Non-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 (  , ). The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 ( ). 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 ( ). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (, ). Within the TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self-aggregation (, ). Acts as a tumor suppressor . Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (By similarity). Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 . Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity . Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins . Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (, ).
Subcellular locations: Lysosome membrane, Cytoplasm, Cytosol
Recruited to lysosomal membranes in a RHEB-dependent process in absence of nutrients . In response to nutrients, the complex dissociates from lysosomal membranes and relocalizes to the cytosol .
Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney . Also expressed in embryonic kidney cells .