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.
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Acknowledgements
We thank D. Rothwarf for discussions and help with the IKK activation and association experiments, K. Tsujimura, Y. Obata and T. Takahashi for generating anti-NAK antibody, and M. Shirane for immunohistochemical study. This work was supported by the Ministry of Education, Science, Sports, and Culture of Japan, and the Ministry of Health and Welfare of Japan. Research in M.K. lab was supported by grants from the National Institute of Health (NIH) and the Department of Energy. M.K. is an American Cancer Society Research Professor.
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Tojima, Y., Fujimoto, A., Delhase, M. et al. NAK is an IκB kinase-activating kinase. Nature 404, 778–782 (2000). https://doi.org/10.1038/35008109
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DOI: https://doi.org/10.1038/35008109
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