Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin
tumor because it does not bind to or activate
protein kinase C.
Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect
carcinogenesis. We previously showed that
palytoxin activates three major members of the
mitogen activated protein kinase (MAPK) family,
extracellular signal regulated kinase 1 and 2 (ERK1/2),
c-Jun N-terminal kinase (JNK), and p38. Here we report that
palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major
cell surface receptor for
palytoxin is the Na+,K+-
ATPase. Accordingly,
ouabain blocked the ability of
palytoxin to activate ERK5.
Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-
ATPase.
Cycloheximide,
okadaic acid, and
sodium orthovanadate did not mimic the effect of
palytoxin on ERK5. These results indicate that the stimulation of ERK5 by
palytoxin is not simply due to inhibition of
protein synthesis or inhibition of
serine/
threonine or
tyrosine phosphatases. Therefore, the mechanism by which
palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and
shRNA to block ERK5 action indicate that ERK5 contributes to
palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse
tumor promoter-stimulated signals.