Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.

By K. Inoki, Yong Li, Tian Xu, K. Guan. Genes & Development, 2003

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Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/cd896ae5afa2e274c1b2d95fb187dcf075db587f

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Citations in the corpus

Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. (2007, background): “Rheb exists in two states: the GTP-bound form of Rheb activates mTOR, whereas the GDP-bound form of Rheb cannot activate mTOR (38).”
The mTOR Signalling Pathway in Human Cancer (2012, background): “The phosphorylation of TSC2 prevents TSC1/TSC2 complex formation, which drives the small GTPase Rheb into the GTP-bound active state [40], leading to the activation of mTORC1 at Ser2448 [46,47].”
SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. (2006, background): “TSC2 is also phosphorylated and inactivated by other kinases such as AMPK, ERK1/2, and RSK at sites other than the Akt target residues to positively regulate TORC1 signaling (Inoki et al., 2003; Ma et al., 2005; Roux and Blenis, 2004).”
Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. (2008, background): “Inhibition of TORC1 activity results from TSC2 catalytic function as a GTPase-activating protein (GAP) toward the small GTPase Rheb, a positively acting upstream regulator of TORC1 (Inoki et al. 2003; Tee et al. 2003).”
p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. (2008, positive): “Rheb GTP loading is controlled by the TSC1:TSC2 complex (Garami et al., 2003; Inoki et al., 2003b; Tee et al., 2003).”
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. (2004, background): “Exposure of Tsc2-deficient cells to hypoxia, in contrast to glucose (energy) depletion (Inoki et al. 2003b), did not result in a marked increase in cell death (determined by trypan blue exclusion; data not shown).”
Regulation of mTORC1 by amino acids (2014, positive): “Rheb promotes cell growth as a component of the insulin/TOR signalling network.”