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 mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we show 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 of both the c-Jun and NF-kappa B stress response pathways. Since the I kappa B alpha kinase complex can be independently activated by ubiquitination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF-kappa B.