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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein (MAP) kinase pathway, which includes extracellular signal-regulated protein kinases 1 and 2 (ERK1, ERK2) and MAP kinase kinases 1 and 2 (MKK1, MKK2), is well-known to be required for cell cycle progression from G1 to S phase, but its role in somatic cell mitosis has not been clearly established. We have examined the regulation of ERK and MKK in mammalian cells during mitosis using antibodies selective for active phosphorylated forms of these enzymes. In NIH 3T3 cells, both ERK and MKK are activated within the nucleus during early prophase; they localize to spindle poles between prophase and anaphase, and to the midbody during cytokinesis. During metaphase, active ERK is localized in the chromosome periphery, in contrast to active MKK, which shows clear chromosome exclusion. Prophase activation and spindle pole localization of active ERK and MKK are also observed in PtK1 cells. Discrete localization of active ERK at kinetochores is apparent by early prophase and during prometaphase with decreased staining on chromosomes aligned at the metaphase plate. The kinetochores of chromosomes displaced from the metaphase plate, or in microtubule-disrupted cells, still react strongly with the active ERK antibody. This pattern resembles that reported for the 3F3/2 monoclonal antibody, which recognizes a phosphoepitope that disappears with kinetochore attachment to the spindles, and has been implicated in the mitotic checkpoint for anaphase onset (Gorbsky and Ricketts, 1993. J. Cell Biol. 122:1311-1321). The 3F3/2 reactivity of kinetochores on isolated chromosomes decreases after dephosphorylation with protein phosphatase, and then increases after subsequent phosphorylation by purified active ERK or active MKK. These results suggest that the MAP kinase pathway has multiple functions during mitosis, helping to promote mitotic entry as well as targeting proteins that mediate mitotic progression in response to kinetochore attachment.
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PMID:Activation of the MKK/ERK pathway during somatic cell mitosis: direct interactions of active ERK with kinetochores and regulation of the mitotic 3F3/2 phosphoantigen. 974 82

We have previously shown that the mutation of the Schizosaccharomyces pombe PPZ-like protein phosphatase encoded by the gene pzh1+ results in increased tolerance to sodium and in hypersensitivity to potassium ions. A similar phenotype has also been reported for deletants in the spm1/pmk1 gene, encoding a mitogen-activated protein (MAP) kinase. We have found that the sodium tolerance phenotype of pzh1 deletants is stronger than that of spm1 mutants, and both effects are additive. Therefore, most probably both gene products mediate different pathways on sodium tolerance. In our hands, mutation of the kinase does not alter the tolerance to potassium, but it yields cells more tolerant to magnesium ions. While in budding yeast the mutations are synthetically lethal, fission yeast cells lacking both the phosphatase and the kinase genes are viable. Interestingly, their ability to export H+ to the medium is greatly impaired (although not that of pzh1 or spm1 single mutants). We have observed that, although the amount of the H+-ATPase in the plasma membrane is not altered, the activity of the enzyme is lower than normal and cannot be induced by glucose. These observations suggest that the activity of the H+-ATPase in fission yeast might be regulated by phospho-dephosphorylation mechanisms that might involve the pzh1+ and spm1+ gene products.
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PMID:The Pzh1 protein phosphatase and the Spm1 protein kinase are involved in the regulation of the plasma membrane H+-ATPase in fission yeast. 976 18

Aggregation of high affinity FcR for IgE (Fc epsilon RI) on mast cells activates intracellular signal transduction pathways, including the activation of protein tyrosine kinases, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase C. Binding of stem cell factor (SCF) to its receptor (SCFR, c-Kit) on mast cells also induces increases in intrinsic tyrosine kinase activity and activation of PI3-kinase. Although ligation of both receptors induces Ras and Raf-1 activation, the downstream consequences of these early activation events are not well defined, except for the activation of extracellular signal-regulated kinases (ERK). Addition of Ag (OVA) to mouse bone marrow-derived mast cells (BMMC) sensitized with anti-OVA IgE triggers the activation of three members of the mitogen-activated protein (MAP) kinase family, c-Jun amino-terminal kinase (JNK), p38 MAP kinase (p38), and extracellular signal-regulated kinases. SCF similarly activates all three MAP kinases. Wortmannin, an inhibitor of PI3-kinase, inhibited both Fc epsilon RI- and SCFR-mediated JNK activation and partially inhibited Fc epsilon RI, but not SCFR-mediated p38 activation. Cyclosporin A inhibited Fc epsilon RI-mediated JNK and p38 activation, but did not affect the activation of these kinases when stimulated through the SCFR. Wortmannin and cyclosporin A inhibited Fc epsilon RI-mediated production of TNF-alpha and IL-4 in addition to serotonin release in BMMC. These results indicate that both PI3-kinase and calcineurin may contribute to the regulation of cytokine gene transcription and the degranulation response by modulating JNK activity in BMMC.
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PMID:Mitogen-activated protein kinase activation through Fc epsilon receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells. 997 82

In response to hypoxia, sickle red blood cells (SS RBC) and leukocytes exhibit increased adherence to the vascular endothelium, while diapedesis of leukocytes through the blood vessel increases. However, the cellular signaling pathway(s) caused by hypoxia is poorly understood. We utilized CoCl2 as a mimetic molecule for hypoxia to study cellular signaling pathways. We found that in human umbilical vein endothelial cells (HUVEC), CoCl2 at 2 mM concentration induced the surface expression of a subset of CAMs (VCAM-1) and activation of transcription factor NF-kappaB in the nuclear extracts of HUVEC. Furthermore, CoCl2 also caused time-dependent tyrosine phosphorylation of mitogen-activated protein (MAP) kinase isoform ERK2 without significantly affecting ERK1, indicating ERK2 is the preferred substrate for upstream kinase of the MAPK pathway. Inhibitors of MAP kinase (PD98059) or platelet-activating factor (PAF)- receptor antagonist (CV3988) inhibited the CoCl2-induced NF-kappaB activation and VCAM-1 expression. Augmented expression of VCAM-1 led to increased SS RBC adhesion, inhibitable by a VCAM-1 antibody. Additionally, CoCl2 caused a two- to threefold increase in the rate of transendothelial migration of monocyte-like HL-60 cells and a twentyfold increase in phosphorylation of platelet endothelial cell adhesion molecules (PECAM-1). The transendothelial migration of monocytes was inhibited by an antibody to PECAM-1. Both phosphorylation of PECAM-1 and transendothelial migration of monocytes in response to CoCl2 were inhibited by protein kinase inhibitor (GF109203X) and augmented by protein phosphatase inhibitor (Calyculin A). Our data suggests that CoCl2-induced cellular signals directing increased expression of VCAM-1 in HUVEC involve downstream activation of MAP kinase and NF-kappaB, while the phosphorylation of PECAM-1 occurs as a result of activation of PKC. We conclude that PAF-receptor antagonist inhibits the CoCl2- or hypoxia-induced increase in the adhesion of SS RBC, PECAM-1 phosphorylation, and the concomitant transendothelial migration of monocytes.
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PMID:Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of sickle red blood cells and transendothelial migration of monocyte-like HL-60 cells is blocked by PAF-receptor antagonist. 1008 34

To investigate the involvement of protein kinases in the signaling cascade that leads to hypersensitive cell death, we used a previously established system in which a fungal elicitor, xylanase from Trichoderma viride (TvX), induces a hypersensitive reaction in tobacco (Nicotiana tabacum) cells in culture (line XD6S). The elicitor induced the slow and prolonged activation of a p47 protein kinase, which has the characteristics of a family member of the mitogen-activated protein kinases. An inhibitor of protein kinases, staurosporine, and a blocker of Ca channels, Gd3+ ions, both of which blocked the TvX-induced hypersensitive cell death, inhibited the TvX-induced activation of p47 protein kinase. Moreover, an inhibitor of serine/threonine protein phosphatase alone induced both rapid cell death and the persistent activation of the p47 protein kinase. Thus, the p47 protein kinase might be a component of the signal transduction pathway that leads to hypersensitive cell death, and the regulation of the duration of activation of the p47 protein kinase might be important in determining the destiny of tobacco cells.
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PMID:Slow and prolonged activation of the p47 protein kinase during hypersensitive cell death in a culture of tobacco cells 1019 6

The effects of protein kinase C (PKC) stimulator, phorbol 12-myriatate 13-acetate (PMA), on meiotic cell cycle regulation and mitogen-activated protein (MAP) kinase changes have been studied in mouse oocytes and eggs. The results showed that MAP kinase activation itself was not necessary for germinal vesicle breakdown (GVBD), but the ability of the ooplasm to phosphorylate MAP kinase was a prerequisite for this event. At concentrations of 1.6 nM, PMA effectively inhibited GVBD and MAP kinase activation, suggesting that PMA inhibits GVBD by inhibiting molecule(s) upstream to MAP kinase. At concentrations of 16.2 nM, PMA induced metaphase-interphase transition more effectively in eggs collected 19 hr after human chorionic gonadotropin (hCG) administration than in those collected 15 hr after hCG administration. The degree of MAP kinase activity decrease was well correlated with the time course and proportion of pronuclear formation. On the other hand, when the effect of PMA on cell cycle progression was abolished by protein phosphatase inhibitor, okadaic acid, MAP kinase was superactivated. The biologically inactive 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD) had no evident effects on either GVBD and interphase transition or on MAP kinase activity. Furthermore, the effects of PMA on oocyte GVBD, egg activation, and MAP kinase activity could be overcome by the specific PKC inhibitor, calphostin C, suggesting the possible involvement of this enzyme in the regulation of MAP kinase activity. The results suggest that activation of PKC by PMA entrains a cascade of events that ultimately inhibits MAP kinase activation and GVBD in mouse oocytes and induces MAP kinase inactivation and metaphase-interphase transition in mouse eggs.
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PMID:MAP kinase activity is downregulated by phorbol ester during mouse oocyte maturation and egg activation in vitro. 1020 63

Cellular calcium (Ca2+) and the Ca2+-binding protein calmodulin (CaM) regulate the activities of Ca2+/CaM-dependent protein kinases and protein phosphatase 2B (calcineurin). Functional interactions between CaM kinases and mitogen-activated protein (MAP) kinases were described. In this report, we describe cross-talk between calcineurin and mitogen-activated protein kinase signaling. Calcineurin was found to specifically down-regulate the transcriptional activity of transcription factor Elk1, following stimulation of this activity by the ERK, Jun N-terminal kinase, or p38 MAP kinase pathways. Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity. Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1. The cross-talk between calcineurin and MAP kinases is of physiological significance as low doses of Ca2+ ionophore which by themselves are insufficient for c-fos induction can actually inhibit induction of c-fos expression by activators of MAP kinases. Thus through the effect of calcineurin on Elk1 phosphorylation, Ca2+ can have a negative effect on expression of Elk1 target genes. This mechanism explains why different levels of intracellular Ca2+ can result in very different effects on gene expression.
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PMID:Stimulation of Elk1 transcriptional activity by mitogen-activated protein kinases is negatively regulated by protein phosphatase 2B (calcineurin). 1032 25

A very sensitive method was established for detecting the activity of mitogen-activated protein (MAP) kinase in mouse eggs, and used to follow temporal changes of this kinase during fertilization and spontaneous or chemically-induced parthenogenic activation. MAP kinase activity increased between 1 and 2.5 h post-insemination, at which time the second polar body was emitted and sperm chromatin was dispersed; its activity decreased sharply at 8 h. when pronuclei were formed. Both calcium ionophore A23187 and ethanol simultaneously induced pronuclear formation and MAP kinase inactivation in aged eggs 8 h after incubation but less effectively in fresh eggs. The protein kinase inhibitor staurosporine induced pronuclear formation and MAP kinase inactivation more quickly than other treatments, with MAP kinase inactivation occurring slightly proceeding pronuclear formation. Okadaic acid, a specific inhibitor of protein phosphatase 1 and 2A, induced increase in MAP kinase activity, and overcame pronuclear formation induced by various stimuli. MAP kinase inactivation preceded pronuclear formation in eggs spontaneously activated by aging in vitro, perhaps due to cytoplasmic degeneration and thus delayed response of nuclear envelope precursors to MAP kinase inactivation. These data suggest that MAP kinase is a key protein kinase regulating the events of mouse egg activation. Increased MAP kinase activity is temporally correlated with the second polar body emission and sperm chromatin decondensation. Although different stimuli (including sperm) may initially act through different mechanisms, they finally inactivate MAP kinase, probably by allowing the action of protein phosphatase, and thus induces the transition to interphase.
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PMID:Mitogen-activated protein kinase and cell cycle progression during mouse egg activation induced by various stimuli. 1034 45

The Ras-GRF exchange factor can activate Ras-dependent responses following the activation of heterotrimeric G-protein and calcium signalling. In stable lines of NIH-3T3 fibroblasts that express Ras-GRF, the agonist lysophosphatidic acid (LPA) increases the phosphorylation state and activity of Ras-GRF. The stimulation of Ras-GRF can be demonstrated in vitro, in an assay using recombinant Ras substrate, and in situ, by a selective increase in the ability of LPA to stimulate mitogen-activated protein (MAP) kinase. The increase in Ras-GRF phosphorylation state, which occurs on serine residues, and the increase in exchange factor activity are blocked by pretreatment with pertussis toxin. Activation of Ras-GRF by LPA can also be inhibited by chelation of intracellular calcium and treatment of the Ras-GRF with protein phosphatase 1 (PP1), supporting a model in which Ras-GRF serves to integrate signals from multiple transduction pathways.
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PMID:Activation of the Ras-GRF/CDC25Mm exchange factor by lysophosphatidic acid. 1043 21

Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.
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PMID:Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. 1051 68


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