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The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that has several effects in the inflammation process. When it binds to its cell-surface receptor, IL-1 initiates a signalling cascade that leads to activation of the transcription factor NF-κB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-κB-inducing kinase (NIK) and IκB kinases (IKKs)1,2,3,4,5,6,7. However, the molecular mechanism by which NIK is activated is not understood. Here we show that the MAPKK kinase TAK1 (ref. 8) acts upstream of NIK in the IL-1-activated signalling pathway and that TAK1 associates with TRAF6 during IL-1 signalling. Stimulation of TAK1 causes activation of NF-κB, which is blocked by dominant-negative mutants of NIK, and an inactive TAK1 mutant prevents activation of NF-κB that is mediated by IL-1 but not by NIK. Activated TAK1 phosphorylates NIK, which stimulates IKK-α activity. Our results indicate that TAK1 links TRAF6 to the NIK–IKK cascade in the IL-1 signalling pathway.

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Figure 1: Effect of IL-1 on TAK1.
Figure 2: Effect of TAK1 on NF-κB and JNK activation.
Figure 3: Phosphorylation of NIK.
Figure 4: Interaction of TAK1 with components of the IKK complex.
Figure 5: Activation of IKK-α by TAK1.
Figure 6: Model for the role of TAK1 in the IL-1 signalling pathway.

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Acknowledgements

We thank D. Goeddel for advice and for discussion; P. Baeuerle, T. Fujita, E. Nishida, H. Saito, H. Sakurai, H. Shibuya and D. Wallach for materials; and M. Lamphier and R. Ruggieri for critically reading the manuscript. Supported by special grants for CREST, Advanced Research on Cancer, from the Ministry of Education, Culture and Science of Japan, and by HFSP (K.M.)

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Correspondence to Kunihiro Matsumoto.

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Ninomiya-Tsuji, J., Kishimoto, K., Hiyama, A. et al. The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252–256 (1999). https://doi.org/10.1038/18465

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