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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin induced prostaglandin E(2) release from the Swiss 3T3 fibroblasts, preconditioned with fresh culture medium. Although treatment with genistein for the entire period of preconditioning and incubation with bradykinin attenuated prostaglandin E(2) release, treatment with fresh culture medium and genistein for only the preconditioning period further augmented the prostaglandin E(2) release. In the cells preconditioned with fresh culture medium and genistein, bradykinin caused the phosphorylation of protein tyrosine and mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK), followed by arachidonic acid release. Interestingly, preconditioning with genistein alone also caused phosphorylation and arachidonic acid release, probably reflecting rebound activation after the washout of genistein. However, preconditioning with genistein alone induced neither the augmentation of prostaglandin E(2) release nor the expression of cyclooxygenase-2. The further potentiation of bradykinin-induced prostaglandin E(2) release by combined preconditioning with fresh culture medium and genistein may be due to the activation of the MAPK/ERK-c phospholipase A(2) pathway by preconditioning with genistein.
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PMID:Preconditioning of 3T3 cells by fresh medium together with genistein enhances prostaglandin E(2) release. 1174 Sep 48

Leukotriene B(4) is a potent chemoattractant known to be involved mainly in inflammation, immune responses, and host defense against infection, although the exact signaling mechanisms by which it exerts its effects are not well understood. Here we show that exogenous leukotriene B(4) induces reactive oxygen species (ROS) generation via a Rac-dependent pathway, and that stable expression of Rac(N17), a dominant negative Rac1 mutant, completely blocks leukotriene B(4)-induced ROS generation. In addition, leukotriene B(4)-induced ROS generation is selectively blocked by inhibition of ERK or cytosolic phospholipase A(2), but not p38 kinase, which is indicative of its dependence on ERK activation and synthesis of arachidonic acid. Consistent with those findings, leukotriene B(4) Rac-dependently stimulates ERK and cytosolic phospholipase A(2) activity, and transient transfection with plasmid expressing Rac(V12), a constitutively activated Rac1 mutant, also dose-dependently stimulates ERK activity. Our findings suggest that ERK and cytosolic phospholipase A(2) are situated downstream of Rac, and we conclude that Rac, ERK, and cytosolic phospholipase A(2) all play pivotal roles in mediating the ROS generation that appears to be a prerequisite for leukotriene B(4)-induced chemotaxis and cell proliferation.
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PMID:Leukotriene B(4) stimulates Rac-ERK cascade to generate reactive oxygen species that mediates chemotaxis. 1175 5

THP-1 monocytic cells were stimulated with IgG-ovalbumin equivalence immune complexes (IC) and mAb reacting with both FcgammaRI and FcgammaRIIA. All of these stimuli were capable of activating the cells; however, different patterns of response were observed as regards activation of the p42-MAP/ERK kinase, triggering of the NF-kappaB/Rel system, production of chemotactic cytokines, and induction of the expression of cyclooxygenase-2 (COX-2). Activation of p42-MAP/ERK kinase was a constant finding, which occurred regardless of the type of stimulus applied, for instance, homotypic stimulation of a single type of receptor by cross-linking with specific mAb or heterotypic stimulation with both types of antibodies and IC. However, the activation of the MAP/ERK kinase cascade was not connected to the triggering of cytosolic phospholipase A(2) (cPLA(2)) and arachidonic acid (AA) release. The heterotypic stimulation of FcgammaR induced the expression of COX-2 in a time and dose-dependent manner and activated the NF-kappaB system as judged from the degradation of IkappaB-alpha protein. In summary, the present data indicate that activation of the p42-MAP/ERK pathway occurs after cross-linking FcgammaRI and FcgammaRIIA receptors in monocytic cells; however, this is not coupled to the cPLA(2) route, which leads to the release of AA. Noteworthy,heterotypic activation involving combined cross-linking of both FcgammaRI and FcgammaRIIA has a robust effect on the oxidative metabolism of AA by a mechanism involving kappaB-dependent trans-activation of COX-2.
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PMID:FcgammaR receptors activate MAP kinase and up-regulate the cyclooxygenase pathway without increasing arachidonic acid release in monocytic cells. 1181 57

Human neutrophils (PMN) are potentially a major source of platelet-activating factor (PAF) produced during inflammatory responses. The stimulated synthesis of PAF in PMN is carried out by a phospholipid remodeling pathway involving three enzymes: acetyl-CoA:lyso-PAF acetyltransferase (acetyltransferase), type IV phospholipase A(2) (cPLA(2)) and CoA-independent transacylase (CoA-IT). However, the coordinated actions and the regulatory mechanisms of these enzymes in PAF synthesis are poorly defined. A23187 has been widely used to activate the remodeling pathway, but it has not been shown how closely its actions mimic those of physiological stimuli. Here we address this important problem and compare responses of the three remodeling enzymes and PAF synthesis by intact cells. In both A23187- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN, acetyltransferase activation is blocked by SB 203580, a p38 MAP kinase inhibitor, but not by PD 98059, which blocks activation of the ERKs. In contrast, either agent attenuated cPLA(2) activation. Correlating with these results, SB 203580 decreased stimulated PAF formation by 60%, whereas PD 98059 had little effect. However, the combination of both inhibitors decreased PAF formation to control levels. Although a role for CoA-IT in PAF synthesis is recognized, we did not detect activation of the enzyme in stimulated PMN. CoA-IT thus appears to exhibit full activity in resting as well as stimulated cells. We conclude that the calcium ionophore A23187 and the receptor agonist fMLP both act through common pathways to stimulate PAF synthesis, with p38 MAP kinase regulating acetyltransferase and supplementing ERK activation of cPLA(2).
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PMID:Regulation of platelet-activating factor synthesis in human neutrophils by MAP kinases. 1237 81

We examined the mechanism by which interleukin (IL)-5 causes beta(2)-integrin adhesion of human eosinophils. IL-5 caused time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38alpha in eosinophils as detected by their phosphorylation. Preincubation of eosinophils with U0126, a mitogen-activated protein kinase/ERK kinase inhibitor, suppressed IL-5-induced activation of cytosolic phospholipase A(2) (cPLA(2)) and eosinophil adhesion, and p38 inhibition by SB203580 had neither effect. ERK1/2 phosphorylation and eosinophil adhesion were blocked by inhibition of the src-family tyrosine kinase, Janus tyrosine kinase (JAK)2, or phosphoinositide-3 kinase (PI3K). Coimmunoprecipitation assay demonstrated that Lyn, a src-family tyrosine kinase, was constitutively associated with PI3K. Inhibition of src-tyrosine kinase but not JAK2 suppressed PI3K activation. Our data suggest that IL-5 induces beta(2)-integrin adhesion of human eosinophils by regulation of cPLA(2) activation caused by ERK1/2 phosphorylation. This phosphorylation results from activation of PI3K and protein tyrosine kinases. We also find that src-family tyrosine kinase, possibly Lyn, is the upstream kinase causing PI3K activation.
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PMID:IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2. 1242 28

Extracellular ATP is a pro-inflammatory mediator involved in the release of prostaglandin from articular chondrocytes, but little is known about its effects on intracellular signaling. ATP triggered the rapid release of prostaglandin E(2) (PGE(2)) by acting on P2Y(2) receptors in rabbit articular chondrocytes. We have explored the signaling events involved in this synthesis. ATP significantly increased arachidonic acid production, which involved the activation of the 85-kDa cytosolic phospholipase A(2) (cPLA(2)) but not a secreted form of PLA(2), as demonstrated by various PLA(2) inhibitors and translocation experiments. We also showed that ATP induced the phosphorylation of p38 and ERK1/2 mitogen-activated-protein kinases (MAPKs). Both PD98059, an inhibitor of the ERK pathway, and SB203580, an inhibitor of p38 MAPK, completely inhibited the ATP-induced release of PGE(2). Finally, dominant-negative plasmids encoding p38 and ERK transfected alone into the cells impaired the ATP-induced release of PGE(2) to about the same extent as both plasmids transfected together. These results suggest that PGE(2) production induced by ATP requires the activation of both ERK1/2 and p38 MAPKs. Thus, ATP acts via P2Y(2)-purine receptors to recruit cPLA(2) by activating both ERK1/2 and p38 MAPKs and stimulates the release of PGE(2) from articular chondrocytes.
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PMID:Concomitant recruitment of ERK1/2 and p38 MAPK signalling pathway is required for activation of cytoplasmic phospholipase A2 via ATP in articular chondrocytes. 1259 27

Oxidant stress and phospholipase A2 (PLA2) activation have been implicated in numerous proinflammatory responses of the mesangial cell (MC). We investigated the cross-talk between group IValpha cytosolic PLA2 (cPLA2alpha) and secretory PLA2s (sPLA2s) during H2O2-induced arachidonic acid (AA) release using two types of murine MC: (i). MC+/+, which lack group IIa and V PLA2s, and (ii). MC-/-, which lack groups IIa, V, and IValpha PLA2s. H2O2-induced AA release was greater in MC+/+ compared with MC-/-. It has been argued that cPLA2alpha plays a regulatory role enhancing the activity of sPLA2s, which act on phospholipids to release fatty acid. Group IIa, V, or IValpha PLA2s were expressed in MC-/- or MC+/+ using recombinant adenovirus vectors. Expression of cPLA2alpha in H2O2-treated MC-/- increased AA release to a level approaching that of H2O2-treated MC+/+. Expression of either group IIa PLA2 or V PLA2 enhanced AA release in MC+/+ but had no effect on AA release in MC-/-. When sPLA2 and cPLA2alpha are both present, the effect of H2O2 is manifested by preferential release of AA compared with oleic acid. Inhibition of the ERK and protein kinase C signaling pathways with the MEK-1 inhibitor, U0126, and protein kinase C inhibitor, GF 1092030x, respectively, and chelating intracellular free calcium with 1,2-bis(2-aminophenoyl)ethane-N,N,N',N'-tetraacetic acid-AM, which also reduced ERK1/2 activation, significantly reduced H2O2-induced AA release in MC+/+ expressing either group IIa or V PLA2s. By contrast, H2O2-induced AA release was not enhanced when ERK1/2 was activated by infection of MC+/+ with constitutively active MEK1-DD. We conclude that the effect of group IIa and V PLA2s on H2O2-induced AA release is dependent upon the presence of cPLA2alpha and the activation of PKC and ERK1/2. Group IIa and V PLA2s are regulatory and cPLA2alpha is responsible for AA release.
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PMID:Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release. 1267 27

Previous studies suggested a role for calcium in CYP2E1-dependent toxicity. The possible role of phospholipase A2 (PLA2) activation in this toxicity was investigated. HepG2 cells that overexpress CYP2E1 (E47 cells) exposed to arachidonic acid (AA) +Fe-NTA showed higher toxicity than control HepG2 cells not expressing CYP2E1 (C34 cells). This toxicity was inhibited by the PLA2 inhibitors aristolochic acid, quinacrine, and PTK. PLA2 activity assessed by release of preloaded [3H]AA after treatment with AA+Fe was higher in the CYP2E1 expressing HepG2 cells. This [3H]AA release was inhibited by PLA2 inhibitors, alpha-tocopherol, and by depleting Ca2+ from the cells (intracellular + extracellular sources), but not by removal of extracellular calcium alone. Toxicity was preceded by an increase in intracellular calcium caused by influx from the extracellular space, and this was prevented by PLA2 inhibitors. PLA2 inhibitors also blocked mitochondrial damage in the CYP2E1-expressing HepG2 cells exposed to AA+Fe. Ca2+ depletion and removal of extracellular calcium inhibited toxicity at early time periods, although a delayed toxicity was evident at later times in Ca2+-free medium. This later toxicity was also inhibited by PLA2 inhibitors. Analogous to PLA2 activity, Ca2+ depletion but not removal of extracellular calcium alone prevented the activation of calpain activity by AA+Fe. These results suggest that release of stored calcium by AA+Fe, induced by lipid peroxidation, can initially activate calpain and PLA2 activity, that PLA2 activation is critical for a subsequent increased influx of extracellular Ca2+, and that the combination of increased PLA2 and calpain activity, increased calcium and oxidative stress cause mitochondrial damage, that ultimately produces the rapid toxicity of AA+Fe in CYP2E1-expressing HepG2 cells.
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PMID:Role of phospholipase A2 activation and calcium in CYP2E1-dependent toxicity in HepG2 cells. 1281 50

The Ca2+-sensing receptor (CaR) couples to multiple G proteins involved in distinct signaling pathways: Galphai to inhibit the activity of adenylyl cyclase and activate ERK, Galphaq to stimulate phospholipase C and phospholipase A2, and Gbetagamma to stimulate phosphatidylinositol 3-kinase. To determine whether the receptor also couples to Galpha12/13, we investigated the signaling pathway by which the CaR regulates phospholipase D (PLD), a known Galpha12/13 target. We established Madin-Darby canine kidney (MDCK) cell lines that stably overexpress the wild-type CaR (CaRWT) or the nonfunctional mutant CaRR796W as a negative control, prelabeled these cells with [3H]palmitic acid, and measured CaR-stimulated PLD activity as the formation of [3H]phosphatidylethanol (PEt). The formation of [3H]PEt increased in a time-dependent manner in the cells that overexpress the CaRWT but not the CaRR796W. Treatment of the cells with C3 exoenzyme inhibited PLD activity, which indicates that the CaR activates the Rho family of small G proteins, targets of Galpha12/13. To determine which G protein(s) the CaR couples to in order to activate Rho and PLD, we pretreated the cells with pertussis toxin to inactivate Galphai or coexpressed regulators of G protein-signaling (RGS) proteins to attenuate G protein signaling (RGS4 for Galphai and Galphaq, and a p115RhoGEF construct containing the RGS domain for Galpha12/13). Overexpression of p115RhoGEF-RGS in the MDCK cells that overexpress CaRWT inhibited extracellular Ca2+-stimulated PLD activity, but pretreatment of cells with pertussis toxin and overexpression of RGS4 were without effect. The involvement of other signaling components such as protein kinase C, ADP-ribosylation factor, and phosphatidylinositol biphosphate was excluded. These findings demonstrate that the CaR couples to Galpha12/13 to regulate PLD via a Rho-dependent mechanism and does so independently of Galphai and Galphaq. This suggests that the CaR may regulate cytoskeleton via Galpha12/13, Rho, and PLD.
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PMID:The Ca2+-sensing receptor couples to Galpha12/13 to activate phospholipase D in Madin-Darby canine kidney cells. 1295 3

The role of lysophosphatidylcholine (LPC) in the induction of MCP-1, IL-8 and RANTES, which are chemotactic factors to monocytes, neutrophils and lymphocytes, respectively, by human vascular endothelial cells (EC), was examined. LPC induced the expression of MCP-1 and IL-8 in a concentration- and time-dependent manner in microvascular EC (MVEC) and in large vessel EC from aorta, pulmonary artery and umbilical vein. LPC also induced RANTES in MVEC but not in large vessel EC. Signaling pathways responsible for LPC induction of chemokines were examined in MVEC. LPC and TNFalpha, a cytokine secreted in sites of inflammation, additively stimulated RANTES expression. LPC did not augment TNFalpha induction of MCP-1 or IL-8. A platelet-activating factor receptor antagonist (BN52021) failed to block LPC induction of MVEC chemokines, but the G(i)-protein inhibitor pertussis toxin partially blocked LPC induction of RANTES and IL-8. LPC activated multiple kinases in MVEC; it increased the phosphorylation of ERK1/2, AKT and p38 MAP kinase in a time-dependent manner. An inhibitor of the MAPK/ERK pathway, PD98059, blocked the phosphorylation of ERK1/2 and RANTES induction by LPC, but augmented IL-8 induction. LY294002, a specific inhibitor of phosphoinositide 3 kinase (PI3 kinase), blunted the phosphorylation of AKT and inhibited LPC induction of RANTES more strongly than IL-8. Inhibition of p38 MAP kinase pathway by SB202190 also blocked LPC-induced expression of IL-8 and RANTES. Our results suggest that LPC induction of chemokines in MVEC is distinct from that in large vessel EC, and required the activities of MAP kinases and PI3 kinase for the induction of RANTES and IL-8. We speculate that the presence of LPC, a bioactive lipid product of phospholipase A(2) (PLA(2)) and a constituent of oxidized low-density lipoprotein, can differentially influence the chemotaxis of particular leukocyte subpopulations during inflammation.
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PMID:Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines. 1459 94


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