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

Abstract

Recent evidence indicates that nuclear factor-κB (NF-κB), 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 IκB kinase (IKK) that site-specifically phosphorylates IκB. The IκB protein, which ordinarily sequesters NF-κB in the cytoplasm, is subsequently degraded by the ubiquitin-proteasome pathway, thereby allowing the nuclear translocation of NF-κB. 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-α and IKK-β, induce site- specific IκBα phosphorylation, and, relatively modestly, activate an NF- κB reporter gene. In addition, dominant negative versions of either IKK-α or IKK-β abolish NF-κB activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediate the NF-κB-inducing activities of these MEKKs. In contrast, other MAP3Ks, including MEKK4, ASK1, and MLK3, fail to show evidence of activation of the NF-κB pathway. We conclude that a distinct subset of MAP3Ks can activate NF-κB.