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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.

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.

Pubmed ID: 15878855

Authors

  • Girnita L
  • Shenoy SK
  • Sehat B
  • Vasilcanu R
  • Girnita A
  • Lefkowitz RJ
  • Larsson O

Journal

The Journal of biological chemistry

Publication Data

July 1, 2005

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL 70631
  • Agency: NHLBI NIH HHS, Id: HL16037

Mesh Terms

  • Animals
  • Arrestins
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Immunoprecipitation
  • Ligands
  • Mice
  • Nuclear Proteins
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-mdm2
  • RNA, Small Interfering
  • Receptor, IGF Type 1
  • Receptors, G-Protein-Coupled
  • Time Factors
  • Transfection
  • Ubiquitin