NAK is an IκB kinase-activating kinase

Phosphorylation of I kappa B by the I kappa B kinase (IKK) complex is a critical step leading to IkB degradation and activation of transcription factor NF-kappa B-1. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta, the latter being indispensable for NF-kappa B activation by pro-inflammatory cytokines(2-7). Although IKK is activated by phosphorylation of the IKK beta activation loop(8), the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure(1,9). Here we describe an IKK-related kinase, named NAK (NF-kappa B-activating kinase), that can activate IKK through direct phosphorylation. NAK induces I kappa B degradation and NF-kappa B activity through IKKb. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-kappa B by protein kinase C-epsilon (PKC epsilon). Thus, NAK is an IKK kinase that may mediate IKK and NF-kappa B activation in response to growth factors that stimulate PKC epsilon activity.