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J. Biol. Chem., Vol. 282, Issue 47, 34356-34364, November 23, 2007

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The Direct Involvement of SirT1 in Insulin-induced Insulin Receptor Substrate-2 Tyrosine Phosphorylation^*

From the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas Texas 75390

NAD⁺-dependent Sir2 family deacetylases and insulin signaling pathway are both conserved across species to regulate aging process. The interplay between these two genetic programs is investigated in this study. Protein deacetylase activity of SirT1, the mammalian homologue of Sir2, was suppressed through either nicotinamide treatment or RNA interference in several cell lines, and these cells displayed impaired insulin responses. Suppression of SirT1 activity also selectively inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 2 (IRS-2), whereas it had minimal effect on that of IRS-1. Further analyses showed that both IRS-1 and IRS-2 interacted with SirT1, and the acetylation level of IRS-2 was down-regulated by insulin treatment. Inhibition of SirT1 activity prevented deacetylation and insulin-induced tyrosine phosphorylation of IRS-2. Mutations of four lysine residues to alanine in IRS-2 protein, on the other hand, led to its reduced basal level acetylation and insulin-induced tyrosine phosphorylation. These results suggest a possible regulatory effect of SirT1 on insulin-induced tyrosine phosphorylation of IRS-2, a vital step in insulin signaling pathway, through deacetylation of IRS-2 protein. More importantly, this study may imply a pathway through which Sir2 family protein deacetylases and insulin signaling pathway jointly regulate various metabolic processes, including aging and diabetes.

Received for publication, August 9, 2007 , and in revised form, September 19, 2007.

^* This work was supported by the Center for Human Nutrition Endowment and the Moss Heart Center, University of Texas Southwestern Medical Center at Dallas, TX. 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. S1.

¹ To whom correspondence should be addressed: Rigel Pharmaceutical Co., 1180 Veterans Blvd., South San Francisco, CA 94080. Tel.: 650-624-1105; E-mail: jiandi.zhang{at}gmail.com.

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