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: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

Signal transduction from mouse bradykinin B2 receptors to calcium influx was studied in ras-transformed NIH/3T3 (DT) fibroblasts. DT cells were preloaded with fura-2 and whole-cell voltage-clamped. Activation of B2 receptors resulted in a decrease of cellular fluorescence at the excitation wavelength of 340, or 360 nm after MnCl2 application, in both the presence and absence of external Ca2+ in DT cells, at a holding potential of -40 mV. This Mn2+ entry through the Ca2+ influx pathway increased with membrane hyperpolarization. Internal application of inositol 1,3,4,5-tetrakisphosphate (InsP4), but not of inositol 1,4,5-trisphosphate, mimicked membrane potential-dependent Mn2+ entry. Bradykinin- and InsP4-induced Ca2+ influx was blocked by 10-100 microM genistein, a tyrosine kinase inhibitor. B2 receptor activation induced time-dependent tyrosine phosphorylation of mitogen-activated protein kinase and 120 kDa protein, which was dose-dependently inhibited by genistein. Bradykinin was unable to induce Ca2+ oscillations in genistein-treated DT cells. Our results show that bradykinin-induced Ca2+ influx and oscillations depend upon protein tyrosine phosphorylation. The results suggest that two bradykinin B2 receptor-activated signal pathways, protein tyrosine phosphorylation and formation of InsP4, merge at the Ca2+ influx process in ras-transformed NIH/3T3 fibroblasts.
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PMID:Bradykinin B2 receptor-induced and inositol tetrakisphosphate-evoked Ca2+ entry is sensitive to a protein tyrosine phosphorylation inhibitor in ras-transformed NIH/3T3 fibroblasts. 891 7

Bradykinin stimulates cAMP synthesis in cultured airway smooth muscle (ASM) cells. This occurs via a pathway that involves: (1) the protein kinase C (PKC)-dependent activation of mitogen-activated protein kinase (MAPK); (2) the MAPK-dependent phosphorylation and activation of cytosolic phospholipase A2 (cPLA2) and (3) the utilization of cPLA2-derived arachidonate by the cyclo-oxygenase pathway to produce prostaglandin E2 (PGE2). PGE2 is released and binds to cell surface receptors to stimulate intracellular cAMP synthesis. The signalling pathway was confirmed by the use of PD098059 [the inhibitor of MAPK kinase-1 (MEK-1) activation], AACOCF3 (an inhibitor of cPLA2) and indomethacin (an inhibitor of cyclo-oxygenase), which all reduced bradykinin-stimulated cAMP synthesis. Bradykinin also elicits the inhibition of approx. 60% of the total cAMP phosphodiesterase activity in the cell [Stevens, Pyne, Grady and Pyne (1994) Biochem. J. 297, 233-239]. This is likely to decrease the rate of cAMP degradation markedly and therefore to potentiate PGE2-stimulated cAMP synthesis. Acute treatment of ASM cells with PMA (a direct activator of PKC) also stimulated the MAPK-dependent phosphorylation of cPLA2. However, in contrast with bradykinin, PMA did not stimulate arachidonate release, suggesting that additional signals (e.g. Ca2+ ions) are required for phosphorylation by MAPK to activate cPLA2. PMA was also without effect on PGE2 release and cAMP synthesis. Evidence that PKC can also directly regulate adenylate cyclase was obtained by using cells pretreated with cholera toxin. Under these conditions, PMA stimulated cAMP synthesis independently of arachidonate metabolites. Furthermore the combined treatment of cells with PMA (to activate PKC) and PGE2 (to activate Gs) stimulated synergistic cAMP synthesis. This might be due to the presence of the type 2 adenylate cyclase, which is synergistically activated by Gs and PKC.
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PMID:Bradykinin stimulates cAMP synthesis via mitogen-activated protein kinase-dependent regulation of cytosolic phospholipase A2 and prostaglandin E2 release in airway smooth muscle. 937 32

Bradykinin (BK)-induced release of arachidonic acid (AA) from Madin-Darby canine kidney (MDCK) D1 cells was investigated. Phorbol 12-myristate 13-acetate (PMA) caused a synergistic increase in BK- and A-23187-induced release of AA but alone had no effect on this release. Inhibition of protein kinase C (PKC) with bisindolmaleimide I (BIS) abolished the synergistic effects of PMA but did not affect AA release caused by BK or A-23187 alone. Downregulation of PKC with 100 nM PMA resulted in a reduction of AA release induced by BK or A-23187 addition, which corresponded to a decrease in cytoplasmic phospholipase A2 (cPLA2) activity as measured in cell extracts. Although Western blotting revealed no differences in cPLA2 expression as a result of PMA treatment, phosphorylation of the enzyme, as assessed by phosphoserine content, was significantly reduced in PKC-depleted cells. These results imply that, with PKC downregulation, subsequent BK stimulation results in a Ca(2+)-dependent translocation of a less phosphorylated, less active form of cPLA2. Any stimulation of PKC by BK addition did not appear as a significant event in onset responses leading to AA release. On the other hand, inhibition of the mitogen-activated protein kinase (MAPK) cascade with the MAPK kinase inhibitor, PD-98059, significantly decreased BK-induced release of AA, a finding that, with our other results, points to the existence of a PKC-independent route for stimulation of MAPK and the propagation of onset responses.
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PMID:Bradykinin-stimulated arachidonic acid release from MDCK cells is not protein kinase C dependent. 937 46

In Swiss 3T3 fibroblasts, changing the culture medium prior to stimulation resulted in an augmentation of bradykinin-induced prostaglandin E2 synthesis. The augmentation depended on the duration of the exposure to the fresh medium, with a maximum effect at 1 h. Fetal calf serum in the fresh medium was essential for augmented prostaglandin E2 synthesis. The medium change slightly augmented the bradykinin-induced increase in intracellular free Ca2+ concentration and phosphoinositide hydrolysis with a different time course from that for prostaglandin E2 synthesis. 4',5,7-Trihydroxyisoflavone (genistein) and 3,4-dihydroxybenzylidene-malononitrile (tyrphostin 23), inhibitors of tyrosine kinases, and 2'-amino-3'-methoxyflavone (PD98059), an inhibitor of mitogen-activated protein kinase (MAPK) kinase, attenuated the increase in prostaglandin E2 synthesis. Bradykinin caused phosphorylation of cytosolic phospholipase A2 and p42/p44 MAPK, which was augmented by the medium change. From the results, it is concluded that activation of MAPK and cytosolic phospholipase A2 is involved in the augmentation of prostaglandin E2 synthesis produced by the medium change.
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PMID:Medium change amplifies mitogen-activated protein kinase-mediated prostaglandin E2 synthesis in Swiss 3T3 fibroblasts. 976 28

Bradykinin (BK) has a direct hypertrophic effect on rat ventricular cardiomyocytes (VCM) as defined by an increase in protein synthesis and an increase in atrial natriuretic peptide mRNA and secretion. In the current study, we have examined the dependence of BK-induced protein synthesis on activation of 90-kDa ribosomal S6 kinase (p90(rsk)) and 70-kDa S6 kinase (p70(S6K)). Both of these kinases possess the ability to phosphorylate the ribosomal protein S6, which plays an important role in initiating mRNA translation. Stimulation of adult VCM with 10 microM BK increased p90(rsk) activity by 2.5 +/- 0.3-fold and increased p70(S6K) activity by 2.0 +/- 0.3-fold. p90(rsk) is a terminal kinase in the mitogen-activated protein (MAP) kinase pathway. Inhibition of MAP kinase kinase activation by Raf in the MAP kinase pathway with PD-098059 (25 microM) blocked BK-stimulated activation of p90(rsk) by 70% and unexpectedly blocked p70(S6K) by 72%. Rapamycin inhibited BK-stimulated p70(S6K) activity by 93% but had no effect on p90(rsk) activation by BK. Inhibition of the MAP kinase pathway and p70(S6K) with PD-098059 was paralleled by changes in protein synthesis. BK (10 microM) increased [3H]phenylalanine incorporation by 27 +/- 3 and 39 +/- 6% in cultured adult and neonatal VCM, respectively. Treatment with PD-098059 or rapamycin abolished the increase in protein synthesis stimulated by BK. These results suggest that 1) BK activates p70(S6K) and p90(rsk); 2) although both p70(S6K) and p90(rsk) have the potential to phosphorylate the ribosomal S6 protein, p70(S6K) and not p90(rsk) is the predominant kinase involved in increasing protein synthesis by BK; and 3) p70(S6K) activation is dependent on stimulation of the MAP kinase pathway at a point distal to Raf.
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PMID:Bradykinin-stimulated protein synthesis by myocytes is dependent on the MAP kinase pathway and p70(S6K). 1019 67

Recent evidence suggests that serine/threonine phosphorylation and internalization of beta2-adrenergic receptors play critical roles in signalling to the mitogen-activated protein kinase cascade. To investigate whether this represents a general mechanism employed by G protein-coupled receptors, we studied the requirement of these processes in the activation of mitogen-activated protein kinase by G alpha(q)-coupled bradykinin B2 receptors. Mutant B2 receptors impaired in receptor phosphorylation and internalization are fully capable to activate mitogen-activated protein kinase. Bradykinin-induced long-term effects on mitogenic signalling monitored by measuring the transcriptional activity of Elk1 were identical in cells expressing the wild-type or mutant B2 receptors. Therefore, G protein-coupled bradykinin receptors activate the mitogen-activated protein kinase pathway independently of receptor phosphorylation and internalization.
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PMID:Activation of mitogen-activated protein kinase by the bradykinin B2 receptor is independent of receptor phosphorylation and phosphorylation-triggered internalization. 1037 Dec 16

Activation of the bradykinin B2 receptor in endothelial cells initiates a complex array of cellular responses mediated by diverse signaling pathways, including stimulation of the mitogen-activated protein (MAP) kinase cascade and activation of the endothelial isoform of nitric-oxide synthase (eNOS). Several protein kinases have been implicated in eNOS regulation, but the role of MAP kinases remains less well understood. We explored the interactions between eNOS and components of the MAP kinase pathway in bovine aortic endothelial cells (BAEC). Using co-immunoprecipitation experiments, we isolated eNOS in a complex with the MAP kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as the protein kinases Raf-1 and Akt. Within minutes of adding bradykinin to BAEC, the eNOS-Raf-1-ERK-Akt heteromeric complex dissociated, and it subsequently reassociated following more prolonged agonist stimulation. Bradykinin treatment of BAEC led to the activation of ERK, associated with an increase in phosphorylation of eNOS; phosphorylation of eNOS by ERK in vitro significantly reduced eNOS enzyme activity. Evidence for the direct phosphorylation of eNOS by MAP kinase in BAEC came from "back-phosphorylation" experiments using [gamma-(32)P]ATP and ERK in vitro to phosphorylate eNOS isolated from cells previously treated with bradykinin or the MAP kinase inhibitor PD98059. The ERK-catalyzed in vitro (32)P phosphorylation of eNOS isolated from BAEC treated with bradykinin was significantly attenuated compared with untreated cells, indicating that bradykinin treatment led to the phosphorylation of ERK-sensitive sites in cells. Conversely, eNOS isolated from endothelial cells pretreated with the MAP kinase inhibitor PD98059 showed increased ERK-promoted phosphorylation in vitro. Taken together, our results suggest that bradykinin-induced activation of ERK leads to eNOS phosphorylation and enzyme inhibition, a process influenced by the reversible associations of members of the MAP kinase pathway with eNOS.
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PMID:Bradykinin-regulated interactions of the mitogen-activated protein kinase pathway with the endothelial nitric-oxide synthase. 1089 67

Bradykinin (BK) is a major kinin with well-documented pharmacological properties including vascular leakage and induction of a variety of cytokines. However, the intracellular signalling mechanisms by which BK induced proinflammatory cytokine production have not been fully elucidated. This study investigated the role of the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in the BK-induced interleukin (IL)-6 and IL-8 production by human lung fibroblasts. Lung fibroblasts were stimulated with BK in the presence or in the absence of PD98059, a specific MAPK/ERK kinase-1 inhibitor, or SB203580, a specific p38 MAPK inhibitor, and IL-6 or IL-8 production and their gene expression was examined. BK-induced ERK 1/2 or p38 MAPK phosphorylation was also analysed by Western blot analysis. BK at nanomolar concentrations stimulated lung fibroblasts to produce IL-6 and IL-8 along with increased ERK 1/2 and p38 MAPK phosphorylation. BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist. Furthermore, PD98059 or SB203580 significantly suppressed BK-induced IL-6 and IL-8 production and their gene expression. These results indicate that bradykinin-induced interleukin-6 and interleukin-8 production are at least partly mediated through the extracellular signal-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathway-dependent activation in human lung fibroblasts, and suggest that bradykinin appears to be involved in the inflammatory reaction leading to acute lung injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts.
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PMID:Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. 1102 59

Bradykinin has been linked to the development of restenosis in response to vascular injury. We therefore examined the effect of bradykinin on vascular smooth muscle cell growth and neointimal formation in organ culture. Bradykinin stimulated both RNA and DNA synthesis (by 175%) in smooth muscle cells from either porcine or human coronary arteries and increased cell number in a concentration-dependent manner. Both p42/44 mitogen-activated protein kinase (MAPK) and p38 kinase were also activated. Treatment with [Hyp(3),Tyr(Me)(8)]bradykinin, a B(2) receptor agonist, stimulated thymidine incorporation by 146%, whereas B(1)-selective Lys-des-Arg(9)-bradykinin had no effect. Addition of the B(2) antagonist HOE-140 reduced the stimulation by 56%, whereas B(1)-selective des-Arg-HOE-140 had no significant effect. Similarly, HOE-140 attenuated angioplasty-induced neointimal formation in organ culture with an efficacy approaching 100% inhibition. These experiments suggest that bradykinin promotes smooth muscle proliferation after vascular injury, presumably via B(2) receptor-dependent activation of MAPK family pathways, and may explain the negative outcome of angiotensin converting enzyme inhibitor therapy on restenosis in nonrodent models.
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PMID:Bradykinin receptor antagonists attenuate neointimal proliferation postangioplasty. 1155 55


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