title: Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1.
abstract: Tumor necrosis factor-alpha (TNF) has been suggested to be the mediator of insulin resistance in infection, tumor cachexia, and obesity. We have previously shown that TNF diminishes insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1). The current work examines potential mechanisms that mediate this event. TNF effect on IRS-1 in Fao hepatoma cells was not associated with a significant reduction in insulin receptor tyrosine kinase activity as measured in vitro but impaired the association of IRS-1 with phosphatidylinositol 3-kinase, localizing TNF impact to IRS-1. TNF did not increase protein-tyrosine phosphatase activity and protein-tyrosine phosphatase inhibition by vanadate did not change TNF effect on IRS-1 tyrosine phosphorylation, suggesting that protein-tyrosine phosphatases are not involved in this TNF effect. In contrast, TNF increased IRS-1 phosphorylation on serine residues, leading to a decrease in its electrophoretic mobility. TNF effect on IRS-1 tyrosine phosphorylation was not abolished by inhibiting protein kinase C using staurosporine, while inactivation of Ser/Thr phosphatases by calyculin A and okadaic acid mimicked it. Our data suggest that TNF induces serine phosphorylation of IRS-1 through inhibition of serine phosphatases or activation of serine kinases other than protein kinase C. This increased serine phosphorylation interferes with insulin-induced tyrosine phosphorylation of IRS-1 and impairs insulin action.
authors.affiliation: Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Kanety
authors.forename: R
authors.initials: R
authors.lastname: Feinstein
authors.forename: M Z
authors.initials: MZ
authors.lastname: Papa
authors.forename: R
authors.initials: R
authors.lastname: Hemi
authors.forename: A
authors.initials: A
authors.lastname: Karasik
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D019311:Staurosporine; D013912:Threonine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000470:Alkaloids; D004791:Enzyme Inhibitors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases; D019311:Staurosporine