Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha 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-alpha. In this study, we show that the kinase-independent modulation of Rok-alpha signaling is also ... the basis of the antiapoptotic function of Raf-1. Fas activation stimulates the formation of Raf-1-Rok-alpha complexes, and Rok-alpha 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-alpha 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.
Mesh Terms:
Animals, Apoptosis, Cells, Cultured, Cytoskeletal Proteins, Death Domain Receptor Signaling Adaptor Proteins, Dose-Response Relationship, Drug, Embryonic Development, Fibroblasts, Flow Cytometry, Fluorescent Antibody Technique, Genes, Lethal, Intracellular Signaling Peptides and Proteins, Liver, Membranes, Mice, Mice, Mutant Strains, Models, Biological, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Receptors, Tumor Necrosis Factor, Sensitivity and Specificity, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, rho-Associated Kinases
Animals, Apoptosis, Cells, Cultured, Cytoskeletal Proteins, Death Domain Receptor Signaling Adaptor Proteins, Dose-Response Relationship, Drug, Embryonic Development, Fibroblasts, Flow Cytometry, Fluorescent Antibody Technique, Genes, Lethal, Intracellular Signaling Peptides and Proteins, Liver, Membranes, Mice, Mice, Mutant Strains, Models, Biological, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Receptors, Tumor Necrosis Factor, Sensitivity and Specificity, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, rho-Associated Kinases
J. Cell Biol.
Date: Dec. 19, 2005
PubMed ID: 16365167
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