Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta - PubMed (original) (raw)

. 1999 Mar 26;274(13):8355-8.

doi: 10.1074/jbc.274.13.8355.

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Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta

Q Zhao et al. J Biol Chem. 1999.

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Abstract

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

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