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 effects of phorbol 12-myristate 13-acetate (PMA) on the activities of phospholipase D (PLD3), mitogen-activated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) were studied in Jurkat, a human T cell line, and EL4, a murine T-cell line. PMA treatment rapidly activated PLD in Jurkat, as detected either in intact or broken cells. In contrast, PMA did not stimulate PLD activity in EL4 cells. PLD activity was not detected in membranes prepared from EL4 cells. Jurkat, but not EL4, expresses a 120-kDa protein recognized by an anti-PLD antibody. In both Jurkat and EL4 cells, PMA caused activation of ERKs. Incubation of EL4 cells with bacterial PLD increased phosphatidic acid levels, but did not activate ERK. In both EL4 and Jurkat cells, co-stimulation with PMA and ionomycin stimulated JNK activity. These results show that activation of PLD is not required for activation of ERKs or JNKs by PMA in T-cell lines. Thus, while PLD activity is expressed in some T-cell lines, the role of this enzyme and its products in T-cell activation remain to be elucidated.
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PMID:Effects of phorbol ester on phospholipase D and mitogen-activated protein kinase activities in T-lymphocyte cell lines. 902 81

Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-gamma, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.
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PMID:Angiotensin II signaling in vascular smooth muscle. New concepts. 903 29

The role of phosphatidylcholine (PC) hydrolysis in activation of the mitogen-activated protein kinase (MAPK) pathway by platelet-derived growth factor (PDGF) was studied in Rat-1 fibroblasts. PDGF induced the transient formation of phosphatidic acid, choline, diacylglycerol (DG), and phosphocholine, the respective products of phospholipase D (PLD) and phospholipase C (PC-PLC) activity, with peak levels at 5-10 min. PLD-catalyzed transphosphatidylation (with n-butyl alcohol) diminished DG formation at 5 min but not at later stages of PDGF stimulation. Phorbol ester-induced down-regulation of protein kinase C (PKC) completely blocked PLD activation but not the formation of DG and phosphocholine at 10 min of PDGF stimulation. Collectively, these data indicate that PDGF activates both PLD and PC-PLC. In contrast, epidermal growth factor did not activate PC-PLC in these cells, and it activated PLD only weakly. DG formation by itself, through Bacillus cereus PC-PLC treatment of cells, was sufficient to mimic PDGF in activation of MAPK independent of phorbol ester-sensitive PKC. Since PKC down-regulation blocked PDGF-induced PLD but not MAPK activation, we conclude that PLD is not involved in MAPK signaling. In contrast, MAPK activation by exogenous (bacterial) PLD was not affected by PKC down-regulation, indicating that signals evoked by exogenous PLD differ from endogenous PLD. D609 (2-10 microg/ml), an inhibitor of PC-PLC, blocked PDGF- but not epidermal growth factor-induced MAPK activation. However, D609 should be used with caution since it also affects PLD activity. The results suggest that PC-PLC rather than PLD plays a critical role in the PDGF-activated MAPK pathway.
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PMID:Involvement of phosphatidylcholine-specific phospholipase C in platelet-derived growth factor-induced activation of the mitogen-activated protein kinase pathway in Rat-1 fibroblasts. 911 Sep 92

1. The expression and functional roles of protein kinase C (PKC) isoenzymes in purinoceptor signalling have been examined in rat renal mesangial cells. 2. It is observed that rat mesangial cells express four PKC isoenzymes, PKC-alpha, -delta, -epsilon and zeta, as determined by Western blot analysis. No PKC-beta, -gamma, -eta, -theta, or -mu isoforms were detected. 3. By using specific PKC inhibitors and down-regulation experiments we provide evidence that PKC alpha acts as a negative feedback regulator of ATP- and UTP-stimulated phosphoinositide turnover, whereas PKC epsilon triggers arachidonic acid release and subsequent prostaglandin synthesis and stimulates a phosphatidylcholine-hydrolysing phospholipase D. Moreover, PKC delta may activate the mitogen-activated protein kinase cascade and thus promote mesangial cell proliferation in response to extracellular ATP and UTP. 4. In summary our data identify mesangial cells in culture as an excellently characterized cell culture system with well-defined functions of PKC isoenzymes. Functional identification of PKC isoenzymes involved in specific cell responses is one of the most promising steps towards understanding of molecular mechanisms of cell regulation and identifies new targets for drug development.
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PMID:Regulatory functions of protein kinase C isoenzymes in purinoceptor signalling in mesangial cells. 913 6

1. Glomerular diseases frequently cause chronic renal failure which ultimately requires dialysis and kidney transplantation. The events leading to destruction of the glomerular filtration apparatus include injury of glomerular cells, aggregation of thrombocytes and infiltration of immune cells into the glomerulus. 2. Nucleotides (e.g. ATP and UTP) are present in all glomerular cell types as well as in thrombocytes. The release of nucleotides into the extracellular space occurs after damage of glomerular cells and aggregation of thrombocytes. Several in vitro and in vivo findings indicate that extracellular nucleotides may play a role as pro-inflammatory mediators in glomerulonephritis. 3. A hallmark finding in kidney biopsies from patients with glomerulonephritis is proliferation of glomerular mesangial cells. Cell culture studies demonstrated that extracellular ATP (10-300 microM) stimulated growth of mesangial cells. The mitogenic effect of ATP was potentiated in the presence of multiple growth factors. 4. Nucleotide-induced signalling in mesangial cells included an increase of intracellular calcium, activation of phosphatidylinositol-specific phospholipase C and phospholipase D, inhibition of adenylylcyclase, stimulation of mitogen-activated protein kinase and increased expression of the immediate early genes, c-fos, c-jun and Egr-1. 5. In previous studies of experimental mesangioproliferative glomerulonephritis, exogenously given ADP beta S and ATP gamma S have been shown to aggravate the course of the disease, while 2-chloroadenosine had beneficial effects. 6. Taken together, these findings support the concept that nucleotides may function as proinflammatory mediators in glomerulonephritis while adenosine may have antiinflammatory effects.
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PMID:Extracellular nucleotides as signalling molecules for renal mesangial cells. 913 21

Phosphatidic acid (PA), generated by phospholipase D activation, has been linked to the activation of the neutrophil respiratory burst enzyme, NADPH oxidase; however, the intracellular enzyme targets for PA remain unclear. We have recently shown (McPhail, L. C., Qualliotine-Mann, D., and Waite, K. A. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7931-7935) that a PA-activated protein kinase is involved in the activation of NADPH oxidase in a cell-free system. This protein kinase phosphorylates numerous endogenous proteins, including p47-phox, a component of the NADPH oxidase complex. Phospholipids other than PA were less effective at inducing endogenous protein phosphorylation. Several of these endogenous substrates were also phosphorylated during stimulation of intact cells by opsonized zymosan, an agonist that induces phospholipase D activation. We sought to identify the PA-activated protein kinase that phosphorylates p47-phox. The PA-dependent protein kinase was shown to be cytosolic. cis-Unsaturated fatty acids were poor inducers of protein kinase activity, suggesting that the PA-activated protein kinase is not a fatty acid-regulated protein kinase (e.g. protein kinase N). Chromatographic techniques separated the PA-activated protein kinase from a number of other protein kinases known to be activated by PA or to phosphorylate p47-phox. These included isoforms of protein kinase C, p21 (Cdc42/Rac)-activated protein kinase, and mitogen-activated protein kinase. Gel filtration chromatography indicated that the protein kinase has an apparent molecular size of 125 kDa. Screening of cytosolic fractions from several cell types and rat brain suggested the enzyme has widespread cell and tissue distribution. The partially purified protein kinase was sensitive to the same protein kinase inhibitors that diminished NADPH oxidase activation and was independent of guanosine 5'-3-O-(thio)triphosphate and Ca2+. Phosphoamino acid analysis showed that serine and tyrosine residues were phosphorylated on p47-phox by this kinase(s). These data indicate that one or more potentially novel protein kinases are targets for PA in neutrophils and other cell types. Furthermore, a PA-activated protein kinase is likely to be an important regulator of the neutrophil respiratory burst by phosphorylation of the NADPH oxidase component p47-phox.
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PMID:Phosphatidic acid-mediated phosphorylation of the NADPH oxidase component p47-phox. Evidence that phosphatidic acid may activate a novel protein kinase. 918 94

We found that natural (long-chain) ceramide 1-phosphate can be dispersed into aqueous solution when dissolved in an appropriate mixture of methanol/dodecane (49:1, v/v). This solvent mixture facilitates the interaction of this phosphosphingolipid with cells. Under these conditions, incubation of EGFR T17 fibroblasts with natural ceramide 1-phosphate caused a potent stimulation of DNA synthesis. This effect was accompanied by an increase in the levels of proliferating-cell nuclear antigen. Concentrations of natural ceramide 1-phosphate that stimulated the synthesis of DNA did not inhibit adenylate cyclase activity, nor did they stimulate phospholipase D. Natural ceramide 1-phosphate did not alter the cellular phosphorylation state of tyrosine residues or of mitogen-activated protein kinase. Furthermore, natural ceramide 1-phosphate failed to induce the expression of the proto-oncogenes c-myc and c-fos. Both the stimulation of DNA synthesis and the induction of proliferating-cell nuclear antigen by natural ceramide 1-phosphate were inhibited by natural ceramides. This work suggests that the use of methanol and dodecane to deliver natural ceramide 1-phosphate to cells may be useful for elucidation of the biological function(s) and mechanism(s) of action of ceramide 1-phosphate.
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PMID:Stimulation of DNA synthesis by natural ceramide 1-phosphate. 923 Jan 25

Treatment of primary cultured rat hepatocytes with hepatocyte growth factor (HGF) gives rise to inositol phosphate formation, cytosolic calcium oscillation, activation of mitogen-activated protein (MAP) kinase and phospholipase D (PLD), and arachidonic acid release, leading to DNA synthesis. Pretreatment of cultured hepatocytes with pertussis toxin (PT), which is known to adenosine diphosphate-ribosylate Gi and Go guanine nucleotide -binding proteins and to inhibit their functions, partially inhibited HGF-induced [3H]thymidine incorporation in a concentration-dependent manner. These results suggest that HGF-mediated DNA synthesis of hepatocytes is partly regulated via PT-sensitive guanine nucleotide-binding protein. Therefore, the effects of PT treatment on HGF-induced signal-transduction pathways were investigated. HGF-induced MAP kinase activation and arachidonic acid release were decreased by PT treatment, whereas PLD activation was diminished by PT to the level of unstimulated control. PT also interfered with HGF-induced inositol phosphate formation and cytosolic calcium oscillation. These results suggest that both PT-sensitive and PT-insensitive pathways are involved in HGF-induced signaling.
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PMID:Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor-induced signal transduction in cultured rat hepatocytes: pertussis toxin treatment inhibits activation of phospholipid signaling, calcium oscillation, and mitogen-activated protein kinase. 925 37

We investigated the effect of bioflavonoid quercetin on tyrosine phosphorylation and phospholipase D (PLD, EC 3.1.4.4) activation in rabbit peritoneal neutrophils stimulated by N-formylmethionyl-leucyl-phenylalanine (fMLP). The quercetin dose-dependently inhibited degranulation and superoxide production in fMLP-stimulated neutrophils. A strong inhibitory effect of quercetin on the tyrosine phosphorylation of several proteins (40, 42, 43, 45, 46 and 75 kDa) was observed when the neutrophils were pretreated with different concentrations of quercetin. Furthermore, quercetin inhibited mitogen activated protein kinase (MAP kinase) and PLD activation induced by fMLP in a dose-dependent manner. The reduction in PLD activity was 30% at 0.1 microM and 70% at 100 microM of quercetin. These results suggest that impairment of neutrophil functions by quercetin may be due, at least in part, to inhibition of tyrosine phosphorylation and PLD activation.
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PMID:Inhibition of N-formylmethionyl-leucyl-phenylalanine-stimulated tyrosine phosphorylation and phospholipase D activation by quercetin in rabbit neutrophils. 926 Aug 78

In human neutrophils, the choline-containing phosphoglycerides contain almost equal amounts of alkylacyl- and diacyl-linked subclasses. In contrast to phosphatidylinositol hydrolysis which yields diacylglycerol, hydrolysis of choline-containing phosphoglycerides by phospholipase D coupled with phosphohydrolase yields both alkylacyl- and diacylglycerol. While diacylglycerol activates protein kinase C, alkylacylglycerol does not, and its role is unclear. Yet previous studies have shown that exogenous alkylacyl- and diacylglycerols can prime for the release of radiolabeled arachidonic acid (AA) in intact neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine. We have now examined the effects of both diacylglycerol (1-oleoyl-2-acetylglycerol; OAG) and alkylacylglycerol (1-O-hexadecyl-2-acetylglycerol; EAG) on the activation of mitogen-activated protein (MAP) kinase and the 85-kDa cytosolic phospholipase A2 (cPLA2) in human neutrophils. We observed that while OAG could effectively activate p42 and p44 MAP kinases along with cPLA2 in a time- and concentration-dependent manner, EAG could not. A novel p40 MAP kinase isoform is also present and activated in response to OAG treatment; the behavior of this MAP kinase isoform is discussed. The activation of cPLA2 and MAP kinase by 20 microM OAG could be inhibited by pretreatment with 1 microM GF-109203X, a selective inhibitor of protein kinase C. Although only OAG activated cPLA2, both OAG and EAG primed for the release of AA mass as determined by gas chromatography/mass spectrometry. The priming of AA release by OAG may be explained by the phosphorylation of cPLA2 through the activation of protein kinase C linked to MAP kinase. However, priming by EAG appears to involve a separate mechanism that is dependent on a different PLA2. Our results support a role for phospholipase D-derived products modulating the activation of cPLA2, further supporting the idea of cross-talk among various phospholipases.
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PMID:Comparison of alkylacylglycerol vs. diacylglycerol as activators of mitogen-activated protein kinase and cytosolic phospholipase A2 in human neutrophil priming. 929 67


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