PP1γ2 and PPP1R11 Are Parts of a Multimeric Complex in Developing Testicular Germ Cells in which their Steady State Levels Are Reciprocally Related

Cheng, Lina; Pilder, Stephen H.; Nairn, Angus C.; Ramdas, Shandilya; Vijayaraghavan, Srinivasan

doi:10.1371/journal.pone.0004861

Cited by 28 publications

(44 citation statements)

References 39 publications

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“…However protein phosphatase activity is higher in sperm lacking GSK3A compared to WT sperm. It is possible that PP1 regulators other than I-2, PPP1R11 (I-3) and PPP1R11 (sds22), known to be present in sperm [45,46], may be activated/inactivated in the absence of GSK3A. The ability of I-3 and sds22 to bind and inhibit PP1 gamma2 (PPP1CC2) may depend on an inhibitory or activating phosphorylation effected by GSK3A along with yet another protein kinase such as PKA.…”

Section: Discussionmentioning

confidence: 99%

Targeted Disruption of Glycogen Synthase Kinase 3a (Gsk3a) in Mice Affects Sperm Motility Resulting in Male Infertility1

Bhattacharjee

Goswami

Dudiki

et al. 2015

Biology of Reproduction

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The signaling enzyme glycogen synthase kinase 3 (GSK3) exists as two isoforms-GSK3A and GSK3B. Protein phosphorylation by GSK3 has important signaling roles in several cells. In our past work, we found that both isoforms of GSK3 are present in mouse sperm and that catalytic GSK3 activity correlates with motility of sperm from several species. Here, we examined the role of Gsk3a in male fertility using a targeted gene knockout (KO) approach. The mutant mice are viable, but have a male infertility phenotype, while female fertility is unaffected. Testis weights of Gsk3a(-/-) mice are normal and sperm are produced in normal numbers. Although spermatogenesis is apparently unimpaired, sperm motility parameters in vitro are impaired. In addition, the flagellar waveform appears abnormal, characterized by low amplitude of flagellar beat. Sperm ATP levels were lower in Gsk3a(-/-) mice compared to wild-type animals. Protein phosphatase PP1 gamma2 protein levels were unaltered, but its catalytic activity was elevated in KO sperm. Remarkably, tyrosine phosphorylation of hexokinase and capacitation-associated changes in tyrosine phosphorylation of proteins are absent or significantly lower in Gsk3a(-/-) sperm. The GSK3B isoform was present and unaltered in testis and sperm of Gsk3a(-/-) mice, showing the inability of GSK3B to substitute for GSK3A in this context. Our studies show that sperm GSK3A is essential for male fertility. In addition, the GSK3A isoform, with its highly conserved glycine-rich N terminus in mammals, may have an isoform-specific role in its requirement for normal sperm motility and fertility.

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Section: Discussionmentioning

confidence: 99%

Targeted Disruption of Glycogen Synthase Kinase 3a (Gsk3a) in Mice Affects Sperm Motility Resulting in Male Infertility1

Bhattacharjee

Goswami

Dudiki

et al. 2015

Biology of Reproduction

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“…This residue also appears to be phosphorylated in mouse sperm (53). Phosphatases PP1␥2 and PP2A neither co-localize (53) nor co-elute in chromatographically purified sperm protein fractions (54), suggesting the existence of distinct phosphatase pools with presumably different roles. The possibility that PP2A is inactivated during capacitation warrants more investigation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ser/Thr Phosphatases Induces Capacitation-associated Signaling in the Presence of Src Kinase Inhibitors

Krapf

Arcelay

Wertheimer

et al. 2010

Journal of Biological Chemistry

137

154

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Signaling events leading to mammalian sperm capacitation rely on activation/deactivation of proteins by phosphorylation. This cascade includes soluble adenylyl cyclase, an atypical bicarbonate-stimulated adenylyl cyclase, and is mediated by protein kinase A and the subsequent stimulation of protein tyrosine phosphorylation. Recently, it has been proposed that the capacitation-associated increase in tyrosine phosphorylation is governed by Src tyrosine kinase activity. This conclusion was based mostly on the observation that Src is present in sperm and that the Src kinase family inhibitor SU6656 blocked the capacitation-associated increase in tyrosine phosphorylation. Results in the present manuscript confirmed these observations and provided evidence that these inhibitors were also able to inhibit protein kinase A phosphorylation, sperm motility, and in vitro fertilization. However, the block of capacitation-associated parameters was overcome when sperm were incubated in the presence of Ser/Thr phosphatase inhibitors such as okadaic acid and calyculin-A at concentrations reported to affect only PP2A. Altogether, these data indicate that Src is not directly involved in the observed increase in tyrosine phosphorylation. More importantly, this work presents strong evidence that capacitation is regulated by two parallel pathways. One of them requiring activation of protein kinase A and the second one involving inactivation of Ser/Thr phosphatases.The capacitation process is the major prerequisite for mammalian sperm to fertilize. This highly complex phenomenon occurs in the female reproductive tract, and renders the spermatozoa capable of binding and fusing with the oocyte (1). The commonly accepted end point of capacitation is the time when sperm have obtained the ability to fertilize an egg. However, different physiological modifications of sperm have been correlated with the capacitated state. These include: cholesterol loss from the sperm plasma membrane, increased membrane fluidity, changes in intracellular ion concentrations (2), hyperpolarization of the sperm plasma membrane (3), and increased protein tyrosine phosphorylation (4).Among ion fluxes that occur during capacitation, the transport of HCO 3 Ϫ into sperm promotes cAMP synthesis by the activation of an atypical soluble adenylyl cyclase (SACY) 2 (5) and subsequent PKA activation. cAMP-dependent phosphorylation of Ser/Thr residues is known to be a key regulator of tyrosine phosphorylation events linked to the process of capacitation. In mouse sperm exposed to HCO 3 Ϫ , cAMP rises to a maximum in Ͻ60 s, followed immediately by an increase in PKA-dependent phosphorylation (2). However, tyrosine phosphorylation is only observed after incubations for at least 30 min in conditions conducive to capacitation (6). Despite the lack of temporal correlation of PKA-induced phosphorylation and the increase in tyrosine phosphorylation, it has been shown that PKA inhibition blocks the onset of tyrosine phosphorylation (7). The one or more tyrosine kinases responsible f...

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“…There appears to be a direct reciprocal relationship between levels of PP1g2 and its regulator PPP1R11 [ID: T3-488]. It is suggested that the complex formed by these polypeptides may prevent proteolysis of PPP1R11 and hence germ cell apoptosis (Cheng et al, 2009).…”

Section: Basic-loop-helixmentioning

confidence: 99%

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: Intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage‐gated channels, methylation/acetylation, and transcription factors

Hermo

Pelletier

Cyr

et al. 2009

Microscopy Res & Technique

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As germ cells divide and differentiate from spermatogonia to spermatozoa, they share a number of structural and functional features that are common to all generations of germ cells and these features are discussed herein. Germ cells are linked to one another by large intercellular bridges which serve to move molecules and even large organelles from the cytoplasm of one cell to another. Mitochondria take on different shapes and features and topographical arrangements to accommodate their specific needs during spermatogenesis. The nuclear envelope and pore complex also undergo extensive modifications concomitant with the development of germ cell generations. Apoptosis is an event that is normally triggered by germ cells and involves many proteins. It occurs to limit the germ cell pool and acts as a quality control mechanism. The ubiquitin pathway comprises enzymes that ubiquitinate as well as deubiquitinate target proteins and this pathway is present and functional in germ cells. Germ cells express many proteins involved in water balance and pH control as well as voltage-gated ion channel movement. In the nucleus, proteins undergo epigenetic modifications which include methylation, acetylation, and phosphorylation, with each of these modifications signaling changes in chromatin structure. Germ cells contain specialized transcription complexes that coordinate the differentiation program of spermatogenesis, and there are many male germ cell-specific differences in the components of this machinery. All of the above features of germ cells will be discussed along with the specific proteins/genes and abnormalities to fertility related to each topic.

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PP1γ2 and PPP1R11 Are Parts of a Multimeric Complex in Developing Testicular Germ Cells in which their Steady State Levels Are Reciprocally Related

Cited by 28 publications

References 39 publications

Targeted Disruption of Glycogen Synthase Kinase 3a (Gsk3a) in Mice Affects Sperm Motility Resulting in Male Infertility1

Targeted Disruption of Glycogen Synthase Kinase 3a (Gsk3a) in Mice Affects Sperm Motility Resulting in Male Infertility1

Inhibition of Ser/Thr Phosphatases Induces Capacitation-associated Signaling in the Presence of Src Kinase Inhibitors

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: Intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage‐gated channels, methylation/acetylation, and transcription factors

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