Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst by 2',5'-dihydroxy-2-furfurylchalcone (DHFC) was investigated in rat neutrophils, and the underlying mechanism of this inhibition was assessed. DHFC concentration-dependently inhibited superoxide anion (O(2)) generation (IC(50) 4.2+/-1.2 microM), reaching a plateau within 5-10 min preincubation time, and inhibited oxygen consumption (IC(50) 6.9+/-1.9 microM) in rat neutrophils. In cell-free systems, DHFC failed to scavenge the generated during dihydroxyfumaric acid auto-oxidation. DHFC was less effective in the inhibition of both phorbol 12-myristate 13-acetate-activated neutrophil particulate NADPH oxidase activity and arachidonic acid-induced NADPH oxidase activation. In rat neutrophils, DHFC did not exert a cAMP-elevating effect, nor did it affect fMLP-induced [Ca(2+)](i) change to a considerable extent. DHFC slightly reduced fMLP-induced phosphatidylinositol 3-kinase (PI3 K) activation but showed moderate inhibition of Akt phosphorylation. fMLP-induced cellular phospholipase D (PLD) activation was markedly inhibited by DHFC (IC(50) 8.9+/-2.0 microM). In addition, DHFC effectively attenuated the membrane association of protein kinase C (PKC)-alpha, ADP-ribosylation factor (ARF) and Rho A in fMLP-stimulated cells. However, DHFC had no effect on the membrane association of ARF and Rho A caused by guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) in cell lysate. fMLP-stimulated protein tyrosine phosphorylation was weakly attenuated by DHFC. DHFC was more efficient in the inhibition of extracellular signal-regulated kinase (ERK) phosphorylation than p38 mitogen-activated protein kinase (MAPK) phosphorylation. Collectively, these results indicate that the suppression of fMLP-induced respiratory burst by DHFC in rat neutrophils is probably mainly attributable to the inhibition of PLD activation, via the blockade of PKC-alpha, ARF and Rho A membrane association.
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PMID:The blockade of formyl peptide-induced respiratory burst by 2',5'-dihydroxy-2-furfurylchalcone involves phospholipase D signaling in neutrophils. 1292 64

Steroid hormones regulate target cells through traditional nuclear mechanisms as well as by membrane mechanisms. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 bind membrane receptors (mVDR) and mediate their effects on the physiological responses of musculoskeletal cells via protein kinase C (PKC). In cultures of costochondral growth plate chondrocytes, 1alpha,25(OH)2D3 binds the 1,25-mVDR in growth zone cells, activating phospholipase C (PLC), leading to diacylglycerol (DAG) production and PKC translocation to the plasma membrane. It also activates PLA2, increasing arachidonic acid release and prostaglandin synthesis. 24R,25(OH)2D3 binds its membrane receptor in resting zone chondrocytes, activating phospholipase D (PLD), and increasing DAG and PKC activity, but translocation does not occur. PLA2 activity is decreased, reducing arachidonic acid and prostaglandin production. 17Beta-estradiol (E2) activates PKC in both cartilage cells, but DAG is not involved. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 also increase PKC in osteoblasts in a cell-specific manner. Antibodies to the 1,25-mVDR block PKC activation. Membrane-mediated events influence gene expression via signaling cascades, including the ERK1/2 MAP kinases. The ability of steroid hormones to initiate events nongenomically is important for regulation of matrix vesicle (MV) function in the extracellular matrix. MVs have mVDRs, but ligand binding inhibits PKC-zeta (PKCzeta) via a mechanism that differs from PKCalpha activation in the plasma membranes. Treatment of MVs from growth zone chondrocyte cultures with 1alpha,25(OH)2D3 releases stromelysin-1 (MMP-3) and increases TGF-beta activation. MMP-3 is also involved in proteoglycan degradation, facilitating calcification. 24R,25(OH)2D3 inhibits PKCzeta in MV from resting zone cell cultures and inhibits MMP-3 release. Chondrocytes and osteoblasts produce 1,25(OH)2D3, 24,25(OH)2D3, and E2; thus, locally produced steroids may function as autocrine regulators of matrix events, including matrix vesicle enzyme activity and matrix protein remodelling during longitudinal growth, calcification, and growth factor activation.
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PMID:Steroid hormone action in musculoskeletal cells involves membrane receptor and nuclear receptor mechanisms. 1295 86

It is generally thought that Galpha(12) and Galpha(13)-induced responses are exclusively mediated by small G protein Rho. However, Galpha(12) and Galpha(13) elicit divergent cellular responses: phospholipase C-epsilon activation, phospholipase D activation, cytoskeletal change, oncogenic response, apoptosis, MAP kinase activation and Na/H-exchange activation. In addition to Rho activation through RhoGEF, it has been recently demonstrated that Galpha(12) and Galpha(13) interact with several proteins and regulate their activities. However, physiological importance of the interaction of Galpha(12) and Galpha(13) with these proteins has not fully established. I summarize the recent progress of Galpha(12) and Galpha(13)-mediated signaling cascade.
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PMID:Galpha12 and Galpha13 as key regulatory mediator in signal transduction. 1460 42

Several factors for the hydrogen peroxide (H(2)O(2))-induced PLD stimulation have been proposed, including protein kinase C (PKC), tyrosine kinase, mitogen-activated protein kinase and Ca(2+), but their precise roles remain to be defined. As for involvement of PKC, there has been some discrepancy. Our previous study has demonstrated that phospholipase D (PLD) activity was increased by exposure of PC12 cells to 0.5mM H(2)O(2) in modified Krebs-Ringer buffer (KRB) and suggested that the PLD activation was independent of PKC activity. However, we have shown here that the H(2)O(2)-induced PLD stimulation was much greatly enhanced by incubation in Dulbecco's modified Eagle's medium (DMEM) and further that it was PKC-dependent. These results indicated that the markedly enhanced PLD activation and its PKC dependence were modulated by pH changes during incubation in DMEM. Furthermore, evidence has been presented for possible involvement of alkaline phosphatase in this pH-dependent profile of PLD activation by H(2)O(2).
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PMID:Hydrogen peroxide-induced phospholipase D activation and its PKC dependence are modulated by pH changes in PC12 cells. 1465 83

Aggregation of receptors for immunoglobulin G (FcgammaRs) on myeloid cells activates a series of events that are key in the inflammatory response and that can ultimately lead to targeted cell killing by antibody-directed cellular cytotoxicity. Generation of lipid-derived proinflammatory mediators is an important component of the integrated cellular response mediated by receptors for the constant region of immunoglobulins (Fc). We have demonstrated previously that, in interferon-gamma-primed U937 cells, the high affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D, sphingosine kinase, calcium transients, and protein kinase C isoforms, leading to the activation of the NADPH-oxidative burst. Here, we investigate the nature of the phospholipase that regulates arachidonic acid and eicosanoid production. Our data show that FcgammaRI couples to iPLA(2)beta for the release of arachidonic acid and the generation of leukotriene B(4) and prostaglandin E(2). Activation of iPLA(2)beta was protein kinase C-dependent; on the other hand, platelet-activating factor triggered cPLA(2)alpha by means of the mitogen-activated protein kinase pathway. These studies demonstrate that intracellular PLA(2)s can be selectively regulated by different stimuli and suggest a critical role for iPLA(2)beta in the intracellular signaling cascades initiated by FcgammaRI and its functional role in the generation of key inflammatory mediators.
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PMID:Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells. 2356 2

Stimulation of the neuronal cell adhesion molecule L1 in cerebellar granule neurons (CGNs) enhances neurite outgrowth and this response is inhibited by the primary alcohol ethanol. Because primary alcohols suppress the formation of the signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation prompted us to investigate whether PLD plays a role in the L1-mediated neurite outgrowth in CGNs. In the cerebellum of postnatal day 8 mice, PLD2 protein was abundantly expressed, while PLD1 expression was not detected. The L1-stimulated neurite outgrowth was inhibited by primary alcohols and by overexpression of lipase-deficient PLD2. Increases in cellular PA levels by direct PA application or overexpression of wild-type PLD2 mimicked the L1-dependent stimulation of neurite outgrowth. Furthermore, it was found that L1 stimulation in CGNs increased PLD activity concomitantly with phosphorylation of extracellular signal-regulated kinase (ERK), both of which were inhibited by the MAP kinase-ERK kinase (MEK) inhibitor. These results provide evidence that PLD2 functions as a downstream signaling molecule of ERK to mediate the L1-dependent neurite outgrowth of CGNs, a mechanism that may be related to alcohol-related neurodevelopmental disorders.
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PMID:Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons. 1503 Mar 98

This study was conducted on human Jurkat T-cells to investigate the role of depletion of intracellular Ca(2+) stores in the phosphorylation of two mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated kinase (ERK) 1 and ERK2, and their modulation by a polyunsaturated fatty acid, docosahexaenoic acid (DHA). We observed that thapsigargin (TG) stimulated MAPK activation by store-operated calcium (SOC) influx via opening of calcium release-activated calcium (CRAC) channels as tyrphostin-A9, a CRAC channel blocker, and two SOC influx inhibitors, econazole and SKF-96365, diminished the action of the former. TG-stimulated ERK1/ERK2 phosphorylation was also diminished in buffer containing EGTA, a calcium chelator, further suggesting the implication of calcium influx in MAPK activation in these cells. Moreover, TG stimulated the production of diacylglycerol (DAG) by activating phospholipase D (PLD) as propranolol (PROP) (a PLD inhibitor), but not U73122 (a phospholipase C inhibitor), inhibited TG-evoked DAG production in these cells. DAG production and protein kinase C (PKC) activation were involved upstream of MAPK activation as PROP and GF109203X, a PKC inhibitor, abolished the action of TG on ERK1/ERK2 phosphorylation. Furthermore, DHA seems to act by inhibiting PKC activation as this fatty acid diminished TG- and phorbol 12-myristate 13-acetate-induced ERK1/ERK2 phosphorylation in these cells. Together these results suggest that Ca(2+) influx via CRAC channels is implicated in PLD/PKC/MAPK activation which may be a target of physiological agents such as DHA.
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PMID:Thapsigargin-stimulated MAP kinase phosphorylation via CRAC channels and PLD activation: inhibitory action of docosahexaenoic acid. 1509 63

Human-amniotic WISH cells express the lysophosphatidic acid (LPA) receptor, LPA(1), LPA(2) but not LPA(3). When WISH cells were stimulated with LPA, phospholipase D (PLD) activation was dramatically induced via a cytosolic calcium increase and protein kinase C activation. We also found that LPA stimulated two kinds of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and p38 kinase via PLD-dependent signaling pathways in WISH cells. In terms of the LPA-mediated functional modulation of WISH cells, we observed that LPA stimulates the induction of two early genes (c-Jun and c-Fos) and cellular proliferation in WISH cells. We examined the signaling pathways involved in LPA-mediated cellular responses. LPA-induced early gene induction was completely blocked by normal butanol (n-butanol) but not by t-butanol, suggesting that PLD activity is essentially required for the process. PD98059 (2'-amino-3'-methoxyflavone) but not SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) also significantly blocked LPA-induced early gene induction, suggesting a crucial role for ERK. Pertussis toxin (PTX) did not affect on the LPA-induced early gene induction and ERK activation, ruling out the role of Gi/o protein(s) in the process. The cellular proliferation of WISH cells was also dramatically inhibited by n-butanol or PD98059. This study demonstrates the physiological role of LPA on the modulation of early gene induction and on WISH cell proliferation, and the crucial role played by PLD in the process.
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PMID:Stimulation of early gene induction and cell proliferation by lysophosphatidic acid in human amnion-derived WISH cells: role of phospholipase D-mediated pathway. 1519 5

The Cladosporium fulvum (Cf)-4 gene of tomato confers resistance to the fungus C. fulvum, expressing the corresponding avirulence (Avr)4 gene, which codes for an elicitor protein. Little is known about how such mechanisms work, but previous studies have shown that elicitor recognition activates Ca(2+) signalling and protein kinases, such as mitogen-activated protein kinase (MAPK) and calcium-dependent protein kinase (CDPK). Here, we provide evidence that a new signalling component, the lipid second messenger phosphatidic acid (PA), is produced within a few minutes of AVR4/Cf-4 interaction. Using transgenic tobacco cells expressing the tomato Cf-4-resistance gene as a model system, phospholipid signalling pathways were studied by pre-labelling the cells with (32)P(i) and assaying for the formation of lipid signals after challenge with the fungal elicitor AVR4. A dramatic rapid response was an increase in (32)P-PA, together with its metabolic product diacylglycerol pyrophosphate (DGPP). AVR4 increased the levels of PA and DGPP in a Cf-4(+)-, time- and dose-dependent manner, while the non-matching elicitor AVR9 did not trigger any response. In general, PA signalling can be triggered by two different pathways: via phospholipase D (PLD), which generates PA directly by hydrolysing structural phospholipids like phosphatidylcholine (PC), or via PLC, which generates diacylglycerol (DAG) that is subsequently phosphorylated to PA by DAG kinase (DGK). To determine the origin of the AVR4-induced PA formation, a PLD-specific transphosphatidylation assay and a differential (32)P-labelling protocol were used. The results clearly demonstrated that most PA was produced via the phosphorylation of DAG. Neomycin and U73122, inhibitors of PLC activity, inhibited AVR4-induced PA accumulation, suggesting that the increase in DGK activity was because of increased PLC activity producing DAG. Lastly, evidence is provided that PLC signalling and, in particular, PA production could play a role in triggering responses, such as the AVR4-induced oxidative burst. For example, PLC inhibitors inhibited the oxidative burst, and when PA was added to cells, an oxidative burst was induced.
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PMID:Phosphatidic acid accumulation is an early response in the Cf-4/Avr4 interaction. 1520 Jun 38

Little is known about the effect of epigallocatechin-3 gallate (EGCG), a major constituent of green tea, on the expression of cyclooxygenase (COX)-2. Here, we studied the role of phospholipase D (PLD) isozymes in EGCG-induced COX-2 expression. Stimulation of human astrocytoma cells (U87) with EGCG induced formation of phosphatidylbutanol, a specific product of PLD activity, and synthesis of COX-2 protein and its product, prostaglandin E(2) (PGE(2)). Pretreatment of cells with 1-butanol, but not 3-butanol, suppressed EGCG-induced COX-2 expression and PGE synthesis. Furthermore, evidence that PLD was involved in EGCG-induced COX-2 expression was provided by the observations that COX-2 expression was stimulated by overexpression of PLD1 or PLD2 isozymes and treatment with phosphatidic acid (PA), and that prevention of PA dephosphorylation by 1-propranolol significantly potentiated COX-2 expression induced by EGCG. EGCG induced activation of p38 mitogen-activated protein kinase (p38 MAPK), and specific inhibition of p38 MAPK dramatically abolished EGCG-induced PLD activation, COX-2 expression, and PGE(2) formation. Moreover, protein kinase C (PKC) inhibition suppressed EGCG-induced p38 MAPK activation, COX-2 expression, and PGE(2) accumulation. The same pathways as those obtained (2)in the astrocytoma cells were active in primary rat astrocytes, suggesting the relevance of the findings. Collectively, our results demonstrate for the first time that PLD isozymes mediate EGCG-induced COX-2 expression through PKC and p38 in immortalized astroglial line and normal astrocyte cells.
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PMID:Phospholipase D isozymes mediate epigallocatechin gallate-induced cyclooxygenase-2 expression in astrocyte cells. 1521 Jul 17


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