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J. Biol. Chem., Vol. 281, Issue 48, 36662-36672, December 1, 2006

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Regulation of AMP-activated Protein Kinase by Multisite Phosphorylation in Response to Agents That Elevate Cellular cAMP^*>

Rebecca L. Hurley, Laura K. Barré, Sumintra D. Wood, Kristin A. Anderson, Bruce E. Kemp^¶1, Anthony R. Means, and Lee A. Witters²

From the Departments of Medicine and Biochemistry, Dartmouth Medical School, and the Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755, ^¶St. Vincent's Institute and Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies, Fitzroy, Victoria 3065, Australia, and the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710

The AMP-activated protein kinase (AMPK) and cAMP signaling systems are both key regulators of cellular metabolism. In this study, we show that AMPK activity is attenuated in response to cAMP-elevating agents through modulation of at least two of its subunit phosphorylation sites, viz. -Thr¹⁷² and 1-Ser⁴⁸⁵/2-Ser⁴⁹¹, in the clonal -cell line INS-1 as well as in mouse embryonic fibroblasts and COS cells. Forskolin, isobutylmethylxanthine, and the glucose-dependent insulinotropic peptide inhibited AMPK activity and reduced phosphorylation of the activation loop -Thr¹⁷² via inhibition of calcium/calmodulin-dependent protein kinase kinase- and -, but not LKB1. These agents also enhanced phosphorylation of -Ser^485/491 by the cAMP-dependent protein kinase. AMPK -Ser^485/491 phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. We show that AMPK -Ser^485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators. Thus, our findings not only demonstrate cross-talk between the cAMP/cAMP-dependent protein kinase and AMPK signaling modules, but also describe a novel mechanism by which multisite phosphorylation of AMPK contributes to regulation of its enzyme activity.

Received for publication, July 13, 2006 , and in revised form, August 30, 2006.

^* This work was supported by National Institutes of Health Grant DK35712 (to L. A. W.) and Grants DK074701 and GM33976 (to A. R. M.). 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 Fig. 1.

¹ Australian Research Council Federation Fellow supported by grants from the Australian Research Council, the National Health and Medical Research Council, and the National Heart Foundation.

² To whom correspondence should be addressed: Dartmouth Medical School, Remsen 322, N. College St., Hanover, NH 03755-3833. Tel.: 603-650-1909; Fax: 603-650-1727; E-mail: lee.a.witters{at}dartmouth.edu.

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