Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase.
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.
Doronin
Sergey
S
Department of Pharmacology, Physiology & Biophysics, Diabetes & Metabolic Diseases Research Program, Health Sciences Center, State University of New York, Stony Brook, New York 11794, USA.
Wang Hy
Hsien-yu
HY
Malbon
Craig C
CC
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
D004791:Enzyme Inhibitors; D007328:Insulin; D018343:Receptors, Adrenergic, beta-2; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin