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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)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P49815"}],"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 (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (By similarity). 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 (By similarity). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (By similarity). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (By similarity). May also interact with the adapter molecule RABEP1 (By similarity). The final complex may contain TSC2 and RABEP1 linked to RAB5 (By similarity). Interacts with HSPA1 and HSPA8 (By similarity). Interacts with NAA10 (via C-terminal domain) (By similarity). Interacts with RRAGA (polyubiquitinated) (By similarity). Interacts with WDR45B (By similarity). Interacts with RPAP3 and URI1. Interacts with YWHAG (By similarity). Interacts with RHEB (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q61037","intActId":"EBI-7924402"},"interactantTwo":{"uniProtKBAccession":"Q9EP53","geneName":"Tsc1","intActId":"EBI-1202690"},"numberOfExperiments":6,"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. In response to insulin signaling and phosphorylation by PKB/AKT1, the complex dissociates from lysosomal membranes and relocalizes to the cytosol"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"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":"24529379"}],"value":"Cytoplasm, cytosol","id":"SL-0091"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"G"},"isoformIds":["Q61037-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"A"},"isoformIds":["Q61037-2"],"sequenceIds":["VSP_004473"],"isoformSequenceStatus":"Described"},{"name":{"value":"B"},"isoformIds":["Q61037-3"],"sequenceIds":["VSP_004474"],"isoformSequenceStatus":"Described"},{"name":{"value":"C"},"isoformIds":["Q61037-4"],"sequenceIds":["VSP_004476"],"isoformSequenceStatus":"Described"},{"name":{"value":"D"},"isoformIds":["Q61037-5"],"sequenceIds":["VSP_004478"],"isoformSequenceStatus":"Described"},{"name":{"value":"E"},"isoformIds":["Q61037-6"],"sequenceIds":["VSP_004477","VSP_004478","VSP_004479"],"isoformSequenceStatus":"Described"},{"name":{"value":"F"},"isoformIds":["Q61037-7"],"sequenceIds":["VSP_004475","VSP_004477","VSP_004478","VSP_004479","VSP_004480"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8833243"}],"value":"Widely expressed"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P49815"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24529379"}],"value":"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)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P49815"}],"value":"Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. 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