TNFR1-induced activation of the classical NF-κB pathway

FEBS J. 2011 Apr;278(6):862-76. doi: 10.1111/j.1742-4658.2011.08015.x. Epub 2011 Feb 8.


The molecular mechanisms underlying activation of the IκB kinase (IKK) complex are presumably best understood in the context of tumor necrosis factor (TNF) receptor-1 (TNFR1) signaling. In fact, it seems that most, if not all, proteins relevant for this process have been identified and extensive biochemical and genetic data are available for the role of these factors in TNF-induced IKK activation. There is evidence that protein modification-independent assembly of a core TNFR1 signaling complex containing TNFR1-associated death domain, receptor interacting kinase 1, TNF receptor-associated factor 2 and cellular inhibitor of apoptosis protein 1 and 2 starts a chain of nondegrading ubiquitination events that culminate in the recruitment and activation of IKK complex-stimulating kinases and the IKK complex itself. Here, we sum up the known details of TNFR1-induced IKK activation, address arising contradictions and discuss possible explanations resolving the apparent discrepancies.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Line
  • GTPase-Activating Proteins / physiology
  • Humans
  • I-kappa B Kinase / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • NF-kappa B / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / physiology*
  • Signal Transduction / physiology
  • TNF Receptor-Associated Death Domain Protein / physiology
  • TNF Receptor-Associated Factor 1 / metabolism
  • TNF Receptor-Associated Factor 2 / metabolism
  • Ubiquitination


  • GTPase-Activating Proteins
  • NF-kappa B
  • Ralbp1 protein, mouse
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases