TGF-BETA-ACTIVATED KINASE-1 STIMULATES NF-KAPPA-B ACTIVATION BY AN NF-KAPPA-B-INDUCING KINASE-INDEPENDSNT MECHANISM

Several mitogen-activated protein kinase kinase kinases (MAPKKKs), inc luding NF-kappa B-inducing kinase (NIK), play critical roles in NF-kap pa B activation, We isolated cDNA for human TGF-beta activated kinase 1 (TAK1), a member of the MAPKKK family, and evaluated its ability to stimulate NF-kappa B activation. Overexpression of TAK1 together with its activator protein, TAK1 binding protein 1 (TAB1), induced the nucl ear translocation of NF-kappa B p50/p65 heterodimer accompanied by the degradation of I kappa B alpha and I kappa B beta, and the expression of kappa B-dependent reporter gene. A dominant negative mutant of NIK did not inhibit TAK1-induced NF-kappa B activation. These results sug gest that TAK1 induces NF-kappa B activation through a novel NIK-indep endent signaling pathway. (C) 1998 Academic Press.