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)

This study reviews the putative mechanism of ethanol (ETOH)-mediated downregulation of inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) and protein and upregulation of constitutive NOS activity (ecNOS) in immunocompetent cells and endothelium, in vivo. Current evidence supports the hypothesis that ETOH inhibits the phospholipase D-tyrosine kinase pathway involved in the phosphorylation and activation of NADPH oxidase and myeloperoxidase, which upregulates the formation of reactive oxygen intermediates and mitogen-activated protein kinase cascade, including the extracellular receptor-linked kinase 1 and 2 (erk1 and erk2). This decreases reactive oxygen intermediate formation, tyrosine kinase-induced phosphorylation, and activation of transcription factors that, in turn, decreases the expression of iNOS mRNA. Also, ETOH-mediated attenuation of endotoxin-induced downregulation of nuclear protein kinase C activity appears to decrease the stability of expressed iNOS mRNA. ETOH-mediated inhibition of tyrosine kinase activity may also explain the ability of ETOH to upregulate ecNOS enzymatic activity, because tyrosine kinase activity suppresses ecNOS enzymatic activity.
 ...
PMID:The potential mechanism of induction of inducible nitric oxide synthase mRNA in alveolar macrophages by lipopolysaccharide and its suppression by ethanol, in vivo. 972 48

Proinflammatory agents were assessed for their capacity to stimulate the expression of the inducible cyclooxygenase isoform (COX-2) in human neutrophils. A number of agents, including PMA, opsonized bacteria and zymosan, LPS, GM-CSF, TNF-alpha, and fMLP, induced COX-2 protein expression through signaling pathways involving transcription and protein synthesis events. Northern blots showed that freshly isolated neutrophils expressed low levels of COX-2 mRNA, which rapidly increased after incubation with inflammatory agents. A characterization of the signal transduction pathways leading to COX-2 protein expression was initiated. In LPS-treated neutrophils, efficient induction of COX-2 required the presence of serum and involved ligand binding to the CD14 surface antigen. The specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB 203580, had little effect on the induction of COX-2 expression in neutrophils, in contrast to what had been previously observed with other inflammatory cell types. Depending on the agonist present, ethanol differentially blocked the stimulated expression of COX-2, raising the possibility that phospholipase D activation might take part in the process of COX-2 induction. Major COX-2-derived prostanoids synthesized by inflammatory neutrophils were identified by liquid-chromatography and tandem mass-spectrometry as TXA2 and PGE2. The agonist-induced synthesis of TXA2 and PGE2 was effectively blocked by cycloheximide and by the specific COX-2 inhibitor NS-398. These results show that COX-2 can be induced in an active state by different classes of inflammatory mediators in the neutrophil. They support the concept that, in these cells, the COX-2 isoform is preeminent over COX-1 for the stimulated-production of prostanoids, and also suggest that neutrophil COX-2 displays a distinct profile of expression among circulatory cells.
 ...
PMID:Expression and activity of prostaglandin endoperoxide synthase-2 in agonist-activated human neutrophils. 973 14

Myocardial adaptation to ischemia has been shown to activate protein tyrosine kinase, potentiating activation of phospholipase D, which leads to the stimulation of mitogen-activated protein (MAP) kinases and MAP kinase-activated protein (MAPKAP) kinase 2. The present study sought to further examine the signal transduction pathway for the MAPKAP kinase 2 activation during ischemic adaptation. Isolated perfused rat hearts were adapted to ischemic stress by repeated ischemia and reperfusion. Hearts were pretreated with genistein to block tyrosine kinase, whereas SB-203580 was used to inhibit p38 MAP kinases. Western blot analysis demonstrated that p38 MAP kinase is phosphorylated during ischemic stress adaptation. Phosphorylation of p38 MAP kinase was blocked by genistein, suggesting that activation of p38 MAP kinase during ischemic adaptation is mediated by a tyrosine kinase signaling pathway. MAPKAP kinase 2 was estimated by following in vitro phosphorylation with recombinant human heat shock protein 27 as specific substrate for MAPKAP kinase 2. Again, both genistein and SB-203580 blocked the activation of MAPKAP kinase 2 during myocardial adaptation to ischemia. Immunofluorescence microscopy with anti-p38-antibody revealed that p38 MAP kinase is primarily localized in perinuclear regions. p38 MAP kinase moves to the nucleus after ischemic stress adaptation. After ischemia and reperfusion, cytoplasmic striations in the myocytes become obvious, indicating translocation of p38 MAP kinase from nucleus to cytoplasm. Corroborating these results, myocardial adaptation to ischemia improved the left ventricular functions and reduced myocardial infarction that were reversed by blocking either tyrosine kinase or p38 MAP kinase. These results demonstrate that myocardial adaptation to ischemia triggers a tyrosine kinase-regulated signaling pathway, leading to the translocation and activation of p38 MAP kinase and implicating a role for MAPKAP kinase 2.
 ...
PMID:Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. 981 94

We have previously reported that hydrogen peroxide (H2O2) induced a considerable increase of phospholipase D (PLD) activity and phosphorylation of mitogen-activated protein (MAP) kinase in PC12 cells. H2O2-induced PLD activation and MAP kinase phosphorylation were dose-dependently inhibited by a specific MAP kinase kinase inhibitor, PD 098059. In contrast, carbachol-mediated PLD activation was not inhibited by the PD 098059 pretreatment whereas MAP kinase phosphorylation was prevented. These findings indicated that MAP kinase is implicated in the PLD activation induced by H2O2, but not by carbachol. In the present study, H2O2 also caused a marked release of oleic acid (OA) from membrane phospholipids in PC12 cells. As we have previously shown that OA stimulates PLD activity in PC12 cells, the mechanism of H2O2-induced fatty acid liberation and its relation to PLD activation were investigated. Pretreatment of the cells with methylarachidonyl fluorophosphonate (MAFP), a phospholipase A2 (PLA2) inhibitor, almost completely prevented the release of [3H]OA by H2O2 treatment. From the preferential release of OA and sensitivity to other PLA2 inhibitors, the involvement of a Ca2+-independent cytosolic PLA2-type enzyme was suggested. In contrast to OA release, MAFP did not inhibit PLD activation by H2O2. The inhibitory profile of the OA release by PD 098059 did not show any correlation with that of MAP kinase. These results lead us to suggest that H2O2-induced PLD activation may be mediated by MAP kinase and also that H2O2-mediated OA release, which would be catalyzed by a Ca2+-independent cytosolic PLA2-like enzyme, is not linked to the PLD activation in PC12 cells.
 ...
PMID:Possible involvement of mitogen-activated protein kinase in phospholipase D activation induced by H2O2, but not by carbachol, in rat pheochromocytoma PC12 cells. 983 25

One mechanism of long-term agonist-promoted desensitization of alpha2AR function is downregulation of the cellular levels of the alpha subunit of the inhibitory G protein, Gi. In transfected CHO cells expressing the human alpha2AAR, a 40.1 +/- 3.3% downregulation of Galphai2 protein occurred after 24 h of exposure of the cells to epinephrine, which was not accompanied by a decrease in Galphai2 mRNA. The essential step that targets Gi for degradation by agonist occupancy of the receptor was explored using mutated alpha2AAR lacking specific structural or functional elements. These consisted of 5HT1A receptor and beta2AR sequences substituted at residues 113-149 of the second intracellular loop and 218-235 and 355-371 of the N- and C-terminal regions of the third intracellular loop (altered Gi and Gs coupling), deletion of Ser296-299 (absent GRK phosphorylation), and substitution of Cys442 (absent palmitoylation and receptor downregulation). Of these mutants, only those with diminished Gi coupling displayed a loss of agonist-promoted Gi downregulation, thus excluding Gs coupling and receptor downregulation, palmitoylation, and phosphorylation as necessary events. Furthermore, coupling-impaired receptors consisting of mutations in the second or third loops ablated Gi downregulation, suggesting that a discreet structural motif of the receptor is unlikely to represent a key element in the process. While pertussis toxin ablated Gi downregulation, blocking downstream intracellular consequences of alpha2AAR activation or mimicking these pathways by heterologous means failed to implicate cAMP/adenylyl cyclase, phospholipase C, phospholipase D, or MAP kinase pathways in alpha2AAR-mediated Gi downregulation. Taken together, agonist-promoted Gi downregulation requires physical alpha2AAR-Gi interaction which targets Gi for degradation in a manner that is independent of alpha2AAR trafficking, regulation, or second messengers.
 ...
PMID:Agonist-mediated downregulation of G alpha i via the alpha 2-adrenergic receptor is targeted by receptor-Gi interaction and is independent of receptor signaling and regulation. 984 77

The enzymes phospholipase D and diacylglycerol kinase generate phosphatidic acid which is considered to be a mitogen. Here we report that sphingosine produced a significant amount of phosphatidic acid in vascular smooth muscle cells from the rat aorta. The diacylglycerol kinase inhibitor R59 949 partially depressed sphingosine induced phosphatidic acid formation, suggesting that activation of phospholipase C and diacylglycerol kinase can not account for the bulk of phosphatidic acid produced and that additional pathways such as phospholipase D may contribute to this. Further, we have shown that phosphatidylethanol was produced by sphingosine when vascular smooth muscle cells were stimulated in the presence of ethanol. Finally, as previously shown for other cell types, sphingosine stimulated mitogen-activated protein kinase in vascular smooth muscle cells.
 ...
PMID:Sphingosine induces phospholipase D and mitogen activated protein kinase in vascular smooth muscle cells. 986 54

The intracellular events involved in normal pancreatic growth have been extensively investigated in response to cholecystokinin. Recent data indicate that tyrosine kinase, phospholipase D, phosphatidylinositol 3-kinase, and p42/p44 MAPK are stimulated in rat pancreatic acinar cells. Although we begin to understand the intracellular signaling pathways activated in normal pancreas, such information is not yet available in pancreatic cancer cells. This study was undertaken to identify the growth factors and hormones involved in cell proliferation of two human pancreatic cancer cell lines of ductal origin, the MIA PaCa-2, and PANC-1 cells, and to establish the intracellular events involved in the control of their growth. We demonstrated that FGF-2, IGF-1, cerulein, and gastrin but not FGF-1, HGF, secretin, and PACAP, stimulated proliferation of MIA PaCa-2 and PANC-1 cells. Autocrine factors such as gastrin and IGF-1 were also responsible for their proliferation. In response to EGF, FGF-2, IGF-1, cerulein, gastrin and bombesin, tyrosine kinase, and tyrosine phosphatase activities were stimulated in both cell lines. The close relationship established between cell growth and tyrosine kinase activation results from the observation that maximal growth stimulation paralleled with maximal enzyme activation and that genistein, the tyrosine kinase inhibitor, blocked cell growth and enzyme activation. The implication of PLD in growth-stimulated processes is doubtful since all growth factors and hormones tested failed to stimulate an already very active PLD activity. We finally observed a constitutive activity of p44 MAPK in both cell lines and of p42 in MIA PaCa-2 cells. However, p38 and p42 were stimulated in MIA PaCa-2 and PANC-1 cells, respectively, by all growth factors and hormones.
 ...
PMID:Growth effects of regulatory peptides and intracellular signaling routes in human pancreatic cancer cell lines. 986 51

The primary known function of phospholipase D (PLD) is to generate phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine. However, the functional role of PA is not well understood. We report here evidence that links the activation of PLD by insulin and the subsequent generation of PA to the activation of the Raf-1-mitogen-activated protein kinase (MAPK) cascade. Brefeldin A (BFA), an inhibitor of the activation of ADP-ribosylation factor proteins, inhibited insulin-dependent production of PA and MAPK phosphorylation. The addition of PA reversed the inhibition of MAPK activation by BFA. Overexpression of a catalytically inactive variant of PLD2, but not PLD1, blocked insulin-dependent activation of PLD and phosphorylation of MAPK. Real time imaging analysis showed that insulin induced Raf-1 translocation to cell membranes by a process that was inhibited by BFA. PA addition reversed the effects of BFA on Raf-1 translocation. However, PA did not activate Raf-1 in vitro or in vivo, suggesting that the primary function of PA is to enhance the recruitment of Raf-1 to the plasma membrane where other factors may activate it. Finally, we found that the recruitment of Raf-1 to the plasma membrane was transient, but Raf-1 remained bound to endocytic vesicles.
 ...
PMID:Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway. 987 61

Guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) induces respiratory burst (O-2 generation) in permeabilized human neutrophils. The signal pathway from GTPgammaS to the enzyme responsible for O-2 generation (NADPH oxidase) is not well defined. To elucidate the signaling pathway activated by GTPgammaS, we used selective inhibitors to test for the involvement of several enzymes, comparing the effects of these inhibitors on fMet-Leu-Phe (fMLP) activation. GTPgammaS-induced respiratory burst was not influenced by genistein, a selective inhibitor of tyrosine kinase, while fMLP-induced response was completely abolished. The respiratory burst by GTPgammaS was efficiently inhibited by the protein kinase C inhibitor GF109203X even more than fMLP activation. The mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 showed a partial inhibition of both GTPgammaS and fMLP activation. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, completely blocked fMLP activation, but had no effect on the GTPgammaS-induced respiratory burst. Using U73122, phospholipase C is shown to be essential in GTPgammaS signaling as well as fMLP signaling. Butanol blocked fMLP signaling but not GTPgammaS signaling, indicating that only fMLP activation involves phospholipase D. These results suggest that there are several differences between GTPgammaS- and fMLP-induced activation, but both activators share a common pathway including phospholipase C, protein kinase C, and MAPK kinase.
 ...
PMID:Guanosine 5'-O-(3-thiotriphosphate)-induced O-2 generation in permeabilized neutrophils requires protein kinase C and phospholipase C but not tyrosine kinase or phospholipase D. 988 54

The early signaling mechanism of sphingosine 1-phosphate (S1P) on extracellular signal-regulated kinase (ERK) activation was investigated in C6 glioma cells. S1P activated the enzyme in association with a shift in the mobility on electrophoresis reflecting phosphorylation of both ERK1/ERK2 at as low as 10 nM. The lipid-induced ERK1/2 activation was partially inhibited by treatment of the cells with either phorbol 12-myristate 13-acetate (a long-term treatment to desensitize protein kinase C) or pertussis toxin (PTX) and was completely inhibited by a simultaneous treatment with both agents. Similarly, either calphostin C, an inhibitor of protein kinase C, or U73122, an inhibitor of phospholipase C, partially inhibited the S1Pinduced ERK1/2 activation in the nontreated cells with PTX and completely in the toxin-treated cells. On the other hand, the S1P-induced ERK activation was hardly affected by ethanol, which switched the product of phospholipase D from phosphatidic acid to metabolism-resistant phosphatidylethanol. S1P was able to activate ERK1/2 without a detectable increase in the intracellular content of the lipid, but sphingosine, a substrate of sphingosine kinase, which is an enzyme for S1P generation in the cells, hardly affected the ERK1/2 activation in spite of a marked elevation of intracellular S1P accumulation. This indicates that intracellular increase in S1P is not necessary for the S1P-induced ERK activation, and hence suggests the extracellular action mechanism of S1P. Supporting this idea, mRNAs of recently identified S1P specific receptors, Edg-1 and AGR16/H218, were expressed in C6 cells. Taken together, these results suggested that S1P acts on C6 cells extracellularly possibly through S1P receptors which are linked to at least two signaling pathways, i.e., the PTX-sensitive Gi/Go protein pathway and the toxin-insensitive Gq/G11-phospholipase C-PKC pathway, resulting in the activation of ERK.
 ...
PMID:Possible involvement of cell surface receptors in sphingosine 1-phosphate-induced activation of extracellular signal-regulated kinase in C6 glioma cells. 988 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>