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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Direct activation of the stress-activated protein kinase ( SAPK) and extracellular signal- regulated protein kinase ( ERK) pathways by an inducible mitogen-activated protein Kinase/ ERK kinase kinase 3 ( MEKK) derivative.

The extracellular signal-regulated kinase ( ERK) pathway, the stress-activated protein kinase ( SAPK) pathway, and the p38 pathway are three major mitogen-activated protein kinase ( MAPK) cascades known to participate in the regulation of cellular responses to a variety of extracellular signals. Upstream regulatory components of these kinase cascades, the MAPK/ERK kinase kinases ( MEKK), have been described in several systems. We have isolated a cDNA encoding human MEKK3. Transfected MEKK3 has the ability to activate both SAPK and ERK pathways, but does not induce p38 activity, in agreement with a previous report on murine MEKK3 (Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., and Johnson, G. L. (1996) J. Biol. Chem. 271, 5361-5368). We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. Utilizing an estrogen ligand-activated MEKK3 derivative, we furthermore demonstrate that MEKK3 regulates the SAPK and the ERK pathway directly. Consistent with the fact that several SAPK-inducing agents activate the transcription factor NFkappaB, we now show that MEKK3 also enhances transcription from an NFkappaB-dependent reporter gene in cotransfection assays. The ability of MEKK3 to simultaneously activate the SAPK and ERK pathways is remarkable, given that they have divergent roles in cellular homeostasis.[1]


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