TNFR1‐induced activation of the classical NF‐κB pathway

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.