{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P49815","secondaryAccessions":["A7E2E2","B4DIL8","B4DIQ7","B4DRN2","B7Z2B8","C9J378","O75275","Q4LE71","Q8TAZ1"],"uniProtkbId":"TSC2_HUMAN","entryAudit":{"firstPublicDate":"1996-10-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2009-11-24","entryVersion":249,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9045618"}],"value":"Tuberin"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"7558029"}],"value":"Tuberous sclerosis 2 protein"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"7558029"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:12363"}],"value":"TSC2"},"synonyms":[{"value":"TSC4"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P49816"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12172553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12271141"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12820960"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12842888"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12906785"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15340059"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22819219"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28215400"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33436626"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35772404"}],"value":"Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379, PubMed:28215400, PubMed:33436626, PubMed:35772404). Within the TSC-TBC complex, TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:12172553, PubMed:12820960, PubMed:12842888, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379, PubMed:33436626). In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12906785, PubMed:22819219, PubMed:24529379, PubMed:28215400, PubMed:35772404). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (PubMed:12172553, PubMed:24529379). Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10585443"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12172553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12842888"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12906785"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15963462"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16464865"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20145209"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22795129"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25816988"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25936802"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28215400"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28561026"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28561066"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29127155"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33436626"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33473107"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9045618"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9580671"}],"value":"Component of the TSC-TBC complex (also named Rhebulator complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 molecule of TBC1D7 (PubMed:10585443, PubMed:12172553, PubMed:12842888, PubMed:12906785, PubMed:15963462, PubMed:22795129, PubMed:24529379, PubMed:28215400, PubMed:33436626, PubMed:9580671). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (PubMed:16464865). May also interact with the adapter molecule RABEP1 (PubMed:9045618). The final complex may contain TSC2 and RABEP1 linked to RAB5 (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462). Interacts with NAA10 (via C-terminal domain) (PubMed:20145209). Interacts with RRAGA (polyubiquitinated) (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). Interacts with YWHAG (PubMed:33473107). Interacts with RHEB (PubMed:25816988)"}],"commentType":"SUBUNIT"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18407068"}],"value":"(Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"Q9NRD5","geneName":"PICK1","intActId":"EBI-79165"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"P62136","geneName":"PPP1CA","intActId":"EBI-357253"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"O00141","geneName":"SGK1","intActId":"EBI-1042854"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"Q96EB6","geneName":"SIRT1","intActId":"EBI-1802965"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"Q92574","geneName":"TSC1","intActId":"EBI-1047085"},"numberOfExperiments":13,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"P31946","geneName":"YWHAB","intActId":"EBI-359815"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P49815","intActId":"EBI-396587"},"interactantTwo":{"uniProtKBAccession":"P63104","geneName":"YWHAZ","intActId":"EBI-347088"},"numberOfExperiments":9,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"value":"Recruited to lysosomal membranes in a RHEB-dependent process in absence of nutrients (PubMed:24529379). In response to insulin signaling and phosphorylation by PKB/AKT1, the complex dissociates from lysosomal membranes and relocalizes to the cytosol (PubMed:24529379)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25816988"}],"value":"Lysosome membrane","id":"SL-0157"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"value":"Peripheral membrane protein","id":"SL-9903"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10585443"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"value":"Cytoplasm, cytosol","id":"SL-0091"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["P49815-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["P49815-2"],"sequenceIds":["VSP_004470"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["P49815-3"],"sequenceIds":["VSP_004471"],"isoformSequenceStatus":"Described"},{"name":{"value":"4"},"isoformIds":["P49815-4"],"sequenceIds":["VSP_004472"],"isoformSequenceStatus":"Described"},{"name":{"value":"5"},"isoformIds":["P49815-5"],"sequenceIds":["VSP_004471","VSP_004472"],"isoformSequenceStatus":"Described"},{"name":{"value":"6"},"isoformIds":["P49815-6"],"sequenceIds":["VSP_038355","VSP_004470","VSP_004472"],"isoformSequenceStatus":"Described"},{"name":{"value":"7"},"isoformIds":["P49815-7"],"sequenceIds":["VSP_054163","VSP_004470","VSP_004472"],"isoformSequenceStatus":"Described"},{"name":{"value":"8"},"synonyms":[{"value":"H"},{"value":"I"}],"isoformIds":["P49815-8"],"sequenceIds":["VSP_055896","VSP_055897"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8269512"}],"value":"Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12150915"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12172553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14651849"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15342917"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15963462"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18974095"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"value":"Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 in response to insulin signaling and growth factor stimulation inhibits the ability of the TSC-TBC complex to suppress mTORC1 signaling: phosphorylation promotes dissociation of the TSC-TBC complex from lysosomal membranes, leading to activation of mTORC1 by RHEB (PubMed:12150915, PubMed:12172553, PubMed:24529379). Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1 (PubMed:15963462). Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex (PubMed:14651849). Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling (PubMed:15342917). Phosphorylated by DAPK1 (PubMed:18974095)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18308511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18381890"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27278822"}],"value":"Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation (PubMed:18381890, PubMed:27278822). Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination (PubMed:18308511)"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Tuberous sclerosis 2","diseaseAccession":"DI-02846","acronym":"TSC2","description":"An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes.","diseaseCrossReference":{"database":"MIM","id":"613254"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10069705"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10205261"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10533067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10570911"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10607950"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10732801"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10735580"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12271141"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12820960"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15024740"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15340059"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15595939"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15963462"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8824881"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9302281"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9463313"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9829910"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Lymphangioleiomyomatosis","diseaseAccession":"DI-01919","acronym":"LAM","description":"Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex.","diseaseCrossReference":{"database":"MIM","id":"606690"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10823953"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11829138"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Focal cortical dysplasia 2","diseaseAccession":"DI-04980","acronym":"FCORD2","description":"A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells.","diseaseCrossReference":{"database":"MIM","id":"607341"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28215400"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"May be due to an intron retention"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 8"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAE06082.1","note":"Extended N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"Atlas of Genetics and Cytogenetics in Oncology and Haematology","resourceUrl":"https://atlasgeneticsoncology.org/gene/184/TSC2","ftp":false},{"commentType":"WEB RESOURCE","resourceName":"Tuberous sclerosis database Tuberous sclerosis 2 (TSC2)","resourceUrl":"https://databases.lovd.nl/shared/genes/TSC2","ftp":false,"note":"Leiden Open Variation Database (LOVD)"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":1807,"modifier":"EXACT"}},"description":"Tuberin","featureId":"PRO_0000065654"},{"type":"Domain","location":{"start":{"value":1531,"modifier":"EXACT"},"end":{"value":1758,"modifier":"EXACT"}},"description":"Rap-GAP","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00165"}]},{"type":"Region","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":400,"modifier":"EXACT"}},"description":"Required for interaction with 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