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Molecular and Cellular Biology, September 2002, p. 6272-6285, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6272-6285.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating ß-Arrestin-1

Stéphane Dalle,1,{dagger} Takeshi Imamura,1 David W. Rose,1 Dorothy Sears Worrall,1 Satoshi Ugi,1 Christopher J. Hupfeld,1 and Jerrold M. Olefsky1,2,3*

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-0673,1 Veterans Affairs Hospital, Research Service, San Diego, California 92161,2 The Whittier Diabetes Institute, La Jolla, California 920373

Received 14 February 2002/ Returned for modification 20 March 2002/ Accepted 3 June 2002

ß-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 ß-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 ~50% decrease in cellular ß-arrestin-1 content due to ubiquitination of ß-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in ß-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 ß-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, ß-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 ß-arrestin-1 association with the ß2-AR as well as a decrease in ß-arrestin-1-Src and Src-ß2-AR association. Ectopic expression of wild-type ß-arrestin-1 in insulin-treated cells in which endogenous ß-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 ß-arrestin-1 degradation. (ii) This downregulation of endogenous ß-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 ß-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 ß-arrestin-1 as a target molecule for this desensitization mechanism.

* Corresponding author. Mailing address: Department of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673. Phone: (858) 534-6651. Fax: (858) 534-6653. E-mail: jolefsky{at}ucsd.edu.

{dagger} Present address: INSERM U376, Endocrinologie des Peptides et Régulation Génique, 34295 Montpellier Cedex 05, France.

Molecular and Cellular Biology, September 2002, p. 6272-6285, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6272-6285.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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