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J. Biol. Chem., Vol. 281, Issue 34, 24293-24303, August 25, 2006

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Activation of Mammalian Target of Rapamycin (mTOR) by Insulin Is Associated with Stimulation of 4EBP1 Binding to Dimeric mTOR Complex 1^*

Lifu Wang, Christopher J. Rhodes, and John C. Lawrence, Jr.¹

From the Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 and the Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122

Insulin stimulates protein synthesis by promoting phosphorylation of the eIF4E-binding protein, 4EBP1. This effect is rapamycin-sensitive and mediated by mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a signaling complex containing mTOR, raptor, and mLST8. Here we demonstrate that insulin produces a stable increase in the kinase activity of mTORC1 in 3T3-L1 adipocytes. The response was associated with a marked increase in 4EBP1 binding to raptor in mTORC1, and it was abolished by disrupting the TOR signaling motif in 4EBP1. The stimulatory effects of insulin on both 4EBP1 kinase activity and binding occurred rapidly and at physiological concentrations of insulin, and both effects required an intact mTORC1. Results of experiments involving size exclusion chromatography and coimmunoprecipitation of epitope-tagged subunits provide evidence that the major insulin-responsive form is dimeric mTORC1, a structure containing two heterotrimers of mTOR, raptor, and mLST8.

Received for publication, April 13, 2006 , and in revised form, May 30, 2006.

^* This work was supported by National Institutes of Health Grants DK52753 and DK28312. 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.

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.: 434-924-1584; Fax: 434-982-3878; E-mail: jcl3p{at}virginia.edu.

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