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

Publication ,  Journal Article
Usui, I; Imamura, T; Huang, J; Satoh, H; Shenoy, SK; Lefkowitz, RJ; Hupfeld, CJ; Olefsky, JM
Published in: Mol Cell Biol
October 2004

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.

Duke Scholars

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

October 2004

Volume

24

Issue

20

Start / End Page

8929 / 8937

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 1
  • Ubiquitin
  • Signal Transduction
  • Serine
  • Receptor, Insulin
  • Rats
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
 

Citation

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MLA
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Usui, I., Imamura, T., Huang, J., Satoh, H., Shenoy, S. K., Lefkowitz, R. J., … Olefsky, J. M. (2004). beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol Cell Biol, 24(20), 8929–8937. https://doi.org/10.1128/MCB.24.20.8929-8937.2004
Usui, Isao, Takeshi Imamura, Jie Huang, Hiroaki Satoh, Sudha K. Shenoy, Robert J. Lefkowitz, Christopher J. Hupfeld, and Jerrold M. Olefsky. “beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1.Mol Cell Biol 24, no. 20 (October 2004): 8929–37. https://doi.org/10.1128/MCB.24.20.8929-8937.2004.
Usui I, Imamura T, Huang J, Satoh H, Shenoy SK, Lefkowitz RJ, et al. beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol Cell Biol. 2004 Oct;24(20):8929–37.
Usui, Isao, et al. “beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1.Mol Cell Biol, vol. 24, no. 20, Oct. 2004, pp. 8929–37. Pubmed, doi:10.1128/MCB.24.20.8929-8937.2004.
Usui I, Imamura T, Huang J, Satoh H, Shenoy SK, Lefkowitz RJ, Hupfeld CJ, Olefsky JM. beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol Cell Biol. 2004 Oct;24(20):8929–8937.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

October 2004

Volume

24

Issue

20

Start / End Page

8929 / 8937

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 1
  • Ubiquitin
  • Signal Transduction
  • Serine
  • Receptor, Insulin
  • Rats
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins