Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quantification of human peripheral blood NK subsets has been made in a group of Kenyan adults and children with acute P. falciparum malaria. Results were compared with data obtained from three age- and sex-matched control cohorts: parasitaemic but asymptomatic children; aparasitaemic children and adults; and adult Caucasians with no previous history of malaria. Separated NK subsets were tested in vitro for cytotoxicity to erythrocytic schizonts of P. falciparum in the presence and absence of cytokines. There was a statistically significant quantitative and qualitative depression of the CD3-CD56+ subset in patients with acute malaria and this was accompanied by an expansion of the 'non-functional' CD3-CD57+CD16-CD56- subset. Both CD3-CD16+ and CD3-CD56+ NK cells from all patients and donors lysed schizonts, and this cytotoxicity was enhanced by the addition of recombinant interferon-alpha and/or IL-2, notably with the CD3-CD56+ subset. Interestingly, asymptomatic donors had the highest levels of CD3-CD56+ NK cells, which also demonstrated an enhanced response to cytokine stimulation. Cytotoxicity to schizonts was accompanied by the release of soluble NK cell lytic factors. Neomycin suppressed cytotoxicity in a dose-dependent manner, indicating that the lysis of schizonts by NK cells involves phospholipase C-mediated phosphoinositide metabolism. Our findings define a role for NK cells in immunity to malaria through the lysis of infected erythrocytes as a first-line defence against the parasite.
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PMID:Cytotoxicity of human natural killer (NK) cell subsets for Plasmodium falciparum erythrocytic schizonts: stimulation by cytokines and inhibition by neomycin. 183

The expression of the neural cell adhesion molecule (N-CAM) on cultured murine oligodendrocytes, their precursors, and myelin was examined by indirect immunofluorescence, biosynthetic radiolabeling followed by immunoprecipitation and Western blot analysis, using antibodies specific for various forms of the molecule. In all culture systems studied, whether the oligodendrocytes were cultured as an enriched fraction containing precursor cells or in the presence of astrocytes and neurons, a similar differentiation-stage-related expression of N-CAM was seen. At early developmental stages many tetanus toxin receptor- and A2B5 antigen-positive putative oligodendrocyte precursors with bipolar morphology were seen and found to express N-CAM in its embryonic form. Of the 04 antigen-positive immature oligodendrocytes with few slender processes most expressed N-CAM, but few the embryonic form of N-CAM. The more mature 01 or 010 antigen-positive oligodendrocytes were found to express exclusively the adult form of N-CAM. Oligodendrocytes synthesized the 120 and 140 kD forms of N-CAM (N-CAM 120 and N-CAM 140), but not N-CAM 180, although with differentiation, N-CAM 120 predominated in oligodendrocytes and also in pure myelin. N-CAM 120 could be released from oligodendrocytes and myelin by phosphatidylinositol-specific phospholipase C, suggesting that in both oligodendrocytes and myelin N-CAM 120 is inserted into the membrane by covalent linkage to phosphatidylinositol.
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PMID:Differentiation-regulated loss of the polysialylated embryonic form and expression of the different polypeptides of the neural cell adhesion molecule by cultured oligodendrocytes and myelin. 266 42

CD55 and CD59 are both glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins found on the surface of most hemopoietic cells. Using three-color cytofluorographic analysis with antibodies recognizing CD56, CD3, and CD59 or CD55 we determined that CD56+CD3- lymphocytes (NK cells) expressed both CD55 and CD59 but at lower levels than CD3+ lymphocytes. Since the CD56+CD3- lymphocyte population is heterogeneous, we examined expression of CD55 and CD59 on selected CD56+CD3- lymphocyte populations by depleting peripheral blood leukocytes of T cells, B cells, and monocytes. Dual staining of the selected CD56+CD3- cells, which were > 95% CD56+, permitted the distiction of two subpopulations: a major CD16brightCD56dimCD55dimCD59dim subpopulation and a minor CD16dim/negCD56brightCD55brightCD59bright subpopulation. Treatment with phosphatidylinositol-specific phospholipase C released both the CD55 and CD59 antigens from the surface of CD56+CD3- cells, indicating that both are GPI-anchored, as they are on other lymphocytes. CD56+CD3- cell subpopulations were individually isolated by anti-CD55 or anti-CD16 negative selection and were functionally compared to the parent CD56+CD3- cell population. The CD16brightCD56dimCD55dimCD59dim cells killed NK targets well but did not proliferate well in response to rIL-2, whereas CD16dim/negCD56brightCD55brightCD59bright cells proliferated well in response to rIL-2 but did not kill NK targets efficiently. We conclude that all CD56+CD3- cells express some levels of the GPI-anchored proteins, CD55 and CD59, and that two CD56+CD3- subpopulations with different functional characteristics can be distinguished by the level of expression of these two antigens.
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PMID:Expression of GPI-anchored complement regulatory proteins CD55 and CD59 differentiates two subpopulations of human CD56+ CD3- lymphocytes (NK cells). 755 95

We present evidence that the neurite out-growth stimulated by the binding of Thy-1 antibodies to PC12 cells is mediated by calcium influx through both N- and L-type calcium channels. PC12 cells cultured on a noncellular substratum in the presence of NGF, or on a cellular substratum in the absence of NGF, responded to soluble Thy-1 antibody by extending longer neurites. The response required bivalent antibody and could be blocked by removing Thy-1 from the surface of PC12 cells with phosphatidylinositol specific phospholipase C. The response could also be blocked by reducing extracellular calcium to 0.25 mM, or by antagonists of L- and N-type calcium channels. Additionally, the response could be fully inhibited by preloading PC12 cells with BAPTA/AM which buffers changes in intracellular calcium. A heterotrimeric G-protein is also implicated in the pathway as the response could be fully inhibited by pertussis toxin. These data suggest that antibody-induced clustering of Thy-1 stimulates neurite outgrowth by activating a second messenger pathway that has previously been shown to underlie cell adhesion molecule (NCAM, N-cadherin, and L1), but not integrin or NGF-dependent neurite outgrowth.
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PMID:Thy-1 antibody-triggered neurite outgrowth requires an influx of calcium into neurons via N- and L-type calcium channels. 810 Feb 30

We have used monolayers of control 3T3 fibroblasts and 3T3 fibroblasts expressing transfected cell adhesion molecules (CAMs)--NCAM, N-cadherin, and L1--as a culture substrate for cerebellar neurones. The transfected CAMs promote neurite outgrowth by activating a second messenger pathway that culminates in calcium influx into neurones through N- and L-type calcium channels. We show that the same neurite outgrowth response can be directly induced by arachidonic acid (10 microM) and that this response can be inhibited by N- and L-type calcium channel antagonists. In cells, arachidonic acid can be generated by phospholipase A2 or by the sequential activities of a phospholipase C (to generate diacylglycerol) and diacylglycerol lipase. In the present study we show the neurite outgrowth stimulated by CAMs (but not by various other agents) can be abolished by an inhibitor of diacylglycerol lipase acting at a site upstream from calcium channel activation. The results suggest that arachidonic acid and/or one of its metabolites is the second messenger that activates calcium channels in the CAM signalling pathway leading to axonal growth, and this is supported by recent evidence that shows the same concentrations of arachidonic acid can increase voltage-dependent calcium currents in cardiac myocytes.
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PMID:The production of arachidonic acid can account for calcium channel activation in the second messenger pathway underlying neurite outgrowth stimulated by NCAM, N-cadherin, and L1. 811 7

Cell adhesion molecules (CAMs) have been shown to stimulate axonal growth. The molecular basis of this response has been extensively studied and a range of agents that promote or inhibit CAM stimulated axonal growth have now been identified. These studies have led to the suggestion that following homophilic and/or heterophilic interactions CAM specific signal transduction pathways are activated which are directly responsible for promotion of axonal growth. In this review we will suggest that the axonal growth response stimulated by three CAMs (NCAM, N-cadherin and L1) can be operationally divided into a number of phases. During the first phase homophilic and/or heterophilic binding between the CAMs expressed on the axonal growth cone and cellular substrate take place. This is followed by an interaction of the neuronal CAMs with the fibroblast growth factor receptor (FGFR), leading to receptor activation by autophosphorylation. This results in the recruitment and activation of additional effector molecules via interactions of their SH2 domains with the activated receptor. In this context the key event in terms of neurite outgrowth appears to be the activation of phospholipase C gamma (PLC gamma) which sets into motion a second messenger cascade that ultimately leads to a modification, most likely by phosphorylation, of cytoskeletal elements that are involved in growth cone motility.
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PMID:Review: a role for the FGF receptor in the axonal growth response stimulated by cell adhesion molecules? 880 88

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.
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PMID:Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. 905 94

A minor fraction of the total ecto-type (E-type) ATPase activity of rat synaptosomes has been detected in immunoprecipitates of the neural cell adhesion molecule, NCAM, indicating that this either is an intrinsic enzymatic activity of NCAM or of an ATPase tightly associated to NCAM [Dzhandzhugazyan & Bock (1993) FEBS Lett. 336, 279-283]. We here demonstrate ATPase activity in preparations of the lipid-anchored as well as the transmembrane NCAM isoforms immunoisolated from transfected L-cells. A fraction of the E-type ATPase activity is spontaneously released from synaptosomes. Released material was fractionated by various chromatographic procedures and an extracellular fragment of NCAM was shown to co-elute with the major part of the enzymatic activity. Furthermore, it was shown that agarose-coupled NCAM-antibodies retained 85% of the ATPase activity released from synaptosomes after treatment with phosphatidylinositol-specific phospholipase C. These findings restricted the association or expression of the enzymatic activity to the extracellular part of NCAM. An affinity reagent, 5'-p-fluorosulfonylbenzoyl adenosine, FSBA, was shown to inhibit ATPase activity of immunoisolated NCAM, and incorporation of FSBA was detected in all three major NCAM isoforms (A, B, and C). An excess of ATP prevented both inactivation of the enzyme and affinity labeling of NCAM. Thus, NCAM contains an ATP-binding site, and this site is localized extracellularly and probably has the catalytic function. Binding of the substrate or FSBA protected a proteolytic cleavage site in NCAM localized close to the membrane presumably by induction of a local conformational change in NCAM, indicating a mechanism by which ATP may regulate NCAM adhesion and adhesion-triggered processes. A possible role of this mechanism in synaptic plasticity and memory consolidation is proposed.
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PMID:Demonstration of an extracellular ATP-binding site in NCAM: functional implications of nucleotide binding. 939 68

The mechanisms underlying nerve growth have been extensively studied, and it has been found that the three cell adhesion molecules (CAMs) L1, NCAM and N-cadherin play a key role in this process. All three CAMs are able to stimulate axonal growth from a variety of neuronal cells, and a range of agents which either mimic or inhibit CAM stimulated neurite outgrowth have been identified and has provided a basis for understanding the nature of the response. Results from these studies suggested that activation of a tyrosine kinase-phospholipase C gamma (PLC gamma) cascade was required for the CAM response. Following the identification of a CAM-homology domain (CHD) within the fibroblast growth factor receptor (FGFR) and a putative CHD-binding motif within each of the CAMs, it was suggested that this might be the tyrosine kinase implicated in the CAM pathway. This has been tested experimentally in a number of ways, including the use of transgenic mice expressing a dominant-negative FGFR, and several results have now demonstrated that a functional FGFR is required for CAM stimulated neurite outgrowth. More recently, treatment of neurons with the CAMs has been shown to stimulate FGFR autophosphorylation and PLC gamma activity which in turn leads to activation of a second messenger cascade involving diacylglycerol and arachidonic acid and results in calcium influx into the neurons. Pharmacological studies have confirmed that this cascade is responsible for the neurite outgrowth response.
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PMID:Signal transduction mechanisms underlying axonal growth responses stimulated by cell adhesion molecules. 968

Tumor-associated lymphocytes (TALs) freshly isolated from patients with cancer usually manifest reduced proliferative and cytolytic functions. To determine whether alterations in signal transduction contribute to functional impairments seen in TALs, we purified populations of T and natural killer (NK) cells by negative selection from ascites of seven patients with ovarian carcinoma. The average purity was 84 +/- 5% for CD3(+) TALs and 77 +/- 10% for CD3(-)CD56(+)CD16(+) TALs. Expression of several signal transduction molecules, including the CD3-epsilon, CD3-zeta, and FcepsilonRI-gamma chains, p56(lck) protein tyrosine kinase, and phospholipase C-gamma1, was studied in these cells using Western blotting. A marked decrease in expression of zeta and FcepsilonRI-gamma associated with CD3 or FcgammaRIIIA was observed in T or NK cells obtained from TALs, as compared to T or NK cells purified from normal peripheral blood. Expression of CD3-epsilon, as assessed using flow cytometry, Western blotting, or ELISA was also reduced in purified TAL-T cells relative to that in normal peripheral blood T cells. Surface expression of CD3 on T cells and FcgammaRIIIA on NK cells obtained from TALs was significantly decreased in comparison to normal peripheral blood lymphocytes (PBLs): the mean fluorescence intensity of CD3 was 277 +/- 18 for TAL-T (n = 7) versus 349 +/- 13 for PBL-T (n = 9) and that of CD16 was 58 +/- 1 for TAL-NK (n = 7) versus 385 +/- 55 for PBL-NK (n = 23) cells. These observations suggest a defect in assembly of T cell receptor and FcgammaRIIIA multicomponent transmembrane receptors, which are zeta and gamma dependent. In addition to alterations in expression, the function of these receptors was also modified, since cross-linking of CD3 on TAL-T and CD16 on TAL-NK cells with the respective monoclonal antibodies resulted in a pattern of protein phosphorylation that was distinct from that observed in normal PBLs. Expression of tyrosine kinase p56(lck) and its kinase activity were also depressed, while expression of phospholipase C-gamma1 appeared to be normal in most preparations of the TALs tested. In vitro proliferation of TAL-T in response to anti-CD3 monoclonal antibody and TAL-NK cells to interleukin 2 were significantly depressed as was the ability to produce IFN-gamma. In contrast, TAL-T cells were able to produce interleukin 10 at levels similar to those secreted by normal PBLs. Thus, in TALs obtained from patients with advanced ovarian cancer, alterations in expression and activity of signaling molecules were associated with reduced cellular functions such as proliferation and production of certain cytokines.
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PMID:Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. 981 3


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