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)

We isolated the rat aldose reductase gene and examined the 5'-flanking sequence for the presence of transcription regulatory element responsive to hyperosmolarity. Deletion of aldose reductase gene up to -1047 bp abolished the transcriptional activation in response to osmotic stimuli in transient transfection experiments. A 17-bp sequence [rat osmotic response element (rORE)], which is located in bp -1073/-1057 and contains the TGGAAAATCAC sequence, confers osmotic response on a heterologous promoter. Electrophoretic mobility shift assays using the 17-bp fragment demonstrated that distinct DNA-protein complexes (I and II) were formed predominantly with nuclear extracts from the cells exposed to hyperosmolarity. When the nuclear extracts were preincubated with calf intestinal alkaline phosphatase or protein phosphatase 1, formation of complexes I and II was reduced to the control level. However, incubation with protein tyrosine phosphatase and addition of antiphosphotyrosine antibody had no effect on the complexes. When the nuclear extracts were preincubated with diamide to oxidize the thiols, complexes I and II were not affected. Pretreatment of the cells with cycloheximide abolished the complexes. All of these data indicate that activation by phosphorylation and/or increased synthesis of rORE-binding protein(s) are the key steps in induction of transcription of the rat aldose reductase gene by hyperosmolarity. Furthermore, we showed that glucose was more effective than NaCl in induction of aldose reductase both in transient transfection experiments and by Northern blot analysis. The results suggest the presence of a glucose-specific mechanism of induction in addition to that by NaCl.
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PMID:Induction of rat aldose reductase gene transcription is mediated through the cis-element, osmotic response element (ORE): increased synthesis and/or activation by phosphorylation of ORE-binding protein is a key step. 992 84

Mitogen-activated protein kinases (MAPKs) play a key role in plant responses to stress and pathogens. Activation and inactivation of MAPKs involve phosphorylation and dephosphorylation on both threonine and tyrosine residues in the kinase domain. Here we report the identification of an Arabidopsis gene encoding a dual-specificity protein phosphatase capable of hydrolysing both phosphoserine/threonine and phosphotyrosine in protein substrates. This enzyme, designated AtDsPTP1 (Arabidopsis thaliana dual-specificity protein tyrosine phosphatase), dephosphorylated and inactivated AtMPK4, a MAPK member from the same plant. Replacement of a highly conserved cysteine by serine abolished phosphatase activity of AtDsPTP1, indicating a conserved catalytic mechanism of dual-specificity protein phosphatases from all eukaryotes.
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PMID:Identification of a dual-specificity protein phosphatase that inactivates a MAP kinase from Arabidopsis. 1003 76

Plasma membranes of caput and cauda epididymal spermatozoa of hamster exhibited protein phosphatase activity. This membrane-associated protein phosphatase was identified as a protein tyrosine phosphatase based on its ability to hydrolyse a substrate specific for PTPase, by inhibition of its activity with a specific inhibitor of PTPase (sodium orthovanadate) and by the inability to inhibit its activity with calyculin, okadaic acid, trifluoperazine, calcium, EGTA, and EDTA, which are specific inhibitors of other protein phosphatases, namely PP-1, PP-2A, PP-2B, and PP-2C respectively. The specific activity of the protein tyrosine phosphatase both in the caput and cauda epididymal sperm plasma membranes was similar, implying that the enzyme may not be solely responsible for the differential phosphorylation of membrane proteins observed during maturation (Uma Devi et al. 1997. Mol Reprod Dev 47:341-350). Thus the significance of the PTPase activity in epididymal maturation still remains to be determined. The membrane-associated PTPase may not be essential for acquisition of motility. However, it appears that the activity is essential for the sustenance of motility since sodium orthovanadate, which specifically inhibits PTPase activity, also inhibits motility of spermatozoa and decreases the overall velocity of the spermatozoa by decreasing the average path velocity, straight line velocity, curvilinear velocity, and amplitude of lateral head displacement of the treated spermatozoa.
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PMID:Plasma membrane-associated protein tyrosine phosphatase activity in hamster spermatozoa. 1023 Aug 15

1. Reactive oxygen species are known for their role in neurotoxicity. However, recent studies indicate that reactive oxygen species also play a role in cell function under physiological conditions. 2. Both superoxide and hydrogen peroxide alter the activity of various protein kinases and protein phosphatases, some of which are involved in hippocampal synaptic plasticity. Specifically, the activity of protein kinase C, extracellular-regulated kinase 2, and a protein tyrosine kinase(s) is increased in the presence of these reactive oxygen species, whereas the activity of protein phosphatases 2A and 2B, and a protein tyrosine phosphatase(s) is decreased. 3. Protein kinase C, extracellular-regulated kinase 2, and protein tyrosine kinases critically participate in the induction and/or early expression of long-term potentiation at glutamatergic synapses in hippocampus. Protein phosphatases 2A and 2B participate in the induction and/or early expression of long-term depression at these synapses. 4. Treatment of hippocampal slices with scavengers of either superoxide or hydrogen peroxide prevents the full expression of long-term potentiation. Long-term potentiation in hippocampus also is attenuated in transgenic mice that overexpress Cu/Zn superoxide dismutase. 5. The link between reactive oxygen species and long-term potentiation may be the activating effect on protein kinases. The inhibiting effect of reactive oxygen species on protein phosphatases may also contribute to long-term potentiation. 6. The authors hypothesize that reactive oxygen species play a critical role in hippocampal long-term potentiation by favoring the activation of a protein kinase over a protein phosphatase signaling cascade.
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PMID:Modulation of protein kinases and protein phosphatases by reactive oxygen species: implications for hippocampal synaptic plasticity. 1037 23

The role of endogenous regucalcin in the regulation of protein tyrosine phosphatase activity in the proliferation of the cloned rat H4-II-E hepatoma cells was investigated. Cells were cultured for 6 to 96 h in a medium containing 1.0 or 10% fetal bovine serum (FBS). Cell numbers were significantly raised by culture with 10% FBS in comparison with that of 1.0% FBS. Protein tyrosine phosphatase activity in the cells was significantly elevated by culture with 10% FBS for 24 to 96 h as compared with that of 1% FBS. Such an increase was not seen in protein phosphatase activity toward phosphoserine or phosphothreonine. The presence of anti-regucalcin monoclonal antibody (50 or 100 ng/ml) in the enzyme reaction mixture caused a remarkable elevation of protein tyrosine phosphatase activity in the cells obtained by culture with 1.0 or 10% FBS. This elevation was completely prevented by the addition of regucalcin (10-6 M). The effect of antibody in elevating protein tyrosine phosphatase activity in the cells was significantly inhibited by the addition of okadaic acid (10-6 M) or vanadate (10(-6) M), an inhibitor of protein phosphatase, in the reaction mixture. The present study suggests that protein tyrosine phosphatase activity in the cloned rat hepatoma cells is increased in serum-stimulated cell proliferation, and that endogenous regucalcin has a suppressive role in the enhancement of the enzyme activity in proliferative cells.
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PMID:Enhancement of protein tyrosine phosphatase activity in the proliferation of cloned rat hepatoma H4-II-E cells: suppressive role of endogenous regucalcin. 1093 98

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
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PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

Regucalcin, a regulatory protein of Ca2+ signaling, is mainly present in liver cells. The role of regucalcin in hepatoma cells, however, has not been clarified. The role of endogenous regucalcin in the regulation of protein tyrosine phosphatase activity in the cloned rat hepatoma cells (H4-II-E) was investigated. Hepatoma cells were cultured for 3 days in a medium containing serum (10% fetal bovine serum). After subconfluency, the cells were used for the assay of protein phosphatase activity toward phosphotyrosine. The expression of regucalcin in hepatoma cells was detected by Western blotting using anti-regucalcin antibody. Protein tyrosine phosphatase activity was exhibited in the cytosol of hepatoma cells. The enzyme activity in the cytosol of hepatoma cells was significantly elevated by the addition of calcium chloride (10(-6)-10(-4) M) in the reaction mixture. This elevation was completely blocked by the addition of trifluoperazine (TFP: 2.5 x 10(-6) M), an antagonist of calmodulin. The addition of regucalcin (10(-7) M) caused a complete inhibition of the calcium (10(-4) M)-increased enzyme activity. The presence of anti-regucalcin monoclonal antibody (25, 50, and 100 ng/ml) in the enzyme reaction mixture produced a significant increase in protein tyrosine phosphatase activity in the cytosols of hepatoma cells and normal liver cells. This increase was completely prevented by regucalcin addition. The effect of antibody (50 ng/ml) in elevating the enzyme activity was partly inhibited by vanadate (10(-4) M). Protein tyrosine phosphatase activity was significantly elevated by the culture with Bay K 8644, a Ca2+-channel agonist. This increase was blocked by TFP addition in the enzyme reaction mixture, and it was enhanced in the presence of anti-regucalcin antibody. The present study demonstrates that regucalcin is expressed in hepatoma cells (H4-II-E), and that the protein may have an inhibitory effect on Ca2+/calmodulin-dependent protein tyrosine phosphatase activity in the cells.
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PMID:Role of endogenous regucalcin in protein tyrosine phosphatase regulation in the cloned rat hepatoma cells (H4-II-E). 1112 57

Extracellular signal-regulated kinases (ERK1/ERK2) have been shown transiently activated and involved in excitotoxicity. We searched for upstream molecules responsible for the regulation of glutamate-induced ERK1/ERK2 activation and ERK1/ERK2-mediated apototic-like death in cultured rat cortical neurons. ERK1/ERK2 activation (monitored by anti-active ERK1/ERK2 antibody) was almost completely prevented by blockage of NMDA receptor (NMDA-R) or elimination of extracellular Ca(2+), but not any other glutamate receptor or L-type voltage-gated Ca(2+) channel. It was prevented largely by inhibition of protein kinase C (PKC), protein-tyrosine kinases (PTK), respectively, but mildly by that of CaM kinase II. Combined inhibition of CaM kinase II (but not PTK) and PKC had an additive effect. Reversion of ERK1/ERK2 activation was largely prevented by inhibition of protein phosphatase (PP) 1 or protein tyrosine phosphatase (PTP). Combined inhibition of PP 1 and PTP had no additive effect. Glutamate-induced apoptotic-like death (determined by DAPI staining) was largely prevented by inhibition of NMDA-R, PKC, CaM kinase II, PTK and MEK1/MEK2 (ERK1/ERK2 kinase), respectively. Combined inhibition of CaM kinase II (but not PKC or PTK) and MEK1/MEK2 had an additive effect. Glutamate-induced apoptotic-like death was promoted by inhibition of PP1 and PTP, respectively. The above results suggested that in glutamate-induced cortical neurotoxicity ERK1/ERK2 activation be mainly mediated by NMDA-R. Subsequently, a pathway dependent on both PKC and PTK was mainly involved, which was also mainly responsible for ERK1/ERK2-mediated apoptotic-like death, and a CaM kinase II-dependent pathway was relatively mildly involved. Reversion of ERK1/ERK2 activation was mainly mediated by a pathway dependent on both PP1 and PTP, which might be involved in the restrain of glutamate-induced neurotoxicity.
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PMID:N-methyl-D-aspartate receptor activation results in regulation of extracellular signal-regulated kinases by protein kinases and phosphatases in glutamate-induced neuronal apototic-like death. 1113 17

Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.
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PMID:CTLA-4 up-regulation plays a role in tolerance mediated by CD45. 1127 92

Calcineurin is ubiquitously distributed phosphatase in the central nervous system. It has various functions, such as modulating channel properties, suppressing transmitter release, and activating transcript factors. Recently the critical role of calcineurin on synaptic plasticity, especially long-term depression, was reported, although the precise mechanism underlying LTD induction is still being debated. Calcineurin, activated by the Ca2+ influx mainly through the NMDA channel and calmodulin, dephosphorylates inhibitor-1, which suppresses PP1 activity. Thus the activation of calcineurin enhances PP1, resulting in facilitating the process leading to LTD induction. The activation of calcineurin modifies the threshold of LTP induction. A recent interesting finding is the gating mechanism from the early phase of LTP to the late phase of LTP by calcineurin activity, a process regulated by cAMP. We have reported a new type of LTD, which is suppressed by calcineurin that is dependent on group 2 mGluR receptor activity. According to the result using whole cell study with a patch pipette, including FK-506, an antagonist of calcineurin, the induction site of this LTD is presynaptic, which defers from conventional LTD. We have also discussed the involvement of murine protein tyrosine phosphatase (MPTP) in LTD induction in the hippocampal CA1 region by using an MPTP delta knockout mouse.
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PMID:[The role of calcineurin on the induction of synaptic plasticity]. 1132 44


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