Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb

Abstract

We show that Rheb acts as a novel mediator of the nutrient signaling input to mTOR and is the molecular target of TSC1 and TSC2 within mammalian cells.

Stress and mTORture signaling

“…See text for a more detailed description. Tee et al, 2003). dRheb overexpression recapitulates dTSC1/2 mutant phenotypes, and reduction in dRheb function rescues larval lethality caused by loss of dTSC1/2 in the fly .…”

Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

“…As a heterodimer, TSC1 and TSC2 repress cell growth by inhibiting cell signal transduction through the mammalian target of rapamycin complex 1 (mTORC1) pathway. 12 TSC1/TSC2 possesses GTPase-activating protein (GAP) activity towards the small G-protein, Ras homologue enriched in brain (Rheb), [13][14][15][16] converting Rheb from its active GTP-bound form to the inactive GDP-bound form. Consequently, inactivation of Rheb by TSC1/TSC2 prevents activity of mTORC1 and phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1, leading to repression of protein translation.…”

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…Along with others, we showed that the small GTPase Rheb is the molecular link between TSC1/2 and mTORC1. Rheb activates mTORC1, and TSC2 inhibits Rheb by acting as a GTPase-activating protein (Castro et al, 2003;Garami et al, 2003;Tee et al, 2003;Inoki et al, 2003a;Zhang et al, 2003b).…”