The inactive transcription factor NF-κB is sequestered in the cytoplasmic compartment through association with the inhibitory molecule IκB. IκB kinases (IKK) phosphorylate IκB whereby NF-κB is released and translocates to the nucleus to induce specific gene expression. IKKκ and IKKβ are critical for the proper regulation of NF-κB activity; however, there are conflicting reports on their specific roles. O'Mahony et al. demonstrated that the presence of IKKα in heterodimers with IKKβ inhibits the high basal activity of IKKβ. Signal-activated IKKα phosphorylated and activated IKKβ leading to the derepression of NF-κB. This chain of phosphorylation was unidirectional, as IKKβ did not phosphorylate IKKα under the conditions used. The MAP kinase kinase kinase Cot/Tpl-2 also phosphorylated catalytically inactive IKKβ in the absence of IKKα; however, the physiological relevance of this observation is unclear.
O'Mahony, A., Lin, X., Geleziunas, R., and Greene, W.C. (2000) Activation of the heterodimeric IκB kinase α (IKKα)-IKKβ complex is directional: IKKα regulates IKKβ under both basal and stimulated conditions. Mol. Cell. Biol. 20: 1170-1178. [Abstract] [Full Text]