TGF-β-activated kinase 1 stimulates NF-κB activation by an NF-κB-inducing kinase-independent mechanism

Several mitogen-activated protein kinase kinase kinases (MAPKKKs), including NF-κB-inducing kinase (NIK), play critical roles in NF-κB activation. We isolated cDNA for human TGF-β activated kinase 1 (TAK1), a member of the MAPKKK family, and evaluated its ability to stimulate NF-κB activation. Overexpression of TAK1 together with its activator protein, TAK1 binding protein 1 (TAB1), induced the nuclear translocation of NF-κB p50/p65 heterodimer accompanied by the degradation of IκBα and IκBβ, and the expression of κB-dependent reporter gene. A dominant negative mutant of NIK did not inhibit TAK1-induced NF-κB activation. These results suggest that TAK1 induces NF-κB activation through a novel NIK-independent signaling pathway.