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Article |
Raf-1 sets the threshold of Fas sensitivity by modulating Rok-
signaling
Correspondence to Manuela Baccarini: manuela.baccarini{at}univie.ac.at
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-
. In this study, we show that the kinase-independent modulation of Rok- signaling is also the basis of the antiapoptotic function of Raf-1. Fas activation stimulates the formation of Raf-1–Rok- complexes, and Rok- 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- 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.
Abbreviations used in this paper: DISC, death-inducing signaling complex; DN, dominant negative; ERK, extracellular regulated kinase; ERM, ezrin–radixin–moesin; FADD, Fas-associating death domain–containing protein; FLIP, FADD-like ice–like inhibitory protein; IP, immunoprecipitate; KC, kinase competent; KD, kinase dead; KO, knockout; MEF, mouse embryonic fibroblast; MEK, mitogen and ERK kinase; PEF, primary MEF; SCR, scrambled; siRNA, small interfering RNA; TNFR, TNF receptor; WT, wild type.
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