JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action?

Abstract

MEKK1 (MEK kinase 1) is a mammalian serine/threonine kinase in the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) group (1). Being the first mammalian homolog of STE11, a MAPKKK that activates the pheromone responsive MAPK cascade of budding yeast, MEKK1 as its name indicates was thought to be an activator of the MAPK kinase (MAPKK) MEK1/2 and thus an activator of the ERK MAPK cascade. It therefore was rather surprising that titration experiments (2) or analysis of cells engineered to express MEKK1 from an inducible promoter (3) revealed that it is a far more potent activator of the JNK MAPK cascade. These observations made by using either the catalytic domain of MEKK1 (MEKK1Δ) or a 672-aa C-terminal fragment recently were confirmed by using full-length human MEKK1 (Y. Xia, Z. Wu, B. Su, B. Murray, and M.K., unpublished work). Most importantly, when different mammalian MAPKKs were examined in vitro or in vivo for phosphorylation and activation by MEKK1, a MAPKK called JNKK1 (MKK4 or SEK1), whose function is JNK (and p38 MAPK) activation (4) was found to be the preferred MEKK1 substrate (Y. Xia, Z. Wu, B. Su, B. Murray, and M.K., unpublished work). Based on specificity constants, MEKK1 phosphorylates JNKK1 45-fold more efficiently than it phosphorylates MEK1/2 (Y. Xia, Z. Wu, B. Su, B. Murray, and M.K., unpublished work), thus providing a clear biochemical explanation for the marked pro-JNK bias of MEKK1. Targets for JNK include transcription factors c-Jun and ATF2, which are components of the AP-1 dimer that are involved in induction of the c-jun protooncogene (5). JNK-mediated phosphorylation enhances the transcriptional activity of both c-Jun and ATF2 (6, 7). Correspondingly, MEKK1 expression plasmids are potent activators of a chimeric c-Jun-GAL4 transcription factor, in which the c-Jun activation domain is fused to the GAL4 DNA binding domain (8 …