Phosphorylation of human insulin receptor substrate-1 at serine 629 plays a positive role in insulin signaling

Moulun Luo, Paul Langlais, Zhengping Yi, Natalie Lefort, Elena A. De Filippis, Hyonson Hwang, Christine Y. Christ-Roberts, Lawrence J. Mandarino

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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) expressinghuman 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 Ser 629 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 Ser636/639. 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.

Original languageEnglish (US)
Pages (from-to)4895-4905
Number of pages11
JournalEndocrinology
Volume148
Issue number10
DOIs
StatePublished - Oct 2007

ASJC Scopus subject areas

  • Endocrinology

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    Luo, M., Langlais, P., Yi, Z., Lefort, N., De Filippis, E. A., Hwang, H., Christ-Roberts, C. Y., & Mandarino, L. J. (2007). Phosphorylation of human insulin receptor substrate-1 at serine 629 plays a positive role in insulin signaling. Endocrinology, 148(10), 4895-4905. https://doi.org/10.1210/en.2007-0049