Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression.
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.
Girnita
Leonard
L
Department of Oncology and Pathology, Division of Cellular and Molecular Tumor Pathology, CCK, R8:04, Karolinska Hospital, SE-171 76 Stockholm, Sweden, and Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Leonard.Girnita@ki.se
Shenoy
Sudha K
SK
Sehat
Bita
B
Vasilcanu
Radu
R
Vasilcanu
Daiana
D
Girnita
Ada
A
Lefkowitz
Robert J
RJ
Larsson
Olle
O
D000818:Animals; D019390:Arrestins / Q000494:pharmacology*; D002453:Cell Cycle; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D025801:Ubiquitin; D000071557:beta-Arrestins; D007334:Insulin-Like Growth Factor I; D051736:Proto-Oncogene Proteins c-mdm2; D017526:Receptor, IGF Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3