JAK1-dependent phosphorylation of insulin receptor substrate-1 (IRS-1) is inhibited by IRS-1 serine phosphorylation

Keith A. Cengel, Gregory G. Freund

Research output: Contribution to journalArticlepeer-review

Abstract

Serine phosphorylation of insulin receptor substrate-1 (IRS-1) reduces its ability to act as an insulin receptor substrate and inhibits insulin receptor signal transduction. Here, we report that serine phosphorylation of IRS-1 induced by either okadaic acid (OA) or chronic insulin stimulation prevents interferon-α (IFN-α)-dependent IRS-1 tyrosine phosphorylation and IFN-α-dependent IRS-1/phosphatidylinositol 3'-kinase (PI3K) association. In addition, we demonstrate that serine phosphorylation of IRS-1 renders it a poorer substrate for JAK1 (Janus kinase-1). We found that treatment of U266 cells with OA induced serine phosphorylation of IRS-1 and completely blocked IFN-α-dependent tyrosine phosphorylation of IRS-1 and IFN-α-dependent IR- 1/PI3K association. Additionally, IRS-1 from OA-treated cells could not be phosphorylated in vitro by lFN-α-activated JAK1. Chronic treatment of U266 cells with insulin led to a 50% reduction in IFN-α-dependent tyrosine phosphorylation of IRS-1 and IRS-1/PI3K association. More importantly, serine-phosphorylated IRS-1-(511-722) could not be phosphorylated in vitro by IFN-α-activated JAK1. Taken together, these data indicate that serine phosphorylation of IRS-1 prevents its subsequent tyrosine phosphorylation by JAK1 and suggest that IRS-1 serine phosphorylation may play a counter- regulatory role in pathways outside the insulin signaling system.

Original languageEnglish (US)
Pages (from-to)27969-27974
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number39
DOIs
StatePublished - Sep 24 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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