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MGP003208

UniProt Annotations

Entry Information
Gene Nametuberous sclerosis 2
Protein EntryTSC2_HUMAN
UniProt IDP49815
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=8; Name=1; IsoId=P49815-1; Sequence=Displayed; Name=2; IsoId=P49815-2; Sequence=VSP_004470; Note=No experimental confirmation available.; Name=3; IsoId=P49815-3; Sequence=VSP_004471; Note=No experimental confirmation available.; Name=4; IsoId=P49815-4; Sequence=VSP_004472; Name=5; IsoId=P49815-5; Sequence=VSP_004471, VSP_004472; Name=6; IsoId=P49815-6; Sequence=VSP_038355, VSP_004470, VSP_004472; Name=7; IsoId=P49815-7; Sequence=VSP_054163, VSP_004470, VSP_004472; Note=No experimental confirmation available.; Name=8; Synonyms=H, I; IsoId=P49815-8; Sequence=VSP_055896, VSP_055897;
DiseaseLymphangioleiomyomatosis (LAM) [MIM:606690]: 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. {ECO:0000269|PubMed:10823953}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseTuberous sclerosis 2 (TSC2) [MIM:613254]: 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. {ECO:0000269|PubMed:10069705, ECO:0000269|PubMed:10205261, ECO:0000269|PubMed:10533067, ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:10732801, ECO:0000269|PubMed:10735580, ECO:0000269|PubMed:15024740, ECO:0000269|PubMed:15595939, ECO:0000269|PubMed:8824881, ECO:0000269|PubMed:9302281, ECO:0000269|PubMed:9463313, ECO:0000269|PubMed:9829910}. Note=The disease is caused by mutations affecting the gene represented in this entry.
FunctionIn 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. {ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:16707451}.
InteractionP62136:PPP1CA; NbExp=2; IntAct=EBI-396587, EBI-357253; Q96EB6:SIRT1; NbExp=2; IntAct=EBI-396587, EBI-1802965; Q92574:TSC1; NbExp=10; IntAct=EBI-396587, EBI-1047085; P31946:YWHAB; NbExp=4; IntAct=EBI-396587, EBI-359815; P63104:YWHAZ; NbExp=7; IntAct=EBI-396587, EBI-347088;
PtmPhosphorylation 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. {ECO:0000269|PubMed:12150915, ECO:0000269|PubMed:15342917, ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:18308511, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:19690332, ECO:0000269|PubMed:20068231}.
PtmUbiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 inependently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination. {ECO:0000269|PubMed:18308511, ECO:0000269|PubMed:18381890}.
Sequence CautionSequence=BAE06082.1; Type=Erroneous initiation; Evidence={ECO:0000305};
SimilarityContains 1 Rap-GAP domain. {ECO:0000255|PROSITE- ProRule:PRU00165}.
Subcellular LocationCytoplasm. Membrane; Peripheral membrane protein. Note=At steady state found in association with membranes.
SubunitInteracts 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. Interacts with NAA10 (via C-terminal domain). {ECO:0000269|PubMed:10585443, ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:18381890, ECO:0000269|PubMed:18974095, ECO:0000269|PubMed:20145209, ECO:0000269|PubMed:9045618, ECO:0000269|PubMed:9580671, ECO:0000305}.
Tissue SpecificityLiver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/TSC2ID184.html";
Web ResourceName=Tuberous sclerosis database Tuberous sclerosis 2 (TSC2); Note=Leiden Open Variation Database (LOVD); URL="http://www.LOVD.nl/TSC2";
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