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Phosphorylation of Human Insulin Receptor Substrate-1 at Serine 629 Plays a Positive Role in Insulin Signaling

Center for Metabolic Biology (M.L., P.L., Z.Y., N.L., E.A.D.F., H.H., C.Y.C.-R., L.J.M.), School of Life Sciences (M.L., Z.Y., E.A.D.F., C.Y.C.-R., L.J.M.), and Department of Kinesiology (P.L., N.L., H.H., L.J.M.), Arizona State University, Tempe, Arizona 85287-3704

Address all correspondence and requests for reprints to: Lawrence J. Mandarino, Ph.D., Director, Center for Metabolic Biology, College of Liberal Arts and Sciences, P.O. Box 873704, Tempe, Arizona 85287-3704. E-mail: lawrence.mandarino{at}asu.edu.

The function of insulin receptor substrate-1 (IRS-1) is regulated by both tyrosine and serine/threonine phosphorylation. Phosphorylation of some serine/threonine residues in IRS-1 dampens insulin signaling, whereas phosphorylation of other serine/threonine residues enhances insulin signaling. Phosphorylation of human IRS-1 at Ser⁶²⁹ was increased by insulin in Chinese hamster ovary cells expressing the insulin receptor (1.26 ± 0.09-fold; P < 0.05) and L6 cells (1.35 ± 0.29-fold; P < 0.05) expressing human IRS-1. Sequence analysis surrounding Ser⁶²⁹ revealed conformity to the consensus phosphorylation sequence recognized by Akt. Phosphorylation of IRS-1 at Ser⁶²⁹ in cells was decreased upon treatment with either an Akt inhibitor or by coexpression with kinase dead Akt, whereas Ser⁶²⁹ phosphorylation was increased by coexpression with constitutively active Akt. In addition, Ser⁶²⁹ of IRS-1 is directly phosphorylated by Akt in vitro. In cells, preventing phosphorylation of Ser⁶²⁹ by a Ser⁶²⁹Ala mutation resulted in increased phosphorylation of Ser⁶³⁶, a known negative regulator of IRS-1, without affecting phosphorylation of Tyr⁶³² or Ser⁶¹⁶. Cells expressing the Ser⁶²⁹Ala mutation, along with increased Ser⁶³⁶ phosphorylation, had decreased insulin-stimulated association of the p85 regulatory subunit of phosphatidylinositol 3'-kinase with IRS-1 and decreased phosphorylation of Akt at Ser⁴⁷³. Finally, in vitro phosphorylation of a Ser⁶²⁹-containing IRS-1 fragment with Akt reduces the subsequent ability of ERK to phosphorylate Ser^636/639. These results suggest that a feed-forward mechanism may exist whereby insulin activation of Akt leads to phosphorylation of IRS-1 at Ser⁶²⁹, resulting in decreased phosphorylation of IRS-1 at Ser⁶³⁶ and enhanced downstream signaling. Understanding the complex phosphorylation patterns of IRS-1 is crucial to elucidating the factors contributing to insulin resistance and, ultimately, the pathogenesis of type 2 diabetes.

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