Mutations in BRAF are common in human melanomas and stimulate tumour-cell proliferation by overactivating the RAS–ERK pathway. Reporting in Cell, Richard Marais, David Barford and colleagues show that even BRAF mutants with decreased kinase activities can have oncogenic effects, through their interaction with another member of the RAF family.

BRAF initiates downstream signalling by phosphorylating MEK, which, in turn, activates ERK. Most cancer-associated BRAF mutations affect residues in the kinase domain, indicating that increased catalytic activity is responsible for oncogenesis. To confirm this, the authors determined the abilities of 22 mutant forms of BRAF — all of which are expressed in human cancers — to activate ERK. All but one of these stimulated ERK activation in the absence of upstream signals and, as expected, most had basal kinase activities that exceeded that of wild-type BRAF. Intriguingly, however, three of the mutants had decreased kinase activities, but were still able to activate ERK.

So, how can kinase-impaired BRAF mutants stimulate downstream signalling? Wild-type BRAF is known to form complexes with CRAF — a related protein that is also able to activate ERK. Marais, Barford and colleagues therefore investigated whether BRAF mutants can exert their oncogenic effects through CRAF, independently of kinase activity. All three of the kinase-impaired mutants that are able to activate ERK were shown to form complexes with CRAF and induce its activation. Reducing CRAF levels by RNA interference suppressed the ability of these BRAF mutants to activate ERK, confirming that their oncogenic activities are mediated through interactions with CRAF.

How these mutants activate CRAF is unclear. They all contain altered residues in their kinase domains, which might lead to a conformational change in this region. The authors suggest that such a change could be transmitted to the CRAF kinase domain, leading to its activation, but further work will be needed to confirm this.