Differential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase ERK kinase kinase-1

NF-kappa B is activated by various stimuli including inflammatory cytokines and stresses, A key step in the activation of NF-kappa B is the phosphorylation of its inhibitors, I kappa Bs, by an I kappa B kinase (IKK) complex, Recently, two closely related kinases, designated IKK alpha and IKK beta, have been identified to be the components of the IKK complex that phosphorylate critical serine residues of I kappa Bs for degradation, A previously identified NF-kappa B-inducing kinase (NIK), which mediates NF-kappa B activation by TNF alpha and IL-1, has been demonstrated to activate IKK alpha, Previous studies showed that mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1), which constitutes the c-Jun N-terminal kinase/ stress-activated protein kinase pathway, also activates NF-kappa B by an undefined mechanism, Here, we show that overexpression of MEKK1 preferentially stimulates the kinase activity of IKK beta, which resulted in phosphorylation of I kappa Bs, Moreover, a catalytically inactive mutant of IKK beta blocked the MEKK1- induced NF-kappa B activation, By contrast, overexpression of NIK stimulates kinase activities of both IKK alpha and IKK beta comparably, suggesting a qualitative difference between NIK and MEKK1-mediated NF-kappa B activation pathways, Collectively, these results indicate that NIK and MEKK1 independently activate the IKK complex and that the kinase activities of IKK alpha and IKK beta are differentially regulated by two upstream kinases, NIK and MEKK1, which are responsive to distinct stimuli.