Protein phosphatase 1 complexes modulate sperm motility and present novel targets for male infertility

Infertility is a growing concern in modern society, with 30% of cases being due to male factors, namely reduced sperm concentration, decreased motility and abnormal morphology. Sperm cells are highly compartmentalized, almost devoid of transcription and translation consequently processes such as protein phosphorylation provide a key general mechanism for regulating vital cellular functions, more so than for undifferentiated cells. Reversible protein phosphorylation is the principal mechanism regulating most physiological processes in eukaryotic cells. To date, hundreds of protein kinases have been identified, but significantly fewer phosphatases (PPs) are responsible for counteracting their action. This discrepancy can be explained in part by the mechanism used to control phosphatase activity, which is based on regulatory interacting proteins. This is particularly true for PP1, a major serine/threonine-PP, for which >200 interactors (PP1 interacting proteins-PIPs) have been indentified that control its activity, subcellular location and substrate specificity. For PP1, several isoforms have been described, among them PP1γ2, a testis/sperm-enriched PP1 isoform. Recent findings support our hypothesis that PP1γ2 is involved in the regulation of sperm motility. This review summarizes the known sperm-specific PP1-PIPs, involved in the acquisition of mammalian sperm motility. The complexes that PP1 routinely forms with different proteins are addressed and the role of PP1/A-kinase anchoring protein complexes in sperm motility is considered. Furthermore, the potential relevance of targeting PP1-PIPs complexes to infertility diagnostics and therapeutics as well as to male contraception is also discussed.