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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After capacitation, mammalian spermatozoa accomplish the acrosome reaction (AR), a well-controlled exocytosis process crucial to fertilize mature oocytes that involves several protein kinases such as protein kinase A (PKA), C (PKC), and tyrosine kinase (PTK). Reactive oxygen species (ROS) are involved in both bovine sperm capacitation and AR. Lactate dehydrogenase C4 (LDH-C4) was associated with bovine and mouse sperm capacitation. Our aims were to study the participation of LDH-C4 to contribute with the status redox required for AR and the role of ROS in the regulation of PKA, PKC, and PTK involved in the exocytotic event. Sodium oxamate, an inhibitor of LDH-C4, prevented the AR induced by lysophosphatidylcholine (LPC) or NADH. Hydrogen peroxide promoted and superoxide dismutase (scavenger of superoxide), catalase (scavenger of hydrogen peroxide), diphenyleneiodinum, diphenyliodonium, cibacron blue, and lapachol (inhibitors of NADPH oxidase) prevented the AR, suggesting that ROS and a sperm oxidase are involved in the AR induced by these compounds. Inhibitors of PKA, PKC, and PTK also prevented the AR induced by LPC or NADH, suggesting the involvement of these kinases in the process. These results suggest that LDH-C4 may participate in the regulation of the redox status required to achieve the AR in bovine spermatozoa and that ROS are key elements in the regulation of protein kinases associated with the AR process.
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PMID:Acrosome reaction in bovine spermatozoa: role of reactive oxygen species and lactate dehydrogenase C4. 1611 12

The contra gestational effects of norethisterone and its main metabolites, 5alpha-NET and 3beta5alpha-NET, has been demonstrated in several species. However, the focus has been mainly on their effects in the uterus. We previously reported that 5alpha-NET inhibits the progesterone-induced AR in pig spermatozoa and induces severe morphological damage to fertilized mouse oocytes. In the present study, we analysed the effects of these compounds on the fertilization process in vitro. Oocytes and spermatozoa were obtained from Balb/c female and C57BL/6J male mice, respectively. Both, the AR assays and the fertilization experiments were performed under different steroid treatment schemes using progesterone as a control. Results showed that norethisterone induced the AR, while 5alpha-NET reduced the percentage of spermatozoa that had undergone progesterone-induced AR. Both 17beta-estradiol and 3beta5alpha-NET induced the AR in a considerably lower percentage of spermatozoa than progesterone. In addition, when 5alpha-NET was added to the medium simultaneously with progesterone at the moment of fertilization, the percentage of fertilized oocytes (two-cell stage) decreased by as much as 77% as compared with the control progesterone-treated group. All results suggest that these compounds can have important effects on the fertilization process.
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PMID:Inhibition of the acrosome reaction (AR) and fertilization capacity of mouse spermatozoa by norethisterone A-ring reduced metabolite (5alpha-NET). 1616 31

Capacitation is part of an oxidative process necessary for bovine spermatozoa to acquire fertilizing capacity. This process includes the generation of reactive oxygen species (ROS) and the participation of protein kinases such as A (PKA), C (PKC) and tyrosine kinase (PTK). A redox status is required to support both sperm motility and capacitation. Our aim was to determine the requirement of lactate dehydrogenase C4 (LDH-C4) and isocitrate dehydrogenase (NADP-ICDH) and of protein kinases in cryopreserved bovine sperm capacitation. The presence of inhibitors of both LDH-C4 and NADP-ICDH prevented the heparin-induced capacitation. H89, GF109203X or genistein blocked capacitation triggered by heparin or the superoxide (O(-*)(2))generator system xanthine-xanthine oxidase-catalase (XXOC) suggesting the requirement of PKA, PKC and PTK in this process. Taken together these results suggest that LDH-C4 and NADP-ICDH contribute with the redox status to support bovine sperm capacitation and that PKA, PKC and PTK are involved in different mechanisms induced by different inducers that lead bovine spermatozoa to be capacitated.
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PMID:Heparin- and superoxide anion-dependent capacitation of cryopreserved bovine spermatozoa: requirement of dehydrogenases and protein kinases. 1651 8

Spermatozoa must undergo capacitation to acquire fertilizing ability. Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide H2O2, and nitric oxide (NO*), are involved in this process. We investigated the roles and interactions of ROS, the ERK cascade, and the phosphoinositide 3-kinase (PI3K)/Akt axis during human sperm capacitation. Two different agents, fetal cord serum ultrafiltrate and bovine serum albumin, similarly promoted capacitation and the associated phosphorylation of protein tyrosine residues (P-Tyr), threonine-glutamine-tyrosine (P-Thr-Glu-Tyr-P) motif, and MEK-like proteins (P-MEK-like proteins). Components of the ERK pathway modulated these phosphorylation events. ROS increased P-MEK-like proteins and NO* induced P-Thr-Glu-Tyr-P, possibly by acting on or downstream of Ras. The PI3K/Akt axis participated in capacitation and phosphorylation of Tyr and Thr-Glu-Tyr but not MEK-like proteins. H2O2 and NO* induced P-Tyr even in the presence of ERK pathway inhibitors, indicating that ROS also act downstream of this pathway. These new results indicate that ROS act on different transduction elements during sperm capacitation and regulate phosphorylation events that occur in parallel pathways that eventually lead to late phosphorylation of Tyr. These new data reinforce the concept that a complex network of differentially modulated pathways is needed for spermatozoa to become capacitated.
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PMID:Reactive oxygen species modulate independent protein phosphorylation pathways during human sperm capacitation. 1654 Apr

The role of reactive oxygen species (ROS) as signal transduction elements in physiological phenomena is a recent concept that changes the paradigm of these active species as harmful molecules that promote deleterious effects and even cell death. Capacitation is a term used to define a complex and not well-characterized process that allows spermatozoa to complete their preparation to fertilize oocytes. Spermatozoa from many species incubated under specific conditions have the ability to produce small amounts of ROS without harming cell function and rather promoting signal transduction pathways associated with capacitation. This review summarizes the findings regarding the role of ROS during mammalian sperm capacitation, specifically as physiological mediators that trigger phosphorylation events. The role of ROS as regulators of protein tyrosine phosphorylation has been known for a decade but other novel phosphorylations, such as those of PKA substrates, of MEK-like proteins, and of proteins with the threonine-glutamine-tyrosine motif, were recently evidenced. Here we stress the involvement of PKA and the ERK pathway as two signal mechanisms acting independently that contribute to the modulation of protein tyrosine phosphorylation required for spermatozoa to achieve capacitation. Moreover, integration of all these data reinforces the concept that although some phosphorylation events are independent of the others, cross talk is also needed among the various pathways involved.
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PMID:Positive role of reactive oxygen species in mammalian sperm capacitation: triggering and modulation of phosphorylation events. 1686 85

We demonstrated in this study that liver receptor homolog-1 (LRH-1) was expressed in the round spermatids in normal monkey testis, and no LRH-1 signal was observed in the Sertoli cells. After local warming (43 C) the monkey testis, however, LRH-1 expression was induced in the Sertoli cells in coincidence with activation of cytokeratin 18 (CK-18), a Sertoli cell dedifferentiated marker. Furthermore, we isolated rat primary Sertoli cells from testes at various stages of development and treated with 43 C water in vitro. The changes in LRH-1 as well as CK-18 expression were analyzed by confocal immunohistochemistry and Western blot. The results showed that LRH-1 was stage-dependently expressed in the Sertoli cells; no LRH-1-positive signal was detected in the cells obtained from the testes of adult rat on d 60 after birth when mature spermatozoa in the testis was completed. However, the mature Sertoli cells were warmed at the 43 C water bath for 15 min, and the LRH-1 signal was remarkably induced in a time-dependent manner, just like the changes of CK-18 expression in the Sertoli cells, suggesting that the heat-induced dedifferentiation of the mature Sertoli cells might be related to LRH-1 regulation. LRH-1 expression induced by the heat treatment was completely inhibited by the addition of ERK inhibitor U0126 in the culture, indicating that the heat-induced LRH-1 expression in the Sertoli cells may be regulated via ERK1/2 activation pathway. Testosterone was found to have no such effect on LRH-1 expression in the monkey and rat Sertoli cells.
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PMID:Heat treatment induces liver receptor homolog-1 expression in monkey and rat sertoli cells. 1717 99

A new pathway of testosterone (T) action in Sertoli cells was recently identified that may be required to support spermatozoa production (spermatogenesis) and fertility. Specifically, T acts via the androgen receptor (AR) to rapidly activate the MAPK cascade and the cAMP response element-binding protein (CREB) transcription factor in Sertoli cells. In further characterizing the signaling pathway that transduces T actions, we now find that a population of AR is localized to the plasma membrane and that AR associates with Src kinase after T stimulation. In addition, we demonstrate that Src kinase is activated by T and that Src kinase activity is required for stimulation of the ERK MAPK and CREB. Furthermore, we determine that activation of the epidermal growth factor receptor downstream of Src contributes to the activation of the MAPK cascade and CREB. The elucidation of this nonclassical pathway of T action in the testis may provide new targets for the control of male fertility.
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PMID:Testosterone activates mitogen-activated protein kinase via Src kinase and the epidermal growth factor receptor in sertoli cells. 1727 94

Reactive oxygen species (ROS), such as the superoxide anion (O(2)(-*)), hydrogen peroxide (H(2)O(2)) and nitric oxide (NO*), when generated at low and controlled levels, act as second messengers. ROS regulate sperm capacitation, which is the complex series of changes allowing spermatozoa to bind to the zona pellucida surrounding the oocyte, induce the acrosome reaction (exocytotic event by which proteolytic enzymes are released) and fertilize the oocyte. Capacitating spermatozoa produce controlled amounts of ROS that regulate downstream events: first, the increase in cAMP, protein kinase A (PKA) activation and phosphorylation of PKA substrates (arginine-X-X-serine/threonine motif; 15-30 min); second, the phosphorylation of MEK (extracellular signal regulated kinase [ERK] kinase)-like proteins (30-60 min) and then that of the threonine-glutamate-tyrosine motif (>1 h); finally, the late tyrosine phosphorylation of fibrous sheath proteins (>2 h). Although all these events are ROS-dependent, the regulation by various kinases, protein kinase C, PKA, protein tyrosine kinases, the ERK pathway, etc. is different. ROS also regulate the acquisition of hyperactivated motility and the acrosome reaction by spermatozoa. ROS action is probably mediated via the sulfhydryl/disulfide pair on sperm proteins. Redundancy, cross talk, and multiple systems acting in parallel point to an array of safeguards assuring the timely function of spermatozoa.
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PMID:Sperm activation: role of reactive oxygen species and kinases. 1792 Mar 43

Testis-specific protein kinases are important because of their potential role in spermiogenesis, sperm maturation, and sperm function. In the present study, a novel serine-threonine kinase with high identity to human serine-threonine kinase 31 (STK31) was cloned from equine testis and expression of the protein was characterized in equine testis and ejaculated spermatozoa. Five over-lapping independent clones were plaque purified after screening of a lambda ZAP cDNA expression library constructed from equine testis. Sequence analysis and alignment of all five clones showed high identity with human STK31 with approximately 200 bp of the equine N-terminal sequence incomplete. The putative full-length coding sequence of this testis specific equine cDNA was completed by amplification of a 200-bp fragment using a human primer upstream of the reported translational start site with equine specific nested primers. Northern blot analysis using the equine STK31 cDNA detected an RNA transcript of approximately 3.1 kb present in testis but not in other reproductive or somatic tissues. Immunolocalization of the protein in equine testis and spermatozoa demonstrated that STK31 was present in post-meiotic germ cells with localization to the equatorial segment of testicular spermatozoa. Analysis of the domain structure of equine STK31 revealed a protein kinase domain along with a putative RNA-binding region. The post-meiotic expression of this protein along with its domain structure suggests that STK31 may have a role in reorganization of sperm chromatin during spermiogenesis. The cloning of this novel, testis-specific equine STK provides a new tool to explore the role of kinases in sperm function.
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PMID:Characterization of a novel, testis-specific equine serine/threonine kinase. 1824 30

Mature spermatozoa acquire progressive motility only after ejaculation. Their journey in the female reproductive tract also includes suppression of progressive motility, reactivation, capacitation, and hyperactivation of motility (whiplash), the mechanisms of which are obscure. MAPKs are key regulatory enzymes in cell signaling, participating in diverse cellular functions such as growth, differentiation, stress, and apoptosis. Here we report that ERK1/2 and p38 MAPK are primarily localized to the tail of mature human spermatozoa. Surprisingly, c-Jun N-terminal kinase 1/2, which is thought to be ubiquitously expressed, could not be detected in mature human spermatozoa. ERK1/2 stimulation is downstream to protein kinase C (PKC) activation, which is also present in the human sperm tail (PKCbetaI and PKCepsilon). ERK1/2 stimulates and p38 inhibits forward and hyperactivated motility, respectively. Both ERK1/2 and p38 MAPK are involved in the acrosome reaction. Using a proteomic approach, we identified ARHGAP6, a RhoGAP, as an ERK substrate in PMA-stimulated human spermatozoa. Inverse correlation was obtained between the relative expression level of ERK1 or the relative activation level of p38 and sperm motility, forward progression motility, sperm morphology, and viability. Therefore, increased expression of ERK1 and activated p38 can predict poor human sperm quality.
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PMID:Identification of extracellular signal-regulated kinase 1/2 and p38 MAPK as regulators of human sperm motility and acrosome reaction and as predictors of poor spermatozoan quality. 1837 45


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