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/
H. Ellingerziegelbauer et al., 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 Journal of biological chemistry, 272(5), 1997, pp. 2668-2674
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.