Modulation of protein kinase signaling cascades by palytoxin

Abstract

Although known for its acutely toxic action, palytoxin has also been identified as a type of carcinogenic agent called a tumor promoter. In general tumor promoters do not damage DNA, but instead contribute to carcinogenesis by disrupting the regulation of cellular signaling. The identification of palytoxin as a tumor promoter, together with the recognition that the Na(+), K(+)-ATPase is its receptor, led to research on how palytoxin triggers the modulation of signal transduction pathways. This review focuses on mitogen activated protein (MAP) kinases as mediators of palytoxin-stimulated signaling. MAP kinases are a family of serine/threonine kinases that relay a variety of signals to the cellular machinery that regulates cell fate and function. The studies discussed in this review investigated how palytoxin stimulates MAP kinase activity and, in turn, how MAP kinases mediate the response of cells to palytoxin.

Fig. 1

MAP kinases are regulated by protein kinase cascades. The cell receives a signal that stimulates the activation of a MAP kinase kinase kinase (MAPKK kinase). The MAPKK kinase then phosphorylates and activates a MAP kinase kinase (MAPK kinase or MEK). The MAPK kinase then phosphorylates and activates a MAP kinase. The phosphorylated, active MAP kinase can translocate from the cytoplasm to the nucleus and then phosphorylate and activate transcription factors (TF), resulting in changes in gene expression. For example, EGF stimulates the activation of the GTPase Ras. Ras activates Raf (a MAPKK kinase). Raf phosphorylates and activates MEK1/2 (the MAPK kinases MEK1 and MEK2). MEK1/2 phosphorylates and activates ERK1/2 (MAP kinases). ERK1/2 can then translocate from the cytoplasm to the nucleus to phosphorylate transcription factors such as Elk-1, which regulates the expression of c-Fos.

Fig. 2

p38, JNK, and ERK5 are regulated by different protein kinase cascades. Various MAPKK kinases, including MLK3, and TAK, can regulate p38. MEK3 and MEK6 are MAPK kinases that phosphorylate and activate p38 (a MAP kinase). MEKK1 and MEKK4 are among the MAPKK kinases that regulate JNK. MEK4 and MEK7 are MAPK kinases that phosphorylate and activate JNK (a MAP kinase). MEKK2 and MEKK3 are MAPKK kinases that can regulate ERK5. MEK5 is a MAPK kinase that phosphorylates and activates ERK5 (a MAP kinase).

Fig. 3

Palytoxin modulates MAP kinase activity by several mechanisms. (A) Palytoxin stimulates the activation of JNK, p38, and ERK5 through the stimulation of upstream protein kinase cascades. (B) In cells that express oncogenic Ras, palytoxin can increase ERK1/2 activity by stimulating the loss of MKP-3, a dual specificity protein phosphatase that specifically dephosphorylates and inactivates ERK1/2. (C) In Balb/c 3T3 cells, palytoxin stimulates ERK1/2 activation through an autocrine mechanism that involves the production of prostaglandins.

Fig. 4

MAP kinases transmit palytoxin-stimulated signals to the nucleus. The transcription factor AP-1, a dimer made up of Jun and Fos family members, is an important target in tumor promotion. Palytoxin can modulate AP-1 through different mechanisms that involve MAP kinases. Palytoxin can stimulate JNK activation; JNK can directly phosphorylate c-Jun and modulate AP-1 transcriptional activity. Palytoxin can stimulate ERK1/2 and ERK5 activation, which results in an increase in c-Fos gene expression, which in turn can alter the composition and function of AP-1 dimers.