Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl.
The 120 kD product of the c-Cbl oncogene is a prominent substrate of protein tyrosine kinases that lacks a known catalytic activity but possesses an array of binding sites for cytoplasmic signalling proteins. An oncogenic form of Cbl was recently identified in the 70Z/3 pre-B cell lymphoma which has a ... small deletion at the N-terminus of the Ring finger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced level of tyrosine phosphorylation compared with c-Cbl. Here we demonstrate that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulated cells. In serum-starved cells this results in EGF receptor autophosphorylation and the recruitment of Grb2, Shc and Sos1 but does not induce a corresponding increase in MAP kinase activity. Furthermore the expression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylation of the protein tyrosine phosphatase SHP-2. We also show that the Cbl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/Shc/Sos1 complex that associates with the EGF receptor. These findings therefore demonstrate a biochemical effect of an oncogenic Cbl protein and support predictions from C. elegans that Cbl functions as regulator of receptor tyrosine kinases.
Mesh Terms:
3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Cell Line, Transformed, Culture Media, Serum-Free, Cyclin-Dependent Kinases, Epidermal Growth Factor, GRB2 Adaptor Protein, Guanine Nucleotide Exchange Factors, Humans, Lymphoma, B-Cell, Mice, Oncogene Protein v-cbl, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Retroviridae Proteins, Oncogenic, Tumor Cells, Cultured, Tyrosine, Ubiquitin-Protein Ligases
3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Cell Line, Transformed, Culture Media, Serum-Free, Cyclin-Dependent Kinases, Epidermal Growth Factor, GRB2 Adaptor Protein, Guanine Nucleotide Exchange Factors, Humans, Lymphoma, B-Cell, Mice, Oncogene Protein v-cbl, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Retroviridae Proteins, Oncogenic, Tumor Cells, Cultured, Tyrosine, Ubiquitin-Protein Ligases
Oncogene
Date: Dec. 11, 1997
PubMed ID: 9416834
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