Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of cAMP/cGMP, protein kinases and intracellular calcium ( [Ca2+]i) in pentoxifylline-stimulated hamster sperm capacitation and the acrosome reaction (AR) in vitro. Treatment with pentoxifylline (0.45 mM) initially increased sperm cAMP values 2.8-fold, compared with untreated controls (396 +/- 9.2 versus 141 +/- 6.0 fmoles/10(6) spermatozoa; mean +/- SEM, n = 6) after 15 min, although by 3 h, cAMP values were similar (503-531 fmoles/10(6) spermatozoa). cGMP values ( approximately 27 fmoles/10(6) spermatozoa) were the same in treated and control spermatozoa. Both sperm capacitation and the AR, determined from the absence of an acrosomal cap, were stimulated by pentoxifylline; these were almost completely inhibited by a Cl-/ HCO3- antiporter inhibitor (4,4-diisothiocyanato-stilbene-2,2 disulphonic acid; 1 mM) defined from the degree of sperm motility and by a protein kinase A inhibitor (H89; 10 microM). A protein kinase C inhibitor (staurosporine, 1 nM) did not affect pentoxifylline-stimulated capacitation but inhibited the AR by 50%. A protein tyrosine kinase inhibitor (tyrphostin A-47, 0.1 mM) had no effect on either pentoxifylline-stimulated capacitation or AR. A phospholipase A2 inhibitor (aristolochic acid, 0.4 mM) markedly inhibited the pentoxifylline-stimulated AR but not capacitation. When intracellular sperm calcium [Ca2+/-]i was measured using fura-2-AM, there was an early rise (271 nM at 0.5 h) in pentoxifylline-treated spermatozoa; this appeared to be due to intracellular mobilization rather than to uptake. In the absence of extracellular Ca2+, sperm motility was maintained in the presence of pentoxifylline, but capacitation did not occur; spermatozoa exhibited a low level of hyperactivated motility and had a poor rate of AR (20.5 +/- 2.3%). These results suggest that: (i) the pentoxifylline-stimulated early onset of sperm capacitation may be mediated by an early rise in cAMP and [Ca2+/-]i and involves protein kinase A activity; and (ii) pentoxifylline-stimulated AR may require phospholipase A2 and protein kinase C activity.
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PMID:Pentoxifylline-stimulated capacitation and acrosome reaction in hamster spermatozoa: involvement of intracellular signalling molecules. 1038 16

Sperm motility is regulated by the cAMP-dependent protein kinase (protein kinase-A)-mediated phosphorylation of a group of largely unidentified flagellar proteins. Human AKAP82 (hAKAP82) and its precursor protein, pro-hAKAP82, are members of the A-kinase anchor protein (AKAP) family. These proteins tether protein kinase-A to the fibrous sheath of human spermatozoa and presumably localize the activity of the kinase near specific targets in the sperm flagellum. In this way, pro-hAKAP82 and hAKAP82 may be involved in regulating sperm motility. Similar to its homologues in other species, pro-hAKAP82 is proteolytically processed to hAKAP82. However, the amount of processing of pro-hAKAP82 in human spermatozoa is less than the amount of processing of the precursor in other species. We postulated that this lower extent of processing may be related to lower percentages of human sperm motility. In addition, both pro-hAKAP82 and hAKAP82 are tyrosine phosphorylated in a capacitation-dependent manner. Since capacitation is associated with hyperactivated motility, we postulated that tyrosine phosphorylation of pro-hAKAP82/hAKAP82 is associated with changes in motility. However, using a combination of immunofluorescence and immunoblotting approaches, we found no evidence for an association between either processing or tyrosine phosphorylation of pro-hAKAP82/hAKAP82 and significant differences in motility in spermatozoa from normal men.
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PMID:Relationship between sperm motility and the processing and tyrosine phosphorylation of two human sperm fibrous sheath proteins, pro-hAKAP82 and hAKAP82. 1046 Feb 19

Protein kinase casein kinase II (Ck2) is a cyclic-AMP and calcium-independent serine-threonine kinase that is composed of two catalytic subunits (alpha and alpha') and two regulatory beta-subunits. Ck2 is not a casein kinase in vivo, but over 100 substrates are known. The highly conserved amino acid sequences of its subunits and their broad expression suggest that Ck2 may have a fundamental role in cell function. Ck2 has been implicated in DNA replication, regulation of basal and inducible transcription, translation and control of metabolism. The Ck2alpha and Ck2alpha' isoforms (products of the genes Csnk2a1 and Csnk2a2, respectively) are highly homologous, but the reason for their redundancy and evolutionary conservation is unknown. We find here that Csnk2a2 is preferentially expressed in late stages of spermatogenesis, and male mice in which Csnk2a2 has been disrupted are infertile, with oligospermia and globozoospermia ('round-headed' spermatozoa). This is the first demonstration of a unique role for a Ck2 isoform in development. The primary spermatogenic defect in Csnk2a2-/- testis is a specific abnormality of anterior head shaping of elongating spermatids; this is the first defined gene that regulates sperm head morphogenesis. As the germ cells differentiate, they are capable of undergoing chromatin condensation, although many abnormal cells are deleted through apoptosis or Sertoli cell phagocytosis. The few that survive to populate the epididymis exhibit head abnormalities similar to those described in human globozoospermia, thus Csnk2a2 may be a candidate gene for these inherited syndromes.
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PMID:Globozoospermia in mice lacking the casein kinase II alpha' catalytic subunit. 1047 12

Binding to the zona pellucida of an egg stimulates the spermatozoon to undergo the acrosome reaction, a process that enables it to penetrate the egg. Before this binding, the spermatozoon undergoes a series of biochemical transformations in the female reproductive tract, collectively called capacitation. Only capacitated spermatozoa can bind to the zona pellucida and undergo the acrosome reaction. Protein kinases may be involved in the regulation of intracellular Ca2+ during capacitation and the acrosome reaction. The first event in capacitation is the increase in intracellular calcium, bicarbonate and hydrogen peroxide, which collectively activate adenylyl cyclase to produce cyclic AMP, which activates protein kinase A to phosphorylate certain proteins. During capacitation, there is an increase in membrane-bound phospholipase C, and this binding is highly stimulated by the addition of epidermal growth factor to the cells. The capacitated spermatozoon binds to the zona pellucida of the egg via specific receptors and it is suggested that the zona pellucida binds to at least two different receptors in the sperm head plasma membrane. One is a Gi-coupled receptor that can activate phospholipase Cbeta1 and may regulate adenylyl cyclase to further increase cyclic AMP concentrations. The cyclic AMP activates protein kinase A to open a calcium channel in the outer acrosomal membrane, resulting in a relatively small increase in cytosolic calcium. This increase in Ca2+ leads to activation of phospholipase Cgamma, which is coupled to the second tyrosine kinase receptor. The products of phosphatidyl-inositol bisphosphate hydrolysis by phospholipase C, diacylglycerol and inositol-trisphosphate, induce the activation of protein kinase C and a calcium channel in the outer acrosomal membrane, respectively. Protein kinase C opens a calcium channel in the plasma membrane and, together with the inositol-trisphosphate-activated calcium channel, leads to a second and higher increase in cytosolic calcium. In addition, the depletion of calcium in the acrosome activates a capacitative calcium entry mechanism in the plasma membrane, leading to a rapid increase in cytosolic calcium (300-500 nmol l(-1)). This increase in intracellular calcium concentration (and pH) leads to membrane fusion and the acrosome reaction.
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PMID:Protein kinases in mammalian sperm capacitation and the acrosome reaction. 1052 Nov 52

Protein tyrosine phosphorylation has been associated with both capacitation and motility of mammalian sperm. During capacitation, human spermatozoa undergo tyrosine phosphorylation of a characteristic set of proteins, only one of which has thus far been cloned and localized. We report here the sequence of a fibrous sheath protein of 95 kDa (FSP95) that undergoes tyrosine phosphorylation during capacitation of human spermatozoa and has similarity to sperm A-kinase anchor proteins (AKAPs). FSP95 is both auto- and iso-antigenic in humans as it is recognized by sera containing antisperm antibodies from infertile men and women. The 853-residue protein has a calculated molecular weight of 94.6 kDa and an isoelectric point (pI) of 6.0, and it contains multiple potential phosphorylation sites for protein kinase C and casein kinase II as well as one potential tyrosine kinase phosphorylation site at amino acid 435. The sequence has amino acid homology to mouse sperm fibrous sheath AKAP82 (pro-mAKAP82, 34% identity) and to human sperm fibrous sheath AKAP82 (pro-hAKAP82, 32% identity). The gene encoding FSP95 has 5 exons separated by 4 introns and is located on chromosome 12 at locus p13.3. Northern analysis detected a single transcript of approximately 3.0 kilobases, and Northern dot blot analysis of 50 human tissues revealed FSP95 mRNA expression only in testis. By employing sperm immobilization, indirect immunofluorescence, and immunoelectron microscopy with antisera to purified recombinant FSP95, the protein was localized to the ribs of the fibrous sheath in the principal piece of the sperm tail. FSP95 is the second fibrous sheath protein to be cloned, sequenced and localized in human spermatozoa.
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PMID:FSP95, a testis-specific 95-kilodalton fibrous sheath antigen that undergoes tyrosine phosphorylation in capacitated human spermatozoa. 1052 64

Protein tyrosine phosphorylation is an important intracellular event accompanying the in-vitro capacitation of mouse, bovine and human spermatozoa. Here, we demonstrate that bovine serum albumin (BSA) and NaHCO(3) are required for protein tyrosine phosphorylation in ejaculated human spermatozoa. The absence of protein tyrosine phosphorylation in media minus these two constituents could be recovered by addition to the media of cAMP analogues and/or phosphodiesterase inhibitors. Since BSA is postulated to modulate capacitation by removal of cholesterol from the sperm plasma membrane, we determined whether cholesterol release leads to changes in protein tyrosine phosphorylation. Incubation of spermatozoa in media containing BSA resulted in the release of significant amounts of cholesterol when compared with media devoid of BSA. Preloading BSA with cholesterol-SO(4) inhibited protein tyrosine phosphorylation, as well as capacitation, and this inhibitory effect was overcome by the addition of dibutyryl cAMP plus isobutylmethylxanthine (IBMX). The functional significance of BSA-mediated cholesterol release, protein tyrosine phosphorylation and capacitation was confirmed by examining the effects of the cholesterol-binding heptasaccharides, methyl-beta-cyclodextrin or OH-propyl-beta-cyclodextrin. Both cyclodextrins caused cholesterol efflux from the spermatozoa, increased protein tyrosine phosphorylation, and stimulated capacitation. Therefore, cholesterol release is associated with the activation of a signal transduction pathway involving protein kinase A and tyrosine kinase second messenger systems, and resulting in protein tyrosine phosphorylation and capacitation.
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PMID:Regulation of human sperm capacitation by a cholesterol efflux-stimulated signal transduction pathway leading to protein kinase A-mediated up-regulation of protein tyrosine phosphorylation. 1054 63

Males heterozygous for the t-haplotype form of mouse chromosome 17 preferentially transmit the t-chromosome to their progeny. Several distorter/sterility loci carried on the t-haplotype together impair flagellar function in all spermatozoa whereas the responder, Tcr, rescues t-sperm but not wild-type sperm. Thus, t-sperm have an advantage over wild-type sperm in fertilizing egg cells. We have isolated Tcr by positional cloning and show that it is a member of a novel protein kinase gene family, designated Smok, which is expressed late during spermiogenesis. Smok kinases are components of a signal cascade which may control sperm motility. Tcr has a reduced kinase activity, which may allow it to counterbalance a signalling impairment caused by the distorter/sterility loci. Tcr transgene constructs cause non-mendelian transmission of chromosomes on which they are carried, which leads to sex-ratio distortion when Tcr cosegregates with the Y chromosome.
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PMID:A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. 1064

The proliferation and differentiation of testicular progenitor stem cells into highly specialized germ cells (spermatozoa) are largely controlled by the hormonally (FSH and testosterone) regulated adjacent supporting Sertoli cells. However, the factors involved in this control remain largely unknown. In the present study, the technique of differential display PCR was used to identify target transcripts to FSH action in cultured murine Sertoli cells. Among these target transcripts, we identified the oligodendrocyte-specific protein (OSP), also known as claudin 11, which had recently been shown to play a key role in the formation of the hematotesticular barrier. Our data show that the testicular expression of OSP is dependent upon male gonad development and systemic and local signaling molecules. Indeed, OSP is expressed early in fetal development in Sertoli cells, immediately after the peak of SRY (sex-determining region, Y gene) expression, but just before that of the anti-Mullerian hormone. Postnatally, OSP expression starts to increase from day 3 to reach a plateau between days 6 and 16 postnatally. In the prepubertal and adult testes, an apparent decline in OSP messenger RNA (mRNA) levels was found, probably because of the increasing number of germ cells (which do not express OSP). Among the signaling molecules that control testicular OSP expression, we have identified FSH and tumor necrosis factor-alpha (TNFalpha). Indeed, using a model of purified cultured mouse Sertoli cells, we demonstrate that FSH inhibits, in a dose (ED50 = 4 ng/ml)- and time (maximal effect after 24 h)-dependent manner, the levels of OSP mRNA. Such an inhibitory effect was mimicked by 8-bromo-cAMP, suggesting that FSH may use the cAMP/protein kinase A pathway to inhibit OSP mRNA levels. TNFalpha was also shown to inhibit OSP expression in cultured Sertoli cells. The maximal effect was observed after 48 h of TNFalpha treatment with an ED50 of 4.5 ng/ml. Together, our results indicate that OSP expression 1) starts during fetal life at a critical period, probably under SRY control and during testicular formation; and 2) is regulated by hormones (FSH) and cytokines (TNFalpha) in the adult testis, suggesting a critical role for these molecules in the (re)modeling process of the hematotesticular barrier during spermatogenesis.
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PMID:Developmental and hormonal regulation of the expression of oligodendrocyte-specific protein/claudin 11 in mouse testis. 1091 90

Hydrogen hexachloroplatinate, H2PtCl6, has been shown to induce the human sperm acrosome reaction in vitro. However, the molecular mechanism underlying this exocytic process has not been studied. Therefore, two structurally and chemically different platinum (Pt) compounds, the potent sensitizer sodium-hexachloro-platinate-(IV), Na2[PtCl6], and the nonimmunogenic tetraamineplatinum-(II)-chloride, [Pt(NH3)4]Cl2, were selected for the experiments. Their effects on human sperm function and second messenger pathways were investigated. Washed human spermatozoa were treated with different concentrations of both Pt salts (0.5-1000 microM) during or after capacitation for 3 h at 37 degrees C. In addition, spermatozoa were incubated with Pt salts in calcium-free medium or in the presence of the protein kinase A+C inhibitor H7. Sperm motility was evaluated by computer-assisted sperm analysis; acrosomal loss was detected by triple staining. Compared with the controls (6.6+/-2.4%), the percentages of living acrosome-reacted spermatozoa showed a significant dose-dependent increase (P<0.001) after 3 h of incubation with Na2[PtCl6] (7.9+/-4.2% for 0.5 microM 25.0+/-2.9% for 1 mM) and [Pt(NH3)4]Cl2 (7.9+/-3.9% to 21.0+/-5.8%). Sperm motility was markedly reduced in samples containing the highest concentrations of the Pt salts. The acrosome reaction was also significantly increased when spermatozoa had first been capacitated and then treated with both Pt salts. Calcium-free medium had no effect on the ability of both Pt salts to induce the acrosome reaction. However, incubation of Na2[PtCl6] in the presence of H7 tendentiously decreased the percentage of acrosome-reacted spermatozoa. In conclusion, complex Pt salts such as Na2[PtCl6] or [Pt(NH3)4]Cl2 influence human sperm functions by inducing the acrosome reaction during or after capacitation. This stimulatory effect is independent of calcium and seems to be dependent on protein kinase A or C.
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PMID:Effect of two complex platinum salts on human sperm motility and acrosome reaction. 1102 23

We studied the possibility of using the spermatozoa of the loach Misgurnus fossilis L. for identification of centrosome proteins. It has been shown that the centrosome of the loach spermatozoa consists of a pair of centrioles of the standard structure and contains the marker protein gamma-tubulin, cytoplasmic microtubules branch out from it, and it does not contain any additional structures characteristic of the centrosomes of spermatozoa of many other fishes. A preparation enriched with intact centrosomes has been obtained from the loach spermatozoa. These centrosomes contained gamma-tubulin although they lost their ability to induce polymerization of microtubules. The preparation of loach centrosomes was successfully used to obtain a set of monoclonal antibodies against the mammalian centrosome. A new protein kinase LOSTEK was identified with the help of one of these monoclonal antibodies, SN2-3D2, which was localized in the centrosome and on then microtubules in both loach spermatozoa and cultured mammalian cells. Hence, the loach spermatozoa are a promising object for identification of new proteins of the mammalian centrosome.
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PMID:[Spermatozoa of the loach Misgurnus fossilis as a test system for identification of new centromere proteins]. 1123 92


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