The kinase TAK1 can activate the NIK-IκB 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 profess. When it binds to its cell-surface receptor, H-l initiates a signalling cascade that leads to activation of the transcription factor NF-kappa B and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappa B-inducing kinase (NIK) and I kappa B kinases (IKKs)(1-7). 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-kappa B, which is blocked by dominant-negative mutants of NIK, and an inactive TAK1 mutant prevents activation of NF-kappa B 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 MIK-IKK cascade in the IL-1 signalling pathway.