Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling
Copyright policy )Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling
Growth factor receptor-binding protein-2 (Grb2) plays a key role in signal transduction initiated by Bcr/Abl oncoproteins and growth factors, functioning as an adaptor protein through its Src homology 2 and 3 (SH2 and SH3) domains. We found that Grb2 was tyrosine-phosphorylated in cells expressing BCR/ABL and in A431 cells stimulated with epidermal growth factor (EGF). Phosphorylation of Grb2 by Bcr/Abl or EGF receptor reduced its SH3-dependent binding to Sos in vivo, but not its SH2-dependent binding to Bcr/Abl. Tyr209 within the C-terminal SH3 domain of Grb2 was identified as one of the tyrosine phosphorylation sites, and phosphorylation of Tyr209 abolished the binding of the SH3 domain to a proline-rich Sos peptide in vitro. In vivo expression of a Grb2 mutant where Tyr209 was changed to phenylalanine enhanced BCR/ABL-induced ERK activation and fibroblast transformation, and potentiated and prolonged Grb2-mediated activation of Ras, mitogen-activated protein kinase and c-Jun N-terminal kinase in response to EGF stimulation. These results suggest that tyrosine phosphorylation of Grb2 is a novel mechanism of down-regulation of tyrosine kinase signaling.
- Beth Israel Deaconess Medical Center United States
- Harvard University United States
- Jackson Laboratory United States
- Vanderbilt University Medical Center United States
- University of California, San Francisco United States
Enzyme-Activation, Phosphopeptides, Spectrum-Analysis-Mass, Time Factors, DNA Mutational Analysis, Fusion Proteins, bcr-abl, Protein-Structure-Tertiary, Blotting-Western, Mass Spectrometry, Precipitin-Tests, Mice, bcr-abl: metabolism, Phosphopeptides: chemistry, MAP-Kinase-Signaling-System, SUPPORT-U-S-GOVT-P-H-S, Fibroblasts: metabolism, Phosphorylation, Cell Line, Transformed, Drosophila: metabolism, Cultured, src-Homology-Domains, Cell-Line-Transformed, Blotting, Tumor-Cells-Cultured, Adaptor Proteins, 3T3 Cells, Cell-Line, Dose-Response-Relationship-Drug, Fusion-Proteins-bcr-abl, Tumor Cells, ErbB Receptors, Transformation-Genetic, K562-Cells, Mitogen-Activated-Protein-Kinases, Drug, Western, Epidermal Growth Factor: metabolism, Human, Protein Binding, Receptor, Signal Transduction, ras Proteins: metabolism, 570, Protein Structure, Binding-Sites, Signal-Transduction, Son-of-Sevenless-Protein-Drosophila, MAP Kinase Signaling System, Blotting, Western, 610, Down-Regulation, Transfection, Peptide Mapping, Tyrosine: metabolism, Transformation, Cell Line, Dose-Response Relationship, src Homology Domains, Genetic, Mitogen-Activated Protein Kinases: metabolism, Animals, Humans, SUPPORT-NON-U-S-GOVT, Receptor-Epidermal-Growth-Factor, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Binding Sites, Peptide-Mapping, Dose-Response Relationship, Drug, Animal, Son of Sevenless Protein, Signal Transducing, JNK Mitogen-Activated Protein Kinases, Proteins, Fusion Proteins, Time-Factors, Fibroblasts, Precipitin Tests, Proteins: metabolism, Enzyme Activation, Transformed, Mutation, DNA-Mutational-Analysis, Tyrosine, ras-Proteins, K562 Cells, Protein-Binding, Tertiary
Enzyme-Activation, Phosphopeptides, Spectrum-Analysis-Mass, Time Factors, DNA Mutational Analysis, Fusion Proteins, bcr-abl, Protein-Structure-Tertiary, Blotting-Western, Mass Spectrometry, Precipitin-Tests, Mice, bcr-abl: metabolism, Phosphopeptides: chemistry, MAP-Kinase-Signaling-System, SUPPORT-U-S-GOVT-P-H-S, Fibroblasts: metabolism, Phosphorylation, Cell Line, Transformed, Drosophila: metabolism, Cultured, src-Homology-Domains, Cell-Line-Transformed, Blotting, Tumor-Cells-Cultured, Adaptor Proteins, 3T3 Cells, Cell-Line, Dose-Response-Relationship-Drug, Fusion-Proteins-bcr-abl, Tumor Cells, ErbB Receptors, Transformation-Genetic, K562-Cells, Mitogen-Activated-Protein-Kinases, Drug, Western, Epidermal Growth Factor: metabolism, Human, Protein Binding, Receptor, Signal Transduction, ras Proteins: metabolism, 570, Protein Structure, Binding-Sites, Signal-Transduction, Son-of-Sevenless-Protein-Drosophila, MAP Kinase Signaling System, Blotting, Western, 610, Down-Regulation, Transfection, Peptide Mapping, Tyrosine: metabolism, Transformation, Cell Line, Dose-Response Relationship, src Homology Domains, Genetic, Mitogen-Activated Protein Kinases: metabolism, Animals, Humans, SUPPORT-NON-U-S-GOVT, Receptor-Epidermal-Growth-Factor, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Binding Sites, Peptide-Mapping, Dose-Response Relationship, Drug, Animal, Son of Sevenless Protein, Signal Transducing, JNK Mitogen-Activated Protein Kinases, Proteins, Fusion Proteins, Time-Factors, Fibroblasts, Precipitin Tests, Proteins: metabolism, Enzyme Activation, Transformed, Mutation, DNA-Mutational-Analysis, Tyrosine, ras-Proteins, K562 Cells, Protein-Binding, Tertiary
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