{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.
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
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
J. Biol. Chem.
Date: Jul. 01, 2005
PubMed ID: 15878855
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