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J. Biol. Chem., Vol. 280, Issue 9, 7511-7518, March 4, 2005

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S-Nitrosylation-dependent Inactivation of Akt/Protein Kinase B in Insulin Resistance^*

Takashi Yasukawa, Eriko Tokunaga, Hidetaka Ota, Hiroki Sugita, J. A. Jeevendra Martyn, and Masao Kaneki

From the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Shriners Hospital for Children, Harvard Medical School, Boston, Massachusetts 02114

Inducible nitric-oxide synthase (iNOS) has been implicated in many human diseases including insulin resistance. However, how iNOS causes or exacerbates insulin resistance remains largely unknown. Protein S-nitrosylation is now recognized as a prototype of a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe the mechanism of inactivation of Akt/protein kinase B (PKB) in NO donor-treated cells and diabetic (db/db) mice. NO donors induced S-nitrosylation and inactivation of Akt/PKB in vitro and in intact cells. The inhibitory effects of NO donor were independent of phosphatidylinositol 3-kinase and cGMP. In contrast, the concomitant presence of oxidative stress accelerated S-nitrosylation and inactivation of Akt/PKB. In vitro denitrosylation with reducing agent reactivated recombinant and cellular Akt/PKB from NO donor-treated cells. Mutated Akt1/PKB (C224S), in which cysteine 224 was substituted by serine, was resistant to NO donor-induced S-nitrosylation and inactivation, indicating that cysteine 224 is a major S-nitrosylation acceptor site. In addition, S-nitrosylation of Akt/PKB was increased in skeletal muscle of diabetic (db/db) mice compared with wild-type mice. These data suggest that S-nitrosylation-mediated inactivation may contribute to the pathogenesis of iNOS- and/or oxidative stress-involved insulin resistance.

Received for publication, October 19, 2004 , and in revised form, December 17, 2004.

The on-line version of this article (available at http://www.jbc.org) contains Table I and Fig. 1.

^* This work was supported by National Institutes of Health Grants R01DK058127 (to M. K.), R01GM031569, R01GM055082, R01GM061411, and GM21700 Project IV (to J. A. J. M.), and grants from the Shriners Hospital Philanthropy for Children (to J. A. J. 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.

To whom correspondence should be addressed: Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth St., Rm. 6604, Charlestown, MA 02129. Tel.: 617-726-8122; Fax: 617-726-8134; E-mail: mkaneki{at}helix.mgh.harvard.edu.

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