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Molecular and Cellular Biology, October 2004, p. 8929-8937, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.8929-8937.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Isao Usui,1 Takeshi Imamura,1 Jie Huang,1 Hiroaki Satoh,1 Sudha K. Shenoy,2 Robert J. Lefkowitz,3 Christopher J. Hupfeld,1 and Jerrold M. Olefsky1,4*

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.

* Corresponding author. Mailing address: Department of Medicine (0673), University of California, San Diego, Stein Bldg, Room 210, 9500 Gilman Dr., La Jolla, CA 92093-0673. Phone: (858) 534-6651. Fax: (858) 534-6653. E-mail: jolefsky{at}ucsd.edu.

Molecular and Cellular Biology, October 2004, p. 8929-8937, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.8929-8937.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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