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J. Biol. Chem., Vol. 281, Issue 29, 19793-19797, July 21, 2006

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Hyperactivation of Mammalian Target of Rapamycin (mTOR) Signaling by a Gain-of-Function Mutant of the Rheb GTPase^*

From the Institute of Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, 237 Fulham Road, London SW7 6JB, United Kingdom

Gain-of-function mutants of Ras and Rho family small GTPases have proven to be important tools in analyzing signaling downstream of these small GTPases. The Ras-related GTPase Rheb has emerged as a key player downstream of TSC1–2 in activating signaling to mammalian target of rapamycin (mTOR) effectors of cell growth such as S6K and 4E-BP1. The TSC1–2 tumor suppressor complex has been shown to act as a RhebGAP, converting Rheb from a GTP-bound to a GDP-bound form. Here we report the identification of a mutant Rheb (S16HRheb) that exhibits gain-of-function properties. At endogenous levels of expression S16HRheb exhibits increased GTP loading in vivo and is resistant to TSC1–2 GAP in vitro. Compared with wild-type Rheb, S16HRheb is more active at promoting the phosphorylation of the mTOR effectors S6K1 and 4E-BP1. Thus S16HRheb will help to identify proximal signaling events downstream of Rheb and allow potential Rheb-independent functions downstream of TSC1–2 to be investigated.

Received for publication, February 9, 2006 , and in revised form, May 15, 2006.

^* This work was supported by grants from the Tuberous Sclerosis Association (to R. J.) and Cancer Research UK and an Institute of Cancer Research Studentship (to G. M. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and Figs. S1–S4.

¹ To whom correspondence should be addressed. Tel.: 44-207-153-5348; E-mail: Richard.Lamb{at}icr.ac.uk.

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