NF-κB Activation: The IκB Kinase Revealed?

(Baeuerle and Baltimore, 1996). More than a decade ago, the transcriptional activator In vivo, phosphorylation of IkB occurs when it is comNF-kB was described as a protein that bound to a speplexed with NF-kB and does not cause dissociation of cific DNA site in the intronic enhancer of the immunothe complex. Rather, it signals ubiquitination of IkB, globulin k light chain gene (Sen and Baltimore, 1986). which in turn leads to proteasome-mediated degradaFollowing the cloning of genes encoding the p50 and tion of the inhibitor, releasing free NF-kB (Baldwin, 1996; p65 subunits of NF-kB, it became evident that both Baeuerle and Baltimore, 1996). subunits are members of the larger NF-kB/Rel family of This understanding of the sites and roles of phosphortranscriptional regulator proteins. Since its initial deylation has allowed a systematic search for the kinase(s) scription, our view of the role of NF-kB in immune and responsible for IkBphosphorylation, a major component inflammatory responses has broadened significantly (for of the signal transduction pathways leading to NF-kB reviews, see Baldwin, 1996; Baeuerle and Baltimore, activation. 1996). In 1996, Maniatis’ laboratory was the first to report the NF-kB regulation is part of a cellular response system identification of a high molecular weight kinase complex to many different noxious stimuli. NF-kB is activated by that specifically phosphorylated IkBa at S32 and S36 a vast number of agents including cytokines like tumor (Chen et al., 1996). The 700 kDa complex was purified necrosis factor a (TNFa) and interleukin-1 (IL-1), bactefrom an unstimulated HeLa cell cytoplasmic extract and rial LPS, viral infection and expression of certain viral required ubiquitin and the ubiquitination enzymes for proteins like Tax of human T-cell leukemia virus, (HTLV-1), activity. Although it was shown that a component of the