The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation

Immunity. 2000 Apr;12(4):419-29. doi: 10.1016/s1074-7613(00)80194-6.


The death domain kinase RIP and the TNF receptor-associated factor 2 (TRAF2) are essential effectors in TNF signaling. To understand the mechanism by which RIP and TRAF2 regulate TNF-induced activation of the transcription factor NF-kappaB, we investigated their respective roles in TNF-R1-mediated IKK activation using both RIP-/- and TRAF2-/- fibroblasts. We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation. Moreover, we demonstrated that IKK is recruited to the TNF-R1 complex through TRAF2 upon TNF treatment and that IKK activation requires the presence of RIP in the same complex.

MeSH terms

  • Antigens, CD / analysis
  • Antigens, CD / chemistry
  • Antigens, CD / physiology*
  • Apoptosis / physiology*
  • Cells, Cultured
  • Enzyme Activation
  • Fibroblasts / cytology
  • Humans
  • I-kappa B Kinase
  • Macromolecular Substances
  • NF-kappa B / physiology*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteins / physiology*
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor / analysis
  • Receptors, Tumor Necrosis Factor / chemistry
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 2
  • Transcription, Genetic*
  • Transfection


  • Antigens, CD
  • Macromolecular Substances
  • NF-kappa B
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 2
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human