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

Jun Ninomiya-Tsuji, Kazuya Kishimoto, Atsushi Hiyama, Jun-ichiro Inoue, Zhaodan Cao and Kunihiro Matsumoto ()
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Jun Ninomiya-Tsuji: Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation
Kazuya Kishimoto: Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation
Atsushi Hiyama: Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation
Jun-ichiro Inoue: Institute of Medical Science, University of Tokyo
Zhaodan Cao: Tularik Inc. Two Corporate Drive
Kunihiro Matsumoto: Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation

Nature, 1999, vol. 398, issue 6724, 252-256

Abstract: 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.

Date: 1999
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DOI: 10.1038/18465

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