Human Gene TSC2 (ENST00000219476.9_10) from GENCODE V47lift37
Description: 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:12906785, PubMed:12842888, PubMed:28215400, PubMed:35772404, PubMed:15340059, PubMed:22819219, PubMed:24529379, PubMed:33436626). 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:12906785, PubMed:12842888, PubMed:15340059, PubMed:12820960, 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:12906785, PubMed:12842888, 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). (from UniProt P49815) Gencode Transcript: ENST00000219476.9_10 Gencode Gene: ENSG00000103197.20_16 Transcript (Including UTRs) Position: hg19 chr16:2,097,986-2,139,492 Size: 41,507 Total Exon Count: 42 Strand: + Coding Region Position: hg19 chr16:2,098,617-2,138,611 Size: 39,995 Coding Exon Count: 41
ID:TSC2_HUMAN DESCRIPTION: RecName: Full=Tuberin; AltName: Full=Tuberous sclerosis 2 protein; FUNCTION: In complex with TSC1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. Acts as a GTPase- activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling. Stimulates weakly the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 in vitro. Mutations in TSC2 lead to constitutive activation of RAP1A in tumors. SUBUNIT: Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1. May also interact with the adapter molecule RABEP1. The final complex contains TSC2 and RABEP1 linked to RAB5 (Probable). Interacts with HSPA1 and HSPA8. Interacts with DAPK1 and FBXW5. INTERACTION: P62136:PPP1CA; NbExp=2; IntAct=EBI-396587, EBI-357253; Q96EB6:SIRT1; NbExp=2; IntAct=EBI-396587, EBI-1802965; Q92574:TSC1; NbExp=7; IntAct=EBI-396587, EBI-1047085; SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane protein. Note=At steady state found in association with membranes. TISSUE SPECIFICITY: Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta. PTM: Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr- 1462 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negatively regulates the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1. PTM: Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. DISEASE: Defects in TSC2 are the cause of tuberous sclerosis type 2 (TSC2) [MIM:613254]. TSC2 is 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 symptoms can range from benign hypopigmented macules of the skin to profound mental retardation with intractable seizures to premature death from a variety of disease-associated causes. DISEASE: Defects in TSC2 are a cause of lymphangioleiomyomatosis (LAM) [MIM:606690]. LAM is a 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. SIMILARITY: Contains 1 Rap-GAP domain. SEQUENCE CAUTION: Sequence=BAE06082.1; Type=Erroneous initiation; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/TSC2ID184.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TSC2"; WEB RESOURCE: Name=Tuberous sclerosis database Tuberous sclerosis 2 (TSC2); Note=Leiden Open Variation Database (LOVD); URL="http://www.LOVD.nl/TSC2";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF02145 - Rap/ran-GAP PF03542 - Tuberin PF11864 - Domain of unknown function (DUF3384)
SCOP Domains: 48371 - ARM repeat 48431 - Lipovitellin-phosvitin complex, superhelical domain 48552 - Serum albumin-like 47938 - Functional domain of the splicing factor Prp18 111347 - Rap/Ran-GAP
ModBase Predicted Comparative 3D Structure on P49815
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001843 neural tube closure GO:0006469 negative regulation of protein kinase activity GO:0006606 protein import into nucleus GO:0006897 endocytosis GO:0007507 heart development GO:0008104 protein localization GO:0008285 negative regulation of cell proliferation GO:0014067 negative regulation of phosphatidylinositol 3-kinase signaling GO:0016032 viral process GO:0016192 vesicle-mediated transport GO:0016239 positive regulation of macroautophagy GO:0030100 regulation of endocytosis GO:0030178 negative regulation of Wnt signaling pathway GO:0032007 negative regulation of TOR signaling GO:0043276 anoikis GO:0043491 protein kinase B signaling GO:0043547 positive regulation of GTPase activity GO:0046626 regulation of insulin receptor signaling pathway GO:0046627 negative regulation of insulin receptor signaling pathway GO:0048009 insulin-like growth factor receptor signaling pathway GO:0050918 positive chemotaxis GO:0051056 regulation of small GTPase mediated signal transduction GO:0051726 regulation of cell cycle GO:0051898 negative regulation of protein kinase B signaling GO:1901525 negative regulation of macromitophagy
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
