Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer.
DOC-2/DAB2 is a potent tumor suppressor in many cancer types including prostate cancer. In prostate cancer, expression of DOC-2/DAB2 can inhibit its growth. Our recent studies demonstrate that DOC-2/DAB2 can suppress both protein kinase C and peptide growth factor-elicited signal pathways via the Ras-mitogen-activated protein kinase pathway. In this study, ... we further showed that the proline-rich domain of DOC-2/DAB2 could also interact with proteins containing the Src homology 3 domain, such as Src and Fgr. The binding of c-Src to DOC-2/DAB2 was enhanced in cells treated with growth factor, and this interaction resulted in c-Src inactivation. The c-Src inactivation was evidenced by the decreased tyrosine 416 phosphorylation of c-Src and reduced downstream effector activation. It appears that DOC-2/DAB2 can bind to Src homology 3 domain of c-Src and maintain it in an inactive conformation. Thus, this study provides a new mechanism for modulating c-Src in prostatic epithelium and cancer.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, COS Cells, Enzyme Activation, Enzyme Inhibitors, Genes, Tumor Suppressor, Glutathione Transferase, Humans, Male, Mitogen-Activated Protein Kinases, Models, Biological, Mutation, Peptides, Phosphorylation, Precipitin Tests, Prostate, Prostatic Neoplasms, Protein Binding, Protein Biosynthesis, Protein Conformation, Protein Kinase C, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Recombinant Fusion Proteins, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured, Tyrosine
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, COS Cells, Enzyme Activation, Enzyme Inhibitors, Genes, Tumor Suppressor, Glutathione Transferase, Humans, Male, Mitogen-Activated Protein Kinases, Models, Biological, Mutation, Peptides, Phosphorylation, Precipitin Tests, Prostate, Prostatic Neoplasms, Protein Binding, Protein Biosynthesis, Protein Conformation, Protein Kinase C, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Recombinant Fusion Proteins, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured, Tyrosine
J. Biol. Chem.
Date: Feb. 28, 2003
PubMed ID: 12473651
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