Coordinate Regulation of I?B Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-?B-Inducing Kinase

ABSTRACTI?B kinases (IKKa and IKKß) are key components of the IKK complex that mediates activation of the transcription factor NF-?B in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-?B-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-a) and interleukin-1 and can potentiate the stimulatory effect of TNF-a on IKK and NF-?B activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-a. MEKK1 interacts with and stimulates the activities of both IKKa and IKKß in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.