NAK is an IκB kinase-activating kinase

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Abstract
Phosphorylation of IκB by the IκB kinase (IKK) complex is a critical step leading to IκB degradation and activation of transcription factor NF-κB1. The IKK complex contains two catalytic subunits, IKKα and IKKβ, the latter being indispensable for NF-κB activation by pro-inflammatory cytokines2,3,4,5,6,7. Although IKK is activated by phosphorylation of the IKKβ activation loop8, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure1,9. Here we describe an IKK-related kinase, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IκB degradation and NF-κB activity through IKKβ. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-κB by protein kinase C-ε (PKCε). Thus, NAK is an IKK kinase that may mediate IKK and NF-κB activation in response to growth factors that stimulate PKCε activity.