Abstract
Polo-like kinases are important regulators of cell cycle progression and mitosis. They constitute a family of conserved serine/threonine kinases which are highly related in their catalytic domains and contain polo boxes involved in protein-protein interactions and subcellular localization. In mammals, five Plks (Plk 1-5) encompass diverse roles in centrosome dynamics, spindle formation, intra S-phase and G2/M checkpoints and DNA damage response. Plk1 is a key positive regulator of mitosis and is overexpressed in various types of cancers. Plk4 is a divergent member of the Plk family, with essential functions in centriole duplication. Homozygous disruption of Plk1 or Plk4 in mice is lethal in embryos. Two Plk members SmPlk1 and SmSak, homologous to Plk1 and Plk4 respectively, are present in the parasitic platyhelminth Schistosoma mansoni. Structural and functional analyses of SmPlk1 have demonstrated its conserved function in the regulation of cell cycle G2/M transition in Xenopus oocytes. The anti-cancer drug BI 2536 (the most potent and selective Plk1 inhibitor) inhibits specifically the catalytic activity of SmPlk1 and induced profound alterations in schistosome gonads, indicating a role of SmPlk1 in parasite gametogenesis and its potential as a novel chemotherapeutic target against schistosomiasis. Functions of SmSak in cell cycle regulation and schistosome gonad development are currently investigated.
Highlights
SCHISTOSOME BIOLOGY AND PROTEIN KINASESMating and sexual maturation of adult male and female worms of S. mansoni in the human host lead to the production of numerous eggs which are responsible for transmission, and for the pathology of schistosomiasis
Polo-like kinases are important regulators of cell cycle progression and mitosis
Mating and sexual maturation of adult male and female worms of S. mansoni in the human host lead to the production of numerous eggs which are responsible for transmission, and for the pathology of schistosomiasis
Summary
Mating and sexual maturation of adult male and female worms of S. mansoni in the human host lead to the production of numerous eggs which are responsible for transmission, and for the pathology of schistosomiasis. Further data showed that a dead kinase version of SmPlk (SmPlk1DK) completely inhibited GVBD induced by progesterone in normal oocytes, indicating that it could block as a negative dominant mutant the endogenous Plx activity during mitotic signalling Very likely this inhibition was due to the conserved polo-box motifs present in the inactive kinase SmPlk1DK that assure its adequate subcellular localization, and as a consequence its competition with Plx for specific partners. These results have demonstrated the conserved function and activity of SmPlk, which is able both to recognize the same partners as Plx in the oocyte and to undergo a conserved mechanism of activation requiring its phosphorylation of the residue T182 (Long et al 2010). This result confirmed the high selectivity of the inhibitor BI 2536 for Plk proteins (Steegmaier et al 2007)
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