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.
Protein phosphorylation is a major regulatory mechanism of signal transduction cascades in eukaryotic cells, catalysed by kinases and reversed by protein phosphatases (PPs). Sequencing of entire genomes has revealed that ~3% of all eukaryotic genes encode kinases or PPs. Surprisingly, there appear to be 2-5 times fewer PPs than kinases. Over the past two decades it has become apparent that the diversity of Ser/Thr-specific PPs (STPP) was achieved not only by the evolution of new catalytic subunits, but also by the ability of a single catalytic subunit to interact with multiple interacting proteins. PP1, a STPP, is involved in the control of important cellular mechanisms. Several isoforms of PP1 are known in mammals: PP1α, PP1β and PP1γ. The various isoforms are highly similar, except for the N- and C-termini. The current view is that since PPs possess exquisite specificities in vivo, the key control mechanism must reside in the nature of the PP1 Interacting Protein (PIP) to which they bind. An increasing number of PIPs have been identified that are responsible for regulating the catalytic activity of PPs. Indeed, the diversity of such PIPs explains the need for relatively few catalytic subunit types, and makes them attractive targets for pharmacological intervention. This review will summarize the PIPs identified using the Yeast Two Hybrid methodology and alternative techniques, for instance bioinformatic and proteomic approaches. Further, it compiles 129 PP1-PIP relevant physiological interactions that are well documented in the literature. Finally, the use of PIPs as therapeutic targets will be addressed.
Protein Phosphatase 1 (PP1) is a major serine/threonine-phosphatase whose activity is dependent on its binding to regulatory subunits known as PP1 interacting proteins (PIPs), responsible for targeting PP1 to a specific cellular location, specifying its substrate or regulating its action. Today, more than 200 PIPs have been described involving PP1 in panoply of cellular mechanisms. Moreover, several PIPs have been identified that are tissue and event specific. In addition, the diversity of PP1/PIP complexes can further be achieved by the existence of several PP1 isoforms that can bind preferentially to a certain PIP. Thus, PP1/PIP complexes are highly specific for a particular function in the cell, and as such, they are excellent pharmacological targets. Hence, an in-depth survey was taken to identify specific PP1a PIPs in human brain by a high-throughput Yeast Two-Hybrid approach. Sixty-six proteins were recognized to bind PP1a, 39 being novel PIPs. A large protein interaction databases search was also performed to integrate with the results of the PP1a Human Brain Yeast Two-Hybrid and a total of 246 interactions were retrieved.
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