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J. Biol. Chem., Vol. 279, Issue 34, 35298-35305, August 20, 2004
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From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
Inhibitory serine phosphorylation is a potential molecular mechanism for insulin resistance. We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH2-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. We further identify a new phosphorylation site, Ser-302, and show that this too is necessary for JNK1-mediated disruption. Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. Phosphospecific antibodies that recognize sequences surrounding Ser(P)-302 or Ser(P)-307 were used to determine whether the sites were phosphorylated under relevant conditions. Phosphorylation was promoted at both sites in Fao hepatoma cells by reagents known to promote Ser/Thr phosphorylation, including the phorbol ester phorbol 12-myristate 13-acetate, anisomycin, calyculin A, and insulin. The antibodies further showed that Ser(P)-302 and Ser(P)-307 are increased in animal models of obesity and insulin resistance, including genetically obese ob/ob mice, diet-induced obesity, and upon induction of hyperinsulinemia. These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance.
Received for publication, October 10, 2003 , and in revised form, May 13, 2004.
* These studies were funded by National Institutes of Health Grants DK63225 (to J. L.), DK43123 (to S. E. S.), DK45943 (to S. E. S.), and DK36836 (Joslin Diabetes Center, Diabetes Endocrinology Research Center), National Institutes of Health Fellowship DK09393 (to E. D. W.), and by the Helen and Morton Adler Chair (to S. 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.
These authors contributed equally.
To whom correspondence may be addressed: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Tel.: 617-713-3422; Fax: 617-735-1970; E-mail: Jongsoon.Lee{at}joslin.harvard.edu. ¶ To whom correspondence may be addressed: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Tel.: 617-732-2528; Fax: 617-735-1970; E-mail: Steven.Shoelson{at}joslin.harvard.edu.
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