels, higher palmitate oxidation rates, and altered insulin response to glucose. Lastly, ST18 is transcriptional factor that is induced by hyperlipidemia and cytokines which triggers beta cell apoptosis. Outcome effects: Hyperglycemia induced oxidative stress in pancreatic beta-cells leads to their apoptiosis. Hyperlipidemia may trigger beta-cell death through oxidative stress, ceramide formation or the persistent endoplasmic reticulum (ER) stress. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity is highlighted in blue. Organ: pancreas Organ_System: endocrine system PMID: 22792088 PMID: 23347443 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-f95f525b-3213-4842-ad37-6e20e3f4647c Hyperglycemia and Hyperlipidemia Trigger beta-Cell Apoptosis uuid-f95f525b-3213-4842-ad37-6e20e3f4647c PS:CellType insulin-secreting cell PS:Description Hyperglycemia in beta cells increases glucose oxidation and oxidative stress. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f95f525b-3213-4842-ad37-6e20e3f4647c PS:NodeType Pathway PS:Notes Headnote: Pancreatic beta-cells are any of the insulin-secreting pancreatic cells in the islets of Langerhans. Signaling description: In beta cells, hyperglycemia increases glucose oxidation and oxidative stress. The major source of oxidative stress is most likely the mitochondrial electron transport chain. Pancreatic islets are known for the extremely low level of expression of H2O2-inactivating enzymes such as catalase and glutathione peroxidase and their unusual susceptibility to reactive oxygen species (ROS). Hyperglycemia has been shown to increase the production of LDHA, UCP2, and CREM in rodent beta-cells. The overexpression of CREM in insulin-secreting rat cells directly suppresses the transcriptional activation of the INS promoter. Chronic exposure to long-chain saturated fatty acids (FFA) is another risk factor for the destruction of beta-cells. When fatty acids are esterified to oleate and palmitate in the ER, the ER stress markers such as XBP1 and ATF6 are induced. ER stress is caused by an accumulation of irreversible misfolded or unfolded protein which leads to beta-cell death. Oleate and palmitate also trigger ER stress through the ER calcium depletion. Palmitate induces a rapid degradation of CPE and this may contribute to ER stress due to an accumulation of unprocessed proinsulin. FFA induces apoptosis in beta cell lines, but the mechanisms are not well understood. The specific toxic effects of FFA may be related to ceramide formation. Ceramide was shown to be implicated in cell apoptosis. PPARD attenuates palmitate-induced ER stress by promoting fatty acid oxidation. In addition, pancreatic beta cells that are chronically exposed to fatty acids show higher CPT1A levels, higher palmitate oxidation rates, and altered insulin response to glucose. Lastly, ST18 is transcriptional factor that is induced by hyperlipidemia and cytokines which triggers beta cell apoptosis. Outcome effects: Hyperglycemia induced oxidative stress in pancreatic beta-cells leads to their apoptiosis. Hyperlipidemia may trigger beta-cell death through oxidative stress, ceramide formation or the persistent endoplasmic reticulum (ER) stress. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity is highlighted in blue. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 22792088 PS:PMID 23347443 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f968e228-6e2a-416d-83e0-521e536f5c36 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-f968e228-6e2a-416d-83e0-521e536f5c36 EGF->EMT uuid-f968e228-6e2a-416d-83e0-521e536f5c36 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f968e228-6e2a-416d-83e0-521e536f5c36 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f973a7fe-f06b-4fc8-877a-bc62126ece39 NodeType: Pathway Notes: Congenital cataract is a common cause of visual disability in children. Inherited isolated (nonsyndromic) cataract represents one-third of all observed cases. At least 22 genes associated with isolated inherited cataract have been identified including the crystallin genes. Crystallins are critical proteins in the human eye lens, and they are responsible for the transparency and refractive index of the lens. Mutations in these genes lead to a reduced accumulation of glutathione and ROS, which together participate in the formation of different types of cataract. Mutations in the MIP gene lead to a separation of the lens structural molecules due to water accumulation within the lens cells. Also, impaired crystallin gene expression is observed when MAF is mutated. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: eye Organ_System: sensory system Organelle: plasma membrane PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-f973a7fe-f06b-4fc8-877a-bc62126ece39 3_Congenital cataract uuid-f973a7fe-f06b-4fc8-877a-bc62126ece39 PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f973a7fe-f06b-4fc8-877a-bc62126ece39 PS:NodeType Pathway PS:Notes Congenital cataract is a common cause of visual disability in children. Inherited isolated (nonsyndromic) cataract represents one-third of all observed cases. At least 22 genes associated with isolated inherited cataract have been identified including the crystallin genes. Crystallins are critical proteins in the human eye lens, and they are responsible for the transparency and refractive index of the lens. Mutations in these genes lead to a reduced accumulation of glutathione and ROS, which together participate in the formation of different types of cataract. Mutations in the MIP gene lead to a separation of the lens structural molecules due to water accumulation within the lens cells. Also, impaired crystallin gene expression is observed when MAF is mutated. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ eye PS:Organ_System sensory system PS:Organelle plasma membrane PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f996bda3-5553-4d2b-883a-3b31a2443f2a NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-f996bda3-5553-4d2b-883a-3b31a2443f2a Ca2+ overload in Huntington uuid-f996bda3-5553-4d2b-883a-3b31a2443f2a PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f996bda3-5553-4d2b-883a-3b31a2443f2a PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: cardiac myocyte Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9df7516-29be-4ee7-b41b-788e4bd58957 NodeType: Pathway Organ: heart Organ_System: cardiovascular system PathwayType: network Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases urn:agi-pathway:uuid-f9df7516-29be-4ee7-b41b-788e4bd58957 Proteins Involved in Myocardial Ischemia uuid-f9df7516-29be-4ee7-b41b-788e4bd58957 PS:CellType cardiac myocyte PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9df7516-29be-4ee7-b41b-788e4bd58957 PS:NodeType Pathway PS:Organ heart PS:Organ_System cardiovascular system PS:PathwayType network PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9efb3ac-59ea-4bf5-8892-f3fb5c837317 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-f9efb3ac-59ea-4bf5-8892-f3fb5c837317 Amino sugars synthesis (bacteria) template uuid-f9efb3ac-59ea-4bf5-8892-f3fb5c837317 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f9efb3ac-59ea-4bf5-8892-f3fb5c837317 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: keratinocyte Description: Ichthyosis vulgaris is the most common ichthyosis, with an incidence of 1:250 to 1:1000. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa25ee7c-2edd-474f-bcd8-dce84a2818b2 NodeType: Pathway Notes: Headnote: Ichthyosis is a family of genetic disorders with dry, scaly and thickened skin. Ichthyosis vulgaris (IV) is the most common form of ichthyosis, with an incidence of 1:250 to 1:1000. IV is the mildest form of hereditary non-syndromic ichthyosis, characterized by xerosis, scaling, pruritus and eczema, and is strongly associated with atopic manifestations. IV is considered a single gene disease caused by mutations in the gene encoding profillagrin, which is the precursor for fillagrin (FLG). Signaling description: Profilaggrin is cleaved by several enzymes and converted into functional filaggrin monomer. The profilaggrin linker domain is cleaved by KLK5. Kallikrein-related peptidase 5(KLK5) is a major serine protease found in the skin, secreted from lamellar granules following its expression in the stratum granulosum and activated in the extracellular space of the stratum corneum. Filaggrin monomers, the product of biochemical processing, bind to keratin 1 or keratin 10 and bundle keratin intermediate filaments in the lower stratum corneum. Filaggrin monomers then undergo citrullination mediated by peptidyl arginine deiminase 1 (PADI1) and PADI3. Deiminated filaggrin monomers are cleaved by calpain 1 and caspase-14, yielding free amino acids following degradation by bleomycin hydrolase in the upper stratum corneum. Free aminoacids serve as natural moisturizing factors in human skin. Overall, a significant role of FLG mutations in the pathogenesis of ichthyosis vulgaris has been proven. Outcome effects: Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and the formation of the protective skin barrier. In the outer granular layer of the epidermis, filaggrin is associated with keratin intermediate filaments and it aids their packing into bundles. In terminal differentiation, filaggrin is cross-linked to the cornified cell envelope, which constitutes an insoluble barrier in the stratum corneum to protect the organism against environmental agents and to prevent epidermal water loss. Animal data: Role of Kallikrein-related peptidase 5(KLK5) as the major serine protease found in the skin for profilaggrin was revealed from animal model experiments. Highlighted proteins: Lipids, amino acids and H2O are highlighted in blue in order to illustrate the disruption of protective skin barrier which causes epidermal water loss in the stratum corneum. Mutated proteins: FLG mutated in IV is shown in white-out style. Organ: skin Organ_System: integumentary system PMID: 23301728 PMID: 23870202 PMID: 26844893 PMID: 26945532 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-fa25ee7c-2edd-474f-bcd8-dce84a2818b2 Ichthyosis Vulgaris uuid-fa25ee7c-2edd-474f-bcd8-dce84a2818b2 PS:CellType keratinocyte PS:Description Ichthyosis vulgaris is the most common ichthyosis, with an incidence of 1:250 to 1:1000. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa25ee7c-2edd-474f-bcd8-dce84a2818b2 PS:NodeType Pathway PS:Notes Headnote: Ichthyosis is a family of genetic disorders with dry, scaly and thickened skin. Ichthyosis vulgaris (IV) is the most common form of ichthyosis, with an incidence of 1:250 to 1:1000. IV is the mildest form of hereditary non-syndromic ichthyosis, characterized by xerosis, scaling, pruritus and eczema, and is strongly associated with atopic manifestations. IV is considered a single gene disease caused by mutations in the gene encoding profillagrin, which is the precursor for fillagrin (FLG). Signaling description: Profilaggrin is cleaved by several enzymes and converted into functional filaggrin monomer. The profilaggrin linker domain is cleaved by KLK5. Kallikrein-related peptidase 5(KLK5) is a major serine protease found in the skin, secreted from lamellar granules following its expression in the stratum granulosum and activated in the extracellular space of the stratum corneum. Filaggrin monomers, the product of biochemical processing, bind to keratin 1 or keratin 10 and bundle keratin intermediate filaments in the lower stratum corneum. Filaggrin monomers then undergo citrullination mediated by peptidyl arginine deiminase 1 (PADI1) and PADI3. Deiminated filaggrin monomers are cleaved by calpain 1 and caspase-14, yielding free amino acids following degradation by bleomycin hydrolase in the upper stratum corneum. Free aminoacids serve as natural moisturizing factors in human skin. Overall, a significant role of FLG mutations in the pathogenesis of ichthyosis vulgaris has been proven. Outcome effects: Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and the formation of the protective skin barrier. In the outer granular layer of the epidermis, filaggrin is associated with keratin intermediate filaments and it aids their packing into bundles. In terminal differentiation, filaggrin is cross-linked to the cornified cell envelope, which constitutes an insoluble barrier in the stratum corneum to protect the organism against environmental agents and to prevent epidermal water loss. Animal data: Role of Kallikrein-related peptidase 5(KLK5) as the major serine protease found in the skin for profilaggrin was revealed from animal model experiments. Highlighted proteins: Lipids, amino acids and H2O are highlighted in blue in order to illustrate the disruption of protective skin barrier which causes epidermal water loss in the stratum corneum. Mutated proteins: FLG mutated in IV is shown in white-out style. PS:Organ skin PS:Organ_System integumentary system PS:PMID 23301728 PS:PMID 23870202 PS:PMID 26844893 PS:PMID 26945532 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa30e1ed-7474-46a2-b83a-dac4cec4d4c8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-fa30e1ed-7474-46a2-b83a-dac4cec4d4c8 COVID-19 Mutated genes uuid-fa30e1ed-7474-46a2-b83a-dac4cec4d4c8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa30e1ed-7474-46a2-b83a-dac4cec4d4c8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: sensory hair cell Description: Cochlear hair cell stereocilia proteins mutations are often cause congenital hearing loss due to impairment of stereocilia movement and mechanoelectrical transduction. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa6a3487-fca6-4e47-b29b-595b68e2ad42 NodeType: Pathway Notes: Headnote: Congenital hearing loss is a hearing loss present at birth or developed later due to genetic causes. Genetic factors are thought to cause more than 50% of all incidents of congenital hearing loss. Hereditary hearing loss and deafness may be syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (with no associated visible abnormalities of the external ear or any related medical problems). Hereditary hearing loss can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner, as well as by mitochondrial inheritance. Signaling description: Many genes mutated in congenital hearing loss are implicated in actin-myosin complex organization or associated with it's functioning. A number of myosins may be mutated, such as MYO3A (recessive hearing loss DFNB30), MYO6 (dominant and recessive hearing loss DFNA22 and DFNB37, respectively), MYO7A (dominant and recessive hearing loss DFNA11 and DFNB2, respectively) and MYO15A (recessive hearing loss DFNB3), MYO1A (dominant hearing loss DFNA48), MYO1C and MYO1F. Two non-muscle conventional myosins, MYH9 (dominant hearing loss DFNA17) and MYH14 (dominant hearing loss DFNA4), are associated with non-syndromic hearing loss. MYO7A mutations are also responsible for Usher syndrome type IB. Actin, gamma 1 (ACTG1) mutations are associated with DFNA20/26, a subtype of autosomal dominant hearing loss. HOMER2 exerts its function by regulating actin dynamics in stereocilia through its interaction with CDC42 and may be mutated in non-syndromic hearing loss. DIAPH1 have a role in the regulation of actin polymerization and may be mutated in non-syndromic hearing loss. TPRN may modulate actin dynamics through direct or indirect interaction with pointed ends of actin filaments, particularly within the hair cell stereocilia and may be mutated in non-syndromic hearing loss. CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with RDX, TPRN and MYO6. RDX may be mutated in non-syndromic hearing loss. CEACAM16 is localizes to the tips of the tallest stereocilia and the tectorial membrane (TM). This specific localization suggests a role in maintaining the integrity of the TM as well as in the association of the stereocilia and TM, a linkage essential for mechanical amplification. In agreement with this role, CEACAM16 colocalizes and coimmunoprecipitates with the TM protein TECTA (alpha-tectorin). Mutation of CEACAM16 leads to autosomal dominant nonsyndromic deafness (DFNA4). Mutations in the TECTA gene have been shown to be responsible for autosomal dominant nonsyndromic hearing impairment and a recessive form of sensorineural pre-lingual non-syndromic deafness. PTPRQ and STRC are implicated in side binding between stereocilia. The cytoplasmic domain of PTPRQ associates with a juxtamembrane protein complex (blue spheres), which includes CLIC5, RDX, MYO6, and/or TPRN, thereby linking PTPRQ to actin filaments at the tapered base of stereocilia, as well as linking actin filaments of the cuticular plate and the interstereocilia membrane domain. PTPRQ and STRC mutation cause non-syndromic hearing loss. MARVELD2 (deafness autosomal recessive type 49 (DFNB49)), TJP2 (autosomal dominant deafness-51) and CLDN14 normally take part in tight junctions assembly and may be mutated in non-syndromic hearing loss. SLC26A5 (prestin) is a transmembrane protein and an incomplete anion transporter, it does not allow anions to cross the cell membrane, but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. SLC26A5 contracts and elongates leading to electromotility of outer hair cells. Electromotility is the driving force behind the somatic motor of the cochlear amplifier, which is a mammalian evolution product that increases sensitivity to incoming sound wave freq Organ: ear Organ_System: sensory system PMID: 20624897 PMID: 21165971 PMID: 22544735 PMID: 23732235 PMID: 24105371 PMID: 25816005 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-fa6a3487-fca6-4e47-b29b-595b68e2ad42 Cochlear Hair Cell Stereocilia Proteins Mutations (Congenital Deafness) uuid-fa6a3487-fca6-4e47-b29b-595b68e2ad42 PS:CellType sensory hair cell PS:Description Cochlear hair cell stereocilia proteins mutations are often cause congenital hearing loss due to impairment of stereocilia movement and mechanoelectrical transduction. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fa6a3487-fca6-4e47-b29b-595b68e2ad42 PS:NodeType Pathway PS:Notes Headnote: Congenital hearing loss is a hearing loss present at birth or developed later due to genetic causes. Genetic factors are thought to cause more than 50% of all incidents of congenital hearing loss. Hereditary hearing loss and deafness may be syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (with no associated visible abnormalities of the external ear or any related medical problems). Hereditary hearing loss can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner, as well as by mitochondrial inheritance. Signaling description: Many genes mutated in congenital hearing loss are implicated in actin-myosin complex organization or associated with it's functioning. A number of myosins may be mutated, such as MYO3A (recessive hearing loss DFNB30), MYO6 (dominant and recessive hearing loss DFNA22 and DFNB37, respectively), MYO7A (dominant and recessive hearing loss DFNA11 and DFNB2, respectively) and MYO15A (recessive hearing loss DFNB3), MYO1A (dominant hearing loss DFNA48), MYO1C and MYO1F. Two non-muscle conventional myosins, MYH9 (dominant hearing loss DFNA17) and MYH14 (dominant hearing loss DFNA4), are associated with non-syndromic hearing loss. MYO7A mutations are also responsible for Usher syndrome type IB. Actin, gamma 1 (ACTG1) mutations are associated with DFNA20/26, a subtype of autosomal dominant hearing loss. HOMER2 exerts its function by regulating actin dynamics in stereocilia through its interaction with CDC42 and may be mutated in non-syndromic hearing loss. DIAPH1 have a role in the regulation of actin polymerization and may be mutated in non-syndromic hearing loss. TPRN may modulate actin dynamics through direct or indirect interaction with pointed ends of actin filaments, particularly within the hair cell stereocilia and may be mutated in non-syndromic hearing loss. CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with RDX, TPRN and MYO6. RDX may be mutated in non-syndromic hearing loss. CEACAM16 is localizes to the tips of the tallest stereocilia and the tectorial membrane (TM). This specific localization suggests a role in maintaining the integrity of the TM as well as in the association of the stereocilia and TM, a linkage essential for mechanical amplification. In agreement with this role, CEACAM16 colocalizes and coimmunoprecipitates with the TM protein TECTA (alpha-tectorin). Mutation of CEACAM16 leads to autosomal dominant nonsyndromic deafness (DFNA4). Mutations in the TECTA gene have been shown to be responsible for autosomal dominant nonsyndromic hearing impairment and a recessive form of sensorineural pre-lingual non-syndromic deafness. PTPRQ and STRC are implicated in side binding between stereocilia. The cytoplasmic domain of PTPRQ associates with a juxtamembrane protein complex (blue spheres), which includes CLIC5, RDX, MYO6, and/or TPRN, thereby linking PTPRQ to actin filaments at the tapered base of stereocilia, as well as linking actin filaments of the cuticular plate and the interstereocilia membrane domain. PTPRQ and STRC mutation cause non-syndromic hearing loss. MARVELD2 (deafness autosomal recessive type 49 (DFNB49)), TJP2 (autosomal dominant deafness-51) and CLDN14 normally take part in tight junctions assembly and may be mutated in non-syndromic hearing loss. SLC26A5 (prestin) is a transmembrane protein and an incomplete anion transporter, it does not allow anions to cross the cell membrane, but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. SLC26A5 contracts and elongates leading to electromotility of outer hair cells. Electromotility is the driving force behind the somatic motor of the cochlear amplifier, which is a mammalian evolution product that increases sensitivity to incoming sound wave freq PS:Organ ear PS:Organ_System sensory system PS:PMID 20624897 PS:PMID 21165971 PS:PMID 22544735 PS:PMID 23732235 PS:PMID 24105371 PS:PMID 25816005 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac4b712-2c07-4beb-ae0a-51988895b6f1 NodeType: Pathway Organ: generic Organ_System: generic PMID: 19931639 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-fac4b712-2c07-4beb-ae0a-51988895b6f1 Androgen Receptor non-Genomic Signaling uuid-fac4b712-2c07-4beb-ae0a-51988895b6f1 PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac4b712-2c07-4beb-ae0a-51988895b6f1 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19931639 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: The second generation antipsychotic drug (SGA), olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac537b6-4758-4272-a603-60d767816867 NodeType: Pathway Notes: Headnote: The second generation antipsychotic drug (SGA) olanzapine has been shown to be efficient in treatment of schizophrenia; however, the drug can cause obesity and type II diabetes mellitus. Signaling description: Low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergic-stimulated insulin secretion by blocking CHRM3 expressed on pancreatic beta-cells. Organ: pancreas Organ_System: endocrine system PMID: 15855345 PMID: 21982116 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fac537b6-4758-4272-a603-60d767816867 Olanzapine Effect on Insulin Secretion in Diabetes Mellitus uuid-fac537b6-4758-4272-a603-60d767816867 PS:CellType insulin-secreting cell PS:Description The second generation antipsychotic drug (SGA), olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac537b6-4758-4272-a603-60d767816867 PS:NodeType Pathway PS:Notes Headnote: The second generation antipsychotic drug (SGA) olanzapine has been shown to be efficient in treatment of schizophrenia; however, the drug can cause obesity and type II diabetes mellitus. Signaling description: Low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergic-stimulated insulin secretion by blocking CHRM3 expressed on pancreatic beta-cells. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 15855345 PS:PMID 21982116 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac71f54-2f8a-4ab5-9d72-cb959ae2e317 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-fac71f54-2f8a-4ab5-9d72-cb959ae2e317 Wnt-->IR uuid-fac71f54-2f8a-4ab5-9d72-cb959ae2e317 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fac71f54-2f8a-4ab5-9d72-cb959ae2e317 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fad28742-a6ca-4fd6-818f-5fb66c26b2f0 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-fad28742-a6ca-4fd6-818f-5fb66c26b2f0 Malonate, Propanoate and beta-Alanine Metabolism uuid-fad28742-a6ca-4fd6-818f-5fb66c26b2f0 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fad28742-a6ca-4fd6-818f-5fb66c26b2f0 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Clozapine is an atypical antipsychotic agent used in the treatment of schizophrenia. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb1caa87-b8dd-406c-a418-2122a440c811 NodeType: Pathway Notes: Headnote: Clozapine is an atypical antipsychotic agent used in the treatment of schizophrenia. Signaling description: The use of clozapine requires blood monitoring since it has been shown to cause agranulocytosis, which could prove fatal if not detected early. Agranulocytosis can be a result of hematopoiesis inhibition at the level of cytokines. Granulocyte (CSF3) and granulocyte-macrophage (CSF2) colony-stimulating factors (CSFs) are hematopoietic cytokines produced by monocytes, fibroblasts, and endothelial cells. CSFs are known to have multiple functions in normal, steady-state hematopoiesis such as the regulation of granulocyte production and release from the bone marrow and white blood cell proliferation/differentiation. They are used clinically to repair irradiation and chemotherapy-associated suppression of normal hematopoiesis in cancer patients and to stimulate normal granulocyte development in patients with infantile congenital agranulocytosis. Outcome effects: Clozapine treatment results in an immune system response and decreased production of CSFs. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Pathological Process Tissue: generic urn:agi-pathway:uuid-fb1caa87-b8dd-406c-a418-2122a440c811 Clozapine Induced Granulocytopenia uuid-fb1caa87-b8dd-406c-a418-2122a440c811 PS:CellType generic PS:Description Clozapine is an atypical antipsychotic agent used in the treatment of schizophrenia. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb1caa87-b8dd-406c-a418-2122a440c811 PS:NodeType Pathway PS:Notes Headnote: Clozapine is an atypical antipsychotic agent used in the treatment of schizophrenia. Signaling description: The use of clozapine requires blood monitoring since it has been shown to cause agranulocytosis, which could prove fatal if not detected early. Agranulocytosis can be a result of hematopoiesis inhibition at the level of cytokines. Granulocyte (CSF3) and granulocyte-macrophage (CSF2) colony-stimulating factors (CSFs) are hematopoietic cytokines produced by monocytes, fibroblasts, and endothelial cells. CSFs are known to have multiple functions in normal, steady-state hematopoiesis such as the regulation of granulocyte production and release from the bone marrow and white blood cell proliferation/differentiation. They are used clinically to repair irradiation and chemotherapy-associated suppression of normal hematopoiesis in cancer patients and to stimulate normal granulocyte development in patients with infantile congenital agranulocytosis. Outcome effects: Clozapine treatment results in an immune system response and decreased production of CSFs. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Pathological Process PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb1d0231-9541-4362-ab96-4ba0c04c9527 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-fb1d0231-9541-4362-ab96-4ba0c04c9527 Inositol Phosphate Metabolism uuid-fb1d0231-9541-4362-ab96-4ba0c04c9527 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb1d0231-9541-4362-ab96-4ba0c04c9527 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb3d6053-373b-49cb-8a5f-86b256b30b33 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-fb3d6053-373b-49cb-8a5f-86b256b30b33 ActivinR -> SMAD2/3 Signaling uuid-fb3d6053-373b-49cb-8a5f-86b256b30b33 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb3d6053-373b-49cb-8a5f-86b256b30b33 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: adrenal cortex cell Description: Mineralocorticoids secretion is regulated by ACTH, AVP, AGT and EDN1. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb51a991-1a85-4329-9794-880edfb1b417 NodeType: Pathway Notes: Headnote: Mineralcorticoids are a class of steroid hormones that control salt and water balances. Mineralcorticoids are produced in the zona glomerulosa of the cortex of the adrenal gland and its secretion is principally mediated by angiotensin II (AGT) and adrenocorticotrophic hormone (ACTH) but also by other substances. Signaling description: Cholesterol is the precursor for mineralocorticoids. Cholesterol is transported from cellular stores to the outer mitochondrial membrane, where steroidogenic acute regulatory (STAR) protein facilitates the movement of cholesterol into the inner mitochondrial membrane. STAR mediated transport of cholesterol is the limiting step in corticoid production. In zona glomerulosa of adrenal cortex, CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is hydrolyzed to desoxycorticosterone by CYP21A2. CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. ACTH (adrenocorticotropic hormone) and AVP (vasopressin) bind MC2R and AVPR2 and cause the activation of ADCY/cAMP/PKA/STAR signaling. AGT (angiotensin) and EDN1 (endothelin) activate AGTR1 and EDNRA/B and cause PLCB1/DAG/PKC/CREB1 signaling stimulation. Activation of voltage-dependent L-type calcium channels (CACNA1C/CACNA2D1/CACNB2) increases Ca2+ influx that induces CAMK1, which in turn phosphorylates and activates CREB1. Further, CREB1 promotes STAR expression. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: The secretion of mineralocorticoids is regulated by ACTH, AVP, AGT and EDN1. Organ: adrenal gland Organ_System: endocrine system PMID: 23568484 PMID: 24944029 PMID: 26051166 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Biological Process urn:agi-pathway:uuid-fb51a991-1a85-4329-9794-880edfb1b417 Mineralcorticoids Secretion Regulation uuid-fb51a991-1a85-4329-9794-880edfb1b417 PS:CellType adrenal cortex cell PS:Description Mineralocorticoids secretion is regulated by ACTH, AVP, AGT and EDN1. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb51a991-1a85-4329-9794-880edfb1b417 PS:NodeType Pathway PS:Notes Headnote: Mineralcorticoids are a class of steroid hormones that control salt and water balances. Mineralcorticoids are produced in the zona glomerulosa of the cortex of the adrenal gland and its secretion is principally mediated by angiotensin II (AGT) and adrenocorticotrophic hormone (ACTH) but also by other substances. Signaling description: Cholesterol is the precursor for mineralocorticoids. Cholesterol is transported from cellular stores to the outer mitochondrial membrane, where steroidogenic acute regulatory (STAR) protein facilitates the movement of cholesterol into the inner mitochondrial membrane. STAR mediated transport of cholesterol is the limiting step in corticoid production. In zona glomerulosa of adrenal cortex, CYP11A1 converts cholesterol to pregnenolone and HSD3B2 catalyzes the oxidative conversion of pregnenolone to progesterone. Progesterone is hydrolyzed to desoxycorticosterone by CYP21A2. CYP11B1 and CYP11B2 convert desoxycorticosterone to corticosterone and corticosterone to aldosterone, respectively. ACTH (adrenocorticotropic hormone) and AVP (vasopressin) bind MC2R and AVPR2 and cause the activation of ADCY/cAMP/PKA/STAR signaling. AGT (angiotensin) and EDN1 (endothelin) activate AGTR1 and EDNRA/B and cause PLCB1/DAG/PKC/CREB1 signaling stimulation. Activation of voltage-dependent L-type calcium channels (CACNA1C/CACNA2D1/CACNB2) increases Ca2+ influx that induces CAMK1, which in turn phosphorylates and activates CREB1. Further, CREB1 promotes STAR expression. The described mechanism of molecular signaling is known in general terms and is depicted on the pathway. Outcome effects: The secretion of mineralocorticoids is regulated by ACTH, AVP, AGT and EDN1. PS:Organ adrenal gland PS:Organ_System endocrine system PS:PMID 23568484 PS:PMID 24944029 PS:PMID 26051166 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb5add4e-2248-466c-ada7-7ff8ff97c203 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fb5add4e-2248-466c-ada7-7ff8ff97c203 AVP/Gq -> STAT Expression Targets uuid-fb5add4e-2248-466c-ada7-7ff8ff97c203 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb5add4e-2248-466c-ada7-7ff8ff97c203 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb677b13-c80a-4d58-8fa6-fef22b0d74bb NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-fb677b13-c80a-4d58-8fa6-fef22b0d74bb Omega-3-Fatty Acid Metabolism uuid-fb677b13-c80a-4d58-8fa6-fef22b0d74bb PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb677b13-c80a-4d58-8fa6-fef22b0d74bb PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb6d5491-83d6-41f9-9559-49d2ed03cc9b NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-fb6d5491-83d6-41f9-9559-49d2ed03cc9b SMN1->axonogenesis uuid-fb6d5491-83d6-41f9-9559-49d2ed03cc9b PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb6d5491-83d6-41f9-9559-49d2ed03cc9b PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: Regulatory T (Treg) cells are a component of the immune system that suppresses immune responses of other cells. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb881fd8-5e85-40f4-9f0b-99f963e906b5 NodeType: Pathway Notes: Headnote: Regulatory T (Treg) cells are a component of the immune system that suppresses immune responses of other cells. Signaling description: The most studied Treg cells are those that express CD4, CD25, and FOXP3. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms and also participate in preventing autoimmunity. Treg cell differentiation requires STAT5 activation through IL2 signaling. In addition to IL2, ""natural"" regulatory T-cells (nTregs) and ""induced""regulatory T cells (iTregs) need TGFB1 for their survival in addition to FOXP3 expression. FOXP3 is a transcription factor that determines Treg differentiation and function. FOXP3 can act as a transcriptional activator or repressor since it regulates cytokine gene transcription in effector and Treg cells. FOXP3 and GATA3 physically associate with each other and this direct association and cross-inhibition creates a balancing act between transcription factor dominance and T-cell differentiation. Outcome effects: Treg cells can decrease effector T-lymphocyte IL2 expression, however, it is not known if this is a direct effect by Treg cells on T-cells or an indirect effect caused by Treg inhibition of T-cell proliferation. Organ: lymph node Organ_System: lymphatic system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Biological Process urn:agi-pathway:uuid-fb881fd8-5e85-40f4-9f0b-99f963e906b5 Treg-Cell Differentiation uuid-fb881fd8-5e85-40f4-9f0b-99f963e906b5 PS:CellType T-cell PS:Description Regulatory T (Treg) cells are a component of the immune system that suppresses immune responses of other cells. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb881fd8-5e85-40f4-9f0b-99f963e906b5 PS:NodeType Pathway PS:Notes Headnote: Regulatory T (Treg) cells are a component of the immune system that suppresses immune responses of other cells. Signaling description: The most studied Treg cells are those that express CD4, CD25, and FOXP3. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms and also participate in preventing autoimmunity. Treg cell differentiation requires STAT5 activation through IL2 signaling. In addition to IL2, ""natural"" regulatory T-cells (nTregs) and ""induced""regulatory T cells (iTregs) need TGFB1 for their survival in addition to FOXP3 expression. FOXP3 is a transcription factor that determines Treg differentiation and function. FOXP3 can act as a transcriptional activator or repressor since it regulates cytokine gene transcription in effector and Treg cells. FOXP3 and GATA3 physically associate with each other and this direct association and cross-inhibition creates a balancing act between transcription factor dominance and T-cell differentiation. Outcome effects: Treg cells can decrease effector T-lymphocyte IL2 expression, however, it is not known if this is a direct effect by Treg cells on T-cells or an indirect effect caused by Treg inhibition of T-cell proliferation. PS:Organ lymph node PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb8e9c56-06de-4b56-98bc-d5576e91a394 NodeType: Pathway Notes: Mutated genes and the related dysfunction of immune system, environmental stress, and an unhealthy lifestyle exhaust the pancreas and lead to apoptosis of pancreatic cells. Pathogens, viruses, and apoptotic signals from dying cells drive the acceleration of beta-cell apoptosis, and in addition, they stimulate pancreatic antigen-presenting cells first followed by T-cell activation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-fb8e9c56-06de-4b56-98bc-d5576e91a394 1_Antigen-presenting cells promote islet dysfunction and immune system activation in T1D uuid-fb8e9c56-06de-4b56-98bc-d5576e91a394 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb8e9c56-06de-4b56-98bc-d5576e91a394 PS:NodeType Pathway PS:Notes Mutated genes and the related dysfunction of immune system, environmental stress, and an unhealthy lifestyle exhaust the pancreas and lead to apoptosis of pancreatic cells. Pathogens, viruses, and apoptotic signals from dying cells drive the acceleration of beta-cell apoptosis, and in addition, they stimulate pancreatic antigen-presenting cells first followed by T-cell activation. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb9ce934-26fb-4af6-8db3-5b3b1ef87d0c NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fb9ce934-26fb-4af6-8db3-5b3b1ef87d0c TNF -> NF-kB Expression Targets uuid-fb9ce934-26fb-4af6-8db3-5b3b1ef87d0c PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fb9ce934-26fb-4af6-8db3-5b3b1ef87d0c PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fbb5d3a2-b37c-4def-ad31-dfbcc96bbe30 NodeType: Pathway Notes: The stabilization of the three-dimensional structure and the membrane surface provides stable support of the structure and activity of dendritic spine. Pathway is built manually using published studies. Organ: brain Organ_System: nervous system PMID: 20962234 PMID: 21423166 PMID: 22767509 PMID: 23839597 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-fbb5d3a2-b37c-4def-ad31-dfbcc96bbe30 Dendritic Spine Morphogenesis and Stabilization uuid-fbb5d3a2-b37c-4def-ad31-dfbcc96bbe30 PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fbb5d3a2-b37c-4def-ad31-dfbcc96bbe30 PS:NodeType Pathway PS:Notes The stabilization of the three-dimensional structure and the membrane surface provides stable support of the structure and activity of dendritic spine. Pathway is built manually using published studies. PS:Organ brain PS:Organ_System nervous system PS:PMID 20962234 PS:PMID 21423166 PS:PMID 22767509 PS:PMID 23839597 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fbe34808-e6e8-4b17-8fed-1c148a682a41 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fbe34808-e6e8-4b17-8fed-1c148a682a41 IGF2 -> CEBPA/FOXO1A Expression Targets uuid-fbe34808-e6e8-4b17-8fed-1c148a682a41 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fbe34808-e6e8-4b17-8fed-1c148a682a41 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc1b633a-a062-45d8-8d21-9d06782702ec NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-fc1b633a-a062-45d8-8d21-9d06782702ec Ergosterol biosynthesis template uuid-fc1b633a-a062-45d8-8d21-9d06782702ec PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc1b633a-a062-45d8-8d21-9d06782702ec PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Eukaryotic translation is the process by which messenger RNA (mRNA) is translated into polypeptides. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc2e420b-bcd2-49ea-88a6-e6c1c144e700 NodeType: Pathway Notes: Headnote: RNA gene silencing is the process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. Signaling description: In all organisms, the mechanism for RNA silencing involves cutting of double-stranded RNA (dsRNA) into smaller pieces. When dsRNA is exogenous, such as viral RNA, it is imported directly into the cytoplasm and cleaved into short fragments. The initiating dsRNA may also be endogenous, originating in the cell, and expressed from RNA-coding genes in the genome. The cutting of dsRNA into smaller pieces is carried out by DICER1 in an ATP-dependent reaction. DICER1 cleaves dsRNA into two classes of smaller RNAs including microRNAs (miRNAs) and small interfering RNAs (siRNAs) that are 21-25 nucleotides long. The miRNAs are expressed polycistronically and endogenously. Let-7 (miR-let-7) family genes code for miRNAs that are highly conserved across species in sequence and function. The miRNA genes are generally transcribed by RNA polymerase II. The dsRNA structure of the hairpins in primary-miRNA (pri-miRNA) is recognized by DGCR8 which cleaves the RNA and releases the hairpins to form precursor-miRNA (pre-miRNA). Pre-miRNA hairpins are exported from the nucleus in a process involving exportin 5 (XPO5). Silencing RNA (siRNA) is a short dsRNA that results from being processed by DICER1 which cleaves exogenous long dsRNAs. The siRNAs have 2 strands with a 5' phosphate group and a 3' hydroxyl group. Outcome effects: As a result, two dsRNA pathways converge at the RISC complex. Each siRNA and miRNA is unwound into two single-stranded RNAs (ssRNAs), the passenger strand and guide strand. The passenger strand is degraded and the guide strand is incorporated into the RISC complex. A recent consensus model suggests that EIF2C2 is the core component of the RISC complex that directly receives the double-stranded siRNA and cleaves the siRNA passenger strand. In siRNA-guided RNA silencing, RISC complex cleaves the target mRNA at a single site in the center of the duplex region between the guide siRNA and the target mRNA, resulting in gene silencing. In contrast, miRNAs typically have incomplete base pairing to a target and thus may inhibit translation of many different mRNAs with similar sequences. Cellular proteins interacting with DICER1, such as FMR, TARBP2, and PRKRA, are also key regulators of RISC complex and DICER1 activity. Organ: generic Organ_System: generic PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Cell Process Tissue: generic urn:agi-pathway:uuid-fc2e420b-bcd2-49ea-88a6-e6c1c144e700 Translation uuid-fc2e420b-bcd2-49ea-88a6-e6c1c144e700 PS:CellType generic PS:Description Eukaryotic translation is the process by which messenger RNA (mRNA) is translated into polypeptides. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc2e420b-bcd2-49ea-88a6-e6c1c144e700 PS:NodeType Pathway PS:Notes Headnote: RNA gene silencing is the process of downregulation or entire suppression of gene expression in a sequence-specific manner at the mRNA level by noncoding RNA molecules. Signaling description: In all organisms, the mechanism for RNA silencing involves cutting of double-stranded RNA (dsRNA) into smaller pieces. When dsRNA is exogenous, such as viral RNA, it is imported directly into the cytoplasm and cleaved into short fragments. The initiating dsRNA may also be endogenous, originating in the cell, and expressed from RNA-coding genes in the genome. The cutting of dsRNA into smaller pieces is carried out by DICER1 in an ATP-dependent reaction. DICER1 cleaves dsRNA into two classes of smaller RNAs including microRNAs (miRNAs) and small interfering RNAs (siRNAs) that are 21-25 nucleotides long. The miRNAs are expressed polycistronically and endogenously. Let-7 (miR-let-7) family genes code for miRNAs that are highly conserved across species in sequence and function. The miRNA genes are generally transcribed by RNA polymerase II. The dsRNA structure of the hairpins in primary-miRNA (pri-miRNA) is recognized by DGCR8 which cleaves the RNA and releases the hairpins to form precursor-miRNA (pre-miRNA). Pre-miRNA hairpins are exported from the nucleus in a process involving exportin 5 (XPO5). Silencing RNA (siRNA) is a short dsRNA that results from being processed by DICER1 which cleaves exogenous long dsRNAs. The siRNAs have 2 strands with a 5' phosphate group and a 3' hydroxyl group. Outcome effects: As a result, two dsRNA pathways converge at the RISC complex. Each siRNA and miRNA is unwound into two single-stranded RNAs (ssRNAs), the passenger strand and guide strand. The passenger strand is degraded and the guide strand is incorporated into the RISC complex. A recent consensus model suggests that EIF2C2 is the core component of the RISC complex that directly receives the double-stranded siRNA and cleaves the siRNA passenger strand. In siRNA-guided RNA silencing, RISC complex cleaves the target mRNA at a single site in the center of the duplex region between the guide siRNA and the target mRNA, resulting in gene silencing. In contrast, miRNAs typically have incomplete base pairing to a target and thus may inhibit translation of many different mRNAs with similar sequences. Cellular proteins interacting with DICER1, such as FMR, TARBP2, and PRKRA, are also key regulators of RISC complex and DICER1 activity. PS:Organ generic PS:Organ_System generic PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Cell Process PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc3484b1-94f5-4634-a776-da07942c12fc NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fc3484b1-94f5-4634-a776-da07942c12fc FGF7 -> AP-1/CREB/CREBBP/MYC Expression Targets uuid-fc3484b1-94f5-4634-a776-da07942c12fc PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc3484b1-94f5-4634-a776-da07942c12fc PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: osteoclast Description: Osteoclast-mediated bone resorption occurs via ruffled-border membrane. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc44b5bf-4406-406e-8af3-145c713717c9 NodeType: Pathway Notes: Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Excessive bone resorption by osteoclasts is one of the fundamental pathological processes in osteoporosis. Signaling description: Osteoclast-mediated bone resorption occurs via ruffled-border membrane and can be divided into two steps: demineralization by secretion of protons onto the bone surface and proteolytic resorption of exposed organic matrix primarily composed by collagen type I. Bone surface undergoes demineralization due to increased proton secretion by activated osteoclasts. Protons are formed within osteoclasts as a result of the dissociation of carbonic acid produced by CA2 (carbonic anhydrase 2) from CO2 and H2O and pumped out by V-ATPase. In addition, CTSK elevation occurs in osteoporosis. TNF, IFNG, TNFSF11, and the decrease of estrogens provide increased expression of the protein. Outcome effects: Protons on the bone surface provide the low pH required for the activation and function of CTSK and also promotes the release of Ca2+ from hydroxylapatite. CTSK degrades collagen type I in the telopeptide regions and cleaves the triple helical domains at multiple sites. The degradation of bone matrix and demineralization causes bone loss in osteoporosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 15876399 PMID: 16322775 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-fc44b5bf-4406-406e-8af3-145c713717c9 Bone Resorption by Osteoclasts in Osteoporosis uuid-fc44b5bf-4406-406e-8af3-145c713717c9 PS:CellType osteoclast PS:Description Osteoclast-mediated bone resorption occurs via ruffled-border membrane. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc44b5bf-4406-406e-8af3-145c713717c9 PS:NodeType Pathway PS:Notes Headnote: Osteoporosis is a disease characterized by loss of bone strength which increases the risk of fragility fractures. Excessive bone resorption by osteoclasts is one of the fundamental pathological processes in osteoporosis. Signaling description: Osteoclast-mediated bone resorption occurs via ruffled-border membrane and can be divided into two steps: demineralization by secretion of protons onto the bone surface and proteolytic resorption of exposed organic matrix primarily composed by collagen type I. Bone surface undergoes demineralization due to increased proton secretion by activated osteoclasts. Protons are formed within osteoclasts as a result of the dissociation of carbonic acid produced by CA2 (carbonic anhydrase 2) from CO2 and H2O and pumped out by V-ATPase. In addition, CTSK elevation occurs in osteoporosis. TNF, IFNG, TNFSF11, and the decrease of estrogens provide increased expression of the protein. Outcome effects: Protons on the bone surface provide the low pH required for the activation and function of CTSK and also promotes the release of Ca2+ from hydroxylapatite. CTSK degrades collagen type I in the telopeptide regions and cleaves the triple helical domains at multiple sites. The degradation of bone matrix and demineralization causes bone loss in osteoporosis. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Mutated genes: Mutated gene is shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 15876399 PS:PMID 16322775 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: L-cell Description: L-cells produce GCG and PYY and regulate appetite, satiety and insulin release. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc467102-0124-476b-81a6-a31084c0a773 NodeType: Pathway Notes: Headnote: L-cells are located at the distal part of small intestine. These cells produce glucagon and peptide YY and secrete serotonin. Also, L-cells are involved in the intestinal carbohydrate absorption. Signaling description: L-cells can be activated by many nutrients. The taste receptors (heterodimer TAS1R3/ TAS1R2 and TAS2Rs) interact with GNAT3 leading to activation of PLCB2/ITPR1/Ca2+ signaling. Other receptors activate ADCY/cAMP pathway via interaction with G-proteins. Both pathways lead to the activation of PKA and PKC. These protein kinases activate the expression of GCG. In addition, PKA activates the expression of proprotein convertases necessary for GCG processing. PKA and PKC stimulate PYY secretion. Dipeptidyl peptidase 4 (DPP4) is involved in the processing of both peptides: GCG and PYY. PKA regulates the expression of SLC5A1 which is a key player of intestinal carbohydrate absorption. PKC also regulates serotonin secretion. Outcome effects: GCG and PYY produced by L-cells regulate appetite, satiety and insulin release. Organ: colon Organ: intestine Organ: small intestine Organ_System: digestive system PMID: 24061204 PMID: 28096522 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: epithelium urn:agi-pathway:uuid-fc467102-0124-476b-81a6-a31084c0a773 L-cell: GCG, PYY and 5-HT Release uuid-fc467102-0124-476b-81a6-a31084c0a773 PS:CellType L-cell PS:Description L-cells produce GCG and PYY and regulate appetite, satiety and insulin release. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc467102-0124-476b-81a6-a31084c0a773 PS:NodeType Pathway PS:Notes Headnote: L-cells are located at the distal part of small intestine. These cells produce glucagon and peptide YY and secrete serotonin. Also, L-cells are involved in the intestinal carbohydrate absorption. Signaling description: L-cells can be activated by many nutrients. The taste receptors (heterodimer TAS1R3/ TAS1R2 and TAS2Rs) interact with GNAT3 leading to activation of PLCB2/ITPR1/Ca2+ signaling. Other receptors activate ADCY/cAMP pathway via interaction with G-proteins. Both pathways lead to the activation of PKA and PKC. These protein kinases activate the expression of GCG. In addition, PKA activates the expression of proprotein convertases necessary for GCG processing. PKA and PKC stimulate PYY secretion. Dipeptidyl peptidase 4 (DPP4) is involved in the processing of both peptides: GCG and PYY. PKA regulates the expression of SLC5A1 which is a key player of intestinal carbohydrate absorption. PKC also regulates serotonin secretion. Outcome effects: GCG and PYY produced by L-cells regulate appetite, satiety and insulin release. PS:Organ colon PS:Organ intestine PS:Organ small intestine PS:Organ_System digestive system PS:PMID 24061204 PS:PMID 28096522 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue epithelium PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc8c9150-6b07-4443-97e4-6eeb8e4b2db2 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-fc8c9150-6b07-4443-97e4-6eeb8e4b2db2 From GenOMICC GWAS uuid-fc8c9150-6b07-4443-97e4-6eeb8e4b2db2 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fc8c9150-6b07-4443-97e4-6eeb8e4b2db2 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcb2949a-2fc6-450d-bd7c-0a3d41ed5226 NodeType: Pathway PathwayType: signaling Source: Receptor Signaling urn:agi-pathway:uuid-fcb2949a-2fc6-450d-bd7c-0a3d41ed5226 IL6R -> STAT Signaling uuid-fcb2949a-2fc6-450d-bd7c-0a3d41ed5226 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcb2949a-2fc6-450d-bd7c-0a3d41ed5226 PS:NodeType Pathway PS:PathwayType signaling PS:Source Receptor Signaling PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc31a44-92d9-4199-8459-1aa03afcf705 NodeType: Pathway Organ: brain Organ_System: nervous system PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-fcc31a44-92d9-4199-8459-1aa03afcf705 NPY1R -> CRH/POMC Production uuid-fcc31a44-92d9-4199-8459-1aa03afcf705 PS:CellType neuron PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc31a44-92d9-4199-8459-1aa03afcf705 PS:NodeType Pathway PS:Organ brain PS:Organ_System nervous system PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biological Process PS:Tissue nerve tissue PS:Link PS:NodeType PS:Tissue Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc3d668-7fe8-4c5d-9f4d-68aca1f14864 NodeType: Pathway Tissue: endothelium urn:agi-pathway:uuid-fcc3d668-7fe8-4c5d-9f4d-68aca1f14864 Matricellular proteins in corneal cell spreading uuid-fcc3d668-7fe8-4c5d-9f4d-68aca1f14864 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc3d668-7fe8-4c5d-9f4d-68aca1f14864 PS:NodeType Pathway PS:Tissue endothelium PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc50dba-c97c-4c7f-a3bf-01cbd85bc1d2 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fcc50dba-c97c-4c7f-a3bf-01cbd85bc1d2 VEGFA -> FOXO3A Expression Targets uuid-fcc50dba-c97c-4c7f-a3bf-01cbd85bc1d2 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcc50dba-c97c-4c7f-a3bf-01cbd85bc1d2 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fccbcc57-ddc3-497e-ae2e-282380ad69e6 NodeType: Pathway Notes: Headnote: The diversification of the antibody repertoire in addition to the variety of T-cell receptor (TCR) forms are obtained by the largely random recombination of variable (V), diversity (D), and joining (J) gene segments on the heavy chain locus and V and J segments on the light chain locus, immunoglobulin, and TCR genes. Signaling description: V(D)J recombination occurs in developing B-cells and T-cells in the bone marrow under the regulation of recombination activating gene (RAG) 1 and RAG2 proteins. The RAG protein complex binds to 12 and 23 bp spaced recombination signal sequences (RSS). The protein complexes bind to each other and bring the segments to be joined together. The DNA is cleaved to create hairpin structures at the ends of the immunoglobulin or TCR gene segments. The DNA-PK complex (XRCC6, XRCC5, and PRKDC) bind to the hairpins and the cleaved RSS ends. The DNA hairpins are cleaved at random sites, and additional bases may be added by terminal deoxynucleotidyltransferase (DNTT) or subtracted by exonuclease to generate imprecise ends. DNA ligase IV (LIG4) and XRCC4 join the ends of the gene segments to form the coding joint and RSS ends. Outcome effects: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig) in somatic cell lines. These genes encode a unique receptor or Ig structure on each T or B-lymphocyte, respectively. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-fccbcc57-ddc3-497e-ae2e-282380ad69e6 V(D)J Recombination uuid-fccbcc57-ddc3-497e-ae2e-282380ad69e6 PS:CellType B-cell PS:Description V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fccbcc57-ddc3-497e-ae2e-282380ad69e6 PS:NodeType Pathway PS:Notes Headnote: The diversification of the antibody repertoire in addition to the variety of T-cell receptor (TCR) forms are obtained by the largely random recombination of variable (V), diversity (D), and joining (J) gene segments on the heavy chain locus and V and J segments on the light chain locus, immunoglobulin, and TCR genes. Signaling description: V(D)J recombination occurs in developing B-cells and T-cells in the bone marrow under the regulation of recombination activating gene (RAG) 1 and RAG2 proteins. The RAG protein complex binds to 12 and 23 bp spaced recombination signal sequences (RSS). The protein complexes bind to each other and bring the segments to be joined together. The DNA is cleaved to create hairpin structures at the ends of the immunoglobulin or TCR gene segments. The DNA-PK complex (XRCC6, XRCC5, and PRKDC) bind to the hairpins and the cleaved RSS ends. The DNA hairpins are cleaved at random sites, and additional bases may be added by terminal deoxynucleotidyltransferase (DNTT) or subtracted by exonuclease to generate imprecise ends. DNA ligase IV (LIG4) and XRCC4 join the ends of the gene segments to form the coding joint and RSS ends. Outcome effects: V(D)J recombination is an essential characteristic of lymphocyte development and is required for the assembly of V(D)J gene segments of TCR or immunoglobulin (Ig) in somatic cell lines. These genes encode a unique receptor or Ig structure on each T or B-lymphocyte, respectively. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell Description: The antigen presenting cells induce naïve T cells towards Th1 or Th2 cell response. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcce64f0-72be-45be-9387-86d23d62af85 NodeType: Pathway Notes: Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The antigen presenting cells induce naïve T-cells towards Th1 or Th2 cell response. Mucosal dendritic cells loaded with antigen migrate from the lungs to the T-cell area of mediastinal lymph nodes (MLNs). Mature dendritic cells in the MLNs select naive T-cells from the polyclonal repertoire of cells. Within 4 days, this will lead to clonal expansion of antigen-specific Th-cells. Traditionally, asthma has been known as the Th2 cell-mediated disease. T- helper cells are lymphocytes that release cytokines and present antigen-MHC complex on their surface. T-helper cells developed into two major subtypes of cells referred to as Type 1 and Type 2 helper T-cells. Th2 cells play a key role in directing the immune responses against helminthes. Additionally, Th2 cells are crucial for many types of allergic reactions. Outcome effects: Th2-cell response is largely responsible for downstream events that include activation of B-cells, production of IgE and binding of IgE to Fce receptor on the cell surface of mast cells, resulting in mast cell degranulation and airway obstruction. IL4 is the major Th2- cytokine. STAT6 participates in Th2 differentiation, in part, by enhancing the expression of GATA3. STAT6 and GATA3 in concert with IL2-mediated STAT5 activation induce the secretion of IL4, IL5, and IL13. IL5 stimulates the differentiation of eosinophils, whereas IL4 and IL13 stimulate contraction of smooth muscle and overproduction of mucus. Highlighted proteins: Proteins with increased expression are highlighted in red. Organ: lung Organ_System: respiratory system PMID: 20553737 PMID: 23814671 PMID: 24914235 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fcce64f0-72be-45be-9387-86d23d62af85 Th2-Cell Response in Asthma uuid-fcce64f0-72be-45be-9387-86d23d62af85 PS:CellType T-cell PS:Description The antigen presenting cells induce naïve T cells towards Th1 or Th2 cell response. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcce64f0-72be-45be-9387-86d23d62af85 PS:NodeType Pathway PS:Notes Headnote: Asthma is a common long-term lung disorder in which inflammation of the bronchi leads to narrowing of the airways creating breathing difficulties. Signaling description: The antigen presenting cells induce naïve T-cells towards Th1 or Th2 cell response. Mucosal dendritic cells loaded with antigen migrate from the lungs to the T-cell area of mediastinal lymph nodes (MLNs). Mature dendritic cells in the MLNs select naive T-cells from the polyclonal repertoire of cells. Within 4 days, this will lead to clonal expansion of antigen-specific Th-cells. Traditionally, asthma has been known as the Th2 cell-mediated disease. T- helper cells are lymphocytes that release cytokines and present antigen-MHC complex on their surface. T-helper cells developed into two major subtypes of cells referred to as Type 1 and Type 2 helper T-cells. Th2 cells play a key role in directing the immune responses against helminthes. Additionally, Th2 cells are crucial for many types of allergic reactions. Outcome effects: Th2-cell response is largely responsible for downstream events that include activation of B-cells, production of IgE and binding of IgE to Fce receptor on the cell surface of mast cells, resulting in mast cell degranulation and airway obstruction. IL4 is the major Th2- cytokine. STAT6 participates in Th2 differentiation, in part, by enhancing the expression of GATA3. STAT6 and GATA3 in concert with IL2-mediated STAT5 activation induce the secretion of IL4, IL5, and IL13. IL5 stimulates the differentiation of eosinophils, whereas IL4 and IL13 stimulate contraction of smooth muscle and overproduction of mucus. Highlighted proteins: Proteins with increased expression are highlighted in red. PS:Organ lung PS:Organ_System respiratory system PS:PMID 20553737 PS:PMID 23814671 PS:PMID 24914235 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: neuron CellType: thyroid cell CellType: thyrotroph Description: Hypothyroidism is a pathological state caused by the deficiency of thyroid hormones. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fccef23d-1167-4cff-a3b1-947b6df4246c NodeType: Pathway Notes: Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. Many factors influence synthesis of thyroid hormones, particularly levels of hormones of hypothalamus and pituitary, TRH and TSH are important. Because of that, symptoms of hypothyroidism may significantly vary depending on combination of altered functions of upstream regulators of these hormones. Secondary (central) hypothyroidism accounts for less than 10% of hypothyroidism cases. The causes of it could be a trauma, cancer, other hormones that affect pituitary, or molecular genetic causes (see TSH Release pathway). TRH stimulation testing is used for the differential diagnostics of secondary (pituitary disorder) and tertiary (hypothalamic disorder) hypothyroidism. In hypothyroidism due to pituitary disorder, administration of TRH does not lead to increase in TSH level. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. Organ: brain Organ: thyroid gland Organ_System: endocrine system PMID: 15481810 PMID: 21062194 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fccef23d-1167-4cff-a3b1-947b6df4246c Central Hypothyroidism uuid-fccef23d-1167-4cff-a3b1-947b6df4246c PS:CellType neuron PS:CellType thyroid cell PS:CellType thyrotroph PS:Description Hypothyroidism is a pathological state caused by the deficiency of thyroid hormones. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fccef23d-1167-4cff-a3b1-947b6df4246c PS:NodeType Pathway PS:Notes Headnote: Hypothyroidism is pathological state caused by deficiency of thyroid hormones. Many factors influence synthesis of thyroid hormones, particularly levels of hormones of hypothalamus and pituitary, TRH and TSH are important. Because of that, symptoms of hypothyroidism may significantly vary depending on combination of altered functions of upstream regulators of these hormones. Secondary (central) hypothyroidism accounts for less than 10% of hypothyroidism cases. The causes of it could be a trauma, cancer, other hormones that affect pituitary, or molecular genetic causes (see TSH Release pathway). TRH stimulation testing is used for the differential diagnostics of secondary (pituitary disorder) and tertiary (hypothalamic disorder) hypothyroidism. In hypothyroidism due to pituitary disorder, administration of TRH does not lead to increase in TSH level. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue, and proteins with increased expression or activity are highlighted in red. PS:Organ brain PS:Organ thyroid gland PS:Organ_System endocrine system PS:PMID 15481810 PS:PMID 21062194 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcd2a601-0169-4f44-ac49-ab9c530062ea NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-fcd2a601-0169-4f44-ac49-ab9c530062ea 4-hydroxybenzoate biosynthesis template uuid-fcd2a601-0169-4f44-ac49-ab9c530062ea PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcd2a601-0169-4f44-ac49-ab9c530062ea PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcf539db-7d2b-4ee8-81a8-ba0bbebd2842 NodeType: Pathway Organ: eye Organ_System: sensory system PathwayType: network Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-fcf539db-7d2b-4ee8-81a8-ba0bbebd2842 Genes with Mutations Associated with Bardet-Biedl Syndrome and Retinitis Pigmentosa uuid-fcf539db-7d2b-4ee8-81a8-ba0bbebd2842 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fcf539db-7d2b-4ee8-81a8-ba0bbebd2842 PS:NodeType Pathway PS:Organ eye PS:Organ_System sensory system PS:PathwayType network PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd12e519-8b2e-4956-bf0c-468d7557c737 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fd12e519-8b2e-4956-bf0c-468d7557c737 CD72 -> AP-1 Expression Targets uuid-fd12e519-8b2e-4956-bf0c-468d7557c737 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd12e519-8b2e-4956-bf0c-468d7557c737 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: natural killer cell Description: Natural killer (NK) cells are involved in antiviral and anti-tumor responses mainly through the direct killing of target cells or indirectly by producing IFNG. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd13100f-6d24-4220-832f-98f357195038 NodeType: Pathway Notes: Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Natural killer (NK) cells are implicated in the destruction of beta-cells in type 1 diabetes. Signaling description: NK cells are involved in antiviral and anti-tumor responses directly through killing target cells or indirectly by producing IFNG. NK cells have been detected in the pancreas of patients with type 1 diabetes where they have a higher expression of CD25, CD69, PDCD1, and KLRG1. In addition, natural killer group 2, member D, encoded by KLRK1 and NCR1 are expressed by NK cells. Recent studies suggest that their ligands, ULBP and NCR1 ligand, respectively are expressed by diabetic beta-cells. Outcome effects: NK cells may contribute directly or indirectly to the destruction of pancreatic beta-cells. In type 1 diabetes, NK cells exhibit a higher proliferation rate, produce higher levels of IFNG and express LAMP1, a marker of granule exocytosis on their cell surface, reflecting their cytotoxic function. Animal data: NK cells have been detected in the pancreas in large numbers in mouse models of type 1 diabetes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Organ_System: hematological system PMID: 20577267 PMID: 21712017 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fd13100f-6d24-4220-832f-98f357195038 Natural Killer Cell in Diabetes Mellitus Type 1 uuid-fd13100f-6d24-4220-832f-98f357195038 PS:CellType natural killer cell PS:Description Natural killer (NK) cells are involved in antiviral and anti-tumor responses mainly through the direct killing of target cells or indirectly by producing IFNG. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd13100f-6d24-4220-832f-98f357195038 PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus type 1 is an autoimmune disease in which most of the pancreatic beta-cells are attacked and destroyed by T-cells. As a result, the pancreas does not produce an adequate amount of insulin leading to increased blood sugar levels. There is a genetic predisposition to type 1 diabetes. Natural killer (NK) cells are implicated in the destruction of beta-cells in type 1 diabetes. Signaling description: NK cells are involved in antiviral and anti-tumor responses directly through killing target cells or indirectly by producing IFNG. NK cells have been detected in the pancreas of patients with type 1 diabetes where they have a higher expression of CD25, CD69, PDCD1, and KLRG1. In addition, natural killer group 2, member D, encoded by KLRK1 and NCR1 are expressed by NK cells. Recent studies suggest that their ligands, ULBP and NCR1 ligand, respectively are expressed by diabetic beta-cells. Outcome effects: NK cells may contribute directly or indirectly to the destruction of pancreatic beta-cells. In type 1 diabetes, NK cells exhibit a higher proliferation rate, produce higher levels of IFNG and express LAMP1, a marker of granule exocytosis on their cell surface, reflecting their cytotoxic function. Animal data: NK cells have been detected in the pancreas in large numbers in mouse models of type 1 diabetes. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. PS:Organ_System hematological system PS:PMID 20577267 PS:PMID 21712017 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd1964d8-653e-4d6b-8837-0ca535d9fb07 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fd1964d8-653e-4d6b-8837-0ca535d9fb07 BMP7/ACVR2 Expression Targets uuid-fd1964d8-653e-4d6b-8837-0ca535d9fb07 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd1964d8-653e-4d6b-8837-0ca535d9fb07 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:Notes PS:PathwayType PS:Pathway_Author PS:Source Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd317c12-da63-4750-bd2c-4feb280539a1 NodeType: Pathway Notes: Specifically, in response to a high-fat diet, adipose tissues release substances that include proinflammatory cytokines, chemokines, and free fatty acids that in turn provoke the inhibition of insulin (INS) signal transduction in adjacent specialized cells, thereby leading to the disruption of glycogen and essential protein synthesis. Pathway 4. Insulin resistance: FFA-related insulin resistance (Fig. 9). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-fd317c12-da63-4750-bd2c-4feb280539a1 4_3_Insulin resistance: FFA-related insulin resistance uuid-fd317c12-da63-4750-bd2c-4feb280539a1 PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd317c12-da63-4750-bd2c-4feb280539a1 PS:NodeType Pathway PS:Notes Specifically, in response to a high-fat diet, adipose tissues release substances that include proinflammatory cytokines, chemokines, and free fatty acids that in turn provoke the inhibition of insulin (INS) signal transduction in adjacent specialized cells, thereby leading to the disruption of glycogen and essential protein synthesis. Pathway 4. Insulin resistance: FFA-related insulin resistance (Fig. 9). Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: insulin-secreting cell Description: Ghrelin (GHRL) is a gastric peptide hormone. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd470e23-c837-43b5-8161-3fc2d31de70e NodeType: Pathway Notes: Headnote: Ghrelin (GHRL) is a gastric peptide hormone and one of the major hormones that stimulate hunger. Signaling description: Ghrelin peptides exist in two major forms, unacylated ghrelin and acylated ghrelin, and only the latter binds to ghrelin receptor (GHSR). Acylation is catalyzed by MBOAT4. In rat and human pancreatic tissue, GHSR is expressed in most alpha-cells and in certain amount of beta-cells. Despite some controversial results, many studies reveal that ghrelin is able to inhibit insulin secretion in vitro and in vivo. In healthy humans, ghrelin suppresses glucose-stimulated insulin secretion. GHSR is a G-coupled receptor that normally couples to GNAQ which leads to Ca2 mobilization and stimulation rather than inhibition of insulin secretion. However, in rat islet and beta-cells, GHSR couples to GNAI1 instead of GNAQ. GNAI1-related signaling reduces cAMP accumulation and insulin secretion. GHSR coupling to GNAI1 rather than GNAQ requires interaction with SSTR5. When the relative ghrelin/SST ratio is high, ghrelin suppresses cAMP accumulation and when the ratio is low, ghrelin increases Ca2 mobilization. Most of ghrelin's inhibitory influence on insulin secretion is likely due to the enhancement of PTPRN2 expression. PTPRN2 is a membrane glycoprotein localized in secretory granules and is a beta-cell autoantigen for type 1 diabetes. Approximately 50% of newly diagnosed patients have autoantibodies against PTPRN2. In addition, the link between ghrelin and UCP2 has been hypothesized based on the observation that ghrelin knockout mice display a reduced expression of UCP2 in the pancreas. Outcome effects: Ghrelin may have an inhibitory effect on insulin secretion at low concentrations and a stimulatory effect at high concentrations. Further, ghrelin stimulates glucagon (GCG) secretion from pancreatic alpha cells. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity is highlighted in blue. Organ: pancreas Organ_System: endocrine system PMID: 21719535 PMID: 23112170 PMID: 24381790 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fd470e23-c837-43b5-8161-3fc2d31de70e Ghrelin Influence on Insulin Secretion (Hypothesis) uuid-fd470e23-c837-43b5-8161-3fc2d31de70e PS:CellType insulin-secreting cell PS:Description Ghrelin (GHRL) is a gastric peptide hormone. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd470e23-c837-43b5-8161-3fc2d31de70e PS:NodeType Pathway PS:Notes Headnote: Ghrelin (GHRL) is a gastric peptide hormone and one of the major hormones that stimulate hunger. Signaling description: Ghrelin peptides exist in two major forms, unacylated ghrelin and acylated ghrelin, and only the latter binds to ghrelin receptor (GHSR). Acylation is catalyzed by MBOAT4. In rat and human pancreatic tissue, GHSR is expressed in most alpha-cells and in certain amount of beta-cells. Despite some controversial results, many studies reveal that ghrelin is able to inhibit insulin secretion in vitro and in vivo. In healthy humans, ghrelin suppresses glucose-stimulated insulin secretion. GHSR is a G-coupled receptor that normally couples to GNAQ which leads to Ca2 mobilization and stimulation rather than inhibition of insulin secretion. However, in rat islet and beta-cells, GHSR couples to GNAI1 instead of GNAQ. GNAI1-related signaling reduces cAMP accumulation and insulin secretion. GHSR coupling to GNAI1 rather than GNAQ requires interaction with SSTR5. When the relative ghrelin/SST ratio is high, ghrelin suppresses cAMP accumulation and when the ratio is low, ghrelin increases Ca2 mobilization. Most of ghrelin's inhibitory influence on insulin secretion is likely due to the enhancement of PTPRN2 expression. PTPRN2 is a membrane glycoprotein localized in secretory granules and is a beta-cell autoantigen for type 1 diabetes. Approximately 50% of newly diagnosed patients have autoantibodies against PTPRN2. In addition, the link between ghrelin and UCP2 has been hypothesized based on the observation that ghrelin knockout mice display a reduced expression of UCP2 in the pancreas. Outcome effects: Ghrelin may have an inhibitory effect on insulin secretion at low concentrations and a stimulatory effect at high concentrations. Further, ghrelin stimulates glucagon (GCG) secretion from pancreatic alpha cells. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity is highlighted in blue. PS:Organ pancreas PS:Organ_System endocrine system PS:PMID 21719535 PS:PMID 23112170 PS:PMID 24381790 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: blood platelet Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd4b637d-fc93-4f80-84a8-76fc392eda76 NodeType: Pathway Notes: Headnote: The antiphospholipid syndrome is characterized by recurrent thrombosis (arterial or venous, or both) and/or morbidity during pregnancy (recurrent miscarriages/stillbirths) associated with high levels of anti-phospholipid antibodies (aPL). Signaling description: aPL antibodies bind to beta-2GPI (APOH) which in turn binds to platelets receptor LRP8 and GP1BA, and induce cell activation/aggregation through activation of p38 MAPK (MAPK14), phospholipase A2, release of thromboxane A2 and expression of GPIIb/IIIa (alpha2b beta3 integrin), determining a procoagulant state. Additional mechanisms promoting clot formation may be represented by the interaction of aPL with proteins implicated in the coagulation cascade such as PROC, PROS1, F2, and SERPINC1. Organ: blood vessel Organ_System: cardiovascular system PMID: 17894016 PMID: 20822807 PMID: 21556027 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-fd4b637d-fc93-4f80-84a8-76fc392eda76 Antiphospholipid Antibodies in Platelets and Coagulation Cascade uuid-fd4b637d-fc93-4f80-84a8-76fc392eda76 PS:CellType blood platelet PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd4b637d-fc93-4f80-84a8-76fc392eda76 PS:NodeType Pathway PS:Notes Headnote: The antiphospholipid syndrome is characterized by recurrent thrombosis (arterial or venous, or both) and/or morbidity during pregnancy (recurrent miscarriages/stillbirths) associated with high levels of anti-phospholipid antibodies (aPL). Signaling description: aPL antibodies bind to beta-2GPI (APOH) which in turn binds to platelets receptor LRP8 and GP1BA, and induce cell activation/aggregation through activation of p38 MAPK (MAPK14), phospholipase A2, release of thromboxane A2 and expression of GPIIb/IIIa (alpha2b beta3 integrin), determining a procoagulant state. Additional mechanisms promoting clot formation may be represented by the interaction of aPL with proteins implicated in the coagulation cascade such as PROC, PROS1, F2, and SERPINC1. PS:Organ blood vessel PS:Organ_System cardiovascular system PS:PMID 17894016 PS:PMID 20822807 PS:PMID 21556027 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd5518e3-c355-4780-9d38-a77f166b1dd5 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-fd5518e3-c355-4780-9d38-a77f166b1dd5 Basement mebrane damage+>Keratocyte-to-Myofibroblast differentiation uuid-fd5518e3-c355-4780-9d38-a77f166b1dd5 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd5518e3-c355-4780-9d38-a77f166b1dd5 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: epithelial cell CellType: mammary epithelial cell Description: Cowden syndrome (CS) is a rare autosomal dominant hereditary disorder. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b NodeType: Pathway Notes: Headnote: Cowden syndrome (CS), also known as Cowden disease and multiple hamartoma syndrome, is a rare autosomal dominant hereditary disorder. CS is characterized by multiple hamartomas and an increased risk for developing neoplasms, particularly breast, endometrial, thyroid, kidney, and colorectal cancers. CS has been estimated to affect 1 in every 200,000 individuals. Approximately 80% of CS patients have germline mutations in the PTEN gene. Rare cases of CS are caused by germline mutations in SDHB/D, BMPR1A, PIK3CA, and AKT1 genes. Signaling description: Mutations in the PTEN gene cause the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways. Specifically, PIK3CA activates AKT1 via PIP3 and PDPK1. Since PTEN protein dephosphorylates PIP3 and inhibits the AKT-mediated signaling, mutations in PTEN activate AKT1. Also, PTEN dephosphorylates SHC1, which regulates the ERK (MAPK1/3), and mutations in PTEN gene result in the activation of SHC1 and, consequently the ERK signaling. Outcome effects: The constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways which leads to block of apoptosis, loss of differentiation, migration, and redundant proliferation of epithelial cells. Activated AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, whereas MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits GSK3B (glycogen synthase kinase 3 beta) leading to cytosolic CTNNB1 stabilization. Cytosolic CTNNB1 protein then translocates into the nucleus where it interacts with TCF7 (T-cell factor 7) and LEF1 (lymphoid enhancing factor 1) to induce the expression of downstream target genes that are involved in cell proliferation and differentiation. Activated AKT1 also inhibits FOXO1/FOXO3 (forkhead box O1/O3), MAP3K5, and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. PDPK1, via PRKCA induces SRC which regulates Janus kinases 1/2 (JAK1/2) involved in cell growth regulation. FurtherThe ERK (MAPK1/3) signaling pathway induces genes involved in cell proliferation. PTEN dephosphorylates PTK2 that binds BCAR1 involved in cell migration. Lastly, mutations in PTEN gene facilitate cell migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. Organ: breast Organ: intestine Organ: kidney Organ: thyroid gland Organ: uterus Organ_System: digestive system Organ_System: endocrine system Organ_System: integumentary system Organ_System: reproductive system Organ_System: urinary tract PMID: 18678321 PMID: 18781191 PMID: 23246288 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: epithelium urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b Cowden Syndrome uuid-fd651c77-1c77-4357-b506-191f2e130d9b PS:CellType epithelial cell PS:CellType mammary epithelial cell PS:Description Cowden syndrome (CS) is a rare autosomal dominant hereditary disorder. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fd651c77-1c77-4357-b506-191f2e130d9b PS:NodeType Pathway PS:Notes Headnote: Cowden syndrome (CS), also known as Cowden disease and multiple hamartoma syndrome, is a rare autosomal dominant hereditary disorder. CS is characterized by multiple hamartomas and an increased risk for developing neoplasms, particularly breast, endometrial, thyroid, kidney, and colorectal cancers. CS has been estimated to affect 1 in every 200,000 individuals. Approximately 80% of CS patients have germline mutations in the PTEN gene. Rare cases of CS are caused by germline mutations in SDHB/D, BMPR1A, PIK3CA, and AKT1 genes. Signaling description: Mutations in the PTEN gene cause the constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways. Specifically, PIK3CA activates AKT1 via PIP3 and PDPK1. Since PTEN protein dephosphorylates PIP3 and inhibits the AKT-mediated signaling, mutations in PTEN activate AKT1. Also, PTEN dephosphorylates SHC1, which regulates the ERK (MAPK1/3), and mutations in PTEN gene result in the activation of SHC1 and, consequently the ERK signaling. Outcome effects: The constitutive activation of AKT1 and mitogen-activated protein kinase (MAPK) signaling pathways which leads to block of apoptosis, loss of differentiation, migration, and redundant proliferation of epithelial cells. Activated AKT1 phosphorylates and activates CREB1 and MTOR, while inhibiting TP53. CREB1 regulates the transcription of BCL2, whereas MTOR is a central regulator of cellular metabolism, growth, and survival in response to hormones and growth factors. AKT1 inhibits GSK3B (glycogen synthase kinase 3 beta) leading to cytosolic CTNNB1 stabilization. Cytosolic CTNNB1 protein then translocates into the nucleus where it interacts with TCF7 (T-cell factor 7) and LEF1 (lymphoid enhancing factor 1) to induce the expression of downstream target genes that are involved in cell proliferation and differentiation. Activated AKT1 also inhibits FOXO1/FOXO3 (forkhead box O1/O3), MAP3K5, and JNK-cascade. In addition, AKT1 phosphorylates and inhibits BAD resulting in the activation of BCL2 and BCL2L1 and suppression of BAX. This prevents the formation of mitochondrial transition pore, release of cytochrome c from the mitochondria into the cytoplasm, and activation of apoptotic caspase cascade. PDPK1, via PRKCA induces SRC which regulates Janus kinases 1/2 (JAK1/2) involved in cell growth regulation. FurtherThe ERK (MAPK1/3) signaling pathway induces genes involved in cell proliferation. PTEN dephosphorylates PTK2 that binds BCAR1 involved in cell migration. Lastly, mutations in PTEN gene facilitate cell migration. Highlighted proteins: Proteins with increased expression or activity are highlighted in red. Mutated genes: Mutated genes are shown in white-out style. PS:Organ breast PS:Organ intestine PS:Organ kidney PS:Organ thyroid gland PS:Organ uterus PS:Organ_System digestive system PS:Organ_System endocrine system PS:Organ_System integumentary system PS:Organ_System reproductive system PS:Organ_System urinary tract PS:PMID 18678321 PS:PMID 18781191 PS:PMID 23246288 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue epithelium PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdbac686-9cb7-4147-8adb-2350576a6120 NodeType: Pathway Organ: generic Organ_System: generic PathwayType: biochemical signaling Pathway_Author: T. Kulikova Source: Metabolic Pathways Tissue: generic urn:agi-pathway:uuid-fdbac686-9cb7-4147-8adb-2350576a6120 Respiratory Chain and Oxidative Phosphorylation uuid-fdbac686-9cb7-4147-8adb-2350576a6120 PS:CellType generic PS:Description Pathway is built manually using: Michal G, Schomburg D. 2013. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Second Edition (info:doi/10.1002/9781118657072).. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdbac686-9cb7-4147-8adb-2350576a6120 PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PathwayType biochemical signaling PS:Pathway_Author T. Kulikova PS:Source Metabolic Pathways PS:Tissue generic PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:Organelle PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: cardiac myocyte Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdd16e3e-6dbc-4b7a-9f41-303b8b297c3e NodeType: Pathway Notes: Mutations in sarcomeric proteins cause disorganization of myocyte architecture and impaired sarcomere assembly. Sarcomeres are the basic units of muscle contraction made up of thick and thin protein filaments. The overlapping thick and thin filaments attach to each other temporarily and release, allowing the filaments to move relative to one another so that muscles can contract. Mutations in the genes encoding sarcomeric and nonsarcomeric proteins and intracellular Ca2+ overload lead to impaired sarcomere assembly and impaired myofibrillar contraction. This leads to compensatory cardiomyocyte hypertrophy or enlargement of t cardiomyocytes and a thickening of the heart muscle. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: heart Organ_System: cardiovascular system Organelle: endoplasmic reticulum Organelle: sarcomere PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: myocardium urn:agi-pathway:uuid-fdd16e3e-6dbc-4b7a-9f41-303b8b297c3e 1_Sarcomere disorganization and intracellular calcium overload uuid-fdd16e3e-6dbc-4b7a-9f41-303b8b297c3e PS:CellType cardiac myocyte PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdd16e3e-6dbc-4b7a-9f41-303b8b297c3e PS:NodeType Pathway PS:Notes Mutations in sarcomeric proteins cause disorganization of myocyte architecture and impaired sarcomere assembly. Sarcomeres are the basic units of muscle contraction made up of thick and thin protein filaments. The overlapping thick and thin filaments attach to each other temporarily and release, allowing the filaments to move relative to one another so that muscles can contract. Mutations in the genes encoding sarcomeric and nonsarcomeric proteins and intracellular Ca2+ overload lead to impaired sarcomere assembly and impaired myofibrillar contraction. This leads to compensatory cardiomyocyte hypertrophy or enlargement of t cardiomyocytes and a thickening of the heart muscle. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ heart PS:Organ_System cardiovascular system PS:Organelle endoplasmic reticulum PS:Organelle sarcomere PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue myocardium PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdd4c5bd-5c91-42ea-bf0a-03b6d925c64e NodeType: Pathway Notes: General of mechanisms that occur under basal conditions in active dendritic spine is presented on the pathway. The major player in new synapses / memory formation is a protein kinase M zeta (PKMZ). Organ: brain Organ_System: nervous system PMID: 21119699 PMID: 22986281 PMID: 24042850 PMID: 27426863 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-fdd4c5bd-5c91-42ea-bf0a-03b6d925c64e Synaptic Potentiation by PKMZ in LTP Maintenance - Active State uuid-fdd4c5bd-5c91-42ea-bf0a-03b6d925c64e PS:CellType neuron PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdd4c5bd-5c91-42ea-bf0a-03b6d925c64e PS:NodeType Pathway PS:Notes General of mechanisms that occur under basal conditions in active dendritic spine is presented on the pathway. The major player in new synapses / memory formation is a protein kinase M zeta (PKMZ). PS:Organ brain PS:Organ_System nervous system PS:PMID 21119699 PS:PMID 22986281 PS:PMID 24042850 PS:PMID 27426863 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: neuron Description: Vitamin D is associated with multiple sclerosis. One of the links between vitamin D and multiple sclerosis can be folate and its metabolites. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fddaf6bc-5157-4cc8-aa4f-fad139e26e81 NodeType: Pathway Notes: Vitamin D deficiency is associated with multiple sclerosis. One of the links between vitamin D and multiple sclerosis can be folate and its metabolites. Organ: brain Organ_System: nervous system PMID: 22466660 PMID: 22547098 PMID: 24381825 PMID: 26046560 PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: nerve tissue urn:agi-pathway:uuid-fddaf6bc-5157-4cc8-aa4f-fad139e26e81 Vitamin D and Folate in Multiple Sclerosis uuid-fddaf6bc-5157-4cc8-aa4f-fad139e26e81 PS:CellType neuron PS:Description Vitamin D is associated with multiple sclerosis. One of the links between vitamin D and multiple sclerosis can be folate and its metabolites. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fddaf6bc-5157-4cc8-aa4f-fad139e26e81 PS:NodeType Pathway PS:Notes Vitamin D deficiency is associated with multiple sclerosis. One of the links between vitamin D and multiple sclerosis can be folate and its metabolites. PS:Organ brain PS:Organ_System nervous system PS:PMID 22466660 PS:PMID 22547098 PS:PMID 24381825 PS:PMID 26046560 PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue nerve tissue PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdf38efa-b337-4146-bf86-a17dc646a18c NodeType: Pathway Organ: generic Organ_System: generic PMID: 21892142 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-fdf38efa-b337-4146-bf86-a17dc646a18c AMPK Signaling uuid-fdf38efa-b337-4146-bf86-a17dc646a18c PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fdf38efa-b337-4146-bf86-a17dc646a18c PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 21892142 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe084d6a-67f3-4c95-8bed-bec20e5046c5 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fe084d6a-67f3-4c95-8bed-bec20e5046c5 WNT5A Expression Targets uuid-fe084d6a-67f3-4c95-8bed-bec20e5046c5 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe084d6a-67f3-4c95-8bed-bec20e5046c5 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: B-cell Description: Class-switch recombination (CSR) is a biological mechanism that changes the Ig class expressed on B cells from IgM to one of the other classes (IgG, IgE, or IgA). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe0c40be-f55d-4f75-a666-bb03dbf5f0ed NodeType: Pathway Notes: Headnote: Class-switch recombination (CSR), also known as immunoglobulin class switching, isotype switching or isotypic commutation, is a biological mechanism that changes the Ig class expressed on B-cells from IgM to one of the other classes (IgG, IgE, or IgA). Signaling description: During the process of Ig class switching, the constant region of the antibody heavy chain is altered, but the variable region stays constant, so antigen specificity is not affected. The antibody retains the affinity for the same antigens, but can interact with different effector molecules. CSR of the immunoglobulin heavy chain locus requires activation-induced cytidine deaminase (AICDA). This enzyme catalyzes the deamination of deoxycytosines to deoxyuracils, thereby initiating immunoglobulin CSR, somatic hypermutation, and gene conversion. The major transcription factors involved in AICDA expression are STAT6, HOXC4, and NF-kB, which require 4 effectors including IL13, IL4, CD40LG, and TNFSF13. Organ_System: lymphatic system PathwayType: signaling Pathway_Author: E. Klimov ORCID:0000-0003-2674-5783 Source: Biological Process Tissue: bone marrow urn:agi-pathway:uuid-fe0c40be-f55d-4f75-a666-bb03dbf5f0ed Immunoglobulin Class-Switch Recombination Activation uuid-fe0c40be-f55d-4f75-a666-bb03dbf5f0ed PS:CellType B-cell PS:Description Class-switch recombination (CSR) is a biological mechanism that changes the Ig class expressed on B cells from IgM to one of the other classes (IgG, IgE, or IgA). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe0c40be-f55d-4f75-a666-bb03dbf5f0ed PS:NodeType Pathway PS:Notes Headnote: Class-switch recombination (CSR), also known as immunoglobulin class switching, isotype switching or isotypic commutation, is a biological mechanism that changes the Ig class expressed on B-cells from IgM to one of the other classes (IgG, IgE, or IgA). Signaling description: During the process of Ig class switching, the constant region of the antibody heavy chain is altered, but the variable region stays constant, so antigen specificity is not affected. The antibody retains the affinity for the same antigens, but can interact with different effector molecules. CSR of the immunoglobulin heavy chain locus requires activation-induced cytidine deaminase (AICDA). This enzyme catalyzes the deamination of deoxycytosines to deoxyuracils, thereby initiating immunoglobulin CSR, somatic hypermutation, and gene conversion. The major transcription factors involved in AICDA expression are STAT6, HOXC4, and NF-kB, which require 4 effectors including IL13, IL4, CD40LG, and TNFSF13. PS:Organ_System lymphatic system PS:PathwayType signaling PS:Pathway_Author E. Klimov ORCID:0000-0003-2674-5783 PS:Source Biological Process PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: vascular smooth muscle cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe46ae56-6997-479b-a6ee-4e8b26a318b4 NodeType: Pathway Notes: High levels of aldosterone and other mediators cause constriction of smooth muscle cells that leads to a narrowing of the lumen of blood vessels and lead to high blood pressure. Strengthened vasoconstriction is believed to be an early component during the development of arterial hypertension and is associated with smooth muscle cell (SMC) dysfunction. Redundant levels of angiotensin II, norepinephrine (noradrenaline), vasopressin (AVP) and endothelin 1 (EDN1) promote smooth muscle cell proliferation and cellular growth and induce muscular contraction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: Blood Vessels Organ_System: cardiovascular system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas Tissue: muscles urn:agi-pathway:uuid-fe46ae56-6997-479b-a6ee-4e8b26a318b4 3_Dysfunction of smooth muscle cells in hypertension uuid-fe46ae56-6997-479b-a6ee-4e8b26a318b4 PS:CellType vascular smooth muscle cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe46ae56-6997-479b-a6ee-4e8b26a318b4 PS:NodeType Pathway PS:Notes High levels of aldosterone and other mediators cause constriction of smooth muscle cells that leads to a narrowing of the lumen of blood vessels and lead to high blood pressure. Strengthened vasoconstriction is believed to be an early component during the development of arterial hypertension and is associated with smooth muscle cell (SMC) dysfunction. Redundant levels of angiotensin II, norepinephrine (noradrenaline), vasopressin (AVP) and endothelin 1 (EDN1) promote smooth muscle cell proliferation and cellular growth and induce muscular contraction. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ Blood Vessels PS:Organ_System cardiovascular system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Tissue muscles PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe46d4e6-ee9e-451d-acff-5e63c7cf8fda NodeType: Pathway PathwayType: network Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fe46d4e6-ee9e-451d-acff-5e63c7cf8fda Congenital Hypothyroidism Anatomy and Molecular Biomarkers uuid-fe46d4e6-ee9e-451d-acff-5e63c7cf8fda PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe46d4e6-ee9e-451d-acff-5e63c7cf8fda PS:NodeType Pathway PS:PathwayType network PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe5e4a4e-19b7-4b3d-9017-bf09aee4dcef NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-fe5e4a4e-19b7-4b3d-9017-bf09aee4dcef IGF1/2 Promotes Muscle Growth uuid-fe5e4a4e-19b7-4b3d-9017-bf09aee4dcef PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe5e4a4e-19b7-4b3d-9017-bf09aee4dcef PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe5eff2f-7298-429b-96a1-ffe8cd879fb8 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Diseases urn:agi-pathway:uuid-fe5eff2f-7298-429b-96a1-ffe8cd879fb8 COVID19 genetic risk factors from UK Biobank uuid-fe5eff2f-7298-429b-96a1-ffe8cd879fb8 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe5eff2f-7298-429b-96a1-ffe8cd879fb8 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe63fab7-1086-4c7d-8929-a5ef419a034f NodeType: Pathway Organ: generic Organ_System: generic PMID: 19897402 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Receptor Signaling Tissue: generic urn:agi-pathway:uuid-fe63fab7-1086-4c7d-8929-a5ef419a034f BMPR2 Signaling uuid-fe63fab7-1086-4c7d-8929-a5ef419a034f PS:CellType generic PS:Description Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe63fab7-1086-4c7d-8929-a5ef419a034f PS:NodeType Pathway PS:Organ generic PS:Organ_System generic PS:PMID 19897402 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Receptor Signaling PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe67fcc7-0c49-4e09-9f77-cbe3b45853db NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 urn:agi-pathway:uuid-fe67fcc7-0c49-4e09-9f77-cbe3b45853db Ca-|Insulin resistance uuid-fe67fcc7-0c49-4e09-9f77-cbe3b45853db PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe67fcc7-0c49-4e09-9f77-cbe3b45853db PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: vascular smooth muscle cell Description: Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds, derived from increased glucose and fatty acid oxidation. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe88d51f-d8e4-452b-bc9a-ffc5c70bff0a NodeType: Pathway Notes: Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds, derived from increased glucose and fatty acid oxidation in endothelial cells. AGE signaling in the vessel wall provokes vascular occlusion and leukocyte recruitment. AGE interacts with the vascular wall by binding to its cellular receptor, AGER. HMGB1, S100A8, and S100A12 also bind and activate AGER in diabetes. The AGE-AGER interaction induces NADPH oxidase activation. The enzyme is involved in reactive oxygen species (ROS) generation and thereby cellular oxidant stress. ROS affect HRAS and NF-kB directly. HRAS, along with KRAS also mediates NF-kB activation, transducing the signal through PI3K. Generated by PI3K, PIP3 initiates AKT1 activation by PDPK1. AKT1 provokes the release of NF-kB from its inhibitor, NFKBIA. Outcome effects: Free NF-kB promotes ICAM1, VCAM1, SERPINE1, and EDN1 transcription. A critical consequence of VCAM1 and ICAM1 expression on the endothelial surface is the attraction of mononuclear phagocytes into the vessel wall that promote inflammation. SERPINE1 transcription contributes to vascular occlusion because it inhibits plasminogen activators (PLAT and PLAU) preventing fibrinolysis. EDN1 expression promotes vasoconstriction. Therefore, impaired blood flow and inflammation in the vessel wall are the main consequences of AGEs. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. Organ: blood vessel Organ_System: endocrine system PMID: 18230954 PMID: 18332897 PMID: 18533366 PMID: 18793542 PMID: 22211895 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases urn:agi-pathway:uuid-fe88d51f-d8e4-452b-bc9a-ffc5c70bff0a Advanced Glycation End Products Pathway in Diabetic Microangiopathy uuid-fe88d51f-d8e4-452b-bc9a-ffc5c70bff0a PS:CellType vascular smooth muscle cell PS:Description Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds, derived from increased glucose and fatty acid oxidation. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe88d51f-d8e4-452b-bc9a-ffc5c70bff0a PS:NodeType Pathway PS:Notes Headnote: Diabetes mellitus refers to a group of disorders characterized by abnormally high blood sugar levels and insulin resistance. Diabetic microangiopathy is one of the major chronic complications of diabetes affecting small blood vessels. Microangiopathy in peripheral tissue is a diabetic complication which can have severe consequences such as the development of an ulcer. Signaling description: Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds, derived from increased glucose and fatty acid oxidation in endothelial cells. AGE signaling in the vessel wall provokes vascular occlusion and leukocyte recruitment. AGE interacts with the vascular wall by binding to its cellular receptor, AGER. HMGB1, S100A8, and S100A12 also bind and activate AGER in diabetes. The AGE-AGER interaction induces NADPH oxidase activation. The enzyme is involved in reactive oxygen species (ROS) generation and thereby cellular oxidant stress. ROS affect HRAS and NF-kB directly. HRAS, along with KRAS also mediates NF-kB activation, transducing the signal through PI3K. Generated by PI3K, PIP3 initiates AKT1 activation by PDPK1. AKT1 provokes the release of NF-kB from its inhibitor, NFKBIA. Outcome effects: Free NF-kB promotes ICAM1, VCAM1, SERPINE1, and EDN1 transcription. A critical consequence of VCAM1 and ICAM1 expression on the endothelial surface is the attraction of mononuclear phagocytes into the vessel wall that promote inflammation. SERPINE1 transcription contributes to vascular occlusion because it inhibits plasminogen activators (PLAT and PLAU) preventing fibrinolysis. EDN1 expression promotes vasoconstriction. Therefore, impaired blood flow and inflammation in the vessel wall are the main consequences of AGEs. Highlighted proteins: Entities with increased level or activity are highlighted in red, and entities with decreased level or activity are highlighted in blue. PS:Organ blood vessel PS:Organ_System endocrine system PS:PMID 18230954 PS:PMID 18332897 PS:PMID 18533366 PS:PMID 18793542 PS:PMID 22211895 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe8c5a6a-3fa7-4b9b-b4ce-435ebbadff25 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-fe8c5a6a-3fa7-4b9b-b4ce-435ebbadff25 Cornea-|immune system uuid-fe8c5a6a-3fa7-4b9b-b4ce-435ebbadff25 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fe8c5a6a-3fa7-4b9b-b4ce-435ebbadff25 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:Description PS:Link PS:NodeType PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fea55462-2138-4d98-bdd2-05eebb1b7c1b NodeType: Pathway Organ: bone Organ_System: skeletal system PathwayType: network Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-fea55462-2138-4d98-bdd2-05eebb1b7c1b Proteins with Altered Expression in Rheumatoid Arthritis uuid-fea55462-2138-4d98-bdd2-05eebb1b7c1b PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fea55462-2138-4d98-bdd2-05eebb1b7c1b PS:NodeType Pathway PS:Organ bone PS:Organ_System skeletal system PS:PathwayType network PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: B-cell CellType: cancer cell Description: Follicular lymphoma is the second most common type of non-Hodgkin lymphoma. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fea803fe-56c1-460e-a850-5f3f9b2327fd NodeType: Pathway Notes: Headnote: Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and it occurs at an average age of 60 years. It is indolent and characterized by slow progression with a high response to therapy. Nonetheless, most patients eventually develop increasingly resistant disease, and in up to 45% of cases, the original indolent lymphoma transforms into an aggressive subtype. FL generally involves the lymph nodes (LN), spleen, bone marrow (BM), and peripheral blood. The majority of patients present with stage III/IV disease at the time of diagnosis. Morphologically, FL is defined as a mature B-cell neoplasm resulting from the malignant transformation of germinal center derived follicular B-cells. Neoplastic cells are organized in follicles. FL is subdivided into grades 1, 2, 3a, and 3b based on morphology criteria (number of centroblasts); grade 1 has the most favorable prognosis while grade 3b is the most aggressive. Signaling description: Over 85% of FL cases display t(14;18) translocation which results in IGH/BCL2 fusion formation and constant BCL2 activation. The current (Hypothesis) of FL pathogenesis recognizes t(14;18)-positive circulating B-cells as potentially tumor-initiating cells but it is challenged by the observation that similar cells can be detected in the blood of 50-70% of healthy individuals who are not prone to developing FL. Additional oncogenic events are clearly required for full malignant transformation. They include genetic and epigenetic changes. Genetic changes are represented by TNFRSF14, TNFAIP3, EPHA7, and histone-modifying genes (EZH2, MLL2, CREBBP, EP300, and MEF2B) mutations. Epigenetic changes include aberrant methylation of the CDKN2A, CDKN2B, CDKN1C, GSTP1, PLK2, PTPN6, DAPK1, GADD45G, IL12RB2, and androgen receptor (AR) genes. In addition, the transformation of FL into aggressive lymphomas occurs due to MYC and BCL-6 activating mutations as well as TP53, ATM, CDKN2A, CDKN2B, and FAS deletions or inactivating mutations. Furthermore, microenvironment plays an important role in FL development. Beneficial signals for growth and survival include IL-4, IL-21, CXCL12, and CXCL13. B-cell receptor (BCR) signaling occurs through the stimulation of BCR by the innate immune system through N-glycans or by specific antigen presentation. T-helper cells interact with FL cells through their T-cell receptor, MHC class II and CD40L/CD40, providing survival signals. In conclusion, as any indolent lymphoma, FL in early stages has a good response to standard chemotherapy (includes Cytoxan, vincristine, doxorubicin, prednisolone) plus anti-CD20 antibodies (rituximab). The median overall survival time reaches 10 years or more with current treatment. Outcome effects: Overall, the genetic changes in FL result in block of apoptosis and /or activation of proliferation and inhibit plasma cell differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: lymph node Organ_System: lymphatic system PMID: 12959350 PMID: 17039231 PMID: 21083019 PMID: 21970951 PMID: 22224767 PMID: 22973275 PMID: 23023713 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases urn:agi-pathway:uuid-fea803fe-56c1-460e-a850-5f3f9b2327fd Follicular Lymphoma uuid-fea803fe-56c1-460e-a850-5f3f9b2327fd PS:CellType B-cell PS:CellType cancer cell PS:Description Follicular lymphoma is the second most common type of non-Hodgkin lymphoma. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fea803fe-56c1-460e-a850-5f3f9b2327fd PS:NodeType Pathway PS:Notes Headnote: Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and it occurs at an average age of 60 years. It is indolent and characterized by slow progression with a high response to therapy. Nonetheless, most patients eventually develop increasingly resistant disease, and in up to 45% of cases, the original indolent lymphoma transforms into an aggressive subtype. FL generally involves the lymph nodes (LN), spleen, bone marrow (BM), and peripheral blood. The majority of patients present with stage III/IV disease at the time of diagnosis. Morphologically, FL is defined as a mature B-cell neoplasm resulting from the malignant transformation of germinal center derived follicular B-cells. Neoplastic cells are organized in follicles. FL is subdivided into grades 1, 2, 3a, and 3b based on morphology criteria (number of centroblasts); grade 1 has the most favorable prognosis while grade 3b is the most aggressive. Signaling description: Over 85% of FL cases display t(14;18) translocation which results in IGH/BCL2 fusion formation and constant BCL2 activation. The current (Hypothesis) of FL pathogenesis recognizes t(14;18)-positive circulating B-cells as potentially tumor-initiating cells but it is challenged by the observation that similar cells can be detected in the blood of 50-70% of healthy individuals who are not prone to developing FL. Additional oncogenic events are clearly required for full malignant transformation. They include genetic and epigenetic changes. Genetic changes are represented by TNFRSF14, TNFAIP3, EPHA7, and histone-modifying genes (EZH2, MLL2, CREBBP, EP300, and MEF2B) mutations. Epigenetic changes include aberrant methylation of the CDKN2A, CDKN2B, CDKN1C, GSTP1, PLK2, PTPN6, DAPK1, GADD45G, IL12RB2, and androgen receptor (AR) genes. In addition, the transformation of FL into aggressive lymphomas occurs due to MYC and BCL-6 activating mutations as well as TP53, ATM, CDKN2A, CDKN2B, and FAS deletions or inactivating mutations. Furthermore, microenvironment plays an important role in FL development. Beneficial signals for growth and survival include IL-4, IL-21, CXCL12, and CXCL13. B-cell receptor (BCR) signaling occurs through the stimulation of BCR by the innate immune system through N-glycans or by specific antigen presentation. T-helper cells interact with FL cells through their T-cell receptor, MHC class II and CD40L/CD40, providing survival signals. In conclusion, as any indolent lymphoma, FL in early stages has a good response to standard chemotherapy (includes Cytoxan, vincristine, doxorubicin, prednisolone) plus anti-CD20 antibodies (rituximab). The median overall survival time reaches 10 years or more with current treatment. Outcome effects: Overall, the genetic changes in FL result in block of apoptosis and /or activation of proliferation and inhibit plasma cell differentiation. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ lymph node PS:Organ_System lymphatic system PS:PMID 12959350 PS:PMID 17039231 PS:PMID 21083019 PS:PMID 21970951 PS:PMID 22224767 PS:PMID 22973275 PS:PMID 23023713 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fedba574-c56a-476a-9231-734ff03a1d94 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fedba574-c56a-476a-9231-734ff03a1d94 Dopamine/Gs Expression Targets uuid-fedba574-c56a-476a-9231-734ff03a1d94 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fedba574-c56a-476a-9231-734ff03a1d94 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:Description PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Description: Pathway is built using manually curated ResNet data. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fef7c694-68c7-417f-b72b-77902ed20153 NodeType: Pathway PathwayType: signaling Pathway_Author: P. Golovatenko-Abramov Source: Biomarkers urn:agi-pathway:uuid-fef7c694-68c7-417f-b72b-77902ed20153 EREG -> CREB Expression Target uuid-fef7c694-68c7-417f-b72b-77902ed20153 PS:Description Pathway is built using manually curated ResNet data. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fef7c694-68c7-417f-b72b-77902ed20153 PS:NodeType Pathway PS:PathwayType signaling PS:Pathway_Author P. Golovatenko-Abramov PS:Source Biomarkers PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: bone marrow stromal cell CellType: cancer cell CellType: osteoblast CellType: osteoclast CellType: plasma cell Description: Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff0a30b6-617e-410c-a940-64b9b51b7905 NodeType: Pathway Notes: Headnote: Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Signaling description: The primary genetic events that are involved include: 1) in non-hyperdiploid group - translocations between IgH gene and protooncogenes (observed in 60-80% of patients): IGH-MMSET - t(4;14)(p16;q32), IGH-MAF - t(14;16)(q32;q23), IGH-MAFB - t(14;20)(q32;q11), IGH-CCND1 - t(11;14)(q13;q32), IGH-CCND3 - t(6;14)(p21;q32), 2) in hyperdiploid group - trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. All of these events directly or indirectly lead to cyclin D1, 2, and 3 deregulation, which are critical in MM plasma cell proliferation. In addition, the secondary genetic events involved include mutations in NF-kB, TRAF2 and 3, BIRC2, MAP3K14, CYLD, LTBR, TP53, RB2, MYC, TGFR3, NRAS, KRAS, BRAF, CDKN1A, CDKN2C, and other genes which lead to block of apoptosis, cell immortalization, and increased proliferation. The central pathways abnormally activated in MM plasma cells are NF-kB (classical and alternative), JAK/STAT, PI3K/Akt, RAS/MAPK, and NOTCH cascades. In addition, interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) produced by bone marrow stromal cells (BMSCs) and by MM cells are major regulators implicated in MM plasma cells proliferation. Furthermore, the interaction between bone marrow mesenchymal stem cells (BMSCs) and MM plasma cells via ICAM/ITGB2, VCAM/ITGA4, CXCL12 /CXCR4 also plays a critical role in MM cell proliferation. Outcome effects: One of the most prominent features of MM is bone destructions due to osteoclast activation and osteoblast inhibition. Osteoblasts are inhibited by DKK1 and IL3 which are produced by MM cells and osteoclasts. Osteoclasts are activated through TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction. Normally, the balance between bone synthesis and resorption is regulated by TNFSF11 and its decoy receptor, TNFRSF11B. In MM bone disease, there is a remarkable imbalance between them with the highly overexpressed TNFSF11 and suppressed TNFRSF11B. TNFSF11 interacts with TNFRSF11A and activates NF-kB, MAPK/FOS-JUN and calcineurin/NFATC1 pathways leading to osteoclast adhesion, activation, fusion, and bone resorption. In conclusion, the overexpression of VEGFA, IGF1, HGF, and IL6 by MM plasma cells and BMSCs leads to the increased vascularization of the tumor. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Organ_System: skeletal system PMID: 16239913 PMID: 16917004 PMID: 17351339 PMID: 20416379 PMID: 20430962 PMID: 20890394 PMID: 21378363 PMID: 21411443 PMID: 21652011 PMID: 23023717 PathwayType: signaling Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Source: Diseases Tissue: bone marrow urn:agi-pathway:uuid-ff0a30b6-617e-410c-a940-64b9b51b7905 Multiple Myeloma uuid-ff0a30b6-617e-410c-a940-64b9b51b7905 PS:CellType bone marrow stromal cell PS:CellType cancer cell PS:CellType osteoblast PS:CellType osteoclast PS:CellType plasma cell PS:Description Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff0a30b6-617e-410c-a940-64b9b51b7905 PS:NodeType Pathway PS:Notes Headnote: Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Signaling description: The primary genetic events that are involved include: 1) in non-hyperdiploid group - translocations between IgH gene and protooncogenes (observed in 60-80% of patients): IGH-MMSET - t(4;14)(p16;q32), IGH-MAF - t(14;16)(q32;q23), IGH-MAFB - t(14;20)(q32;q11), IGH-CCND1 - t(11;14)(q13;q32), IGH-CCND3 - t(6;14)(p21;q32), 2) in hyperdiploid group - trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. All of these events directly or indirectly lead to cyclin D1, 2, and 3 deregulation, which are critical in MM plasma cell proliferation. In addition, the secondary genetic events involved include mutations in NF-kB, TRAF2 and 3, BIRC2, MAP3K14, CYLD, LTBR, TP53, RB2, MYC, TGFR3, NRAS, KRAS, BRAF, CDKN1A, CDKN2C, and other genes which lead to block of apoptosis, cell immortalization, and increased proliferation. The central pathways abnormally activated in MM plasma cells are NF-kB (classical and alternative), JAK/STAT, PI3K/Akt, RAS/MAPK, and NOTCH cascades. In addition, interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) produced by bone marrow stromal cells (BMSCs) and by MM cells are major regulators implicated in MM plasma cells proliferation. Furthermore, the interaction between bone marrow mesenchymal stem cells (BMSCs) and MM plasma cells via ICAM/ITGB2, VCAM/ITGA4, CXCL12 /CXCR4 also plays a critical role in MM cell proliferation. Outcome effects: One of the most prominent features of MM is bone destructions due to osteoclast activation and osteoblast inhibition. Osteoblasts are inhibited by DKK1 and IL3 which are produced by MM cells and osteoclasts. Osteoclasts are activated through TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction. Normally, the balance between bone synthesis and resorption is regulated by TNFSF11 and its decoy receptor, TNFRSF11B. In MM bone disease, there is a remarkable imbalance between them with the highly overexpressed TNFSF11 and suppressed TNFRSF11B. TNFSF11 interacts with TNFRSF11A and activates NF-kB, MAPK/FOS-JUN and calcineurin/NFATC1 pathways leading to osteoclast adhesion, activation, fusion, and bone resorption. In conclusion, the overexpression of VEGFA, IGF1, HGF, and IL6 by MM plasma cells and BMSCs leads to the increased vascularization of the tumor. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. PS:Organ_System skeletal system PS:PMID 16239913 PS:PMID 16917004 PS:PMID 17351339 PS:PMID 20416379 PS:PMID 20430962 PS:PMID 20890394 PS:PMID 21378363 PS:PMID 21411443 PS:PMID 21652011 PS:PMID 23023717 PS:PathwayType signaling PS:Pathway_Author S. Sozin www.researchgate.net/profile/Sergey-Sozin PS:Source Diseases PS:Tissue bone marrow PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: generic Description: The molecular mechanism of action of thyroid hormones may be genomic or non-genomic. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff2117b9-2d22-4af2-8779-1376de7d4d0b NodeType: Pathway Notes: Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. Signaling description: The molecular mechanism of action of thyroid hormones can be genomic or non-genomic. In case of genomic regulation, thyroid hormone nuclear receptors (TH receptors) mediate the biological activities of triiodothyronine (T3) via transcriptional regulation. Two TH receptor genes (THRA and THRB) encode four T3-binding receptor isoforms. TH receptor isoforms have tissue-dependent and time-dependent expression. The major TH receptor isoform in the brain, heart, and bone is THRA, while in the kidney and thyroid it is THRB. T3 and thyroxine (T4) penetrate the target cell with the help of SLCO1C1 and SLC16A2 transporters. The pro-hormone, T4 is converted into the active T3 by type 1 (DIO1) or type 2 (DIO2) deiodinase in the cell. Type 3 deiodinase (DIO3) inactivates T3 and T4. The transcriptional activity of TH receptors is regulated at multiple levels. T3 binds to TH receptor. The binding of T3 causes the dissociation of corepressors and binding of coactivators of TH receptors, which recruit histone acetylases, leading to chromatin remodeling. In addition, TH receptors compete with RA receptor, VDR, and PPAR for retinoid-X receptor (RXR) heterodimerization, but may also form homodimers. Unliganded RXR-TR heterodimers bind thyroid response elements and mediate transcription repression via the nuclear receptor corepressor of RA receptor, which has histone deacetylase activity. The binding of thyroid receptor-associated protein, TRAP220 (MED1) recruits other TRAPs, thereby promoting active transcription. Since these corepressors and coactivators are common for many nuclear receptors, crosstalk may result from competitive binding. Promiscuous binding to thyroid hormone response elements could also mediate nuclear receptor crosstalk. Outcome effects: The TH receptor can activates various cellular processes including cholesterol and lipid metabolism in the liver. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Organ: generic Organ_System: endocrine system PMID: 11427693 PMID: 20051527 PMID: 22945636 PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Diseases Tissue: generic urn:agi-pathway:uuid-ff2117b9-2d22-4af2-8779-1376de7d4d0b Thyroid Hormones Common Genomic Effects in Hyperthyroidism uuid-ff2117b9-2d22-4af2-8779-1376de7d4d0b PS:CellType generic PS:Description The molecular mechanism of action of thyroid hormones may be genomic or non-genomic. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff2117b9-2d22-4af2-8779-1376de7d4d0b PS:NodeType Pathway PS:Notes Headnote: Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland. Symptoms include the enlargement of the thyroid gland, weight loss, muscle weakness, sleeping difficulties, heat intolerance, diarrhea and elevated heart rate. Signaling description: The molecular mechanism of action of thyroid hormones can be genomic or non-genomic. In case of genomic regulation, thyroid hormone nuclear receptors (TH receptors) mediate the biological activities of triiodothyronine (T3) via transcriptional regulation. Two TH receptor genes (THRA and THRB) encode four T3-binding receptor isoforms. TH receptor isoforms have tissue-dependent and time-dependent expression. The major TH receptor isoform in the brain, heart, and bone is THRA, while in the kidney and thyroid it is THRB. T3 and thyroxine (T4) penetrate the target cell with the help of SLCO1C1 and SLC16A2 transporters. The pro-hormone, T4 is converted into the active T3 by type 1 (DIO1) or type 2 (DIO2) deiodinase in the cell. Type 3 deiodinase (DIO3) inactivates T3 and T4. The transcriptional activity of TH receptors is regulated at multiple levels. T3 binds to TH receptor. The binding of T3 causes the dissociation of corepressors and binding of coactivators of TH receptors, which recruit histone acetylases, leading to chromatin remodeling. In addition, TH receptors compete with RA receptor, VDR, and PPAR for retinoid-X receptor (RXR) heterodimerization, but may also form homodimers. Unliganded RXR-TR heterodimers bind thyroid response elements and mediate transcription repression via the nuclear receptor corepressor of RA receptor, which has histone deacetylase activity. The binding of thyroid receptor-associated protein, TRAP220 (MED1) recruits other TRAPs, thereby promoting active transcription. Since these corepressors and coactivators are common for many nuclear receptors, crosstalk may result from competitive binding. Promiscuous binding to thyroid hormone response elements could also mediate nuclear receptor crosstalk. Outcome effects: The TH receptor can activates various cellular processes including cholesterol and lipid metabolism in the liver. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. PS:Organ generic PS:Organ_System endocrine system PS:PMID 11427693 PS:PMID 20051527 PS:PMID 22945636 PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Diseases PS:Tissue generic PS:Link PS:NodeType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff26bb22-113a-4cb5-a108-1405708edd07 NodeType: Pathway Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Biological Process urn:agi-pathway:uuid-ff26bb22-113a-4cb5-a108-1405708edd07 FGF,PDGF+>cornea uuid-ff26bb22-113a-4cb5-a108-1405708edd07 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff26bb22-113a-4cb5-a108-1405708edd07 PS:NodeType Pathway PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Biological Process PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PathwayType PS:Pathway_Author PS:Source CellType: T-cell CellType: epithelial cell Description: published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff27f63f-f2ad-4a7e-8b24-de78535f9067 NodeType: Pathway Notes: Cigarette smoke, air pollutants, and inflammation may induce self-autophagy and apoptosis of alveolar epithelial cells. Loss of alveolar epithelial cells either by apoptosis or by self-autophagy is one of the significant factors in the development of pulmonary emphysema (i.e., the loss of lung parenchyma with the concomitant enlargement of air spaces), a prominent hallmark of COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. Organ: lung Organ_System: respiratory system PathwayType: signaling Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Source: Atlas urn:agi-pathway:uuid-ff27f63f-f2ad-4a7e-8b24-de78535f9067 2_Cigarette smoke and inflammation cause alveolar epithelial cell death in COPD uuid-ff27f63f-f2ad-4a7e-8b24-de78535f9067 PS:CellType T-cell PS:CellType epithelial cell PS:Description published in: Disease Pathways: An Atlas of Human Disease Pathways, 2019 https://www.elsevier.com/books/disease-pathways/nesterova/978-0-12-817086-1 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff27f63f-f2ad-4a7e-8b24-de78535f9067 PS:NodeType Pathway PS:Notes Cigarette smoke, air pollutants, and inflammation may induce self-autophagy and apoptosis of alveolar epithelial cells. Loss of alveolar epithelial cells either by apoptosis or by self-autophagy is one of the significant factors in the development of pulmonary emphysema (i.e., the loss of lung parenchyma with the concomitant enlargement of air spaces), a prominent hallmark of COPD. Entitiy with increased expression or activity is highlighted in red. Entity with low activity is highlighted in blue. Mutated genes are shown in white-out style. Viral proteins are grey. PS:Organ lung PS:Organ_System respiratory system PS:PathwayType signaling PS:Pathway_Author A. Nesterova ORCID:0000-0002-9448-8101 PS:Source Atlas PS:Link PS:NodeType PS:PathwayType PS:Pathway_Author PS:Source Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff58a35f-95f6-4d59-8623-237e132dac07 NodeType: Pathway PathwayType: biochemical signaling Pathway_Author: A. Yuryev ORCID:0000-0003-1021-4849 Source: Metabolic Pathways urn:agi-pathway:uuid-ff58a35f-95f6-4d59-8623-237e132dac07 Sesquiterpenoid biosynthesis template uuid-ff58a35f-95f6-4d59-8623-237e132dac07 PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff58a35f-95f6-4d59-8623-237e132dac07 PS:NodeType Pathway PS:PathwayType biochemical signaling PS:Pathway_Author A. Yuryev ORCID:0000-0003-1021-4849 PS:Source Metabolic Pathways PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: T-cell Description: Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ffab1905-0dfc-494a-a8bb-90ae759533fa NodeType: Pathway Notes: Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to an ongoing swelling and redness. AD is associated with the impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Airborne or food allergens may enter the skin with defective barrier function and are picked up by the Langerhans cells (LCs). LCs, inflammatory dendritic epidermal cells, and plasmacytoid dendritic cells play a key role in AD and have an impact on the mechanisms underlying AD such as the recruitment of inflammatory cells, T-cell priming, and the release of cytokines and chemokines. Outcome effects: Mature LCs express high levels of MHC class II antigens, co-stimulatory molecules such as CD80 and CD86, and chemokine receptors which are all important for antigen presentation. Antigen-loaded LCs migrate to lymph nodes and stimulate naive CD4 T- cells (Th0) to differentiate into Th2-cells, which in turn promote differentiation of B-cells into IgE-producing plasma cells. Furthermore, AD is associated with increased IgE levels and decreased IFNG production. Highlighted proteins: IFNG with decreased expression is highlighted in blue. Organ: skin Organ_System: integumentary system PMID: 21249468 PMID: 22561834 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases Tissue: epidermis urn:agi-pathway:uuid-ffab1905-0dfc-494a-a8bb-90ae759533fa Atopic Dermatitis Onset uuid-ffab1905-0dfc-494a-a8bb-90ae759533fa PS:CellType T-cell PS:Description Atopic dermatitis (AD) is a chronic skin disorder that involves scaly and itchy rashes. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ffab1905-0dfc-494a-a8bb-90ae759533fa PS:NodeType Pathway PS:Notes Headnote: Atopic dermatitis (AD) is a chronic skin disorder characterized by scaly and itchy rashes. It typically involves a skin reaction similar to an allergy, which leads to an ongoing swelling and redness. AD is associated with the impaired skin barrier function and IgE-mediated sensitization to food and environmental allergens. Signaling description: Airborne or food allergens may enter the skin with defective barrier function and are picked up by the Langerhans cells (LCs). LCs, inflammatory dendritic epidermal cells, and plasmacytoid dendritic cells play a key role in AD and have an impact on the mechanisms underlying AD such as the recruitment of inflammatory cells, T-cell priming, and the release of cytokines and chemokines. Outcome effects: Mature LCs express high levels of MHC class II antigens, co-stimulatory molecules such as CD80 and CD86, and chemokine receptors which are all important for antigen presentation. Antigen-loaded LCs migrate to lymph nodes and stimulate naive CD4 T- cells (Th0) to differentiate into Th2-cells, which in turn promote differentiation of B-cells into IgE-producing plasma cells. Furthermore, AD is associated with increased IgE levels and decreased IFNG production. Highlighted proteins: IFNG with decreased expression is highlighted in blue. PS:Organ skin PS:Organ_System integumentary system PS:PMID 21249468 PS:PMID 22561834 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:Tissue epidermis PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source CellType: dendritic cell CellType: macrophage CellType: mast cell Description: Chronic and relapsing inflammation is at the core of inflammatory bowel disease (IBD), which is characterized by activation of the pro-inflammatory transcription factor nuclear factor-kB (NF-kB). Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ffed7a6d-b696-49b5-be6e-256bbdcdd024 NodeType: Pathway Notes: Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Chronic and relapsing inflammation is at the core of IBD and is associated with the activation of the pro-inflammatory transcription factor nuclear factor-kB (NF-kB). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. Organ: colon Organ: intestine Organ_System: digestive system PMID: 21810260 PathwayType: signaling Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X Source: Diseases urn:agi-pathway:uuid-ffed7a6d-b696-49b5-be6e-256bbdcdd024 Nicotine anti-Inflammatory Effect in Ulcerative Colitis uuid-ffed7a6d-b696-49b5-be6e-256bbdcdd024 PS:CellType dendritic cell PS:CellType macrophage PS:CellType mast cell PS:Description Chronic and relapsing inflammation is at the core of inflammatory bowel disease (IBD), which is characterized by activation of the pro-inflammatory transcription factor nuclear factor-kB (NF-kB). Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ffed7a6d-b696-49b5-be6e-256bbdcdd024 PS:NodeType Pathway PS:Notes Headnote: Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBD) characterized by chronic inflammation in the lining of the large intestine. Signaling description: Chronic and relapsing inflammation is at the core of IBD and is associated with the activation of the pro-inflammatory transcription factor nuclear factor-kB (NF-kB). Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Proteins with increased expression or activity are highlighted in red. PS:Organ colon PS:Organ intestine PS:Organ_System digestive system PS:PMID 21810260 PS:PathwayType signaling PS:Pathway_Author V. Sobolev ORCID:0000-0003-4779-156X PS:Source Diseases PS:CellType PS:Description PS:Link PS:NodeType PS:Notes PS:Organ PS:Organ_System PS:PMID PS:PathwayType PS:Pathway_Author PS:Source PS:Tissue CellType: osteoblast Description: Hypoparathyroidism is a metabolic disorder characterized by deficient or absent secretion of PTH, which functions as a major mediator of bone remodeling. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fff1e56c-9d96-439d-a6d2-79171444b232 NodeType: Pathway Notes: Headnote: Hypoparathyroidism is an endocrine disorder characterized by deficient or absent secretion of parathyroid hormone (PTH), which functions as a major mediator of bone remodeling. This disorder is characterized by increased bone mass that may leads to brittleness of bone. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. Organ: bone Organ_System: skeletal system PMID: 11814673 PMID: 19127545 PMID: 25166046 PathwayType: signaling Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411 Source: Diseases Tissue: bone tissue urn:agi-pathway:uuid-fff1e56c-9d96-439d-a6d2-79171444b232 Osteoblast Dysfunction in Hypoparathyroidism uuid-fff1e56c-9d96-439d-a6d2-79171444b232 PS:CellType osteoblast PS:Description Hypoparathyroidism is a metabolic disorder characterized by deficient or absent secretion of PTH, which functions as a major mediator of bone remodeling. Pathway is built manually using published studies. PS:Link https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-fff1e56c-9d96-439d-a6d2-79171444b232 PS:NodeType Pathway PS:Notes Headnote: Hypoparathyroidism is an endocrine disorder characterized by deficient or absent secretion of parathyroid hormone (PTH), which functions as a major mediator of bone remodeling. This disorder is characterized by increased bone mass that may leads to brittleness of bone. Highlighted proteins: Entities with increased expression or activity are highlighted in red, and entities with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PS:Organ bone PS:Organ_System skeletal system PS:PMID 11814673 PS:PMID 19127545 PS:PMID 25166046 PS:PathwayType signaling PS:Pathway_Author M. Zharkova  ORCID:0000-0001-8706-9411 PS:Source Diseases PS:Tissue bone tissue ppse2obo 1.2