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.
Ellinger-Ziegelbauer
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Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1876, USA.
Brown
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Kelly
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Siebenlist
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D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D004789:Enzyme Activation; D015723:Gene Library; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D051379:Mice; D048291:Mitogen-Activated Protein Kinase 12; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012568:Schizosaccharomyces / Q000201:enzymology; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000201:enzymology; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D011994:Recombinant Proteins; D011494:Protein Kinases; D048291:Mitogen-Activated Protein Kinase 12; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases