ACTIVATION OF THE I-KAPPA-B-ALPHA KINASE COMPLEX BY MEKK1, A KINASE OF THE JNK PATHWAY

Both NF-kappa B and c-Jun are activated by cytokines such as TNF-alpha and by stresses such as UV irradiation. A key step in the activation of NF-kappa B is the phosphorylation of its inhibitor, I kappa B alpha , by a ubiquitination-inducible multiprotein kinase complex (I kappa B alpha kinase). A central kinase in the c-Jun activation pathway is mi togen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we s how that MEKK1 induces the site-specific phosphorylation of I kappa B alpha in vivo and, most strikingly, can directly activate the I kappa B alpha kinase complex in vitro. Thus, MEKK1 is a critical component o f both the c-Jun and NF-kappa B stress response pathways. Since the I kappa B alpha kinase complex can be independently activated by ubiquit ination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF -kappa B.