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J. Biol. Chem., Vol. 280, Issue 25, 23433-23436, June 24, 2005
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From the Diabetes Unit and Medical Services and the Department of Molecular Biology, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114
The removal of extracellular amino acids or leucine alone inhibits the ability of the mammalian target of rapamycin (mTOR) to signal to the raptor-dependent substrates, p70 S6 kinase and 4E-BP. This inhibition can be overcome by overexpression of the Rheb GTPase. Rheb binds directly to the amino-terminal lobe of the mTOR catalytic domain, and activates mTOR kinase in a GTP-dependent manner. Herein we show that the binding of Rheb to endogenous and recombinant mTOR is reversibly inhibited by withdrawal of all extracellular amino acids or just leucine. The effect of amino acid withdrawal is not attributable to changes in Rheb-GTP charging; amino acid withdrawal does not alter the GTP charging of recombinant Rheb. Moreover, the binding of mTOR to Rheb mutants that are unable to bind guanyl nucleotide in vivo is also inhibited by amino withdrawal. The inhibitory effect of amino acid withdrawal is exerted through an action on mTOR, at a site largely distinct from that responsible for the binding of Rheb; deletion of the larger, carboxyl-terminal lobe of the mTOR catalytic domain eliminates the inhibitory effect of amino acid withdrawal on Rheb binding, without altering Rheb binding per se. The lesser ability of the mTOR catalytic domain to bind Rheb after amino acid withdrawal does not persist after extraction and purification of the mTOR polypeptide. Amino acid withdrawl may generate an inhibitor of the Rheb-mTOR interaction that interferes with the signaling function of TOR complex 1.
Received for publication, April 18, 2005 , and in revised form, May 3, 2005.
* This work was supported in part by National Institutes of Health (NIH) Grants DK17776 and CA73818 (to J. A.). 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 Fig. 1.
Supported in part by a postdoctoral research fellowship award from the Massachusetts General Hospital Fund for Medical Discovery.
Both authors were supported in part by NIH Training Grant DK007028.
¶ To whom correspondence should be addressed: Dept. of Molecular Biology, 50 Blossom St., Wellman 11, Boston, MA 02114. Tel.: 617-726-6909; Fax: 617-726-5649; E-mail: avruch{at}molbio.mgh.harvard.edu.
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