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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References
Karin,M. The beginning of the end: IκB kinase (IKK) and NF-κB activation. J. Biol. Chem. 274, 27339–27342 (1999).
Hu,Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316–320 (1999).
Takeda,K. et al. Limb and skin abnormalities in mice lacking IKKα. Science 284, 313–316 ( 1999).
Tanaka,M. et al. Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice. Immunity 10 , 421–429 (1999).
Li,Q., Van Antwerp,D., Mercurio, F., Lee,K.-F. & Verma,I. M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999).
Li,Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999).
Li,Z. W. et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 ( 1999).
Delhase,M., Hayakawa,M., Chen,Y. & Karin,M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284, 309–313 (1999).
Karin,M. & Delhase,M. JNK or IKK, AP-1 or NF-κB, which are the targets for MEK kinase 1 action. Proc. Natl Acad. Sci. USA 95, 9067–9069 ( 1998).
Shimada,T. et al. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int. Immunol. 8, 1357–1362 (1999).
Ling,L., Cao,Z. & Goeddel,D. V. NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc. Natl Acad. Sci. (USA) 95, 3792–3797 (1998).
Brockman,J. A. et al. Coupling of a signal response domain in IκBα to multiple pathways for NF-κB activation. Mol. Cell. Biol. 15, 2809–2818 ( 1995).
Brown,K., Gerstberger,S., Carlson,L., Franzoso,G. & Siebenlist,U. Control of IκB-α proteolysis by site-specific, signal-induced phosphorylation. Science 267, 1485–1488 (1995).
Traencker,E. B.-M. et al. Phosphorylation of human IκB-α on serines 32 and 36 controls IκB-α proteolysis and NF-κB activation in response to diverse stimuli. EMBO J. 14, 2876– 2883 (1995).
DiDonato,J. A. et al. Mapping of the inducible IκB phosphorylation sites that signal its ubiquitination and degradation. Mol. Cell. Biol. 16, 1295–1304 (1996).
Yaron,A. et al. Identification of the receptor component of the IκBα-ubiquitin ligase. Nature 396, 590– 594 (1998).
Hatakeyama,S. et al. Ubiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cullin/F-box protein FWD1. Proc. Natl Acad. Sci. USA 96, 3859–3863 (1999).
Baeuerle,P. A. & Baltimore,D. NF-κB: ten years after. Cell 87, 13– 20 (1996).
Verma,I. M., Stevenson,J. K., Schwarz, E. M., Van Antwerp,D. & Miyamoto,S. Rel/NF-κB/IκB family: intimate tales of association and dissociation. Genes Dev. 9, 2723–2735 (1995).
Baldwin,A. S. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–683 (1996).
Barnes,P. J. & Karin,M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 ( 1997).
Nishizuka,Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258, 607– 614 (1992).
Gray,M. O., Karliner,J. S. & Mochly-Rosen, D. A selective ε-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J. Biol. Chem. 272, 30945–30951 (1997).
Mayne,G. C. & Murray,A. W. Evidence that protein kinase Cε mediates phorbol ester inhibition of calphostin C- and tumor necrosis factor-α-induced apoptosis in U937 histiocytic lymphoma cells. J. Biol. Chem. 273, 24115–24121 (1998).
Liu,Z. G., Hsu,H., Goeddel,D. V. & Karin,M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565–576 (1996).
Pomerantz,J. L. & Baltimore,D. NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 18, 6694– 6704 (1999).
Moriya,S. et al. Platelet-derived growth factor activates protein kinase Cε through redundant and independent signaling pathways involving phospholipase Cγ or phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 93, 151–155 ( 1996).
Suemori,H. et al. A mouse embryonic stem cell line showing pluripotency of differentiation in early embryos and ubiquitous beta-galactosidase expression. Cell Differ. Dev. 29, 181–186 (1990).
DiDonato,J. A., Hayakawa,M., Rothwarf,D. M., Zandi,E. & Karin,M. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548–554 (1997).
Werlen,G., Jacinto,E., Xia,Y. & Karin,M. Calcineurin preferentially synergizes with PKC-theta to activate JNK and IL-2 promoter in T lymphocytes. EMBO J. 17, 3101–3111 (1997).
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