The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins

Abstract

Phosphoprotein phosphatases (PPPs) constitute one of three otherwise unrelated families of enzymes that specialize in removing the phosphate group from phosphorylated serine and threonine residues. The involvement of PPP enzymes in the regulation of processes such as gene expression, DNA replication, morphogenesis, synaptic transmission, glycogen metabolism, and apoptosis has underscored their potential as targets for the treatment of a variety of conditions such as cancer, diabetes, or Alzheimer's disease. Interestingly, PPP enzymes also constitute the physiological target of multiple naturally occurring toxins, including microcystins from cyanobacteria and cantharidin from beetles. This review is devoted to the PPP family of enzymes--with a focus on the human PPPs--and the naturally occurring toxins that are known to potently impair their activity. The interaction of the toxins with the enzymes is evaluated in atomic detail to obtain insight on two complementary aspects: (1) which specific structural differences within the similarly folded catalytic core of the PPP enzymes explain their diverse sensitivities to toxin inhibition and (2) which structural features presented by the various toxins account for the differential inhibitory potency towards each PPP. These analyses take advantage of numerous site-directed mutagenesis studies, structure-activity evaluations, and recent crystallographic structures of PPPs bound to different toxins.

Dephosphorylation and inactivation of NPR2 guanylyl cyclase in granulosa cells contributes to the LH-induced decrease in cGMP that causes resumption of meiosis in rat oocytes

“…These results indicate that the activity of PPP family phosphatases is required for the dephosphorylation of NPR2 in response to LH and that dephosphorylation is required for the LH-induced decrease in NPR2 activity. Among the PPP family phosphatases, our results with cantharidin argue against an important function for PPP3 (also known as PP2B or calcineurin) because PPP3 is insensitive to 100 μM cantharidin (Honkanen, 1993;Pereira et al, 2011).…”

“…The rat genome contains 13 PPPfamily genes, encoding seven subfamilies of PPP-family phosphatases (Pereira et al, 2011). We detected mRNA encoding all of these phosphatases, although the fractions of those encoding PPP4, PPP5 and PPP7 were each <2% of the total (Fig.…”

“…These toxin results do not distinguish between other PPP family phosphatases because PPP1, PPP2, PPP4, PPP5 and PPP6 are all inhibited by the concentrations of cantharidin and okadaic acid that we applied to the follicles (Swingle et al, 2007;Pereira et al, 2011). Other toxins with greater specificities for particular PPP-family phosphatases (fostriecin, cytostatin and rubratoxin) were also tested and found to have no consistent effects under the conditions used (data not shown).…”

“…Serine-threonine phosphatases belong to two main families -PPP or PPM ( protein phosphatase Mg 2+ or Mn 2+ dependent); in addition, there is a smaller family (FCP) whose only known function is to dephosphorylate RNA polymerase II (Cohen, 2004;Swingle et al, 2007). Among these, only the PPP family is inhibited by the natural toxins cantharidin and okadaic acid (Swingle et al, 2007;Pereira et al, 2011). PPM family phosphatases (also known as PP2C) are not inhibited by 100 μM cantharidin (Li et al, 1993) or by 10 μM okadaic acid (Wang et al, 1995).…”

Potential Use of Chemoprotectants against the Toxic Effects of Cyanotoxins: A Review

“…With regard to the toxic mechanisms of MCs, they are mainly associated with inhibition of protein phosphatases 1 and 2A (PP1 and PP2A) and disruption of the cellular phosphorylation balance [19,20,21], affecting numerous signaling pathways. MCs can also induce oxidative stress by two primary pathways [22].…”