COORDINATE REGULATION OF I-KAPPA-B KINASES BY MITOGEN-ACTIVATED PROTEIN-KINASE KINASE KINASE-1 AND NF-KAPPA-B-INDUCING KINASE

I kappa B kinases (IKK alpha and IKK beta) are key components of the I KK complex that mediates activation of the transcription factor NF-kap pa B in response to extracellular stimuli such as inflammatory cytokin es, viral and bacterial infection, and UV irradiation. Although NF-kap pa B-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mito gen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate u pstream kinase of the IKK complex. MEKK1 is activated by tumor necrosi s factor alpha (TNF-alpha) and interleukin-1 and can potentiate the st imulatory effect of TNF-alpha on IKK and NF-kappa B activation. The do minant negative mutant of MEKK1, on the other hand, partially blocks a ctivation of IKK by TNF-alpha. MEKK1 interacts with and stimulates the activities of both IKK alpha and IKK beta in transfected HeLa and COS -1 cells and directly phosphorylates the IKKs in vitro. Furthermore, M EKK1 appears to act in parallel to NIK, leading to synergistic activat ion of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of th e IKK complex by various extracellular signals.