c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

The protooncogenic protein c-Cbl has been shown to act as a multivalent ada ptor and a negative regulator of protein tyrosine kinase-mediated signaling , Recent studies have implicated it in the regulation of cell adhesion-rela ted events. We have previously shown that c-Cbl facilitates adhesion and sp reading of v-Abl-transformed fibroblasts, and that these effects are depend ent on its tyrosine phosphorylation, However, the mechanisms mediating effe cts of c-Cbl on fibroblast adhesion remain poorly understood. In this study we demonstrate that the tyrosine phosphorylation-dependent effect of c-Cbl on adhesion of v-Abl-transformed fibroblasts is primarily mediated by an i ncrease in fibronectin matrix deposition by these cells. This increase in f ibronectin matrix deposition and, hence, in cell adhesion is dependent on c ytoskeletal rearrangements induced by RhoA, Rad and, possibly, Rapt activat ion caused by c-Cbl, The observed activation of these GTPases is mediated b y the recruitment of phosphatidylinositol-3' kinase, CrkL and Vav2 to the C -terminal tyrosine residues of c-Cbl, The results of this study also demons trate that ubiquitination is essential for the observed effects of c-Cbl on fibronectin matrix production and cell adhesion.