FIGURE 1

Pathways leading to activation of NF-B. NF-B complexes can be induced by a variety of mechanisms. The 'canonical' pathway is IKK dependent and results in the phosphorylation of IB at serines 32 and 36, leading to its ubiquitination by -TrCP and subsequent degradation by the proteasome. The RelA (p65) NF-B subunit can also be directly phosphorylated by IKK at Ser-536. IKK-dependent activation of NF-B can also occur following some genotoxic stresses. Here, however, IKK (NEMO) becomes sumoylated and nuclear localized, whereupon it is ubiquitinated in a manner dependent upon the ATM checkpoint kinase before relocating back to the cytoplasm. The noncanonical pathway results in the phosphorylation of the p100 NF-B subunit by IKK. Similar to the canonical pathway, this results in its ubiquination by TrCP and C-terminal degradation by the proteasome, resulting in the generation of p52 NF-B. In addition, a number of IKK-independent, 'atypical' pathways have been described which still involve the phosphorylation of IB. These include CK2- and tyrosine kinase-dependent pathways, which phosphorylate IB at sites distinct from those seen with IKK. CK2- dependent activation of NF-B can result in degradation of IB by calpain, while the Tyr-42 phosphorylation of IB can result either in its degradation of merely disassociation from NF-B. Not shown are IKK phosphorylation and subsequent processing of p105 NF-B, the targeting of other IB subunits and the induction of the wide variety of NF-B complexes that exist in the cell. Some of the consequences of differential activation of NF-B by these pathways are indicated. RHD=Rel homology domain; TAD=transcriptional activation domain; ANK=ankyrin repeat domain