The canonical NF-κB activation pathway. Binding of TNFα trimers to TNFR receptors initiates the canonical signaling pathway by activating the upstream kinase IKK. IKK phosphorylates the IκB inhibitor that is bound to NF-κB in the resting state. This targets IκB proteins for the ubiquitin-proteasome system, which leads to IκB destruction by the 26S proteasome and release of NF-κB. Free NF-κB enters the nucleus and activates gene expression of many target genes and induces negative feedback regulation by synthesizing IκB and A20. IκB proteins inhibit NF-κB activity by sequestering NF-κB from the nucleus to form an inner feedback loop, while A20 attenuates stimulus induced IKK kinase activation further upstream in an outer negative feedback loop.
Sheppard et al. BMC Bioinformatics 2011 12:276 doi:10.1186/1471-2105-12-276