title: Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance.
abstract: Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. The regulation of these associations in situations of altered insulin receptor substrate-1 (IRS-1) phosphorylation was not yet investigated. In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism.
authors.affiliation: Department of Internal Medicine, State University of Campinas, SP, Brazil.
authors.forename: Maria Helena M
authors.initials: MH
authors.lastname: Lima
authors.forename: Mirian
authors.initials: M
authors.lastname: Ueno
authors.forename: Ana Cláudia P
authors.initials: AC
authors.lastname: Thirone
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rocha
authors.forename: Carla Roberta O
authors.initials: CR
authors.lastname: Carvalho
authors.forename: Mário J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D000375:Aging; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004195:Disease Models, Animal; D004837:Epinephrine / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004837:Epinephrine; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526296:Irs1 protein, rat; C494920:Akt1 protein, rat