TYROSINE KINASE-ACTIVITY OF THE EGF RECEPTOR IS ENHANCED BY THE EXPRESSION OF ONCOGENIC 70Z-CBL

The 120kD product of the c-Cbl oncogene is a prominent substrate of pr otein tyrosine kinases that lacks a known catalytic activity but posse sses 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 fin ger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced lev el of tyrosine phosphorylation compared with c-Cbl, Here we demonstrat e that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulate d cells, In serum-starved cells this results in EGF receptor autophosp horylation and the recruitment of Grb2, Shc and Sos1 but does not indu ce a corresponding increase in MAP kinase activity, Furthermore the ex pression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylat ion of the protein tyrosine phosphatase SHP-2, We also show that the C bl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/Shc/Sos1 complex that associates with the EGF rec eptor. These findings therefore demonstrate a biochemical effect of an oncogenic Cbl protein and support predictions from C, elegans that Cb l functions as regulator of receptor tyrosine kinases.