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Phosphorylation of Irs1 at SER-522 Inhibits Insulin Signaling

Howard Hughes Medical Institute, Children’s Hospital Boston (J.G., M.H., K.D.C., X.D., S.L.D., M.F.W.), and Joslin Diabetes Center (E.P.F.), Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Morris F. White, Howard Hughes Medical Institute, Division of Endocrinology, Children’s Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Room 04210, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: morris.white{at}childrens.harvard.edu.

Multisite phosphorylation of Irs1 on serine and threonine residues regulates insulin signaling that can contribute to insulin resistance. We identified by mass spectrometry the phosphorylation of Ser522 in rat Irs1 (S522^Irs1). The functional effects of this phosphorylation site were investigated in cultured cells using a sequence-specific phosphoserine antibody. Insulin stimulated the phosphorylation of S522^Irs1 in L6 myoblasts and myotubes. S522^Irs1 phosphorylation was inhibited by wortmannin, whereas PD98059, rapamycin, or glucose-starvation had no effect. Reducing Akt expression with small interfering RNA inhibited insulin-stimulated phosphorylation of S522^Irs1, suggesting the involvement of the phosphatidylinositol 3-kinase Akt cascade. A S522^Irs1A522^Irs1 substitution increased insulin-stimulated tyrosine phosphorylation of Irs1 and signaling, whereas a S522^Irs1E522^Irs1 substitution reduced insulin-stimulated Irs1 tyrosine phosphorylation. Together, these results suggest the phosphatidylinositol 3-kinaseAkt cascade can inhibit insulin signaling through the phosphorylation of S522^Irs1.

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