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{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase.

Publication ,  Journal Article
Girnita, L; Shenoy, SK; Sehat, B; Vasilcanu, R; Girnita, A; Lefkowitz, RJ; Larsson, O
Published in: J Biol Chem
July 1, 2005

The insulin-like growth factor-1 receptor (IGF-1R) plays important roles in physiological growth and aging as well as promoting several crucial functions in cancer cells. However, the molecular mechanisms involved in expression and down-regulation of IGF-1R are still poorly understood. Here we provide evidence that beta-arrestin, otherwise known to be involved in the regulation of G protein-coupled receptors, serves as an adaptor to bring the oncoprotein E3 ubiquitin ligase MDM2 to the IGF-1R. In this way, beta-arrestin acts as a crucial component in the ubiquitination and down-regulation of the receptor. Both MDM2 and beta-arrestin co-immunoprecipitated with the IGF-1R. The beta-arrestin isoform 1 appeared to be more strongly associated with the receptor than isoform 2, and in a molecular context it was 4-fold more efficient in inducing polyubiquitination of IGF-1R, a reaction that required the presence of beta-arrestin and MDM2. Ligand stimulation accelerated IGF-1R ubiquitination. In mouse P6 cells (overexpressing human IGF-1R) absence of beta-arrestin 1, but not of beta-arrestin 2, blocked ubiquitination of IGF-1R. Conversely, in the two studied human melanoma cell lines both beta-arrestin isoforms seemed to be involved in IGF-1R ubiquitination. However, because depletion of beta-arrestin 1 almost completely eliminated degradation, and IGF-1 induced down-regulation of the receptor in these cells, whereas beta-arrestin 2 only had a partial effect, beta-arrestin 1 seems to the more important isoform in affecting the expression of IGF-1R. To our knowledge this is the first study demonstrating a defined molecular role of beta-arrestin with direct relevance to cell growth and cancer.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 1, 2005

Volume

280

Issue

26

Start / End Page

24412 / 24419

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Arrestin 1
  • Ubiquitin
  • Transfection
  • Time Factors
  • Receptors, G-Protein-Coupled
  • Receptor, IGF Type 1
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-mdm2
 

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Girnita, L., Shenoy, S. K., Sehat, B., Vasilcanu, R., Girnita, A., Lefkowitz, R. J., & Larsson, O. (2005). {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem, 280(26), 24412–24419. https://doi.org/10.1074/jbc.M501129200
Girnita, Leonard, Sudha K. Shenoy, Bita Sehat, Radu Vasilcanu, Ada Girnita, Robert J. Lefkowitz, and Olle Larsson. “{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase.J Biol Chem 280, no. 26 (July 1, 2005): 24412–19. https://doi.org/10.1074/jbc.M501129200.
Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, et al. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005 Jul 1;280(26):24412–9.
Girnita, Leonard, et al. “{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase.J Biol Chem, vol. 280, no. 26, July 2005, pp. 24412–19. Pubmed, doi:10.1074/jbc.M501129200.
Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005 Jul 1;280(26):24412–24419.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 1, 2005

Volume

280

Issue

26

Start / End Page

24412 / 24419

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Arrestin 1
  • Ubiquitin
  • Transfection
  • Time Factors
  • Receptors, G-Protein-Coupled
  • Receptor, IGF Type 1
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-mdm2