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J. Biol. Chem., Vol. 282, Issue 25, 18069-18082, June 22, 2007

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Energy Depletion Inhibits Phosphatidylinositol 3-Kinase/Akt Signaling and Induces Apoptosis via AMP-activated Protein Kinase-dependent Phosphorylation of IRS-1 at Ser-794^*

From the Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111

Energy depletion activates AMP-activated protein kinase (AMPK) and inhibits cell growth via TSC2-dependent suppression of mTORC1 signaling. Long term energy depletion also induces apoptosis by mechanisms that are not well understood to date. Here we show that AMPK, activated by energy depletion, inhibited cell survival by binding to and phosphorylating IRS-1 at Ser-794. Phosphorylation of IRS-1 at this site inhibited phosphatidylinositol 3-kinase/Akt signaling, suppressed the mitochondrial membrane potential, and promoted apoptosis. Of the treatments promoting energy depletion, glucose deprivation, hypoxia, and inhibition of ATP synthesis in the mitochondria stimulated phosphorylation of IRS-1 at Ser-794 via an LKB1/AMPK-dependent manner, whereas oxidative stress and 2-deoxyglucose stimulated phosphorylation at this site via a Ca²⁺/calmodulin-dependent protein kinase kinase /AMPK axis. These data define a novel pathway that cooperates with other adaptive mechanisms to formulate the cellular response to energy depletion.

Received for publication, October 30, 2006 , and in revised form, April 16, 2007.

^* This work was supported by National Institutes of Health Grant R01 CA57436 (to P. T.). 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–S10.

¹ To whom correspondence should be addressed: Molecular Oncology Research Inst., Tufts-New England Medical Center, 750 Washington St., #5609, Boston, MA 02111. Tel.: 617-636-6111; Fax: 617-636-6127; E-mail: ptsichlis{at}tufts-nemc.org.

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