1. β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression
- Author
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Leonard Girnita, Robert J. Lefkowitz, Daiana Vasilcanu, Bita Sehat, Sudha K. Shenoy, Ada Girnita, Radu Vasilcanu, and Olle Larsson
- Subjects
MAPK/ERK pathway ,Arrestins ,Biochemistry ,Cell Line ,Receptor, IGF Type 1 ,Mice ,Ubiquitin ,Arrestin ,Animals ,Humans ,Insulin-Like Growth Factor I ,Phosphorylation ,Receptor ,Molecular Biology ,beta-Arrestins ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,biology ,Cell Cycle ,Proto-Oncogene Proteins c-mdm2 ,Cell Biology ,Cell cycle ,Ubiquitin ligase ,Cell biology ,Enzyme Activation ,Protein Transport ,Mutation ,biology.protein ,Mdm2 ,Tyrosine kinase ,Signal Transduction - Abstract
Beta-arrestin1, which regulates many aspects of seven transmembrane receptor (7TMR) biology, has also been shown to serve as an adaptor, which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor-1 receptor (IGF-1R), leading to its proteasome-dependent destruction. Here we demonstrate that IGF-1R stimulation also leads to ubiquitination of beta-arrestin1, which regulates vesicular trafficking and activation of ERK1/2. This beta-arrestin1-dependent ERK activity can occur even when the classical tyrosine kinase signaling is impaired. siRNA-mediated suppression of beta-arrestin1 in human melanoma cells ablates IGF-1-stimulated ERK and prolongs the G1 phase of the cell cycle. These data suggest that beta-arrestin-dependent ERK signaling by the IGF-1R regulates cell cycle progression and may thus be an important regulator of the growth of normal and malignant cells.
- Published
- 2007
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