Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts.
The protooncogenic protein c-Cbl becomes tyrosine phosphorylated in normal cells in response to a variety of external stimuli, as well as in cells transformed by oncogenic protein tyrosine kinases. Tyrosine phosphorylation of c-Cbl upregulates its binding to multiple crucial signaling molecules. However, the biological consequences of c-Cbl-mediated signaling are insufficiently ... understood. To analyse the biological functions of c-Cbl, we overexpressed wild-type c-Cbl and its tyrosine phosphorylation-defective mutant form in v-Abl-transformed NIH3T3 fibroblasts. In this system, wild-type c-Cbl facilitated adhesion and spreading of v-Abl-transformed fibroblasts on the extracellular matrix, while reducing anchorage independence of these cells, as measured by their colony-forming efficiency in soft agar. Therefore, overexpression of wild-type c-Cbl exhibits an overall transformation-suppressing effect. By contrast, overexpression of a tyrosine phosphorylation-defective form of c-Cbl increases neither adhesion nor anchorage dependence of v-Abl-transformed fibroblasts. Analysis of the role of individual tyrosine phosphorylation sites of c-Cbl in these phenomena indicates that both phosphatidylinositol-3' kinase and the CrkL adaptor protein may be involved in the observed effects of c-Cbl. To summarize, the results presented in this report indicate that c-Cbl is involved in regulation of cell adhesion and cytoskeletal rearrangements, and that these effects of c-Cbl are dependent on its tyrosine phosphorylation.
Mesh Terms:
3T3 Cells, Actin Cytoskeleton, Actins, Adaptor Proteins, Signal Transducing, Androstadienes, Animals, Carcinoma, Embryonal, Cell Adhesion, Cell Division, Cell Line, Transformed, Cell Size, Cell Transformation, Viral, Colony-Forming Units Assay, Cytoskeleton, Enzyme Inhibitors, Extracellular Matrix, Genes, abl, Kidney Neoplasms, Mice, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Signal Transduction, Tumor Cells, Cultured, Ubiquitin-Protein Ligases
3T3 Cells, Actin Cytoskeleton, Actins, Adaptor Proteins, Signal Transducing, Androstadienes, Animals, Carcinoma, Embryonal, Cell Adhesion, Cell Division, Cell Line, Transformed, Cell Size, Cell Transformation, Viral, Colony-Forming Units Assay, Cytoskeleton, Enzyme Inhibitors, Extracellular Matrix, Genes, abl, Kidney Neoplasms, Mice, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Signal Transduction, Tumor Cells, Cultured, Ubiquitin-Protein Ligases
Oncogene
Date: Jun. 24, 1999
PubMed ID: 10391678
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