title: Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.
abstract: Insulin receptor substrate (IRS) proteins are important intracellular molecules that mediate insulin receptor tyrosine kinase signaling. A decreased content of IRS proteins has been found in insulin-resistant states in animals, humans, and cultured cells under various conditions. However, the molecular mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process.
authors.affiliation: Endocrinology Division, University of Vermont College of Medicine, Burlington 05405, USA. xsun@zoo.uvm.edu
authors.forename: X J
authors.initials: XJ
authors.lastname: Sun
authors.forename: J L
authors.initials: JL
authors.lastname: Goldberg
authors.forename: L Y
authors.initials: LY
authors.lastname: Qiao
authors.forename: J J
authors.initials: JJ
authors.lastname: Mitchell
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects*
chemical_list: C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases