EC:2.7.11.24 - FACTA Search

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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 effect of alkylglycerol supplementation on protein kinase C (PKC)-mediated signaling events has been studied in fibroblasts from Zellweger patients (SF 3271 cells). Western blotting analysis established that Zellweger fibroblasts express PKC alpha, epsilon, and zeta. Incubation with bradykinin induced a rapid transient translocation of PKC alpha and a more sustained translocation of PKC epsilon to the particulate fraction; translocation of PKC zeta was unaffected. Bradykinin-induced translocation and activation of PKC alpha, but not translocation of PKC epsilon, was blocked in SF 3271 cells which had been incubated with 1-O-hexadecylglycerol (1-O-HDG; 20 micrograms/ml) for 24 h and then incubated in the absence of 1-O-HDG and serum for a further 24 h. Supplementation with 1-O-HDG increased the mass of ether-linked phospholipid. Bradykinin initiated a transient increase in cytosolic Ca2+ concentration in both control and 1-O-HDG supplemented cells, indicating that the initial receptor linked events were not affected by 1-O-HDG supplementation. Bradykinin also caused a rapid activation of phospholipase D (PLD), measured by phosphatidylbutanol accumulation, and mitogen-activated protein kinase (MAPK) determined by myelin basic protein phosphorylation of Mono Q fractions. Both events were blocked by preincubation of the cells with 12-O-tetradecanoylphorbol-13-acetate for 24 h to deplete PKC protein. 1-O-HDG supplementation prevented the bradykinin-induced activation of PLD, but had no effect on the stimulation of MAPK activity. These results establish that modulation of the ether lipid composition of membranes can alter PKC isozyme translocation and indicate that a PKC isozyme other than PKC alpha, most likely PKC epsilon, is involved in MAPK activation.
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PMID:Evidence that the bradykinin-induced activation of phospholipase D and of the mitogen-activated protein kinase cascade involve different protein kinase C isoforms. 753 66

Interleukin-11 (IL-11) stimulated [3H]phosphatidic acid (PA) formation in [3H]arachidonic acid (AA) prelabelled quiescent mouse 3T3-L1 cells. When IL-11 stimulated 3T3-L1 cells were incubated with NaF, a phosphatidic acid phosphohydrolase (PAP) inhibitor, increased PA formation was observed. In the presence of ethanol, phosphatidylethanol accumulated at the expense of PA. These results indicated that the formation of PA upon IL-11 stimulation was a result of phospholipase D (PLD) activation. Endogenous accumulation of PA by NaF treatment or exogenously added PA enhanced tyrosine phosphorylation of two proteins of 44 KDa (p44) and 47 KDa (p47) whereas tyrosine phosphorylation of other proteins was not affected. Among various PA species, dipalmitoyl PA was found to be most effective in enhancing tyrosine phosphorylation of these proteins. p44 and p47 cross reacted with anti-MAP kinase monoclonal antibody (MoAb) in both immunoprecipitation and western blot analysis. Lysates from IL-11-induced or PA-induced cells stimulated phosphorylation of a synthetic peptide substrate for MAP kinase, indicating the activation of MAP kinase in the induced cells. These studies suggest that one of the cellular signalling mechanisms of IL-11 in 3T3-L1 cells involves the activation of phospholipase D to produce the second messenger PA. The increased level of PA enhances tyrosine phosphorylation of p44 and p47 which belong to the members of MAP kinase family and thus transduces some of the mitogenic signals of IL-11 in this cell line.
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PMID:Interleukin-11 induces phosphatidic acid formation and activates MAP kinase in mouse 3T3-L1 cells. 754 91

Platelet-activating factor (PAF) activated phospholipase D (PLD) in WT-H cells, CHO cells stably expressing cloned guinea-pig PAF receptor. The PLD activation was found to be dependent on extracellular Ca2+, protein kinase C (PKC), and a currently unidentified protein tyrosine kinase (PTK). PTK inhibitors ST-638 and genistein inhibited PLD activation induced by PAF as well as phorbol myristate acetate, indicating that PTK acts downstream of PKC. Furthermore, activation of MAP (mitogen-activated protein) kinases, as assessed by their phosphorylation, was also dependent on Ca2+, PKC, and PTK. The correlation between PLD activity and MAP kinase activation, together with the previously observed MAP kinase activation associated with arachidonic acid release by cPLA2 [Honda et al. (1994) J. Biol. Chem. 269, 2307-2315], led us to examine the involvement of MAP kinase in PLD activation. The results indicate that PLD and MAP kinases are activated through the common pathway consisting of Ca2+, PKC, and the unidentified PTK, which act in parallel, but not in a linear sequence.
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PMID:Activation of phospholipase D in Chinese hamster ovary cells expressing platelet-activating factor receptor. 788 65

Substance P (SP) is a tachykinin involved in the regulation of inflammatory processes. Tachykinins bind to three subtypes of neurokinin (NK) receptors. However, recently we demonstrated that monocytes express a SP binding site that is not one of the known NK receptors. Activation of this SP receptor leads to the stimulation of MAP kinase in monocytes. In the present paper we show that this novel SP binding site is coupled to a GTP binding protein of the Gi alpha 1/2 subclass. Triggering of the SP receptor leads to a rapid rise in cytosolic calcium. In a more sustained way, SP stimulates phospholipase D (PLD) activity in human monocytes. The effects of SP on calcium, PLD, and MAP kinase activity can be blocked by pretreatment of the cells with pertussis toxin, which is in agreement with receptor coupling to Gi. At a functional level, stimulation of the non-NK SP receptor on monocytes results in the induction of IL-6 production. We show here that the order of potency for activation of monocytes by various ligands is directly related to the Ki for displacement of labeled SP by these ligands. Therefore, our data strongly suggest that the effects of SP are mediated via the novel SP receptor we recently described.
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PMID:Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. 793 May 88

Activation of mitogen-activated protein kinases (MAPKs) was examined in the A7r5 rat vascular smooth muscle cell line. Treatment of A7r5 cells with vasopressin, phorbol ester (PMA), or serum resulted in activation of two MAPKs, Erk-1 and Erk-2. Phosphatidylinositol-specific phospholipase C was activated in response to vasopressin but not to PMA. Vasopressin and PMA both caused maximal activation of PLD within 5 minutes. Application of bacterial phospholipase D (PLD) to A7r5 cells increased phosphatidic acid to levels similar to those seen with vasopressin or PMA. Acute exposure of the cells to vasopressin, PMA, or PLD increased phosphorylation of many of the same cytosolic and membrane proteins. However, bacterial PLD did not promote significant activation of Erk-1 and Erk-2. Phosphatidic acid and lysophosphatidic acid (LPA) likewise did not stimulate MAPK activity in A7r5 cells. Serum and vasopressin stimulated DNA synthesis when present for more than 30 min, while PLD, PMA, phosphatidic acid, and LPA were not mitogenic. These data suggest that activations of MAPKs and PLD are concurrent but independent responses to vasopressin in A7r5 cells. Acute activation of these enzymes is not sufficient to simulate DNA synthesis.
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PMID:Activations of mitogen-activated protein kinases and phospholipase D in A7r5 vascular smooth muscle cells. 808 51

Hepatocyte growth factor (HGF) activated phospholipase D (PLD) in primary-cultured rat hepatocytes, as assessed by the formation of phosphatidylbutanol (PBut), a specific and stable product of PLD activity in the presence of 0.3% butanol. PLD hydrolyzes phosphatidylcholine to choline and phosphatidic acid (PA), which is further metabolized to diacylglycerol (DG) by PA phosphohydrolase (PAP). In HGF-stimulated hepatocytes, butanol prevented the formation of PA and DG. A PAP inhibitor, propranolol, inhibited DG production with a reciprocal increase of PA, implying that PLD played a role in the formation of not only PA but DG. Inhibitors for protein kinase C (PKC), Ro31-8425, H-7, and calphostin C, reduced HGF-induced PLD activation. A protein tyrosine kinase (PTK) inhibitor, genistein but not its inactive analogue daidzein, inhibited PLD activation by HGF. Moreover, depletion of extracellular Ca2+ by omission of Ca2+ or by chelating residual Ca2+ with ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) abolished HGF-induced PLD activation. HGF, phorbol myristate acetate (PMA) and a DG analog, oleylacetylglycerol (OAG), activated the expression of c-jun and c-fos messenger RNAs (mRNAs). Ro31-8425, calphostin C, and genistein, which prevented HGF-induced PLD activation, inhibited induction of these immediate early genes. Butanol and propranolol at concentrations which effectively inhibited the formation of DG, suppressed HGF-induced expression of c-jun and c-fos mRNAs. However, HGF-induced mitogen-activated protein kinase (MAPK) activation was not affected by both butanol and propranolol. These results suggest that PTK, PKC, and Ca2+ regulate HGF-induced PLD activation, and that DG produced by PLD pathway may play a role in the induction of immediate early genes, which is activated in MAPK-independent manner, in rat hepatocytes.
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PMID:Phospholipase D activation in hepatocyte growth factor-stimulated rat hepatocytes mediates the expressions of c-jun and c-fos: involvement of protein tyrosine kinase, protein kinase C, and Ca2+. 890 10

While much is known about the beneficial effects of myocardial stress adaptation, relatively less information is available about the adaptive mechanisms. To explore the signaling pathways of stress adaptation, isolated working rat hearts were divided into three groups. Group I was adapted to stress by conventional technique of repeated ischemia and reperfusion consisting of 5 min of ischemia followed by 10 min of reperfusion, repeated four times. Group II was treated with 100 microM of genistein, a tyrosine kinase inhibitor, followed by preconditioning as described for group I. The third group, perfused with buffer only for 60 min, served as control. All hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. The results of our study demonstrated better postischemic myocardial functions in the preconditioned hearts as evidenced by increased aortic flow, coronary flow, developed pressure and lesser amount of tissue injury as evidenced by the decreased creatine kinase release. The preconditioning effects were associated with enhancement of phospholipase D activity in the heart. The preconditioning effect was almost abolished by the genistein treatment which also prevented the enhancement of phospholipase D activities. Additionally, preconditioning of the rat hearts stimulated protein kinase C, MAP kinase, and MAPKAP kinase 2 activities which were inhibited by genistein. The results identifies for the first time tyrosine kinase-phospholipase D as potential signaling pathway for ischemic preconditioning, and implicates the involvement of multiple protein kinases in myocardial adaptation to ischemia.
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PMID:Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. 891 93

The present study was undertaken to determine whether phospholipase D participates in the mitogenic action of arginine vasopressin (AVP) in cultured rat glomerular mesangial cells. AVP promptly increased the phosphatidylethanol formation in a concentration-dependent manner, which indicates the activation of phospholipase D. When cells were preincubated with 2,3-diphosphoglycerate or carbobenzyloxy-leucine-tyrosine-chloromethylketone (zLYCK), inhibitors of phospholipase D, the 1 x 10(-7) M AVP-produced phosphatidylethanol was significantly attenuated. Also, inhibitors of protein kinase C, staurosporine and calphostin C, reduced the AVP-induced increase in phosphatidylethanol. AVP activated mitogen-activated protein (MAP) kinase in a concentration-dependent manner. Such an activation was significantly reduced by 2,3-diphosphoglycerate, zLYCK, or staurosporine. Also, AVP stimulated [3H]thymidine incorporation, an effect significantly less in the presence of 2,3-diphosphoglycerate or zLYCK. Similar results were obtained with exogenous bacterial phospholipase D. Both MAP kinase and [3H]thymidine incorporation were not altered by 2,3-diphosphoglycerate or zLYCK per se. These results indicate that AVP activates phospholipase D and promotes cellular growth mediated through phospholipase D, in addition to a phospholipase C-dependent signal transduction, in glomerular mesangial cells.
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PMID:The activation of phospholipase D participates in the mitogenic action of arginine vasopressin in cultured rat glomerular mesangial cells. 894 Mar 66

Activation of the mitogen-activated protein kinase (MAPK) cascade has been widely associated with cell proliferation; previous studies have shown that angiotensin II (AII), acting on 7-transmembrane G protein-coupled receptors, stimulates the MAPK pathway. In this report we investigate whether the MAPK pathway is required for the mitogenic response to AII stimulation of vascular smooth muscle cells derived from the hypertensive rat (SHR-VSM). AII stimulates the phosphorylation of MAPK, as determined by Western blot specific for the tyrosine 204 phosphorylated form of the protein. This MAPK phosphorylation was inhibited by the presence of the inhibitor of MAPK kinase activation, PD 098059. Using a peptide kinase assay shown to measure the p42 and p44 isoforms of MAPK, the stimulated response to AII was inhibited by PD 098059 with an IC50 of 15.6 +/- 1.6 microM. The AII stimulation of [3H]thymidine incorporation was inhibited by PD 098059 with an IC50 of 17.8 +/- 3.1 microM. PD 098059 had no effect on AII-stimulated phospholipase C or phospholipase D (PLD) activity. When the SHR-VSM cells were stimulated with phorbol ester, there was an activation of MAPK similar in size and duration to the response to AII, but there was no significant enhancement of [3H]thymidine incorporation. There was also no activation of PLD by phorbol ester, while AII produced a robust PLD response. Diversion of the product of the PLD reaction by 1-butanol caused a partial loss of the [3H]thymidine response; this did not occur with tertiary butanol, which did not interfere with the PLD reaction. These results show that in these cells the MAPK cascade is required but not sufficient for the mitogenic response to AII, and suggest that the full mitogenic response requires both MAPK in conjunction with other signaling components, one of which is PLD.
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PMID:Stimulated mitogen-activated protein kinase is necessary but not sufficient for the mitogenic response to angiotensin II. A role for phospholipase D. 894 10

Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysophosphatidate and diacylglycerol. Diacylglycerol is an activator of protein kinase C, whereas phosphatidate and lysophosphatidate stimulate tyrosine kinases and activate the Ras-Raf-mitogen-activated protein kinase pathway. These three lipids can stimulate cell division. Conversely, activation of sphingomyelinase by agonists (e.g., tumor necrosis factor-alpha) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and sphingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activation of phospholipase D by decreasing its interaction with the G-proteins, ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosphatidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a multifunctional phosphohydrolase (the Mg(2+)-independent phosphatidate phosphohydrolase), whereas sphingosine inhibits phosphatidate phosphohydrolase. Tumor necrosis factor-alpha causes insulin resistance, which may be partly explained by ceramide production. Cell-permeable ceramides decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes after 2-24 h, whereas they stimulate basal glucose uptake. These effects do not depend on decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 or the interaction of insulin receptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1-and GLUT4-containing vesicles. It is concluded that there is a significant interaction and "cross-talk" between the sphingolipid and glycerolipid pathways that modifies signal transduction to control vesicle movement, cell division, and cell death.
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PMID:"Cross talk" between the bioactive glycerolipids and sphingolipids in signal transduction. 896 Mar 53

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