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.
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
Nature
Date: Mar. 18, 1999
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