Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1.
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.
Mesh Terms:
3T3 Cells, Adipocytes, Adrenergic beta-Agonists, Animals, Arrestins, Enzyme Inhibitors, Epidermal Growth Factor, GTP-Binding Proteins, Humans, Insulin, Insulin-Like Growth Factor I, Isoproterenol, Lysophospholipids, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Peptide Hydrolases, Phosphatidylinositol 3-Kinases, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins pp60(c-src), Rats, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Signal Transduction, Ubiquitin
3T3 Cells, Adipocytes, Adrenergic beta-Agonists, Animals, Arrestins, Enzyme Inhibitors, Epidermal Growth Factor, GTP-Binding Proteins, Humans, Insulin, Insulin-Like Growth Factor I, Isoproterenol, Lysophospholipids, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Peptide Hydrolases, Phosphatidylinositol 3-Kinases, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins pp60(c-src), Rats, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Signal Transduction, Ubiquitin
Mol. Cell. Biol.
Date: Sep. 01, 2002
PubMed ID: 12167719
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