Cullin–RING–ligase (CRL) complexes comprise the largest known category of E3 ubiquitin ligases. CRLs have an essential role in targeting proteins for ubiquitin-mediated destruction and regulate many dynamic cellular processes. Previous work has shown that the Cullin-5-RING (Cul5) ubiquitin ligase has a role in regulating the transforming ability of activated Src, an endogenous tyrosine kinase; on page 509, Jonathan Cooper and colleagues further investigate how Cul5 is linked to its substrates. The authors show that inhibition of CUL5 expression in the human mammary epithelial cell line MCF10A induces transformation. Although Src is activated in Cul5-deficient cells, its activation alone is not sufficient to induce transformation, suggesting that Cul5 suppresses transformation by inhibiting other proteins in addition to Src. The authors identify the Src substrate p130Cas (BCAR1) as one such candidate. Cas is a Src substrate implicated in transformation, and indeed, it is shown here to be required for the increased proliferation and migration of Cul5-deficient cells, suggesting that Src and Cas function in the same signalling pathway. The Cul5 adaptor protein SOCS6 stimulates the turnover of Cas, and the authors show that removing SOCS6 or expressing degradation-resistant Cas stimulates membrane ruffling but not other aspects of transformation. The authors therefore propose that Cul5 suppresses the transformation of epithelial cells by inhibiting Src–Cas-induced membrane ruffling through SOCS6, although other pathways are also involved.

• © 2014. Published by The Company of Biologists Ltd