DIFFERENTIAL REGULATION OF I-KAPPA-B KINASE-ALPHA AND KINASE-BETA BY 2 UPSTREAM KINASES, NF-KAPPA-B-INDUCING KINASE AND MITOGEN-ACTIVATED PROTEIN-KINASE ERK KINASE KINASE-1

NF-kappa B is activated by various stimuli including inflammatory cyto kines 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 a lpha and IKK beta, have been identified to be the components of the IK K complex that phosphorylate critical serine residues of I kappa Bs fo r degradation, A previously identified NF-kappa B-inducing kinase (NIK ), which mediates NF-kappa B activation by TNF alpha and IL-1, has bee n demonstrated to activate IKK alpha, Previous studies showed that mit ogen-activated protein kinase/ERK kinase kinase-1 (MEKK1), which const itutes the c-Jun N-terminal kinase/ stress-activated protein kinase pa thway, also activates NF-kappa B by an undefined mechanism, Here, we s how 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 MEK K1- 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 N F-kappa B activation pathways, Collectively, these results indicate th at NIK and MEKK1 independently activate the IKK complex and that the k inase activities of IKK alpha and IKK beta are differentially regulate d by two upstream kinases, NIK and MEKK1, which are responsive to dist inct stimuli.