IKKε is part of a novel PMA-inducible IκB kinase complex

Here we report the identification of a novel PMA-inducible I kappa B kinase complex, distinct from the well-characterized high-molecular weight I kappa B kinase complex containing IKK alpha, IKK beta, and IKK gamma. We have characterized one kinase from this complex, which we designate IKK epsilon. Although recombinant IKK epsilon directly phosphorylates only serine 36 of I kappa B alpha, the PMA-activated endogenous IKK epsilon complex phosphorylates both critical serine residues. Remarkably, this activity is due to the presence of a distinct kinase in this complex. A dominant-negative mutant of IKK epsilon blocks induction of NF-kappa B by both PMA and activation of the T cell receptor but has no effect on the activation of NF-kappa B by TNF alpha or IL-1. These observations indicate that the activation of NF-kappa B requires multiple distinct I kappa B kinase complexes, which respond to both overlapping and discrete signaling pathways.