Rheb binds and regulates the mTOR kinase.

By Samuel Long, Yenshou Lin, S. Ortiz-Vega, K. Yonezawa, J. Avruch. Current Biology, 2005

1,026 citations recorded by the source corpus.

BACKGROUND The target of rapamycin (TOR), in complex with the proteins raptor and LST8 (TOR complex 1), phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation. Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb, and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal. The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo. RESULTS Here, we show that Rheb binds to the TOR complex specifically, independently of its ability to bind TSC2, through separate interactions with the mTOR catalytic domain and with LST8. Rheb binding to the TOR complex in vivo and in vitro does not require Rheb guanyl nucleotide charging but is modulated by GTP and impaired by certain mutations (Ile39Lys) in the switch 1 loop. Nucleotide-deficient Rheb mutants, although capable of binding mTOR in vivo and in vitro, are inhibitory in vivo, and the mTOR polypeptides that associate with nucleotide-deficient Rheb in vivo lack kinase activity in vitro. Reciprocally, mTOR polypeptides bound to Rheb(Gln64Leu), a mutant that is nearly 90% GTP charged, exhibit substantially higher protein kinase specific activity than mTOR bound to wild-type Rheb. CONCLUSIONS The TOR complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/aa4fea7eb123ae623c55f73260271cb57777ae29

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “TSC is a heterotrimeric complex comprising TSC1, TSC2, and TBC1D7 (Dibble et al., 2012) and functions as a GTPase activating protein (GAP) for the small GTPase Rheb (Inoki et al., 2003a; Tee et al., 2003), which directly binds and activates mTORC1 (Long et al., 2005; Sancak et al., 2007).”
Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “Since TSC2 serves as a GTPase-activating protein (GAP) and inactivates the small GTPase Rheb, its inhibition subsequently allows Rheb to directly activate mTORC1 (41, 71, 72, 119).”
Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. (2006, background): “It has also been shown that in contrast to raptor, Rheb binds to the mTOR catalytic domain and that its binding is reversibly inhibited by amino acid withdrawal, regardless of GTP or GDP loading ( Long et al., 2005a, 2005b ).”
Resistance exercise increases AMPK activity and reduces 4E‐BP1 phosphorylation and protein synthesis in human skeletal muscle (2006, background): “…that the regulation of downstream signalling of mTOR to 4E-BP1 and S6K1 is complex and may be controlled by other mechanisms such as upstream regulation by TSC2 or directly via phosphorylation and/or binding by raptor (Kim et al. 2002; Inoki et al. 2003; Cheng et al. 2004; Long et al. 2005).”
The mTOR Signalling Pathway in Human Cancer (2012, background): “The exact mechanism by which Rheb activates mTORC1 is unknown, but it was described to entail the interaction of GTP-bound Rheb with the amino-terminal lobe of the mTOR kinase domain [47] and the farnesylation and subsequent localization of Rheb in the Golgi and endomembranes [48,49].”
Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner (2010, background): “This allows activation of Ras homolog enriched in brain (Rheb), required for mTORC1 activation (Garami et al., 2003; Long et al., 2005), whereas PRAS40 suppression relieves its inhibitory effects on mTORC1 (Haas and Hagedorn, 1992; Sancak et al., 2007).”
Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) regulates TOR signaling and cell growth during Drosophila development (2013, background): “A key signaling input that regulates TOR activity is the small GTPase Ras homolog enriched in brain (Rheb) (27).”
Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “Once on the lysosome, the growth factor-stimulated GTP-loaded form of the small GTPase RHEB (RAS homolog enriched in brain) binds and activates mTORC1 (Long et al , 2005).”
Oxidative stress and autophagy: the clash between damage and metabolic needs (2014, background): “RAS homologue enriched in brain (RHEB) that, upon binding to GTP, acts as positive regulator of mTORC1.(22) In agreement with this model, RAGs are the primary sensors that, by means”
mTOR and cancer: insights into a complex relationship (2006, background): “, a GTP-binding protein that activates mTORC1, most probably by binding to i”