IκB kinase α (IKKα) regulation of IKKβ kinase activity

Two related kinases, I kappa B kinase alpha (IKK alpha) and IKK beta, phosphorylate the I kappa B proteins, leading to their degradation and the subsequent activation of gene expression by NF-kappa B. IKK beta has a much higher level of kinase activity for the I kappa B proteins than does IKK alpha and is more critical than IKK alpha in modulating tumor necrosis factor alpha activation of the NF-kappa B pathway. These results indicate an important role for IKK beta in activating the NF-kappa B pathway but leave open the question of the role of IKK alpha in regulating this pathway. In the current study, we demonstrate that IKK alpha directly phosphorylates IKK beta. Moreover, IKK alpha either directly or indirectly enhances IKK beta kinase activity for I kappa B alpha. Finally, transfection studies to analyze NF-kappa B-directed gene expression suggest that IKK alpha is upstream of IKK beta in activating the NF-kappa B pathway. These results indicate that IKK alpha, in addition to its previously described ability to phosphorylate I kappa B alpha, can increase the ability of IKK beta to phosphorylate I kappa B alpha.