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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wound healing is a complex process that involves cell communication, migration, proliferation, and changes in gene expression. One of the first events after injury is the rapid release of Ca(2+) that propagates as a wave to neighboring cells (Klepeis et al. [2001]: J. Cell. Sci. 114:4185-4195). Our goal was to examine the signaling events induced by cellular injury and identify extracellular molecules that induce the activation of extracellular signal responsive kinase (ERK) (p42/44). In this study we demonstrated that injury induced ERK1/2 activation occurred within 2 min and was negligible by 15 min. Treatment of unwounded cells with wound media caused activation of ERK that could be inhibited by apyrase III. Stimulation with epidermal growth factor (EGF) did not mimic the injury response and it was not detected in the wound media. To identify the active component, size fractionation was performed and factor(s) less than 3 kDa that induced the release of Ca(2+) and activation of ERK1/2 were identified. Activity was not altered by heat denaturation, incubation with proteinase K but it was lost by treatment with apyrase. Adenosine triphosphate (ATP), uridine triphosphate (UTP), adenosine diphosphate (ADP), and uridine diphosphate (UDP) promoted activation by 2 min with similar profiles as that generated by injury. Preincubation with phospholipase C inhibitor, U73122, inhibited activation that was induced by injury and/or nucleotides. Lack of activation by alpha-beta-methylATP (alpha, beta-MeATP) and beta-gamma-methylATP (beta, gamma-MeATP) to purinergic (P)2X receptors further indicated that activation occurs via P2Y and not P2X purinergic receptors. These results indicate that injury-induced activation of ERK1/2 is mediated by a P2Y signaling pathway.
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PMID:Cellular injury induces activation of MAPK via P2Y receptors. 1503 29

The mechanisms by which shear stress elevates intracellular Ca(2+) in endothelial cells (EC) are not fully understood. Here we report that endogenously released ATP contributes to shear stress-induced Ca(2+) responses. Application of a flow of Hank's balanced solution to human pulmonary artery EC (HPAEC) elicited shear stress-dependent increases in Ca(2+) concentration. Chelation of extracellular Ca(2+) with EGTA completely abolished the Ca(2+) responses, whereas the phospholipase C inhibitor U-73122 and the Ca(2+)-ATPase inhibitor thapsigargin had no effect, indicating that the response was due to the influx of extracellular Ca(2+). The Ca(2+) influx was significantly suppressed by apyrase, which degrades ATP, and by antisense oligonucleotide targeted to P2X4 receptors. A luciferase luminometric assay showed that shear stress induced dose-dependent release of ATP. When the ATP release was inhibited by the ATP synthase inhibitors angiostatin or oligomycin, the Ca(2+) influx was markedly suppressed but was restored by removal of these inhibitors or addition of extracellular ATP. These results suggest that shear stress stimulates HPAEC to release ATP, which activates Ca(2+) influx via P2X4 receptors.
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PMID:[Shear-stress sensing via P2 purinoceptors in vascular endothelial cells]. 1550 97

In mammals, trefoil factor family (TFF) proteins are involved in mucosal maintenance and repair, and they are also implicated in tumor suppression and cancer progression. A novel two domain TFF protein from frog Bombina maxima skin secretions (Bm-TFF2) has been purified and cloned. It activated human platelets in a dose-dependent manner and activation of integrin alpha(IIb)beta(3) was involved. Aspirin and apyrase did not largely reduce platelet response to Bm-TFF2 (a 30% inhibition), indicating that the aggregation is not substantially dependent on ADP and thromboxane A2 autocrine feedback. Elimination of external Ca(2+) with EGTA did not influence the platelet aggregation induced by Bm-TFF2, meanwhile a strong calcium signal (cytoplasmic Ca(2+) release) was detected, suggesting that activation of phospholipase C (PLC) is involved. Subsequent immunoblotting revealed that, unlike in platelets activated by stejnulxin (a glycoprotein VI agonist), PLCgamma2 was not phosphorylated in platelets activated by Bm-TFF2. FITC-labeled Bm-TFF2 bound to platelet membranes. Bm-TFF2 is the first TFF protein reported to possess human platelet activation activity.
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PMID:Bm-TFF2, a trefoil factor protein with platelet activation activity from frog Bombina maxima skin secretions. 1582 46

Extracellular nucleotides can mediate a variety of cellular functions via interactions with purinergic receptors. We previously showed that mechanical ventilation (MV) induces airway IL-6 and ATP release, modifies luminal nucleotide composition, and alters lung purinoceptor expression. Here we hypothesize that extracellular nucleotides induce secretion of IL-6 by small airway epithelial cells (SAEC). Human SAEC were stimulated with nucleotides in the presence or absence of inhibitors. Supernatants were analyzed for IL-6 and lysates for p38 MAPK activity by ELISA. RNA was analyzed by real-time RT-PCR. Rats (n=51) were randomized to groups as follows: control, small-volume MV, large-volume MV, large-volume MV-intratracheal apyrase, or small-volume MV-intratracheal adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS). After 1 h of MV, bronchoalveolar lavage fluid was analyzed for ATP and IL-6 by luminometry and ELISA. ATP and ATPgammaS increased SAEC IL-6 secretion in a time- and dose-dependent manner, an effect inhibited by apyrase. Agonists were ranked in the following order: ATPgammaS>ATP=UTP>ADP=adenosine>2-methylthio-ADP=control. SB-203580, but not U-0126 or JNK1 inhibitor, decreased nucleotide effects. Additionally, nucleotides induced p38 MAPK phosphorylation. Inhibitors of Ca2+ signaling, phospholipase C, transcription, and translation decreased IL-6 release. Furthermore, nucleotides increased IL-6 expression. In vivo, large-volume MV increased airway ATP and IL-6 concentrations. IL-6 release was decreased by apyrase and increased by ATPgammaS. Extracellular nucleotides induce P2Y2-mediated secretion of IL-6 by SAEC via Ca2+, phospholipase C, and p38 MAPK-dependent pathways. This effect is dependent on transcription and translation. Our findings were confirmed in an in vivo model, thus demonstrating a novel mechanism of nucleotide-induced IL-6 secretion by airway epithelia.
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PMID:Nucleotides induce IL-6 release from human airway epithelia via P2Y2 and p38 MAPK-dependent pathways. 1663 18

Streptokinase (SK) is one of the plasminogen activators currently used in therapeutics. SK antibodies may appear in the blood after thrombolytic therapy with SK or after-hemolytic streptococci infection. Such antibodies may both activate platelets and neutralize the ability of SK to convert plasminogen into plasmin. We previously demonstrated that platelet activation induced by the combination of IgG anti-SK and anisoylated plasminogen-SK activator complex (APSAC) is mediated by Fc gamma RIIa1 receptor. However, the mechanism by which IgG anti-SK and APSAC (or SK) transduce an activating signal across the platelet plasma membrane remains unknown. We have demonstrated in the present study that the platelet aggregation induced by the combination of IgG anti-SK and APSAC is accompanied by an increase in inositol phosphate, Ca2+ mobilization and thromboxane (Tx) A2 generation. Neomycin, erbstatin and GF 109203X, which inhibit phospholipase C (PLC), protein tyrosine kinase (PTK) and protein kinase C (PKC) activities, respectively, abolished platelet aggregation induced by IgG anti-SK plus APSAC, indicating the pivotal roles of the PLC, PTK and PKC pathways in this immunological activation. In addition, TxA2 generation is also important since aspirin, a cyclooxygenase inhibitor and SQ 29548, a TxA2 receptor antagonist, showed significant inhibition of the platelet response. The contribution of released ADP was confirmed using apyrase, which significantly inhibited IgG anti-SK plus APSAC-induced platelet aggregation. Finally, WEB 2086, a platelet-activating factor (PAF) receptor antagonist, was not effective, indicating that PAF is not involved in this process. APSAC- or SKinduced platelet activation may limit the therapeutic effectiveness of the drug and may contribute to the pathogenesis of early reocclusion. The study of the mechanism leading to APSAC-induced platelet activation could be relevant for a better understanding of the physiopathology of immune complex disorder diseases and thrombolytic treatment failure.
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PMID:Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex. 1679 41

In the present report we show that convulxin (Cvx), a C-type lectin from Crotalus durissus terrificus venom, induces platelet agregation and phospholipase C (PLC) activation by a protein tyrosine kinase (PTK)-dependent pathway. In addition, Cvx stimulates a rapid increase in tyrosine phosphorylation of human platelet proteins with molecular masses of 40, 72/74, 78/80 and 120 kDa, followed by dephosphorylation of some proteins. However, platelet aggregation was accompanied by the phosphorylation of a 105-kDa molecular mass protein. Furthermore, Cvx stimulates a rapid-tyrosyl phosphorylation of a 145-kDa protein that was identified as PLC gamma 2. Protein tyrose phosphatase (PTP) induced by Cvx was not blocked when platelets were stimulated in the presence of indomethacin, apyrase, EDTA or RGDS peptide, but inhibited by staurosporine and genistein. These results indicate that PTP is chronologically proximal to Cvx binding to platelets, and it is independent of platelet aggregation or fibrinogen binding to integrin alphaIIbbeta3. On the other hand, the phosphorylation step, and the phosphorylation of the 105-kDa protein, were both inhibited by RGDS and EDTA, which suggests that the integrin alphaIIbbeta3 beta is involved in these steps. Our results, taken together, show that Cvx induces platelet IIb 3 aggregation in a similar manner as collagen and collagen-related peptides that also trigger platelet aggregation by a PTK-dependent pathway, and stimulate tyrosyl-phosphorylation of PLC gamma 2. However, Cvx is unique among platelet receptor agonists, because under test-tube stirring conditions it induces a PTP profile independently of integrin alphaIIbbeta3.
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PMID:Human platelets activation by convulxin is accompanied by tyrosyl-phosphorylation of PLCgamma2 and occurs independently of integrin alphaIIbbeta3. 1679 99

A physiological concentration of extracellular ATP stimulated biphasic Ca(2+) signal, and the Ca(2+) transient was decreased and the Ca(2+) sustain was eliminated immediately after removal of ATP and Ca(2+) in RBA-2 astrocytes. Reintroduction of Ca(2+) induced Ca(2+) sustain. Stimulation of P2Y(1) receptors with 2-methylthioadenosine 5'-diphosphate (2MeSADP) also induced a biphasic Ca(2+) signaling and the Ca(2+) sustains were eliminated using Ca(2+)-free buffer. The 2MeSADP-mediated biphasic Ca(2+) signals were inhibited by phospholipase C (PLC) inhibitor U73122, and completely blocked by P2Y(1) selective antagonist MRS2179 and protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) whereas enhanced by PKC inhibitors GF109203X and Go6979. Inhibition of capacitative Ca(2+) entry (CCE) decreased the Ca(2+)-induced Ca(2+) entry; nevertheless, ATP further enhanced the Ca(2+)-induced Ca(2+) entry in the intracellular Ca(2+) store-emptied and CCE-inhibited cells indicating that ATP stimulated Ca(2+) entry via CCE and ionotropic P2X receptors. Furthermore, the 2MeSADP-induced Ca(2+) sustain was eliminated by apyrase but potentiated by P2X(4) allosteric effector ivermectin (IVM). The agonist ADPbetaS stimulated a lesser P2Y(1)-mediated Ca(2+) signal and caused a two-fold increase in ATP release but that were not affected by IVM whereas inhibited by PMA, PLC inhibitor ET-18-OCH(3) and phospholipase D (PLD) inhibitor D609, and enhanced by removal of intra- or extracellular Ca(2+). Taken together, the P2Y(1)-mediated Ca(2+) sustain was at least in part via P2X receptors activated by the P2Y(1)-induced ATP release, and PKC played a pivotal role in desensitization of P2Y(1) receptors in RBA-2 astrocytes.
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PMID:Functional characterization of P2Y1 versus P2X receptors in RBA-2 astrocytes: elucidate the roles of ATP release and protein kinase C. 1807 86

One of the important functions of vascular endothelial cells is as a barrier between blood and vascular tissue. This led us to speculate that cancer cells affect endothelial cells during metastasis. In the present study, we investigated the influence of human fibrosarcoma cells (HT-1080) on human umbilical vein endothelial cells (HUVEC), particularly intracellular calcium ion levels ([Ca2+]i), which are known to be an important intracellular signal transduction factor. HUVEC were treated with a fluorescent marker, and the fluorescence intensity of [Ca2+]i was then measured by phase contrast microscopic imaging. Extracellular adenosine triphosphate (ATP) release was measured using the chemiluminescence of luciferin-luciferase and a photon counting imaging system. HT-1080 (5x10(4) cells per dish) was found to increase [Ca2+]i in HUVEC. This [Ca2+]i rise was significantly reduced by U-73122 (phospholipase C inhibitor, 1 microM) and thapsigargin (calcium pump inhibitor, 1 microM). Interestingly, the [Ca2+]i rise in HUVEC was also significantly reduced by pyridoxalphosphare-6-azophenyl-2', 4'-disulfonic acid, a P2Y receptor antagonist (100 microM) and apyrase, a nucleotidase inhibitor (2 U/ml). In addition, we observed ATP release from HT-1080. These results suggest that [Ca2+]i in HUVEC was increased through the phospholipase C-IP3 pathway via ATP release from cancer cells. We previously reported that extracellular ATP increased [Ca2+]i and enhanced macromolecular permeability via the P2Y receptor. In tumor metastasis, cancer cells may exploit these regulatory mechanisms in the endothelial cell layer.
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PMID:Effect of P2 receptor on the intracellular calcium increase by cancer cells in human umbilical vein endothelial cells. 1821 93

We examined the effects of lysophosphatidic acid (LPA) on microglia, which may play an important role in the development and maintenance of neuropathic pain. LPA caused membrane ruffling as detected by scanning electron microscopy, and increased the expression of brain-derived neurotrophic factor (BDNF) in a primary culture of rat microglia, which express LPA(3), but not LPA(1) or LPA(2) receptors. These actions were inhibited by a Galpha(q/11)-antisense oligodeoxynucleotide (AS-ODN), U73122, an inhibitor of phospholipase C (PLC), and apyrase, which specifically degrades ATP and ADP. When ATP release was measured using a luciferin-luciferase bioluminescence assay, LPA was shown to increase it in an LPA(3) and PLC inhibitor-reversible manner. However, LPA-induced ATP release was also blocked by the Galpha(q/11) AS-ODN, but not by pertussis toxin. These results suggest that LPA induces the release of ATP from rat primary cultured microglia via the LPA(3) receptor, Galpha(q/11) and PLC, and that the released ATP or ectopically converted ADP may in turn cause membrane ruffling via P2Y(12) receptors and Galpha(i/o) activation, and BDNF expression via activation of P2X(4) receptors.
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PMID:Lysophosphatidic acid-induced membrane ruffling and brain-derived neurotrophic factor gene expression are mediated by ATP release in primary microglia. 1868 May 54

Streptokinase (SK) is one of the plasminogen activators currently used in therapeutics. SK antibodies may appear in the blood after thrombolytic therapy with SK or after ss-hemolytic streptococci infection. Such antibodies may both activate platelets and neutralize the ability of SK to convert plasminogen into plasmin. We previously demonstrated that platelet activation induced by the combination of IgG anti-SK and anisoylated plasminogen-SK activator complex (APSAC) is mediated by Fgamma7RIIal receptor. However, the mechanism by which IgG anti-SK and APSAC (or SK) transduce an activating signal across the platelet plasma membrane remains unknown. We have demonstrated in the present study that the platelet aggregation induced by the combination of IgG anti-SK and APSAC is accompanied by an increase in inositol phosphate, Ca(2+) mobilization and thromboxane (Tx) A2 generation. Neomycin, erbstatin and GF 109203X, which inhibit phospholipase C (PLC), protein tyrosine kinase (PTK) and protein kinase C (PKC) activities, respectively, abolished platelet aggregation induced by IgG anti-SK plus APSAC, indicating the pivotal roles of the PLC, PTK and PKC pathways in this immunological activation. In addition, TxA2 generation is also important since aspirin, a cyclo-oxygenase inhibitor and SQ 29548, a TxA2 receptor antagonist, showed significant inhibition of the platelet response. The contribution of released ADP was confirmed using apyrase, which significantly inhibited IgG anti-SK plus APSAC-induced platelet aggregation. Finally, WEB 2086, a platelet-activating factor (PAF) receptor antagonist, was not effective, indicating that PAF is not involved in this process. APSAC- or SK-induced platelet activation may limit the therapeutic effectiveness of the drug and may contribute to the pathogenesis of early reocclusion. The study of the mechanism leading to APSAC-induced platelet activation could be relevant for a better understanding of the physiopathology of immune complex disorder diseases and thrombolytic treatment failure.
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PMID:Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex. 2029 34


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