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PMID:16365167
| Citation |
Piazzolla, D, Meissl, K, Kucerova, L, Rubiolo, C and Baccarini, M (2005) Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. J. Cell Biol. 171:1013-22 |
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| Abstract |
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. |
| Links |
PubMed PMC2171328 Online version:10.1083/jcb.200504137 |
| Keywords |
Animals; Apoptosis/genetics; Apoptosis/physiology; Cells, Cultured; Cytoskeletal Proteins/metabolism; Death Domain Receptor Signaling Adaptor Proteins; Dose-Response Relationship, Drug; Embryonic Development/physiology; Fibroblasts/metabolism; Flow Cytometry; Fluorescent Antibody Technique; Genes, Lethal; Intracellular Signaling Peptides and Proteins; Liver/embryology; Liver/metabolism; Membranes/metabolism; Mice; Mice, Mutant Strains/embryology; Mice, Mutant Strains/metabolism; Models, Biological; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-raf/genetics; Proto-Oncogene Proteins c-raf/metabolism; Receptors, Tumor Necrosis Factor/metabolism; Sensitivity and Specificity; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism; rho-Associated Kinases |
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Significance
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