Figure 2

The canonical, non-canonical and the atypical NF-κB signaling pathway. (A) In the canonical NF-κB signaling pathway lipopolysaccharides (LPS), tumor necrosis factor α (TNFα) orinterleukin-1 (IL-1) activate Toll-like receptors (TLRs), tumor necrosis factor receptor (TNFR) and interleukin-1 receptor (IL-1R), respectively. Through a variety of adapter proteins and signaling kinases this leads to an activation of IKKβ in the IKK complex, which can then phosphorylate IκBα on Serine residues S32 and S36. This phosphorylation is a prerequisite for its subsequent polyubiquitination, which in turn results in proteasomal degradation of IκBα. NF-κB homo- or heterodimers can then translocate to nucleus and activate target gene transcription. (B) In the non-canonical NF-κB signaling pathway, activation of B-cell activation factor (BAFFR), CD40, receptor activator for nuclear factor kappa B (RANK) or lymphtoxin β-receptor (LTβR), leads to activation of IKKα by the NF-κB-inducing kinase (NIK). IKKα can the phosphorylate p100 on serine residues S866 and S870. This phosphorylation leads to polyubiquitination of p100 and its subsequent proteasomal processing to p52.p52-RelB heterodimers can then activate transcription of target genes. (C) In the atypical NF-κB signaling pathway, genotoxic stress leads to a translocation of NEMO to the nucleus where it is sumoylated and subsequently ubiquitinated. This process is mediated by the ataxia telangiectasia mutated (ATM) checkpoint kinase. NEMO and ATM can then return to the cytosol where they activate IKKβ.