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)

Human UC11 astrocytoma cells were used to investigate the role of protein kinase C (PKC) and other kinases in neurokinin (NK)1 receptor desensitization. The selective NK1 receptor agonist [Sar9,Met(O2)11]-substance P stimulated a biphasic accumulation of [3H]inositol phosphates ([3H]IPs) in the presence of 10 mM LiCl in cells that had been prelabeled with [3H]inositol. An initial rapid phase of [3H]IP accumulation during the first 1 min was followed by a slower sustained phase for up to 90 min. These results demonstrate that the human NK1 receptor desensitizes rapidly but only partially. The selective PKC inhibitor Ro31-8220 did not prevent rapid NK1 receptor desensitization but after a longer incubation significantly potentiated human NK1 receptor agonist-stimulated accumulation of [3H]IPs. These results suggest that, although PKC does not mediate the process of rapid desensitization, it does have an inhibitory role at later times. This conclusion is supported by studies with staurosporine, phorbol dibutyrate, and the protein phosphatase inhibitor okadaic acid. Studies using AlF4-, an agent that can directly activate G proteins, and Ro31-8220 suggested that PKC can exert inhibitory effects 'downstream' of receptor activation, although immunoprecipitation of the G proteins alpha q/alpha 11 demonstrated that they do not undergo phosphorylation in UC11 cells and are unlikely to be the target of PKC-mediated inhibitory feedback. Delayed inhibitory feedback by PKC may be mediated by phosphorylation of phospholipase C, although an additional site of action on the NK1 receptor cannot be ruled out.
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PMID:Protein kinase C mediates delayed inhibitory feedback regulation of human neurokinin type 1 receptor activation of phospholipase C in UC11 astrocytoma cells. 752 12

The nature of the senktide response of the human NK3 receptor expressed in Chinese hamster ovary cells was characterised using the Ca2+ sensitive dye Fura-2 and imaging methods. Application of the NK3 receptor agonist senktide caused an increase in [Ca2+]i in the cells. The profile for NK3 receptor agonists was that senktide was more potent than [beta-Ala8]neurokinin A-(4-10) which was more potent than [Sar9,Met(O2)11]substance P. SR 48968 was a poor antagonist of the senktide response in intact cells confirming the weak affinity of this agent for the NK3 receptor (IC50 of approximately 1 microM) shown in binding assays. The NK3 receptor mediated increase in intracellular Ca2+ was independent of [Ca2+]o, blocked by the microsomal Ca2+ ATPase inhibitor thapsigargin and the phospholipase C inhibitor U73122 but not by ryanodine. Thus the source of the Ca2+ was probably a ryanodine insensitive, inositol triphosphate sensitive intracellular store.
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PMID:Characterization of tachykinin mediated increases in [Ca2+]i in Chinese hamster ovary cells expressing human tachykinin NK3 receptors. 753 Feb 8

The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in mediating neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a condition associated with hyperplasia of airway smooth muscle (ASM), we examined the mitogenic effects and mechanisms of action of tachykinins in cultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-14) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/- SE) maximal increase in cell number of 169 +/- 6.1% of control. In contrast, NKA and NKB had little and no effect on ASM cell growth, respectively. Because SP is nonselective in its binding to the tachykinin receptors, to identify the specific NK receptor subtype(s) mediating the promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala4, Sar9, Met(O2)11]SP-(4-11) induced stimulation of ASM cell growth similar in magnitude to that elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor-specific agonists, [beta-Ala8]NKA-(4-10) and [MePhe7]NKB, respectively, had any effect on ASM cell growth; and 3) the promitogenic action of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreover, in extended experiments, we found that the phospholipase C and phospholipase A2 inhibitors, neomycin and quinacrine, respectively, each inhibited SP-induced ASM cell proliferation by approximately 45%. Collectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 receptor.
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PMID:Tachykinin regulation of airway smooth muscle cell proliferation. 757 67

The SH2 domains of cytoplasmic signaling proteins bind to autophosphorylated growth factor receptors by direct recognition of specific phosphotyrosine-containing sites. To identify the phosphotyrosine involved in association of phospholipase C (PLC)-gamma 1 with the beta platelet-derived growth factor receptor (PDGFR), and to investigate which contiguous residues confer specificity for PLC-gamma 1, phosphotyrosine-containing glutathione S-transferase (GST) fusion proteins possessing different regions of the beta-PDGFR were incubated with lysates of Rat-2 cells that overexpress PLC-gamma 1. The phosphorylated C-terminal tail of the PDGFR bound PLC-gamma 1, but did not associate with phosphatidylinositol (PI) 3'-kinase or GTPase-activating protein (GAP). High-affinity binding of PLC-gamma 1 was dependent on phosphorylation of Tyr-1021. Creation of a new phosphorylation site by replacing Asp-1018 with tyrosine did not restore binding of PLC-gamma 1 in the absence of Tyr-1021, indicating that the location of the phosphorylated tyrosine is important for PLC-gamma 1 binding. Substitution of the proline at the +3 position relative to Tyr-1021 with methionine (Y1021IIP-->Y1021IIM) in the phosphorylated PDGFR tail did not alter PLC-gamma 1 association, but conferred binding activity towards PI 3'-kinase, indicating that this residue is critical in discriminating between PLC-gamma 1 and PI 3'-kinase. Progressive conversion of the three residues C-terminal to Tyr-1021 to the consensus for PI 3'-kinase binding (YMDM) allowed PI 3'-kinase association, but did not block PLC-gamma 1 binding, suggesting that additional residues other than the three residues immediately following the phosphotyrosine may contribute to the association of PLC-gamma 1 with the PDGFR. These results indicate that phosphorylation at Tyr-1021 in the tail of the PDGFR creates a specific binding site for PLC-gamma 1. Proline at the +3 position relative to Tyr-1021 is crucial in conferring specificity for binding to PLC-gamma 1.
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PMID:Identification of residues in the beta platelet-derived growth factor receptor that confer specificity for binding to phospholipase C-gamma 1. 768 24

The activation of the respiratory burst by complement factor 5a (C5a), platelet-activating factor (PAF), formyl-Met-Leu-Phe (fMLP) and neutrophil-activating peptide IL-8 was explored in eosinophils from patients with the hypereosinophilic syndrome. The amplitude of the response increased with increasing concentrations of C5a and PAF, but the time for its induction was unaffected by the amount of stimulus applied. Respiratory burst activity resulting from phorbol 12-myristate, 13-acetate (PMA)-mediated activation of protein kinase C (PKC) produced longer onset times, which shortened with increasing PMA concentrations. Total inhibition of the C5a- and PMA-mediated burst could be achieved with the PKC inhibitor staurosporine at concentrations of 100 and 5nM, respectively. Calcium depletion abolished agonist-induced rises in cytosolic free calcium ([Ca2+]i) and respiratory burst activity, but not PMA-mediated NADPH-oxidase activation. While PMA reduced elevations in [Ca2+]i, it restored the burst response to agonists in Ca(2+)-depleted eosinophils. These results agree with the agonist-induced activation of the NADPH-oxidase via PKC, but suggest a parallel, Ca(2+)-, phospholipase C- and PKC-independent signal transduction pathway. Data obtained with B. pertussis toxin showed that the respiratory burst in eosinophils is blocked by ADP-ribosylation of G(i)-proteins, but that in the presence of PMA portions of the agonist response could be recovered.
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PMID:Activation of the respiratory burst in eosinophil leucocytes--a transduction sequence decoupled from cytosolic Ca2+ rise. 770 83

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active alpha beta heterodimer results from proteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the alpha-chain. The interaction of the alpha-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (alpha and beta). The alpha-subunit is extracellular and heavily glycosylated. The beta-subunit consists of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the beta-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor beta-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. 776 52

We have previously reported that platelet-derived growth factor (PDGF) receptor mutants that lack high affinity binding sites for phosphatidylinositol 3-kinase (PI 3-kinase) fail to concentrate in juxtanuclear vesicular structures after activation with PDGF. We have now identified the point in the endocytic pathway at which PI 3-kinase binding sites are required. Receptor internalization from the plasma membrane, measured as the acquisition of acid resistance of prebound 125I-PDGF, was only slightly decreased in cells expressing a PDGF receptor mutant (F5) lacking PI 3-kinase, GTPase-activating protein (GAP), phospholipase C gamma, and Syp binding sites but not expressing mutants where any of these individual sites were restored nor expressing a mutant lacking exclusively PI 3-kinase binding sites. In contrast, the extent of down-regulation of PDGF binding sites from the cell surface after prolonged incubation with PDGF as well as the degradation of [35S]methionine-labeled receptor were markedly reduced in cells expressing the F5 mutant, mutants restored in GAP, phospholipase C gamma, or Syp binding sites or expressing the mutant exclusively lacking PI 3-kinase binding sites but not in cells expressing the mutant where PI 3-kinase binding sites were restored. Inhibition of PI 3-kinase activity with wortmannin caused a dramatic decrease in the rates of down-regulation and degradation of wild-type receptors. These results suggest that PI 3-kinase binding sites are not required for internalization of PDGF receptor but are required to divert the PDGF receptor to a degradative pathway. Furthermore, the requirement for PI 3-kinase binding sites on the receptor appears to be due to a requirement for PI 3-kinase catalytic activity.
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PMID:Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking. 776 21

The effects of progesterone and GTP gamma S on phospholipid N-methylation and sphingomyelin synthesis were studied in plasma-vitelline membranes isolated from amphibian (Rana pipiens) oocytes. Plasma-vitelline membranes were preincubated with S-adenosyl-L-[methyl-3H]methionine for 2 min at 20 degrees C and total phospholipids extracted at 0, 15, 30 and 60 s after addition of progesterone and/or GTP gamma S. Progesterone levels (3 microM) that induce meiosis in the intact oocyte stimulated [3H-methyl]incorporation into phosphatidylmonomethylethanolamine (PME) 9-10-fold over the first 60 s, with smaller increases in phosphatidyldimethylethanolamine (PDE) and phosphatidylcholine (PC). [methyl-3H] labeling of sphingomyelin (SM) rises after 30 s, approaching that of [methyl-3H]PME by 60 s. 17 beta-Estradiol, a noninducer of meiosis, was inactive. When oocytes were prelabeled with [3H]palmitic acid, it was found that a fall in [3H]ceramide coincides with the transient increase in [3H]SM, indicating that the end product of N-methylation (PC) undergoes a transfer reaction with ceramide to form SM and 1,2-DG. GTP gamma S levels previously reported to stimulate PC-specific phospholipase C activity in oocyte plasma membranes (5 microM) also stimulated both [methyl-3H]PME and [methyl-3H]SM formation. An inhibitor of phospholipid N-methylation, 2-(methyl-amino)ethanol, blocked stimulation of [methyl-3H]SM synthesis by both progesterone and GTP gamma S as well as induction of meiosis by progesterone. Progesterone thus acts at the oocyte plasma membrane to stimulate PE N-methyltransferase and SM synthase. The finding that GTP gamma S mimics progesterone suggests that N-methyltransferase is mediated by G-protein(s). The transient increase in 1,2-DG which we had previously reported to occur within 1-2 min following progesterone stimulation of the Rana oocyte appears to arise from PC by two different pathways: SM synthesis and hydrolysis of PC by phospholipase C.
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PMID:Progesterone-induced phospholipid N-methylation and sphingomyelin synthesis in the amphibian oocyte plasma membrane: a second source of the 1,2-diacylglycerol second messenger associated with the G2/M transition. 780 20

Calcitonin (CT) is a peptide hormone that interacts with the cAMP-and phospholipase C-associated CT receptor subtypes. We investigated whether CT modulates the interaction of human tumoral osteoclast-like (GCT23) cells with a protein of the bone matrix, bone sialoprotein-II (BSP-II). Single GCT23 cells loaded with the intracellular Ca2+ indicator fura-2 were treated with the maximal active dose (300 micrograms/ml) of the 18-mer Arg-Gly-Asp (RGD)-containing BSP-IIA fragment, and the cytosolic free Ca2+ concentration ([Ca2+]i) was measured by dual wavelength microfluorometry. BSP-IIA stimulated an elevation in [Ca2+]i, consisting mainly of a peak, followed by a rapid return toward baseline. Pretreatment with CT induced a modest elevation of [Ca2+]i. However, CT significantly inhibited the response to BSP-IIA in a dose-dependent manner. Maximal inhibition (90% vs. untreated) was observed in the micromolar range. The intracellular mechanisms leading to this effect were investigated by pretreatment of GCT23 cells with the cAMP permeant analog, (Bu2)cAMP, and the protein kinase-C-activating agent, 12-O-tetradecanoylphorbol 13-acetate. Similar to CT, both agents inhibited the response to 300 micrograms/ml BSP-IIA. The effect induced by CT was specific, because an increase in the extracellular Ca2+ concentration, which is also known to inhibit bone resorption, failed to modify the ability of BSP-IIA to alter [Ca2+]i in GCT23 cells. To investigate whether the CT-induced alteration of BSP-IIA-dependent cell signals was due to a modification in the synthesis of cell surface receptors (integrins) for the extracellular matrix macromolecules, 1-h CT-treated [35S]methionine metabolically labeled GCT23 cell lysates were immunoprecipitated with anti-alpha 3-, -alpha v-, -beta 1-, and -beta 3-integrin subunit antibodies. Autoradiography demonstrated that 10(-7)-10(-6) M CT did not alter new synthesis of the alpha v beta 3 and the alpha 3 beta 1 receptors. Similarly, CT did not affect surface expression of these receptors, assessed by enzyme-linked immunosorbent assay. Finally, no alteration of the adhesion rate and spreading of GCT23 cells onto BSP-IIA-coated substrates was observed. This indicates that CT-induced down-regulation of immediate cell signals prompted by BSP-IIA in GCT23 cells is a postintegrin receptor event.
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PMID:Calcitonin down-regulates immediate cell signals induced in human osteoclast-like cells by the bone sialoprotein-IIA fragment through a postintegrin receptor mechanism. 786 71

SH2 domains bind to specific phosphotyrosine-containing sites in a fashion dictated by the amino acids flanking the phosphotyrosine. Attention has focused on the role of the three COOH-terminal positions (+1 to +3) in generating specificity. Autophosphorylation of Tyr1021 in the tail of the beta-receptor for platelet-derived growth factor creates a specific binding site for the COOH-terminal SH2 domain of phospholipase C (PLC)-gamma 1. We show that the residues 4 and 5 amino acids COOH-terminal to Tyr1021 (+4 Leu and +5 Pro) are required for efficient PLC-gamma 1 binding, and that their replacement with the corresponding residues from a phosphatidylinositol 3'-kinase binding site abrogates stable association with PLC-gamma 1. In contrast, replacement of the +3 Pro with Met produces a Tyr1021 site with mixed specificity that binds both PLC-gamma 1 and phosphatidylinositol 3'-kinase. This motif is rendered specific for phosphatidylinositol 3'-kinase by further substitution of the +4 Leu. These results indicate that the +4 and +5 residues are important for the selective binding of specific SH2 domains. This study suggests that phosphotyrosine sites can be tailored to bind one or more SH2 domains with high affinity, depending on the combination of residues in the +1 to +5 positions.
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PMID:Construction of an SH2 domain-binding site with mixed specificity. 787 30


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