Phosphorylation-dependent protein ubiquitylation and degradation provides an irreversible mechanism to terminate protein kinase signaling. Here we report that mammary epithelial cells require Cullin 5 RING E3 ubiquitin ligase complexes (Cul5-CRLs) to prevent transformation by a Src-Cas signaling pathway. Removing Cul5 stimulates growth factor-independent growth and migration, membrane dynamics, and colony dysmorphogenesis, dependent on the endogenous tyrosine kinase, Src. Src is activated in Cul5-deficient cells, but Src activation alone is not sufficient to cause transformation. We found that Cul5 and Src together stimulate degradation of the Src substrate, p130Cas (Crk-associated substrate). Phosphorylation stimulates Cas binding to the Cul5-CRL adaptor protein SOCS6 and consequent proteasome-dependent degradation. Cas is necessary for the transformation of Cul5-deficient cells. Either SOCS6 knockdown or a degradation-resistant Cas mutant stimulates membrane ruffling but not other aspects of transformation. Our results show that endogenous Cul5 suppresses epithelial cell transformation by several pathways, including inhibiting Src-Cas-induced ruffling through SOCS6.