Cbl-transforming variants trigger a cascade of molecular alterations that lead to epithelial mesenchymal conversion

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical s ignals that regulate these events. Multiple signaling proteins are phosphor ylated in epithelial cells during hepatocyte growth factor-induced cell dis persal, including c-Cbl, a protooncogene docking protein with ubiquitin lig ase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cb1) in epithelial cell dispersal. We show that the expression of 70z -Cb1 in Madin-Darby canine kidney epithelial cells resulted in the breakdow n of cell-cell contacts and alterations in cell morphology characteristic o f epithelial-mesenchymal transition. Structure-function studies revealed th at the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosph otyrosine-binding/Src homology domain 2, is sufficient to promote the morph ological changes in cell shape. Moreover, a point mutation at Gly-306 abrog ates the ability of the Cbl Src homology domain 2 to induce these morpholog ical changes. Our results identify a role for Cbl in the regulation of epit helial-mesenchymal transition, including loss of adherens junctions, cell s preading, and the initiation of cell dispersal.