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-ac tivated protein kinase (SAPK) pathway, and the p38 pathway are three m ajor mitogen-activated protein kinase (MAPK) cascades known to partici pate in the regulation of cellular responses to a variety of extracell ular signals. Upstream regulatory components of these kinase cascades, the MAPK/ERK kinase kinases (MEKK), have been described in several sy stems. 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 MEK K3 (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 derivativ e, we furthermore demonstrate that MEKK3 regulates the SAPK and the ER K pathway directly. Consistent with the fact that several SAPK-inducin g agents activate the transcription factor NF kappa B, we now show tha t MEKK3 also enhances transcription from an NF kappa B-dependent repor ter gene in cotransfection assays. The ability of MEKK3 to simultaneou sly activate the SAPK and ERK pathways is remarkable, given that they have divergent roles in cellular homeostasis.