Cells lacking Raf-1 (bottom) migrate poorly.

R af-1 signaling is known to be important for proliferation, differentiation, and survival. Now, Ehrenreiter et al. report that it is required for cell migration and wound healing (page 955). Unlike other Raf-1 functions, this one doesn't require Raf-1 kinase activity, a theme the researchers think will be recurrent in future Raf-1 biology.When Raf-1 is knocked out in the epidermis of animals carrying conditional Raf-1 alleles, the epidermal structure remains normal. However, wounds heal slowly in the absence of Raf-1, despite normal cell proliferation in the epidermis. In culture, Raf-1–deficient cells do not migrate normally and appear rounded and contracted with dense cortical actin structures.

This suggests that either Rho or its downstream effector, Rok-α kinase, is hyperactive. Biochemical experiments showed that Raf-1 was required for Rok-α inhibition in keratinocytes and fibroblasts, and that inhibition of Rok-α activity overcame Raf-1 deficiency. Kinase-dead Raf-1 mutations also rescue the defect, indicating that Raf-1 regulates Rok-α via protein–protein interaction rather than by modifying the target.

Raf-1 is a weak kinase, even when phosphorylating its favored targets such as MEK, so a kinase-independent function is novel but not entirely unexpected. Ehrenreiter et al. think Raf-1 regulates Rok-α by targeting it to proper compartments in the cell and predict that similar functions will be found in other Raf-1 pathways. They are now mapping the Raf-1 domains responsible for Rok-α regulation.