title: Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
abstract: This review will provide insight on the current understanding of the regulation of insulin signaling in both physiological and pathological conditions through modulations that occur with regards to the functions of the insulin receptor substrate 1 (IRS1). While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated responses, the phosphorylation of IRS1 on serine residues has a dual role, either to enhance or to terminate the insulin effects. The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action. Insulin also activates several kinases and these kinases act to induce the phosphorylation of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback control mechanism induced by insulin that leads to termination of its action. Agents such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular stress and hyperinsulinemia, which induce insulin resistance, lead to both activation of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms (SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review. Understanding how these agents inhibit IRS1 functions as well as identification of kinases involved in these inhibitory effects may provide novel targets for development of strategies to prevent insulin resistance.
authors.affiliation: Inserm U 568 (Molecular signaling and obesity); IFR 50; Faculté de medecine, avenue de Valombrose, 06107 Nice cedex 2, France. gual@unice.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D009097:Multienzyme Complexes / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D047488:Retinoid X Receptors / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009097:Multienzyme Complexes; D047492:Peroxisome Proliferator-Activated Receptors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D047488:Retinoid X Receptors; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases