ANTISENSE REPRESSION OF PROTOONCOGENE C-CBL ENHANCES ACTIVATION OF THE JAK-STAT PATHWAY BUT NOT THE RAS PATHWAY IN EPIDERMAL GROWTH-FACTOR RECEPTOR SIGNALING

Many growth factors including epidermal growth factor (EGF) induce tyr osine phosphorylation of the c-Cbl proto-oncogene product, whose funct ion, however, remains unclear. Recently, Sli-1, a Caenorhabditis elega ns homologue of c-Cbl, was found to be a negative regulator of let-23- mediated vulval induction pathway, suggesting that c-Cbl may negativel y regulate EGF receptor (EGFR)-mediated signaling. In this study, by a n antisense RNA approach, we examined the effects of expression level of c-Cbl on EGFR signaling and showed that overexpression of c-Cbl red uces and antisense repression of c-Cbl enhances autophosphorylation of EGF receptors and activation of the JAR-STAT pathway. However, in con trast to the Sli-1 protein, the expressed amount of c-Cbl does not aff ect activation of the Ras pathway, suggesting that the EGFR-mediated s ignaling pathways are differently regulated by c-Cbl among nematodes a nd mammals.