title: Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
abstract: The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
authors.affiliation: Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Copps
authors.affiliation: Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA. morris.white@childrens.harvard.edu.
authors.forename: M F
authors.initials: MF
authors.lastname: White
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013912:Threonine / Q000378:metabolism*
chemical_list: C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D013912:Threonine; D012694:Serine