beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1.

Abstract

beta-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 beta-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) beta-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous beta-arrestin-1 was knocked down by transfection of beta-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 beta-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both beta-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) beta-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) beta-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 beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation; and (iv) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.

Department

Description

Provenance

Subjects

Acetylcysteine, Animals, Arrestins, Cells, Cultured, Cysteine Proteinase Inhibitors, Fibroblasts, Humans, Insulin, Insulin Receptor Substrate Proteins, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Rats, Receptor, Insulin, Serine, Signal Transduction, Ubiquitin, beta-Arrestin 1, beta-Arrestins

Citation

Published Version (Please cite this version)

10.1128/MCB.24.20.8929-8937.2004

Publication Info

Usui, Isao, Takeshi Imamura, Jie Huang, Hiroaki Satoh, Sudha K Shenoy, Robert J Lefkowitz, Christopher J Hupfeld, Jerrold M Olefsky, et al. (2004). beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol Cell Biol, 24(20). pp. 8929–8937. 10.1128/MCB.24.20.8929-8937.2004 Retrieved from https://hdl.handle.net/10161/7794.

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Scholars@Duke

Shenoy

Sudha Kaup Shenoy

Professor in Medicine

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