Mitogen-activated protein kinase ERK kinase kinases 2 and 3 activate nuclear factor-κB through IκB kinase-α and IκB kinase-β

Recent evidence indicates that nuclear factor-kappa B (NF-kappa B), a transcription factor critically important for immune and inflammatory responses, is activated by a protein kinase cascade. The essential features of this cascade are that a mitogen-activated protein kinase kinase kinase (MAP3K) activates an I kappa B kinase (IKK) that site-specifically phosphorylates I kappa B. The I kappa B protein, which ordinarily sequesters NF-kappa B in the cytoplasm, is subsequently degraded by the ubiquitin-proteasome pathway, thereby allowing the nuclear translocation of NF-kappa B. Thus far, only two MAP3Ks, NIK and MEKK1, have been identified that can activate this pathway. We now show that MEKK2 and MEKK3 can in vivo activate IKK-alpha and IKK-beta, induce site-specific I kappa B alpha phosphorylation, and, relatively modestly, activate an NF-kappa B reporter gene. In addition, dominant negative versions of either IKK-alpha or IKK-beta abolish NF-kappa B activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediate the NF-kappa B-inducing activities of these MEKKs, In contrast, other MAP3Ks, including MEKK4, ASK1, and MLK3, fail to show evidence of activation of the NF-kappa B pathway. We conclude that a distinct subset of MAP3Ks can activate NF-kappa B.