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.
Thien
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CB
Department of Pathology, The University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands.
Langdon
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WY
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D016393:Lymphoma, B-Cell; D051379:Mice; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D016895:Culture Media, Serum-Free; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D050722:Oncogene Protein v-cbl; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D018844:Cyclin-Dependent Kinases; C067419:CBL protein, human; C493849:Cbl protein, mouse