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J. Biol. Chem., Vol. 280, Issue 37, 32081-32089, September 16, 2005
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1
From the
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607 and the Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada
The serine/threonine kinase Akt is an upstream positive regulator of the mammalian target of rapamycin (mTOR). However, the mechanism by which Akt activates mTOR is not fully understood. The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR. Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), which is an activator of TSC2. We show that in Akt1/Akt2 DKO cells AMP/ATP ratio is markedly elevated with concomitant increase in AMPK activity, whereas in cells expressing activated Akt there is a dramatic decrease in AMP/ATP ratio and a decline in AMPK activity. Currently, the Akt-mediated phosphorylation of TSC2 and the inhibition of AMPK-mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR. Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK-mediated phosphorylation of TSC2. We propose that the activation of mTOR by Akt-mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo.
Received for publication, March 16, 2005 , and in revised form, July 5, 2005.
* This work was supported by National Institutes of Health (NIH) Grants CA090764 and AG016927 (to N. H.) and by NIH Training Grant T32DK007739 (to J. E. S). 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 and S2.
1 To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, University of Illinois, 900 S. Ashland Ave., Chicago, IL 60607. Tel.: 312-355-1684; Fax: 312-355-2032; E-mail: nhay{at}uic.edu.
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