Rheb promotes cell growth as a component of the insulin/TOR signalling network

Abstract

Insulin signalling is a potent stimulator of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin) [corrected]. Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity [corrected]. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.

Myelination and mTOR

“…The TSC complex, formed by the subunits TSC1, TSC2, and TBC1D7, is responsible for relaying most growth factor signaling pathways to mTORC1 (Ben‐Sahra & Manning, 2017). The TSC complex acts as a GTPase‐activating protein (GAP) complex for the small GTPase Rheb1, a potent mTORC1 activator when loaded with GTP (Patel et al, 2003; Saucedo et al, 2003; Stocker et al, 2003). In the absence of growth factor stimulation, the TSC complex is active and reduces the levels of GTP‐loaded Rheb1.…”

Stress and mTORture signaling

“…TSC2 encodes a GTPase-activating protein (GAP) that is thought to hydrolyse guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the small GTPase Rheb (Ras homolog enriched in brain). Rheb (Rheb1 and Rheb2 in mouse and human, other model organisms have only one isoform; Patel et al, 2003) was identified both in genetic screens and biochemical studies as target of the GAP activity of TSC2 (Castro et al, 2003;Garami et al, 2003;Inoki et al, 2003a;Patel et al, 2003;Saucedo et al, 2003;Stocker et al, 2003; Figure 1 mTOR signaling and stress. mTORC1 promotes growth and protein synthesis through the regulation of S6K and 4E-BP while inhibiting autophagy when sufficient nutrients (e.g.…”

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

“…Recent studies have revealed that TSC2 plays an important role in the cell growth and proliferation pathway, in which TSC2 forms a functional complex with TSC1 and negatively regulates both growth factor and nutrient-dependent activation of mTOR signalling to its downstream targets S6 kinase and 4EBP1 (Gao et al, 2002;Manning and Cantley, 2003;Saucedo et al, 2003;Stocker et al, 2003;Hay and Sonenberg, 2004). The negative regulatory role of the complex is achieved by TSC2 GTPaseactivating protein activity towards Rheb.…”