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J. Biol. Chem., Vol. 282, Issue 27, 20036-20044, July 6, 2007

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PRAS40 Regulates mTORC1 Kinase Activity by Functioning as a Direct Inhibitor of Substrate Binding^*

Lifu Wang¹, Thurl E. Harris, Richard A. Roth, and John C. Lawrence , Jr

From the Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 and Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305-5174

Mammalian target of rapamycin (mTOR) functions in two distinct signaling complexes, mTORC1 and mTORC2. In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. Previously we found that activation of mTOR kinase in response to insulin was associated with increased 4EBP1 binding to raptor. Here we identify prolinerich Akt substrate 40 (PRAS40) as a binding partner for mTORC1. A putative TOR signaling motif, FVMDE, is identified in PRAS40 and shown to be required for interaction with raptor. Insulin stimulation markedly decreases the level of PRAS40 bound by mTORC1. Recombinant PRAS40 inhibits mTORC1 kinase activity in vivo and in vitro, and this inhibition depends on PRAS40 association with raptor. Furthermore, decreasing PRAS40 expression by short hairpin RNA enhances 4E-BP1 binding to raptor, and recombinant PRAS40 competes with 4E-BP1 binding to raptor. We, therefore, propose that PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.

Received for publication, March 20, 2007 , and in revised form, May 15, 2007.

^* This work was supported by National Institutes of Health Grants DK52753 and DK28312 (to J. C. L.). 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 Figs. S1-S3.

This work is dedicated to the memory of Dr. John Lawrence, Jr., deceased December 19, 2006.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Virginia Health System, P. O. Box 800735, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Tel.: 434-924-1582; Fax: 434-982-3878; E-mail: lw6j{at}virginia.edu.

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