Raf-1 sets the threshold of Fas sensitivity by modulating Rok-α signaling

Ablation of the Raf-1 protein causes fetal liver apoptosis, embryonic lethality, and selective hypersensitivity to Fas-induced cell death. Furthermore, Raf-1–deficient cells show defective migration as a result of the deregulation of the Rho effector kinase Rok-α. In this study, we show that the kinase-independent modulation of Rok-α signaling is also the basis of the antiapoptotic function of Raf-1. Fas activation stimulates the formation of Raf-1–Rok-α complexes, and Rok-α signaling is up-regulated in Raf-1–deficient cells. This leads to increased clustering and membrane expression of Fas, which is rescued both by kinase-dead Raf-1 and by interfering with Rok-α or its substrate ezrin. Increased Fas clustering and membrane expression are also evident in the livers of Raf-1–deficient embryos, and genetically reducing Fas expression counteracts fetal liver apoptosis, embryonic lethality, and the apoptotic defects of embryonic fibroblasts. Thus, Raf-1 has an essential function in regulating Fas expression and setting the threshold of Fas sensitivity during embryonic life.