TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation

J Biol Chem. 2003 Sep 19;278(38):36005-12. doi: 10.1074/jbc.M304266200. Epub 2003 Jul 1.


Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to induce angiogenesis, apoptosis in tumor cells, and NF-kappaB activation through binding to its receptor, fibroblast growth factor-inducible 14. We have identified TWEAK as an inducer of constitutive NF-kappaB activation by expression cloning, and we report here sequential regulation by TWEAK of two separate signaling cascades for NF-kappaB activation, the NF-kappaB essential modulator-dependent and -independent signaling pathways. Upon TWEAK stimulation, IkappaBalpha is rapidly phosphorylated, generating NF-kappaB DNA-binding complexes containing p50 and RelA in a manner dependent on the canonical IkappaB kinase complex. Unlike TNF-alpha, TWEAK stimulation results in prolonged NF-kappaB activation with a transition of the DNA-binding NF-kappaB components from RelA- to RelB-containing complexes by 8 h, and the latter remained active in binding at least until 24 h post-stimulation. This long lasting activation is accompanied by the proteasome-mediated processing of NF-kappaB2/p100, which does not depend on the NF-kappaB essential modulator but requires IkappaB kinase 1 and functional NF-kappaB-inducing kinase activity. Finally, we show that fibroblast growth factor-inducible 14 with a mutation at its TNF receptor-associated factor (TRAF)-binding site cannot activate NF-kappaB and that TWEAK fails to induce the p100 processing and IkappaBalpha phosphorylation in cells deficient for TRAF2 and TRAF5. Our results thus identify TWEAK as a novel physiological regulator of the non-canonical pathway for NF-kappaB activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • CD8 Antigens / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cloning, Molecular
  • Cytokine TWEAK
  • DNA / metabolism
  • DNA, Complementary / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Fibroblast Growth Factors / metabolism
  • Flow Cytometry
  • Gene Library
  • Genetic Vectors
  • I-kappa B Kinase
  • Immunoblotting
  • Ligands
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B / metabolism*
  • NF-kappa B p52 Subunit
  • Phosphorylation
  • Protein Binding
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Retroviridae / genetics
  • Signal Transduction
  • Time Factors
  • Transcription Factor RelA
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factors


  • Apoptosis Regulatory Proteins
  • CD8 Antigens
  • Carrier Proteins
  • Cytokine TWEAK
  • DNA, Complementary
  • Ligands
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Tnfsf12 protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors
  • fibroblast growth factor 14
  • Fibroblast Growth Factors
  • DNA
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse