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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.

Pubmed ID: 12529173

Authors

  • Brown SA
  • Richards CM
  • Hanscom HN
  • Feng SL
  • Winkles JA

Journal

The Biochemical journal

Publication Data

April 15, 2003

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-39727
  • Agency: NHLBI NIH HHS, Id: R01 HL039727

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