Q61037
uniprot
Q61037
canonical
amino_acid_sequence
MAKPTSKDSGLKEKFKILLGLGTSRPNPRCAEGKQTEFIITSEILRELSGECGLNNRIRMIGQICDVAKTKKLEEHAVEALWKAVSDLLQPERPPEARHAVLTLLKAIVQGQGDRLGVLRALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELAEFVLQWMDVGLSSEFLLVLVNLVKFNSCYLDEYIASMVHMICLLCIRTVSSVDIEVSLQVLDAVVCYNCLPAESLPLFIITLCRTINVKELCEPCWKLMRNLLGTHLGHSAIYNMCRIMEDRSYMEDAPLLRGAVFFVGMALWGAHRLYSLKNSPTSVLPSFYEAMTCPNEVVSYEIVLSITRLIKKYRKELQAVTWDILLDIIERLLQQLQNLDSPELKTIVHDLLTTVEELCDQNEFHGSQERYYELVESYADQRPESSLLNLISYRAQSIHPAKDGWIQNLQLLMERFFRNECRSAVAIKVLDVLSFVLLIIRQFYEEELINSVVISQLSHIPEDKDHQVRKLATQLLVDLAEGCHTHHFNSLLDIIEKVMARSLSPPPELEERDLAVHSASLEDVKTAVLGLLVILQTKLYTLPASHATRVYESLISHIQLHYKHGYSLPIASSIRLQAFDFLLLLRADSLHRLGLPNKDGVVRFSPYCLCDCMELDRASEKKASGPLSPPTGPPSPVPMGPAVRLGYLPYSLLFRVLLQCLKQESDWKVLKLVLSRLPESLRYKVLIFTSPCSVDQLSSALCSMLSAPKTLERLRGTPEGFSRTDLHLAVVPVLTALISYHNYLDKTRQREMVYCLEQGLIYRCASQCVVALAICSVEMPDIIIKALPVLVVKLTHISATASMAIPLLEFLSTLARLPHLYRNFVPEQYASVFAISLPYTNPSKFNQYIVCLAHHVIAMWFIRCRLPFRKDFVPYITKGLRSNVLLSFDDTPEKDSFRARSTSLNERPKSLRIARAPKQGLNNSPPVKEFKESCAAEAFRCRSISVSEHVVRSRIQTSLTSASLGSADENSMAQADDNLKNLHLELTETCLDMMARYVFSNFTAVPKRSPVGEFLLAGGRTKTWLVGNKLVTVTTSVGTGTRSLLGLDSGDLQGGSDSSSDPSTHVRQTKEAPAKLESQAGQQVSRGARDRVRSMSGGHGLRVGVLDTSAPYSPGGSASLGPQTAVAAKPEKPPAGAQLPTAEKTNLAAYVPLLTQGWAEILVRRPTGNTSWLMSLENPLSPFSSDINNMPLQELSNALMAAERFKEHGHAPVQVIVSATGCTAKPPTLPRSNTVASFSSLYQPSCQGQLHRSVSWADSAMVLEEGSPGETQVPVEPPELEDFEAALGTDRHCQRPDTYSRSSSASSQEEKSHLEELAAGGIPIERAISSEGARPAVDLSFQPSQPLSKSSSSPELQTLQDILGDLGDKIDIGRLSPEAKVRSQSGILDGEAATWSATGEESRITVPPEGPLPSSSPRSPSGLRPRGYTISDSAPSRRGKRVERDNFKSRAAASSAEKVPGINPSFVFLQLYHSPFFGDESNKPILLPNESFERSVQLLDQIPSYDTHKIAVLYVGEGQSSSELAILSNEHGSYRYTEFLTGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFHIATLMPTKDVDKHRCDKKRHLGNDFVSIIYNDSGEDFKLGTIKQGQFNFVHVIITPLDYKCNLLTLQCRKDGPACKCEWWRQPGEIVVWALPVVMELTVTILLCHLQMASQVHHSRSNPTDIYPSKWIARLRHIKRLRQRIREEVHYSNPSLPLMHPPAHTKAPAQAPEATPTYETGQRKRLISSVDDFTEFV
uniprot
proteins
function
FUNCTION: 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:12820960, PubMed:24529379). 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:12820960, PubMed:24529379). 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:12820960, PubMed:24529379). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (PubMed:24529379). Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (PubMed:16707451). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity). {ECO:0000250|UniProtKB:P49816, ECO:0000269|PubMed:12820960, ECO:0000269|PubMed:16707451, ECO:0000269|PubMed:24529379}.
uniprot
proteins
mass_dalton
202071
uniprot
proteins
mutagenesis
MUTAGEN 939; /note="S->A: In TSC2-5A; abolished phosphorylation by PKB/AKT1, leading to constitutive localization to lysosomal membranes; when associated with A-981, 1130-A--A-1132 and A-1465."; /evidence="ECO:0000269|PubMed:24529379"; MUTAGEN 981; /note="S->A: In TSC2-5A; abolished phosphorylation by PKB/AKT1, leading to constitutive localization to lysosomal membranes; when associated with A-939, 1130-A--A-1132 and A-1465."; /evidence="ECO:0000269|PubMed:24529379"; MUTAGEN 1130..1132; /note="SMS->AMA: In TSC2-5A; abolished phosphorylation by PKB/AKT1, leading to constitutive localization to lysosomal membranes; when associated with A-939, A-981 and A-1465."; /evidence="ECO:0000269|PubMed:24529379"; MUTAGEN 1465; /note="T->A: In TSC2-5A; abolished phosphorylation by PKB/AKT1, leading to constitutive localization to lysosomal membranes; when associated with A-939, A-981 and 1130-A--A-1132."; /evidence="ECO:0000269|PubMed:24529379
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-939 and Thr-1465 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:24529379). Phosphorylation at Ser-1388, Ser-1419 or Ser-1421 does not affect interaction with TSC1 (By similarity). Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex (By similarity). Phosphorylated at Ser-1805 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1 (By similarity). {ECO:0000250|UniProtKB:P49815, ECO:0000269|PubMed:24529379}.; PTM: Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination. {ECO:0000250|UniProtKB:P49815}.
uniprot
proteins
pubmed
10584558
uniprot
proteins
pubmed
12820960
uniprot
proteins
pubmed
16707451
uniprot
proteins
pubmed
17242355
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
24529379
uniprot
proteins
pubmed
8777431
uniprot
proteins
pubmed
8833243
uniprot
proteins
pubmed
9743625
uniprot
proteins
sequence_length
1814
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:24529379}; Peripheral membrane protein {ECO:0000269|PubMed:24529379}. Cytoplasm, cytosol {ECO:0000269|PubMed:24529379}. Note=Recruited to lysosomal membranes in a RHEB-dependent process in absence of nutrients. In response to insulin signaling and phosphorylation by PKB/AKT1, the complex dissociates from lysosomal membranes and relocalizes to the cytosol. {ECO:0000269|PubMed:24529379}.
uniprot
proteins