Tak1

TAK1 was originally identified as a mitogen-activated protein kinase kinase kinase (MAPKKK) that could complement a mutation of yeast STE11, a gene encoding a MAPKKK. TAK1 has been shown to be activated by proinflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor (TNF), transforming growth factor β (TGF-β) family ligands and Wnt family ligands. In the IL-1 signaling pathway, stimulation by IL-1 causes TAK1 recruitment to the TNF receptor-associated factor 6 (TRAF6) complex, where it is activated. Activated TAK1 then stimulates a MAPK cascade leading to activation of c-Jun N-terminal kinase (JNK) and p38 MAPKs, as well as IκB kinases (IKKs) leading to the activation of NF-κB. TAK1 was independently isolated as a component of a biochemical fraction required for TRAF6-induced activation of IKK. In this system, IL-1 was shown to induce Lys63-linked ubiquitination of TRAF6. This ubiquitination does not function to target TRAF6 for proteasome-dependent degradation, as might be expected, but rather mediates the activation of TAK1. TRAF6 and TAK1 are also recruited to a receptor-activated NF-κB (RANK) and are likely to participate in RANK-dependent osteoclastogenesis. In addition, TAK1 was found to be involved in a MAP kinase-like pathway that regulates the Wnt signaling pathway. TAK1-deficient mouse embryonic fibroblasts and B cells demonstrate that TAK1 is essential for the activation of JNK and NF-κB mediated by IL-1 receptor ligand, TNF receptor ligand and Toll-like receptor ligand. TAK1-deficent cells are highly sensitive to TNF-induced apoptosis.