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 protei n kinase C. Previous studies demonstrated that palytoxin stimulates a sodium-dependent signaling pathway that activates the c-Jun NH2-termin al kinase/stress-activated protein kinase (JNK) in Swiss 3T3 fibroblas ts. In this study we show that a JNK kinase known as the stress-activa ted protein kinase/extracellular signal-regulated kinase-1 (SEK1) play s an important role in the regulation of JNK by palytoxin. We found th at palytoxin stimulates the sustained activation of both JNK and SEK1 in COS7 and HeLa cells. Transiently expressed SEK1 isolated from palyt oxin-treated cells can phosphorylate and activate JNK, which, in turn, can phosphorylate c-Jun, Furthermore, expression of a dominant negati ve mutant of SEK1 blocks activation of JNK by palytoxin, Sodium appear s to play an important role in the regulation of JNK and SEK1 by palyt oxin. Activation of JNK and SEK1 by palytoxin, but not anisomycin, req uires extracellular sodium, Complementary studies showed that the sodi um ionophore gramicidin can mimic palytoxin by regulating JNK and SEK1 through a sodium-dependent mechanism. Collectively, these results dem onstrate that palytoxin stimulates a sodium-dependent signaling pathwa y that activates the SEK1/JNK/c-Jun protein kinase cascade.