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)

Activation of protein kinase C (PKC) can result from stimulation of the receptor-G protein-phospholipase C (PLCbeta) pathway. In turn, phosphorylation of PLCbeta by PKC may play a role in the regulation of receptor-mediated phosphatidylinositide (PI) turnover and intracellular Ca(2+) release. Activation of endogenous PKC by phorbol 12-myristate 13-acetate inhibited both Galpha(q)-coupled (oxytocin and M1 muscarinic) and Galpha(i)-coupled (formyl-Met-Leu-Phe) receptor-stimulated PI turnover by 50-100% in PHM1, HeLa, COSM6, and RBL-2H3 cells expressing PLCbeta(3). Activation of conventional PKCs with thymeleatoxin similarly inhibited oxytocin or formyl-Met-Leu-Phe receptor-stimulated PI turnover. The PKC inhibitory effect was also observed when PLCbeta(3) was stimulated directly by Galpha(q) or Gbetagamma in overexpression assays. PKC phosphorylated PLCbeta(3) at the same predominant site in vivo and in vitro. Peptide sequencing of in vitro phosphorylated recombinant PLCbeta(3) and site-directed mutagenesis identified Ser(1105) as the predominant phosphorylation site. Ser(1105) is also phosphorylated by protein kinase A (PKA; Yue, C., Dodge, K. L., Weber, G., and Sanborn, B. M. (1998) J. Biol. Chem. 273, 18023-18027). Similar to PKA, the inhibition by PKC of Galpha(q)-stimulated PLCbeta(3) activity was completely abolished by mutation of Ser(1105) to Ala. In contrast, mutation of Ser(1105) or Ser(26), another putative phosphorylation target, to Ala had no effect on inhibition of Gbetagamma-stimulated PLCbeta(3) activity by PKC or PKA. These data indicate that PKC and PKA act similarly in that they inhibit Galpha(q)-stimulated PLCbeta(3) as a result of phosphorylation of Ser(1105). Moreover, PKC and PKA both inhibit Gbetagamma-stimulated activity by mechanisms that do not involve Ser(1105).
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PMID:Molecular mechanism of the inhibition of phospholipase C beta 3 by protein kinase C. 1089 37

The N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-OMe (1) analogues for-Thp-Leu-Ain-OMe (2), for-Thp-Leu-Phe-OMe (3), for-Met-Leu-Ain-OMe (4), for-Met-Delta(z)Leu-Phe-OMe (5), for-Met-Lys-Phe-For-Met-Lys-Phe (6), for-Met-Leu-Pheol-COMe (7), and for-Nle-Leu-Phe-OMe (8) have been studied. Some of these have been found selective towards the activation of different biological responses of human neutrophils. In particular, peptides 2 and 3, which evoke only chemotaxis, are ineffective in enhancing inositol phosphate, as well as cyclic AMP (cAMP) levels. On the contrary, analogues 5 and 7, which induce superoxide anion production and degranulation, but not chemotaxis, significantly increase the levels of the two intracellular messengers, as is the case of the full agonists 1 and 6. The Ca(2+) ionophore A23187 also activates phospholipase C (PLC) and increases the nucleotide levels; when tested in combination with peptide 1 or 5, a supra-additive enhancement of cAMP concentration is obtained. The PLC blocker, U-73122, inhibits the formylpeptide-induced inositol phosphate formation, as well as cAMP increase. Moreover, this drug drastically reduces superoxide anion release triggered by 1 or 5, whereas it inhibits to a much lesser extent neutrophil chemotaxis induced by 1 or 2. Our results suggest that: (i) PLC stimulation is involved in cAMP enhancement by formylpeptides; (ii) the activation of PLC by formylpeptides, in conditions of increased Ca(2+) influx, induces a supra-additive enhancement of the nucleotide; (iii) the inability of pure chemoattractants to significantly alter the PLC activity or cAMP level, differently from full agonists or peptides specific in inducing superoxide anion release, appears as a general property. Thus, the activation of neutrophil PLC seems essential for superoxide anion release, but less involved in the chemotactic response.
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PMID:Modulation of neutrophil phospholipase C activity and cyclic AMP levels by fMLP-OMe analogues. 1130 40

We examined the regulatory role of cytosolic phospholipase A(2) (cPLA(2)) and phosphatidylinositol (PI)-specific phospholipase C (PLC) in the degranulation of human eosinophils and leukotriene (LT) C(4) synthesis. Activation with formyl-Met-Leu-Phe + cytochalasin B (fMLP/B) caused a time-dependent release of eosinophil peroxidase (EPO) and LTC(4), which was inhibited by pertussis toxin. By immunoblotting, eosinophil PLC-beta2 and -gamma2 isoforms were identified, and PLC activation was measured as a function of inositol 1,4,5-trisphosphate concentration. Stimulated release of EPO and intracellular Ca(2+) concentration was inhibited by ET-18-OCH(3), a PI-PLC inhibitor, whereas trifluoromethylketone (TFMK), a cPLA(2) blocker, had no inhibitory effect. Both TFMK and ET-18-OCH(3) attenuated stimulated arachidonate release and LTC(4) secretion, suggesting that activation of both PLC and cPLA(2) is essential for LTC(4) synthesis caused by fMLP/B. The structurally unrelated protein kinase C inhibitors bisindolylmaleimide, Ro-31-8220, and Go-6976 all blocked fMLP/B-induced EPO release but not LTC(4) secretion. 1,2-bis(2-Aminophenoxy)ethane-N,N,N',N'- tetraacetic acid acetoxymethyl ester, an intracellular Ca(2+) chelator, suppressed both EPO release and LTC(4) secretion. We found that fMLP/B-induced LTC(4) secretion from human eosinophils is regulated by PI-PLC through calcium-mediated activation of cPLA(2). However, cPLA(2) does not regulate eosinophil degranulation.
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PMID:Regulation of eosinophil function by phosphatidylinositol-specific PLC and cytosolic PLA(2). 1155 88

A peptide from the C-terminal domain of thrombospondin-1 (Arg-Phe-Tyr-Val-Val-Met-Trp-Lys; known as 4N1-1) has been reported to induce platelet aggregation and to bind to the integrin-associated protein (IAP), which is also known as CD47. In this study, it was discovered that 4N1-1 or its derivative peptide, 4N1K, induces rapid phosphorylation of the Fc receptor (FcR) gamma chain, Syk, SLP-76, and phospholipase C gamma2 in human platelets. A specific inhibitor of Src family kinases, 4-amino-4-(4-methylphenyl)-7-(t-butyl) pyrazola[3,4-d]pyrimidine, prevented phosphorylation of these proteins, abolished platelet secretion, and reduced aggregation by approximately 50%. A similar inhibition of aggregation to 4N1-1 was obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR gamma chain or SLP-76 and in patients with type I Glanzmann thrombasthenia. These results show that 4N1-1 signals through a pathway similar to that used by the collagen receptor glycoprotein (GP) VI. The alphaIIbbeta3-independent aggregation induced by 4N1-1 was also observed in fixed platelets and platelets from patients with Bernard-Soulier syndrome, which are deficient in GPIbalpha. Surprisingly, the ability of 4N1-1 to stimulate aggregation and tyrosine phosphorylation was not altered in platelets pretreated with anti-IAP antibodies and in IAP-deficient mice. These results show that the C-terminal peptide of thrombospondin induces platelet aggregation through the FcR gamma-chain signaling pathway and through agglutination. The latter pathway is independent of signaling events and does not use GPIbalpha or alphaIIbbeta3. Neither of these pathways is mediated by IAP.
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PMID:C-terminal peptide of thrombospondin-1 induces platelet aggregation through the Fc receptor gamma-chain-associated signaling pathway and by agglutination. 1171 73

His-Phe-Tyr-Leu-Pro-Met (HFYLPM) is a synthetic peptide that stimulates Jurkat T cells resulting in intracellular calcium ([Ca2+]i) increase in a pertussis toxin (PTX)-sensitive manner. We have examined the physiological role of the peptide in T cell activity by comparative investigation of intracellular signaling pathways accompanied with HFYLPM-induced T cell chemotaxis with a well-known chemokine, stromal cell-derived factor-1 (SDF-1)-induced signalings. Wortmannin and genistein inhibited both of HFYLPM- and SDF-1-induced Jurkat T cell chemotaxis indicating that phosphoinositide-3-kinase and tyrosine kinase activity were required for the processes. However, U-73122 and BAPTA/AM preferentially blocked HFYLPM- but not SDF-1-induced T cell chemotaxis. It indicates that phospholipase C/calcium signaling is necessary for only chemotaxis by HFYLPM. One of the well-known cellular molecules involving chemotaxis, extracellular signal-regulated protein kinase (ERK), was activated by SDF-1 but not by HFYLPM ruling out a possible role of ERK on the peptide-mediated chemotaxis. These results indicate that the synthetic peptide, HFYLPM, stimulates T cell chemotaxis showing unique signaling and provide a useful tool for the study of T cell activation mechanism.
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PMID:The synthetic peptide, His-Phe-Tyr-Leu-Pro-Met, is a chemoattractant for Jukat T cells. 1179 89

Phospholipase C (PLC)-beta2 plays a major role in platelet activation. Previous studies have described a unique patient with impaired receptor-mediated platelet aggregation, secretion, calcium mobilization, and phospholipase C (PLC) activation associated with a selective decrease in platelet PLC-beta2 isozyme. To identify the mechanisms leading to the defect, platelet RNA from the patient and healthy subjects was subjected to reverse transcription-polymerase chain reaction (RT-PCR) and the products sequenced. The PLC-beta2 cDNA sequence in the patient showed no abnormalities. Platelet PLC-beta2 and beta-actin (internal control) mRNA levels were assessed by RT-PCR; the ratio of PLC-beta2 to beta-actin mRNA levels was 0.80 to 0.95 in 4 healthy subjects and 0.28 in the patient. PLC-beta2 mRNA levels were similarly reduced compared with GPIIb and Galphaq mRNA levels. PLC-gamma2 and platelet factor 4 mRNA levels were normal. Calcium mobilization was studied in neutrophils upon activation with formyl-Met-Leu-Phe (fMLP), adenosine diphosphate (ADP), platelet-activating factor (PAF), interleukin-8 (IL-8), C5a, and leukotriene B(4) (LTB(4)), and it was normal. Neutrophil elastase secretion upon activation with fMLP, ADP, PAF, IL-8, C5a, and LTB(4) was normal, as were neutrophil PLC-beta2 mRNA and PLC-beta2 on immunoblotting. Thus, responses to activation, PLC-beta2 protein, and PLC-beta2 mRNA are decreased in patient platelets but not in neutrophils, providing evidence for a hitherto undescribed lineage (platelet)-specific defect in PLC-beta2 gene expression. These studies provide a physiologically relevant model to delineate regulation of PLC-beta2 gene and its tissue-specific expression. (Blood. 2002;99:905-911)
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PMID:Lineage-specific defect in gene expression in human platelet phospholipase C-beta2 deficiency. 1180 93

Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has been implicated in breast cancer. We previously showed that OPN-induced cell migration of mammary epithelial cells (MEC) depends on binding to cell surface integrins and involves activation of the hepatocyte growth factor (HGF) receptor, Met. Here, we show that OPN-induced migration of MEC also requires activation of the epidermal growth factor (EGF) pathway. Synergism was seen between EGF and OPN in inducing cell migration. Furthermore, incubation of cells with exogenous OPN increased ligand (TGFalpha> EGF) and EGF receptor (EGFR) mRNA expression, as well as EGFR kinase activity. Treatment of cells with anti-TGFalpha or anti-EGFR antibody, or with tyrphostin-25 (EGFR inhibitor), significantly impaired the cell migration response to OPN. Other more broad-spectrum tyrosine kinase inhibitors and the growth factor/ receptor interaction inhibitor, suramin, also inhibited OPN-induced migration. Using specific signal transduction pathway inhibitors, we have screened for involvement of MEK (MAP kinase kinase), phosphatidylinositol 3-kinase, phospholipase C (PLC), and protein kinase C (PKC). Results implicated all of these pathways in OPN-induced cell migration, the most pronounced effect being seen with PLC and PKC inhibitors. These results suggest that induction of MEC migration by OPN involves a cascade of events including at least two growth factor/receptor pathways and multiple downstream signal transduction pathways. A number of potential targets are thus provided for strategies aimed at blocking the malignancy-promoting effects of OPN.
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PMID:Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. 1260 46

The immune recognition receptor complex NKG2D-DAP10 on natural killer cells is stimulated by specific ligands carried on virus-infected and malignant cells. Because DAP10 does not have an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail, its ability to trigger killing has been debated. Here we show that a crucial Tyr-Ile-Asn-Met amino acid motif in the cytoplasmic tail of DAP10 couples receptor stimulation to the downstream activation of phosphatidylinositol 3-kinase, Vav1, Rho family GTPases and phospholipase C. Unlike that of ITAM-containing receptors, the activation of NKG2D-DAP10 proceeds independently of Syk family protein tyrosine kinases. Yet the signals initiated by NKG2D-DAP10 are fully capable of inducing killing. Our findings identify a previously unknown mechanism by which receptor complexes that lack ITAM motifs can trigger lymphocyte activation.
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PMID:NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. 1277 71

The abscisic acid (ABA) stomatal closing signal might be transduced through different pathways, depending on the plant growth temperature (GT) and the applied ABA concentration. This was investigated in epidermal peels of Arabidopsis thaliana (L.) Columbia. Different Ca2+ buffers and guanosine-triphosphate-binding protein (G protein) modulators were tested on stomatal closing under light in response to 3 mumol/L ABA (ABA3 mu) and 30 mumol/L ABA (ABA30 mu) at the 15-17 degrees C and 23-25 degrees C GT ranges. The Ca2+ buffer, 1,2-bis(0-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, used as free acid (BAPTA) or acetoxymethyl ester (BAPTA-AM), similarly inhibited (up to approximately 70% inhibition) stomatal closing to ABA3 mu and ABA30 mu, whereas ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid specifically inhibited (up to approximately 70% inhibition) the ABA3 mu response at the 23-25 degrees C GT range. At the same GT range, the ABA3 mu response was specifically affected by the phospholipase C (PLC) inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). Moreover, the ABA30 mu response was specifically inhibited by the G protein antagonist pGlu-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH2 (GP Ant-2) and by the inactive mastoparan analog, mas 17. The inhibitory effects of GP Ant-2 and mas 17 were additive. None of the tested pharmacological compounds were effective at the 15-17 degrees C GT range. Together, these results confirmed that, depending on GT and the exogenous ABA concentration, stomatal closing to ABA involves either one among two Ca2+ mobilizations or none of them.
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PMID:Two potential Ca(2+)-mobilizing processes depend on the abscisic acid concentration and growth temperature in the Arabidopsis stomatal guard cell. 1280 77

Formyl peptide receptor (FPR) and formyl peptide receptor like 1 (FPRL1) play important roles in inflammation and immunity. Stimulation of FPR and FPRL1 initiates a cascade of signaling events, leading to activation of various phagocyte responses, including chemotaxis, superoxide generation, and exocytosis. Trp-Lys-Tyr-Met-Val-d-Met-NH2 (WKYMVm) is a synthetic peptide that binds to and activates FPR and FPRL1. To develop agonists that selectively activate phagocyte functions and therefore protect host from unwanted tissue damage, we generated various WKYMVm analogs and examined their effects on cellular responses in FPR- or FPRL1-expressing RBL-2H3 cells. Analogs with substitution at the third position such as WKGMVm, WKRMVm, as well as analogs with substitution at the sixth d-Met, selectively altered calcium mobilization in cells expressing FPRL1 but not in cells expressing FPR. Whereas binding of WKYMVm to FPR activates a broad spectrum of cellular signaling events, including phospholipase C-mediated intracellular calcium concentration ([Ca2+]i) mobilization and activation of extracellular signal-regulated kinase (ERK) and Akt, WKGMVm and WKRMVm could only activate ERK and Akt but did not induce [Ca2+]i mobilization. With respect to phagocyte functions, WKYMVm could induce both chemotaxis and exocytosis, but the two analogs WKGMVm and WKRMVm could only induce chemotaxis but not exocytosis. This study demonstrates that a major phagocyte chemoattractant receptor FPR may be activated differentially by distinct peptide ligands. Our results suggest that WKGMVm and WKRMVm may be useful model for further development of pharmacological agents that selectively activate FPR-mediated functions.
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PMID:Differential activation of formyl peptide receptor signaling by peptide ligands. 1450 Jul 40


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