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)

The CD43 coreceptor molecule has been shown to participate in lymphocyte adhesion and activation. Leukocyte homotypic aggregation results from a cascade of intracellular signals delivered to the cells upon engagement of different cell-surface molecules with their natural ligands. This phenomenon requires an active metabolism, reorganization of the cytoskeleton, and relocalization of cell-surface molecules. The aim of this study was to identify some of the key members of the signaling cascade leading to T lymphocyte homotypic aggregation following CD43 engagement. CD43-mediated homotypic aggregation of T lymphocytes required the participation of Src kinases, phospholipase C-gamma2, protein kinase C, phosphatidylinositol-3 kinase, as well as extracellular-regulated kinase 1/2 and p38. Data shown here suggest that these signaling molecules play a central role in regulating actin cytoskeleton remodeling after CD43 ligation. We also evaluated the ability of immunomodulatory drugs such as leflunomide to block the CD43-mediated homotypic aggregation. Leflunomide blocked the recruitment of targets of the Src family kinases as well as actin polymerization, diminishing the ability of T lymphocytes to aggregate in response to CD43-specific signals, suggesting that this drug might control the migration and recruitment of lymphoid cells to inflamed tissues.
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PMID:T cell aggregation induced through CD43: intracellular signals and inhibition by the immunomodulatory drug leflunomide. 1297 8

The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
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PMID:CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2. 1459 37

The small GTPase, Rap1, is a potent activator of leukocyte integrins and enhances the adhesive activity of lymphocyte function-associated antigen-1 (LFA-1) when stimulated by the T cell receptor (TCR) or chemokines. However, the mechanism by which Rap1 is activated remains unclear. Here, we demonstrate that phospholipase C (PLC)-gamma1 plays a critical role in the signaling pathway leading to Rap1 activation triggered by the TCR. In Jurkat T cells, TCR cross-linking triggered persistent Rap1 activation, and SDF-1 (CXCL12) activated Rap1 transiently. A phospholipase C inhibitor, U73122, abrogated Rap1 activation triggered by both the TCR and SDF-1 (CXCL12). PLC-gamma1-deficient Jurkat T cells showed a marked reduction of TCR-triggered Rap1 activation and adhesion to intercellular adhesion molecule-1 (ICAM-1) mediated by LFA-1. In contrast, SDF-1-triggered Rap1 activation and adhesion were not affected in these cells. Transfection of these cells with an expression plasmid encoding PLC-gamma1 restored Rap1 activation by the TCR and the ability to adhere to ICAM-1, accompanied by polarized LFA-1 surface clustering colocalized with regulator of adhesion and polarization enriched in lymphoid tissues (RAPL). Furthermore, when expressed in Jurkat cells, CalDAG-GEFI, a calcium and diacylglycerol-responsive Rap1 exchange factor, associated with Rap1, and resulted in enhanced Rap1 activation and adhesion triggered by the TCR. Our results demonstrate that TCR activation of Rap1 depends on PLC-gamma1. This activity is likely to be mediated by CalDAG-GEFI, which is required to activate LFA-1.
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PMID:Rap1-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-gamma1. 1470 43

Enterovirus 70 (EV70) is one of several human enteroviruses that exhibit a propensity for infecting the central nervous system (CNS). The mechanisms by which neurotropic enteroviruses gain access to and invade the CNS are poorly understood. One possibility is that circulating leukocytes become infected and carry neurotropic enteroviruses to the CNS. We examined the ability of EV70 to infect cell lines derived from lymphoid, myeloid, and monocytic lineages. Most leukocyte cell lines tested bound radiolabeled EV70 and were permissive for EV70 replication, suggesting that EV70, in contrast to other enteroviruses, has an in vitro tropism that includes lymphoid, monocytic, and myeloid cell lines. For some of the cell lines, virus binding and infection correlated with surface expression of decay-accelerating factor (DAF), an attachment protein for EV70 on HeLa cells. However, EV70 also adsorbed to and infected cell lines that expressed little or no DAF. In contrast to what was observed for HeLa cells, neither DAF-specific monoclonal antibodies nor phosphatidylinositol-specific phospholipase C treatment inhibited EV70 binding to permissive leukocyte cell lines, and antibody blockade of DAF had little or no effect on EV70 replication. We also found that neither the human coxsackievirus-adenovirus receptor nor intercellular cell adhesion molecule 1, which mediate the entry of coxsackie B viruses and coxsackievirus A21, respectively, functions as a receptor for EV70. EV70 binding to all cell lines was sensitive to sialidase treatment and to inhibition of O glycosylation by benzyl N-acetyl-alpha-D-galactosaminide. Taken together, these results suggest that a sialylated molecule(s) other than DAF serves as a receptor for EV70 on permissive human leukocyte cell lines.
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PMID:Binding to decay-accelerating factor is not required for infection of human leukocyte cell lines by enterovirus 70. 1499 Jun 87

8p11 myeloproliferative syndrome (EMS) is a hematopoietic stem cell disorder characterized by myeloid hyperplasia and non-Hodgkin's lymphoma with chromosomal translocations fusing several genes, most commonly ZNF198, to fibroblast growth factor receptor-1 (FGFR1). However, patients with BCR-FGFR1 fusion present with typical chronic myeloid leukemia (CML). We demonstrate that ZNF198-FGFR1 induces EMS-like disease in mice, with myeloproliferation and T lymphoma arising from common multipotential progenitors. Mutation of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying phospholipase C-gamma1 as a downstream effector. Bcr-FGFR1 binds Grb2 via Bcr Tyr177 and induces CML-like leukemia in mice, whereas Bcr-FGFR1/Y177F lacks Grb2 binding and causes EMS-like disease. These results implicate different signaling pathways originating from both kinase and fusion partner in the pathogenesis of CML and EMS.
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PMID:Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. 1505 Sep 20

The presence of acetylcholinesterase (AChE) mRNA and activity in the tissues and cells involved in immune responses prompted us to investigate the level and pattern of AChE components in spleen. AChE activity was higher in mouse spleen (0.46 +/- 0.13 micromol of acetylthiocholine split per hour and per mg protein) than in muscle or heart, but lower than in brain. The spleen was essentially free of butyrylcholinesterase (BuChE) activity. About 40% of spleen AChE was extracted with a saline buffer, and a further 40% with 1% Triton X-100. Sedimentation analyses, the splitting of subunits in AChE dimers, phosphatidylinositol-specific phospholipase C (PIPLC) exposure, and phenyl-agarose chromatography showed that hydrophilic (G1H, 43%) and amphiphilic AChE monomers (G1A, 36%), as well as amphiphilic dimers (G2A, 21%), occurred in spleen. All these molecules bound to fasciculin-2-Sepharose, although the extent of binding was higher for G1H (77%) than for G1A (63%) or G2A (48%) forms. Differences in the extent to which wheat germ lectin (WGA) adsorbed with AChE of mouse spleen and of erythrocyte allowed us to discard the blood origin of spleen AChE activity. A 62 kDa protein was labeled in spleen samples using antibodies against human AChE. The protein was attributed to AChE monomers since its size was the same, regardless of whether disulfide bonds were reduced or not. Since cholinergic stimulation modulates proliferation/maturation of lymphoid cells, AChE may be important for regulating the level of acetylcholine (ACh) in the neighborhood of cholinergic receptors (AChR) in spleen and other lymphoid tissues.
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PMID:Molecular properties of acetylcholinesterase in mouse spleen. 1508 30

Adaptor proteins have important functions in coupling stimulation through immunoreceptors with downstream events. The adaptor linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) is expressed in various immune cell types and has a similar domain structure as linker for activation of T cells (LAT). In this study we generated a LAB transgenic mouse to compare the functional differences between LAB and LAT. A LAB transgene expressed in LAT-deficient T cells was able to restore T cell development. However, these mice developed severe organomegaly with disorganized lymphoid tissues. Lymphocytes from these transgenic mice were hyperactivated, and T cells produced large amounts of type II cytokines. In addition, these activities appeared to be uncoupled from the TCR. An examination of the signaling capabilities of these T cells revealed that LAB resembled a LAT molecule unable to bind phospholipase C-gamma1.
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PMID:Linker for activation of B cells: a functional equivalent of a mutant linker for activation of T cells deficient in phospholipase C-gamma1 binding. 1515 99

Metabotropic glutamate receptors (mGluR) are present in cells of the nervous system, where they are activated by one of the main neurotransmitters, glutamate. They are also expressed in cells outside the nervous system. We identified and characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in human cell lines of lymphoid origin and in resting and activated lymphocytes from human peripheral blood. Both are highly expressed in the human Jurkat T cell line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only upon activation via the T cell receptor-CD3 complex. Group I receptors in the central nervous system are coupled to phospholipase C, whereas in blood lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C nor to calcium channels and whose activation does not increase cAMP, activates the mitogen-activated protein kinase cascade. The differential expression of mGluR in resting and activated lymphocytes and the different signaling pathways that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of glutamate in the regulation of T cell physiological function. The study of the signaling pathways (cAMP production and ERK1/2 phosphorylation) and the proliferative response obtained in the presence of glutamate analogs suggests that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported inhibition of cell proliferation evoked by glutamate, which is reverted by the activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite glutamate effects in human lymphocytes.
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PMID:Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation. 1518 89

Cerebrospinal fluid prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with Alzheimer's disease (AD), which suggests that they are involved in neurodegeneration. We previously reported that TNF-alpha derived from human macrophages, in response to beta-amyloid or amyloidogenic C-terminal peptide, is a main mediator of inflammatory neurotoxicity. In a continuation of this work, the present study investigated the direct effect of PGE2, one of the major prostaglandins produced in the brain, on cell viability in SH-SY5Y neuronal cells treated with TNF-alpha. PGE2 did not promote neurotoxicity, but rather had a strong protective effect against TNF-alpha by ameliorating TNF-alpha-induced apoptosis and also by rescuing the intracellular level of beta-catenin, a key transducer of the Wnt signaling pathway. PGE2-mediated stabilization of beta-catenin was accompanied by T-cell factor/lymphoid enhancer factor (Tcf/Lef)-mediated transcriptional activation, which was followed by an increase in the cyclinD1 level. Pharmacological studies provided further evidence supporting the notion that PGE2-mediated neuroprotection against TNF-alpha involves the stimulation of Tcf/Lef signaling through EP1-, EP2-, and EP4-mediated increases of beta-catenin in SH-SY5Y cells. In addition, this PGE2 effect appears to be dependent on the activation of protein kinase A, phosphatidylinositol 3-kinase, phospholipase C, and to a lesser extent protein kinase C. Thus, the molecular mechanism governing the inhibitory effect of PGE2 against TNF-alpha may involve the activation and cross talk of multiple signal transduction and play an important role in regulating the survival of neurons during the neurotoxic inflammatory response associated with neurodegenerative diseases including AD.
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PMID:Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-alpha: possible involvement of multiple signal transduction and beta-catenin/T-cell factor. 1534 93

Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1alpha. Here, we have examined the effect of Hif-1alpha, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1alpha under "normoxic" conditions, we achieved constitutive stabilization of Hif-1alpha through thymic deletion of Vhlh and reversed Hif-1alpha stabilization with double deletion of Vhlh and Hif-1alpha. We found that constitutive activity of Hif-1alpha resulted in diminished Ca(2+) response upon TCR crosslinking despite equivalent activation of phospholipase C(gamma1), normal intracellular Ca(2+) stores, and normal entry of Ca(2+) across the plasma membrane. Altered Ca(2+) response was instead due to accelerated removal of Ca(2+) from the cytoplasm into intracellular compartments, which occurred in association with Hif-1alpha-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1alpha, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.
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PMID:Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. 1628 58


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