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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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Jun Ninomiya-Tsuji & Kazuya Kishimoto & Atsushi Hiyama & Jun-ichiro Inoue & Zhaodan Cao & Kunihiro Matsumoto, 1999. "The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway," Nature, Nature, vol. 398(6724), pages 252-256, March.
    • Handle: RePEc:nat:nature:v:398:y:1999:i:6724:d:10.1038_18465
    DOI: 10.1038/18465
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    Cited by:

    1. Juqi Zou & Satoshi Anai & Satoshi Ota & Shizuka Ishitani & Masayuki Oginuma & Tohru Ishitani, 2023. "Determining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Anirban Roy & Ashok Kumar, 2022. "Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Ying Zhao & Shijie Fan & Hong Zhu & Qingqing Zhao & Zimin Fang & Diyun Xu & Wante Lin & Liming Lin & Xiang Hu & Gaojun Wu & Julian Min & Guang Liang, 2024. "Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Yinan Yang & Huijing Zhou & Xiawei Huang & Chengfang Wu & Kewei Zheng & Jingrong Deng & Yonggang Zheng & Jiahui Wang & Xiaofeng Chi & Xianjue Ma & Huimin Pan & Rui Shen & Duojia Pan & Bo Liu, 2024. "Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Dongdong Wang & Yanxia Li & Hao Yang & Xiaoqi Shen & Xiaolin Shi & Chenyu Li & Yongjing Zhang & Xiaoyu Liu & Bin Jiang & Xudong Zhu & Hanwen Zhang & Xiaoyu Li & Hui Bai & Qing Yang & Wei Gao & Fang Ba, 2024. "Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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