The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.
Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular ... domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory kappaBalpha phosphorylation and transcriptional activation of a nuclear factor-kappaB (NF-kappaB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-kappaB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway.
Mesh Terms:
3T3 Cells, Animals, Apoptosis Regulatory Proteins, Binding Sites, Carrier Proteins, Cell Line, Cloning, Molecular, Cytoplasm, Genes, Reporter, Genetic Vectors, Humans, Luciferases, MAP Kinase Signaling System, Membrane Proteins, Mice, NF-kappa B, Plasmids, Protein Binding, Proteins, Receptors, Tumor Necrosis Factor, Saccharomyces cerevisiae, Spodoptera, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, TNF Receptor-Associated Factor 5, Transfection, Tumor Necrosis Factors
3T3 Cells, Animals, Apoptosis Regulatory Proteins, Binding Sites, Carrier Proteins, Cell Line, Cloning, Molecular, Cytoplasm, Genes, Reporter, Genetic Vectors, Humans, Luciferases, MAP Kinase Signaling System, Membrane Proteins, Mice, NF-kappa B, Plasmids, Protein Binding, Proteins, Receptors, Tumor Necrosis Factor, Saccharomyces cerevisiae, Spodoptera, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, TNF Receptor-Associated Factor 5, Transfection, Tumor Necrosis Factors
Biochem. J.
Date: Apr. 15, 2003
PubMed ID: 12529173
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