Regulation of a c-Jun amino-terminal kinase/stress-activated protein kinase cascade by a sodium-dependent signal transduction pathway.
Palytoxin is a novel skin tumor promoter that does not activate protein kinase C. Previous studies demonstrated that palytoxin stimulates a sodium-dependent signaling pathway that activates the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK) in Swiss 3T3 fibroblasts. In this study we show that a JNK kinase known as the stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1) plays an important role in the regulation of JNK by palytoxin. We found that palytoxin stimulates the sustained activation of both JNK and SEK1 in COS7 and HeLa cells. Transiently expressed SEK1 isolated from palytoxin-treated cells can phosphorylate and activate JNK, which, in turn, can phosphorylate c-Jun. Furthermore, expression of a dominant negative mutant of SEK1 blocks activation of JNK by palytoxin. Sodium appears to play an important role in the regulation of JNK and SEK1 by palytoxin. Activation of JNK and SEK1 by palytoxin, but not anisomycin, requires extracellular sodium. Complementary studies showed that the sodium ionophore gramicidin can mimic palytoxin by regulating JNK and SEK1 through a sodium-dependent mechanism. Collectively, these results demonstrate that palytoxin stimulates a sodium-dependent signaling pathway that activates the SEK1/JNK/c-Jun protein kinase cascade.
Kuroki
D W
DW
Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Minden
A
A
Sánchez
I
I
Wattenberg
E V
EV
D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003064:Cnidarian Venoms; D004789:Enzyme Activation; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D000095702:Polyether Toxins
D000178:Acrylamides; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003064:Cnidarian Venoms; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D012964:Sodium; C482559:MAP2K4 protein, human; C010272:palytoxin; D000095702:Polyether Toxins