The Kinase TAK1 Can Activate the NIK-I kappaB as Well as the MAP Kinase Cascade in the IL-1 Signalling Pathway

Nature. 1999 Mar 18;398(6724):252-6. doi: 10.1038/18465.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Interleukin-1
  • Multienzyme Complexes
  • NF-kappa B
  • Proteins
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 6
  • Threonine
  • Serine
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • NF-kappa B kinase