Human Gene TSC2 (uc002con.3) Description and Page Index
Description: Homo sapiens tuberous sclerosis 2 (TSC2), transcript variant 1, mRNA. RefSeq Summary (NM_000548): Mutations in this gene lead to tuberous sclerosis complex. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. The protein associates with hamartin in a cytosolic complex, possibly acting as a chaperone for hamartin. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]. Transcript (Including UTRs) Position: hg19 chr16:2,097,990-2,138,713 Size: 40,724 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";
Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): TSC2 CDC HuGE Published Literature: TSC2 Positive Disease Associations: Longevity Related Studies:
Longevity Anatoliy I Yashin et al. Aging 2010, Joint influence of small-effect genetic variants on human longevity., Aging.
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.
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.