JAK1-dependent phosphorylation of insulin receptor substrate-1 (IRS-1) is inhibited by IRS-1 serine phosphorylation.
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-alpha (IFN-alpha)-dependent IRS-1 tyrosine phosphorylation and IFN-alpha-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-alpha-dependent tyrosine phosphorylation of IRS-1 and IFN-alpha-dependent IRS-1/PI3K association. Additionally, IRS-1 from OA-treated cells could not be phosphorylated in vitro by IFN-alpha-activated JAK1. Chronic treatment of U266 cells with insulin led to a 50% reduction in IFN-alpha-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-alpha-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.
Cengel
K A
KA
Departments of Pathology and Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Freund
G G
GG
D000818:Animals; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007370:Interferon Type I / Q000494:pharmacology; D053613:Janus Kinase 1; D019319:Okadaic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D055504:Insulin Receptor Substrate Proteins; D007370:Interferon Type I; D053613:Janus Kinase 1; D019319:Okadaic Acid; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D011994:Recombinant Proteins; D012694:Serine; C526292:IRS1 protein, human; C526296:Irs1 protein, rat; C116037:PAS domain kinases; C507904:JAK1 protein, human; C507906:Jak1 protein, rat