TNF-related weak inducer of apoptosis receptor, a TNF receptor superfamily member, activates NF-kappa B through TNF receptor-associated factors

Biochem Biophys Res Commun. 2003 Jun 13;305(4):789-96. doi: 10.1016/s0006-291x(03)00852-0.


TNF-related weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family that induces angiogenesis in vivo. The TWEAK receptor (TweakR) is a recently identified member of the TNF receptor (TNFR) superfamily and is expressed on smooth muscle cells (SMCs) and endothelial cells (ECs). In this report we identify the TNF receptor-associated factor (TRAF) family of signal transducers as important components of TweakR-mediated NF-kappa B activation. Coimmunoprecipitation experiments suggested potential interactions between the cytoplasmic tail of TweakR with TRAFs 1, 2, 3, and 5. Dominant negative forms of TRAF2 and TRAF5 substantially inhibited TweakR-mediated NF-kappa B activation, suggesting a role of TRAFs in regulating smooth muscle and endothelial cell function. Using alanine-scanning analysis, we defined a TRAF-binding motif, PIEET, in TweakR that mediates TRAF binding and NF-kappa B activation. Furthermore, TweakR mutations within the TRAF-binding motif abolished TweakR-stimulated SMC migration, revealing a role for TRAFs in TweakR-induced activation events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Cell Line
  • Cell Movement
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / physiology
  • Mutation
  • NF-kappa B / metabolism*
  • Proteins / genetics
  • Proteins / metabolism
  • Rats
  • Receptors, Tumor Necrosis Factor / chemistry
  • Receptors, Tumor Necrosis Factor / classification
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 5
  • TWEAK Receptor
  • Transcriptional Activation


  • NF-kappa B
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 5
  • TWEAK Receptor