TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of the small G-protein Rheb. This results in the conversion of Rheb:GTP to Rheb:GDP. GDP-bound Rheb is unable to activate mTOR (Inoki et al. 2003, Tee et al. 2003). It is not demonstrated that RHEB hydrolyzes GTP when present in the mTORC1 complex; given the low affinity of RHEB for mTOR, it may dissociate from the mTORC1 complex before TSC2 stimulates hydrolysis of GTP; TSC2 may not have access to critical residues of RHEB when present inside mTORC1.
Tee, AR, Manning, BD, Cantley, LC, Blenis, J, Roux, PP
Inoki, K, Guan, KL, Li, Y, Xu, T
GTPase activity of Active mTORC1 complex [lysosomal membrane]
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