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ß-Arrestin-1 Competitively Inhibits Insulin-Induced Ubiquitination and Degradation of Insulin Receptor Substrate 1

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego,¹ San Diego Veterans Administration Medical Research Service and the Whittier Diabetes Institute, La Jolla, California,⁴ Medicine,² Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina³

Received 5 February 2004/ Returned for modification 12 April 2004/ Accepted 13 July 2004

ß-Arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling. In the present study, we determined whether ß-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) ß-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous ß-arrestin-1 was knocked down by transfection of ß-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced. Insulin stimulated the association of IRS-1 and Mdm2, an E3 ubiquitin ligase, and this association was inhibited to overexpression of WT ß-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both ß-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) ß-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) ß-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on ß-arrestin and the amino terminus of ß-arrestin-1 are required for this effect of ß-arrestin on IRS-1 degradation; and (iv) inhibition of ß-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.

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