RAF kinases are key components of the mitogen-activated protein kinase (MAPK) pathway, where they activate MEK to regulate cell proliferation. Mielgo et al. now report that the CRAF isoform promotes the activation of mitotic kinases in a MEK-independent manner to enhance proliferation and tumour growth (Nat. Med. 17, 1641–1645; 2011).

The authors observed that CRAF deficiency led to mitotic arrest and reduced proliferation in mouse embryonic fibroblasts and cancer cells. Treatment of cancer cells with allosteric, but not ATP-competitive, RAF inhibitors resulted in a similar phenotype that was not rescued by ectopic MEK expression. This suggests that CRAF acts independently of its kinase activity and MEK activation in this context. The authors established the existence of such a pathway using CRAF mutants, and demonstrated that it depends on the phosphorylation of CRAF at Ser 388, a modification previously linked to cancer progression. They showed that Ser-388-phosphorylated CRAF accumulates at centrosomes and spindle poles, where it interacts with the Aurora-A and Plk1 mitotic kinases to enhance their activation for mitotic progression. Expression of a phosphomimetic Ser 338 CRAF mutant in cancer cell lines activated Plk1, but not MEK, and accelerated mitosis and tumour growth in mice. These findings have potential therapeutic implications for the targeting of RAF in cancer.