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Abbreviations: PPs: Protein serine=threonine phosphatases, PP1: Protein phosphatase 1, PIPs: PP1 interacting proteins, cAMP: Cyclic adenosine monophosphate, AKAP: A kinase anchor protein, CAMKII: Calmodulin kinase II, cdKs: Cyclin-dependent kinases, PKA: Protein kinase A, NLS: Nuclear localization signals, NTS: Nucleolar targeting signals, FSH: Follicular stimulating hormone, Spz1: Spermatogenic zip protein 1, GSK: Glycogen synthase kinase 3, DNA: Deoxyribonucleic acid, SARP: Several ankyrin repeat protein, ACE: Angiotensin-converting enzyme, Tesk: Testis-specific protein kinase, ADF: Actin-depolymerizing factor, MOs: Membranous organelles, ATP: Adenosin triphosphate Received 31 December 2006; accepted 26 February 2007. Address correspondence to Yibing Han, Ph.D., Department of Obstetrics and Gynecology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, SAR, China. E-mail: ybhan@cuhk.edu.hk
Mammalian spermatozoa acquire the capacity for motility and fertilization during the transit through the epididymis under the control of different factors, such as cAMP, intracellular pH, intracellular calcium and phosphorylation of sperm proteins. As the acquisition of functional competence including gaining motility during epididymal transit occurs in the complete absence of contemporaneous gene transcription and translation on the part of the spermatozoa, it is widely accepted that post-translational modifications are the only means by which spermatozoa can acquire functionality. Serine-threonine protein phosphatase 1 (PP1) together with their testis= sperm-specific interacting proteins might be involved in this regulatory mechanism. PP1a, PP1b=d, PP1c1 and PP1c2 are all expressed in the testis whereas PP1c2 is the only isoform expressed on spermatozoa. I2, I3, sds22, 14-3-3 and hsp90 are associated with PP1c2 in spermatozoa located on the sperm head and tail. Activity of PP1c2 and the binding pattern to these regulatory proteins changes in spermatozoa recruited from the caput and those from the cauda part of the epididymis. In this review, we summarize the possible roles of PP1 on spermatozoa during spermatogenesis and flagellar motility control. We suggest that PP1 might take part in the inhibition of the sperm motility activation by interacting with AKAPs and CAMKII. A hypothesized signaling pathway of mammalian sperm motility activation and PP1s function has been proposed.
KEYWORDS motility activation, serine=threonine protein phosphatase, sperm, spermatogenesis
INTRODUCTION
Phosphorylation of proteins is a post-translational modification event that acts as one of the cells regulatory mechanisms to control various processes. Given that up to 30% of proteins undergone reversible phosphorylation in eukaryotic cells, it is estimated that protein phosphorylation may influence almost all stages of sperm development in the testis and the epididymis,
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from meiotic division to sperm maturation. In eukaryotic cells, one of the most common mechanisms for regulating protein activity is the addition and=or removal of phosphate groups from serine, threonine or tyrosine residues of protein moieties. Addition or removal of phosphate can induce allosteric modifications resulting in conformational changes in proteins leading either to their activation or inactivation. These processes are regulated by both protein kinases and protein phosphatases. In contrast to protein kinases that add a phosphate group to the hydroxyl group of serine, threonine or tyrosine residues, phosphatases remove it. In mammalian spermatozoa, the ability to actively swim is acquired during the transit through the epididymis under the control of different factors, such as cAMP, intracellular pH, intracellular calcium and phosphorylation of sperm proteins. As the acquisition of functional competence including gaining motility during epididymal transit occurs in the complete absence of contemporaneous gene transcription and translation on the part of the spermatozoa, it is widely accepted that post-translational modifications are the only means by which spermatozoa can become competent.
by dephosphorylation of key regulatory proteins [Cohen 2002; Bollen 2001; Ceulemans et al. 2002; Ceulemans and Bollen, 2004). All PP1s contain a Thr-Pro-Pro-Arg (TPPR) amino acid sequence segment at their carboxyl terminal, which is a consensus sequence for phosphorylation by cyclin-dependent kinases (Cdks). Phosphorylation of PP1 by Cdk1 and Cdk2 in somatic cells reduces the catalytic activity of this enzyme [Cohen 2002; Dohadwala et al. 1994; Kwon et al. 1997; Liu et al. 1999]. PP1s do not exist freely in the cell but are associated with a large variety of polypeptides that determine when and where PP1 acts. These PIPs (also called regulatory subunits) function as activity-modulators, targeting subunits and=or substrates. Hormones, growth factors and metabolites control the function of the PP1 holoenzymes mainly by modulating the interaction of the subunits. The available information suggests that these PIPs interact with PP1 via multiple, short-sequence motifs. The PIPs are structurally quite different, but almost all have a consensus binding motif (RK)-x0-1(VI)-{P}-(FW), where x denotes any residue and {P} any residue except Pro, and it is often called simply the RVxF-motif. The RVxF-motif binds to a hydrophobic channel near the C-terminus of PP1. The binding of the RVxF-motif not only has a PP1 anchoring function but also promotes the interaction of secondary, lower-affinity binding sites, often resulting in an altered activity and=or substrate specificity of PP1. The F-x-x-(RK)-x-(RK) motif represents a new consensus sequence for the recognition and binding of some Bcl-2 proteins to PP1 [Ayllon et al. 2002]. Currently, about 70 mammalian genes coding for more than 60 PIPs have been identified [GarciaGimeno et al. 2003]. Given there are approximately 10,000 phosphoproteins in mammals, many PIPs remain to be discovered. PIPs can be classified into mainly 8 categories of: glycogen metabolism, myofibriella, nuclear, endoplasmic-ribosomal, plasma membrane=cytoskeleton centrosome=microtubule, apoptosis and specific substrates and inhibitors. In addition to inhibitor-1 (I1) and inhibitor-2 (I2) representing two different ways of inhibiting PP1 phosphatase activity, there are also other protein phosphatase inhibitors without a clear mechanism [Garcia-Gimeno et al. 2003; Zhang et al. 1998;
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Hrabchak and Varmuza 2004; Mishra et al. 2003; Vijayaraghavan et al. 1996; Smith et al. 1996]. I1 activity is regulated by cAMP-dependent phosphorylation of a single threonine residue by protein kinase A (PKA) and by calcium=calmodulin-dependent dephosphorylation of the same residue [Shenolikar and Nairn 1991; Cohen 1989]. I2 binds to the catalytic subunit of PP1 to form an inactive cytoplasmic form of the enzyme (PP1I2) that can be converted to active PP1 by phosphorylation of the bound I2 by glycogen synthase kinase-3 [Bollen and Stalmans 1992; Cohen 1989; Hemmings et al. 1982]. In spermatozoa of mice, a novel PP1 inhibitor 3 (I3) containing both the RVxF-motif, nuclear localization signals (NLS) and nuclear targeting signals (NTS) has been discovered [Huang et al. 2005a; Han et al. 2007]. I1, I2 and I3 are heat-stable proteins all enriched in proline [Zhang et al. 1998]. It has been shown that PP1s nuclear translocation and nuclear retention depend on binding to RVxF-motif interactors [Lesage et al. 2004]. The PP1 nuclear interactors include PNUTS, Sds22, NIPP and SIPP1 that have both the RVxF-motif and NLS.
diffuse pool and in a few as-yet-unidentified foci [Twinkle-Mulcahy et al. 2006]. In addition to the nucleus, PP1 is also found within the axoneme. PP1c is anchored in the central pair apparatus of the axoneme in Chlamydomonas flagellar [Yang et al. 2000]. Ciliary and flagellar motility is controlled by phosphorylation [Brokaw 1987; Satir et al. 1993; Tash and Bracho 1994]. PP1 may be involved in the regulation of flagellar motility together with protein kinases [San Agustin and Witman 1994; Chaudhry et al. 1995]. Recently, PP1 was found to be involved in regulating the acquisition of motility [Huang et al. 2004; Huang et al. 2004b; Huang et al. 2005b].
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disrupted giving rise to polyploid spermatids. Interestingly, histones remain complexed with spermatid chromatin beyond when they are normally removed and replaced by protamines. Normal staging is disrupted in PP1 mutants. Some cell types are reduced in number, but none are absolutely missing [Varmuza et al. 1999]. A chimeric testis with wild type of Sertoli cells and PP1c= spermatids revealed intermediate phenotypes when compared with PP1c= . They did not sire pups derived from mutant germ cells, suggesting that expression of PP1c2 genes may be restricted to the spermatozoon [Oppedisano-Wells and Varmuza 2003]. Spermatogenic zip protein 1 (Spz1) has been identified as binding to the PP1c2 splice variant in the mouse testis [Hrabchak and Varmuza 2004]. Spz1 was a member of the basic helix-loop-helix family of transcription factors. Overexpression of spz1 and loss of PP1 c in the testis show similar phenotypes such as spermatogenic arrest and germ cell apoptosis [Hsu et al. 2004].
motility of spermatozoa increase. Three pools of PP1c2 in caudal and caput epididymal spermatozoa are found. The caput pool includes the active form of PP1c2, phosphorylated and an active form of 14-3-3 binding PP1 c2 and the inactive form of hsp90 binding PP1 c2. The cauda pool includes the inactive form of sds22 binding PP1c2 [Mishra et al. 2003], phosphorylated and an active form of 14-3-3 binding PP1c2 and an inactive form of hsp90 binding PP1c2 [Huang et al. 2004a,b]. PP1c2 is inactivated by binding to sds22 and hsp90 while PP1c2 is activated and phosphorylated by binding to 14-3-3 protein [Huang et al. 2004a; Huang et al. 2002]. Sds22 is a mammalian homologue of yeast PP1 binding protein [Huang et al. 2002] belonging to a family of proteins that contain repeats of leucine-rich 22 amino acid segment. The 14-3-3 proteins belong to a family of abundant and widely expressed 2833 kDa acidic polypeptides that spontaneously self-assemble as dimmers. The 14-3-3 proteins bind to phosphoserine= threonine containing motifs in a sequencespecific manner [Yaffe and Elia 2001; Aitken et al. 1992; Tzivion and Avruch 2002]. The Hsp90 is a highly conserved ATP-dependent chaperone [Richter and Buchner 2001] and this protein is subject to tyrosine-phosphorylation during sperm capacitation in mice, rats and humans (Ecroyd et al. 2003). Cytosolic PP1 and GSK-3 activities appear to be inversely related to the motility of monkey epididymal sperm [Smith et al. 1996]. Higher concentration of GSK-3 and PP1 are present in immotile bovine caput epididymal sperm compated with motile cauda epididymal sperm, and may control motility [Vijayaraghavan et al. 1996; Miki et al. 2004; Somanath et al. 2004].
Some Other Estimated PIPs from Database Expressed in the Testis and/or Spermatozoa
As mentioned above, two distinct docking consensus motifs (RK)-x0-1-(VI)-{P}-(FW) and F-x-x-(RK)-x(RK) have been identified in PIPs. The PIPs database at http://pp1signature.pasteur.fr/ includes all discovered proteins containing the two motifs. These include transcription factors, transport proteins as well as kinases. A putative transcription factor or DNA-associated protein called SARP (several ankyrin repeat protein) has been identified as a PIP. SARP has 3 splice
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variants, SARP1, SARP2 and SARP3. SARP1 and=or SARP2 are expressed at high levels in testis and spermatozoa, where they are shown to interact with both PP1c1 and PP1c2. SARP is highly abundant in the nucleus of mammalian cells, consistent with the putative nuclear localization signal at the N-terminus. The presence of a lucine zipper near the C-terminus of SARP1 and SARP2, and the binding of mammalian DNA to SARP2, suggests that SARP1 and SARP2 may be transcription factors or DNA-associated proteins that modulate gene expression [Browne et al. 2007]. Angiotensin-converting enzyme (ACE) is a zinccontaining dipeptidyl carboxypeptidase widely distributed in mammalian tissues and is thought to play a critical role in blood pressure regulation. Testis contain a unique androgen-dependent ACE isozyme, ACE-T, that is initially found in post-meiotic step 3 spermatids and then increases markedly during differentiation. ACE-T is strictly confined to the adluminal membrane face of elongating spermatids and localizing to the neck and midpiece region of released and ejaculated spermatozoa [Pauls et al. 2003]. Male mice homozygous for a disrupted ACE gene are almost infertile, despite showing normal mating behavior, testis histology and sperm parameters Reduced oviduct transport and zona pellucida binding of spermatozoa is observed [Krege et al. 1995; Hagaman et al. 1998]. It is estimated that the unique N-terminal of ACE-T bearing specific binding properties for an oviduct=ovum substrate may yield male sterility [Kessler et al. 2000]. Another putative PIP is testis-specific protein kinase (Tesk) 2 which is a member of the Tesk family with 48% amino acid identity with Tesk1. Tesk2, is predominantly expressed in the nucleus of Sertoli cells. It phosphorylates cofilin=ADF (actindepolymerizing factor) at Ser3 that induces actin reorganization. Since actin-depolymerizing and actin-severing activities of cofilin=ADF are abrogated by phosphorylation at Ser3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin=ADF activity [Toshima et al. 2001]. Fer-1, first discovered in Caenorhabditis elegans is another putative PIP that is mainly expressed in spermatocytes. It is prevalent when membranous organelles (MOs) fuse with the spermatid plasma membrane. Resembling some viral fusion proteins, fer-1 may play a direct role in MO-plasma membrane fusion [Achanzar and Ward 1997].
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and high protein phosphatase activities most likely limit motility in immature spermatozoa. In a number of species, development of sperm motility in the epididymis is associated with increased intrasperm cAMP [Amann et al. 1982; Brandt and Hoskins 1980], associated with decreased glycogen synthase kinase-3 and protein phosphatase 1 activity [Vijayaraghavan et al. 1996]. It is noted that the control factors of phosphatase to sperm motility might be confined to the axoneme [Habermacher and Sale 1996]. This is supported by the observation of the gain of motility after the addition of protein phosphatase 1 inhibitors to demembraned fowl spermatozoa [Ashizawa et al. 1994]. AKAPs [A Kinase Anchor Protein, cAMP-dependent protein kinase anchoring proteins, Miki and Eddy 1998] are the candidate target of PP1 in sperm flagella. AKAPs assemble multi-enzyme signaling complexes in proximity to substrate effector proteins, thus directing and amplifying membranegenerated signals. They form a transduceosome, an autonomous multivalent scaffold that assembles and integrates signals derived from multiple pathways. The AKAP family shares little overall primary sequence similarity excluding their functional domains including the targeting domain (as a scaffold and membrane anchor) and the amphipathic helical tethering domain (binding to regulatory subunits) that are highly conserved. In addition to binding to cAMP-dependent protein kinases such as protein kinase A, some AKAPs associate with protein kinase C and Ser=Thr phosphates. It has been shown that the amino terminus of AKAP121, a potential PIP, interacts with mitochondrial membranes and with tubulin. Tubulin, a heterodimer composed of two similar acidic isoforms (a and b) participates in the organization of eukaryotic microtubule networks. AKAP=PKA or AKAP=PP1 complexes anchored to spindles might regulate the dynamic assembly of microtubules by creating target sites of cAMP action [Cardone et al. 2002]. In contrast to AKAP121, the candidacy of AKAP4 as PIP is additionally experimentally supported. AKAP4 is the major fibrous sheath protein located in the principal piece of spermatozoa. It serves as a scaffold for proteins in signaling pathways involved in sperm maturation, motility, capacitation, hyperactivation and glycolysis. In the principal piece, the fibrous sheath replaces the
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mitochondria sheath. Outer dense fibers 3 and 8 are also substituted by the two longitudinal columns of the fibrous sheath. AKAP4 recruits PKA to the fibrous sheath and facilitates local phosphorylation to regulate flagellum function. Spermatozoa from AKAP4= mice lack motility and are infertile [Miki et al. 2002]. PP1 activity is decreased in the AKAP4= mice and might indicate the functional linkage between PP1 and AKAP4 [Huang et al. 2005b].
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FIGURE 1 cAMP produced by adenylyl cyclase from ATP stimulates the activity of PKA. AKAPs then link the active PKA to both the microtubules of the spermatozoa flagella and the membrane of the mitochondria. PKA, now in the proximity of the flagella, then stimulates the microtubule local factors like dynein ATPase by creating target sites of cAMP and/or other unknown functions and makes the microtubules conditioned with the ability to respond to Ca2 calmodulin stimulation. AKAPs linked to the mitochondria membrane might stimulate production of more ATP. PP1 is involved in this pathway by interacting with AKAPs. We hypothesize that the binding of PP1 to the AKAPs might competitively inhibit their binding to PKA. Before binding to AKAPs, the microtubules are not sensitive to stimulating signals in the absence of key factors. In contrast, the Ca2 CamKII complex could initiate the motility of the conditioned microtubules by immediately activating dynein ATPase. Motility is maintained by the continuous consumption of ATP. PP1 could dephosphorylate and inactivate the CAMKII at Thr286. In both pathways, a decrease in the concentration of PP1 would favor the activation of sperm motility.
first step, motionless spermatozoa in the caput of the epididymis need to be conditioned through the AKAP signal transduction pathway which prepares the microtubules of the spermatozoa to a ready state for motility activation. In the second step, motility of the conditioned spermatozoa is then triggered by Ca2 -CAMKII signal transduction pathway with a functional dynein ATPase. PP1s are involved in the two signal transduction pathways by interacting with AKAPs and regulating activity of CAMKII, respectively.
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ACKNOWLEDGMENT
This work was supported by a direct grant of the Chinese University of Hong Kong c001-2041219.
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