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J. Biol. Chem., Vol. 282, Issue 34, 24514-24524, August 24, 2007

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PRAS40 Is a Target for Mammalian Target of Rapamycin Complex 1 and Is Required for Signaling Downstream of This Complex^*

Bruno D. Fonseca¹, Ewan M. Smith, Vivian H.-Y. Lee, Carol MacKintosh^¶, and Christopher G. Proud²

From the Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, the Division of Molecular Physiology, College of Life Sciences, and the ^¶Medical Research Council Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom

Signaling through the mammalian target of rapamycin complex 1 (mTORC1) is positively regulated by amino acids and insulin. PRAS40 associates with mTORC1 (which contains raptor) but not mTORC2. PRAS40 interacts with raptor, and this requires an intact TOR-signaling (TOS) motif in PRAS40. Like TOS motif-containing proteins such as eIF4E-binding protein 1 (4E-BP1), PRAS40 is a substrate for phosphorylation by mTORC1. Consistent with this, starvation of cells of amino acids or treatment with rapamycin alters the phosphorylation of PRAS40. PRAS40 binds 14-3-3 proteins, and this requires both amino acids and insulin. Binding of PRAS40 to 14-3-3 proteins is inhibited by TSC1/2 (negative regulators of mTORC1) and stimulated by Rheb in a rapamycin-sensitive manner. This confirms that PRAS40 is a target for regulation by mTORC1. Small interfering RNA-mediated knockdown of PRAS40 impairs both the amino acid- and insulin-stimulated phosphorylation of 4E-BP1 and the phosphorylation of S6. However, this has no effect on the phosphorylation of Akt or TSC2 (an Akt substrate). These data place PRAS40 downstream of mTORC1 but upstream of its effectors, such as S6K1 and 4E-BP1.

Received for publication, May 29, 2007 , and in revised form, June 29, 2007.

^* This work was supported in part by funding from the University of British Columbia, the Ajinomoto Amino Acid Research Program, and the Canadian Institutes for Health Research. 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.

This paper is dedicated to the memory of Dr. John C. Lawrence, Jr.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by a Morton Fellowship/University of Dundee School of Life Sciences Alumnus Fund.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Tel.: 604-827-3923; Fax: 604-822-5227; E-mail: cgpr{at}interchange.ubc.ca.

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