The proto-oncogene c-Cbl is a negative regulator of DNA synthesis initiated by both receptor and cytoplasmic tyrosine kinases

In C, elegans, genetic and biochemical data indicate that the Cbl homolog S li-1 attenuates Let-23 (EGFR) signaling. To investigate whether c-Cbl might have a role in mammalian growth factor-mediated mitogenic signaling, me mi croinjected NIH3T3 mouse fibroblasts with expression plasmids encoding wt a nd G306ECbl (a 'loss of function' mutant identified in C. elegans). We obse rved inhibition of PDGF BB- and EGF-induced DNA synthesis by wt Cbl but not the mutant. Microinjection of two different affinity purified polyclonal a ntisera against Cbl boosted a suboptimal PDGF-stimulated mitogenic response . The inhibition of both PDGF BB- and EGF-induced DNA synthesis by,rt Cbl w as reversed by co-expression with Myc but not with Fos, DNA synthesis initi ated by constitutively activated Src was also blocked by Cbl expression, bu t curiously by the G306E mutant as well. These data are all consistent with the proposition that Cbl negatively affects mitogenic signaling in mammali an fibroblasts.