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

Abstract

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.

Hybrid sterility and evolution in Hawaiian Drosophila: differential gene and allele-specific expression analysis of backcross males

“…CG31467 was the top DE gene and plays a role in phosphatase binding and is expressed moderately in the adult testis of D. melanogaster (FlyBase). Protein phosphatases have been known to modulate sperm motility in mammals (Fardilha et al, 2011), and a gene encoding acylphosphatase (Acyp) has been found to be associated with HMS in F 1 and backcross hybrids between D. simulans and D. mauritiana (Michalak and Ma, 2008;Michalak and Noor, 2004). Octbeta3R is homologous to β-adrenergic receptors in vertebrates that play multifunctional roles in insects, and is an octopamine (Farooqui, 2012).…”

PPP1CC2 can form a kinase/phosphatase complex with the testis-specific proteins TSSK1 and TSKS in the mouse testis

“…Moreover, the phosphorylation of the RVxF motif inhibits binding of PPP1CC2. This indicates the involvement of another protein phosphatase in the regulation of this interaction, the identity of which remains unknown, although a number of other nontype 1 protein phosphatases are known to be expressed in the testis (Fardilha et al 2011). Similarly, the kinase responsible for this phosphorylation remains in question.…”

Protein Phosphatase 1α Interacting Proteins in the Human Brain

“…Three genes are known to encode PP1 catalytic subunits, termed PP1a, PP1b, and PP1c, with diversity increased by alternative splicing (da Cruz e Silva et al, 1995b). PP1 regulates a variety of cellular events through the dephosphorylation of multiple substrates and its multifunctionality is due to its association with different regulators and/or targeting subunits (Bollen, 2001;Ceulemans and Bollen, 2004;Fardilha et al, 2010Fardilha et al, , 2011a known as PP1 Interacting Proteins (PIPs). The PP1 isoforms are highly conserved across their large catalytic domain, but are divergent at the N and C termini.…”

“…To exert their dephosphorylation reactions that are important in time and space, the diverse functions of PP1 must be independently regulated. For this reason, PIPs are believed to be much more specific for individual functions and are therefore better targets for specific pathways (Ceulemans and Bollen, 2004;Cohen, 2002;Fardilha et al, 2010Fardilha et al, , 2011aVirshup and Shenolikar, 2009).…”

“…These PIPs function as inhibitors, substrate specifiers, and substrate targeting proteins, or a combination thereof. Sometimes PP1 interactors are themselves substrates for associated PP1 (Bollen, 2001;Ceulemans and Bollen, 2004;Fardilha et al, 2010Fardilha et al, , 2011a. Given the number of protein phosphatases and phosphoprotein substrates encoded in the human genome, a large number of PIPs surely remain to be discovered.…”