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

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-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs). However, the molecular mechanism by which NIK is activated is not understood. Here we show that the MAPKK kinase TAK1 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-kappaB, which is blocked by dominant-negative mutants of NIK, and an inactive TAK1 mutant prevents activation of NF-kappaB that is mediated by IL-1 but not by NIK. Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway.

Pubmed ID: 10094049

Authors

  • Ninomiya-Tsuji J
  • Kishimoto K
  • Hiyama A
  • Inoue J
  • Cao Z
  • Matsumoto K

Journal

Nature

Publication Data

March 18, 1999

Associated Grants

None

Mesh Terms

  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line
  • Enzyme Activation
  • I-kappa B Kinase
  • Interleukin-1
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Multienzyme Complexes
  • Mutagenesis
  • NF-kappa B
  • Phosphorylation
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Recombinant Fusion Proteins
  • Serine
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Threonine
  • Transfection