title: Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1.
abstract: beta-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by beta-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an approximately 50% decrease in cellular beta-arrestin-1 content due to ubiquitination of beta-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in beta-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, beta-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in beta-arrestin-1 association with the beta2-AR as well as a decrease in beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation. (ii) This downregulation of endogenous beta-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type beta-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of beta-arrestin-1 as a target molecule for this desensitization mechanism.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-0673, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dalle
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: David W
authors.initials: DW
authors.lastname: Rose
authors.forename: Dorothy Sears
authors.initials: DS
authors.lastname: Worrall
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hupfeld
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D017667:Adipocytes / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010447:Peptide Hydrolases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: D000318:Adrenergic beta-Agonists; D019390:Arrestins; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D019204:GTP-Binding Proteins; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007545:Isoproterenol; D008246:Lysophospholipids; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; C000605256:Arrb1 protein, rat; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; C061553:ATP dependent 26S protease