title: Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase.
abstract: Insulin counterregulates catecholamine action at several levels, primarily in liver, fat, and adipose tissue. Herein we observe that expression of increased levels of beta(2)-adrenergic receptor increasingly inhibits insulin-stimulated phosphorylation of its primary downstream substrates (IRS-1,2). In Chinese hamster ovary cells, the insulin receptor phosphorylates dominantly Tyr(364) in the C-terminal cytoplasmic domain of the beta-receptor. A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. Upon phosphorylation, the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrates a potent inhibitory feedback action that can block both insulin-stimulated autophosphorylation of the insulin receptor and phosphorylation of IRS-1,2 in NIH mouse 3T3-L1 adipocyte membranes. Studies in vitro with purified insulin receptor and the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrate that the tyrosine-phosphorylated beta-receptor domain is a potent counterregulatory inhibitor of the insulin receptor tyrosine kinase.
authors.affiliation: Department of Pharmacology, Physiology & Biophysics, Diabetes & Metabolic Diseases Research Program, Health Sciences Center, State University of New York, Stony Brook, New York 11794, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Doronin
authors.forename: Hsien-yu
authors.initials: HY
authors.lastname: Wang Hy
authors.forename: Craig C
authors.initials: CC
authors.lastname: Malbon
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D018343:Receptors, Adrenergic, beta-2; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin