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Originally published In Press as doi:10.1074/jbc.M308631200 on November 17, 2003

J. Biol. Chem., Vol. 279, Issue 5, 3447-3454, January 30, 2004
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Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling*

Jodel Giraud, Rebecca Leshan, Yong-Hee Lee, and Morris F. White{ddagger}

From the Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. We used a sequence-specific polyclonal antibody directed against phosphorylated Ser302 to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. Insulin or IGF-I stimulated phosphorylation of Ser302 in various cell backgrounds and in murine muscle. Wortmannin or rapamycin inhibited Ser302 phosphorylation, and amino acids or glucose stimulated Ser302 phosphorylation, suggesting a role for the mTOR cascade. The Ser302 kinase associates with IRS-1 during immunoprecipitation, but its identity is unknown. The NH2-terminal c-Jun kinase did not phosphorylate Ser302. Replacing Ser302 with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70S6K, ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3{beta} phosphorylation. Replacing Ser302 with alanine reduced insulin/IGF-I-stimulated DNA synthesis. We conclude that Ser302 phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth.

Received for publication, August 5, 2003 , and in revised form, October 9, 2003.

* This work was supported in part by National Institutes of Health Grant DK 38712. 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.

{ddagger} To whom correspondence should be addressed: Dept. of Molecular Physiology, Joslin Diabetes Center, One Joslin Place, Rm. 620, Boston, MA 02215. Tel.: 617-732-2578; Fax: 617-732-2593; E-mail: morris.white{at}joslin.harvard.edu.


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