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J Biol Chem, Vol. 274, Issue 39, 27969-27974, September 24, 1999
From the Departments of Pathology and Animal Sciences, University
of Illinois at Urbana-Champaign, Urbana, Illinois 61801
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-
(IFN-)-dependent IRS-1 tyrosine phosphorylation and
IFN--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--dependent tyrosine
phosphorylation of IRS-1 and IFN--dependent IRS-1/PI3K
association. Additionally, IRS-1 from OA-treated cells could not be
phosphorylated in vitro by IFN--activated JAK1. Chronic
treatment of U266 cells with insulin led to a 50% reduction in
IFN--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--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.
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