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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we have shown that reactive oxygen species (ROS) formation induced by phorbol ester in association with vanadate is essential for protein tyrosine phosphorylation and phospholipase A2 (PLA2) activation. Here we show that the interaction of beta-glucan particles (glucanp) or zymosan with complement receptor type 3 (CR3) leads, when associated with vanadate, to a cascade of reactions culminating in PLA2 activation. Vanadate + zymosan (or glucanp) markedly enhance protein tyrosine phosphorylation in bone marrow derived macrophages (BMMs), whereas neither of the agents alone has any effect. The enhancement was due to both sustained activation of protein tyrosine kinase (PTK) and inactivation of protein tyrosine phosphatase (PTP) as assessed in lysates of treated cells. Zymosan elevates membranal PKC, an effect that is potentiated by vanadate. Activation of both PTK and PKC leads to the activation of NADPH oxidase and to ROS formation. The formed ROS together with vanadate are potent inactivators of PTP leading to amplification of tyrosine phosphorylation and myelin basic protein kinase (MBP-K) activation. The activation of the cascade of protein kinases eventually leads to activation of PLA2. All the activation steps, i.e., activation of PTK, NADPH oxidase, MBP-K,PLA2 and the inactivation of PTP are sensitive to the NADPH oxidase inhibitor diphenyleneiodonium (DPI), to antioxidants and to PKC inhibitors. Thus, ROS formation (in the presence of vanadate) is critical for protein phosphorylation processes constituting the regulatory pathway of PLA2 activation by ligand-CR3 interaction.
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PMID:A role for reactive oxygen species in zymosan and beta-glucan induced protein tyrosine phosphorylation and phospholipase A2 activation in murine macrophages. 803 63

Production of reactive oxygen metabolites by the NADPH oxidase is an essential mechanism underlying the microbicidal role of phagocytes. Receptor-mediated activation of the oxidase was originally thought to be mediated by calcium and/or by protein kinase C (PKC). However, recent evidence suggests that additional signalling pathways exist. In this article the possible role of tyrosine phosphorylation is discussed. In addition, results obtained using an in vitro kinase renaturation assay are described. The latter assay revealed the existence of at least four serine/threonine kinases that are activated in cells stimulated with chemoattractants. One of these, of molecular weight 41,000 was identified as a member of the ERK or MAP-kinase family. The existence of multiple, possibly redundant or synergistic signaling pathways is considered.
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PMID:Involvement of multiple kinases in neutrophil activation. 831 67

Neutrophils possess a multicomponent NADPH-oxidase that produces large quantities of superoxide, which can in turn generate other reactive oxygen intermediates. Superoxide and its dismutation product, hydrogen peroxide, are powerful oxidants. Because the activity of certain tyrosine kinases and phosphatases can be affected by their redox state, we considered the possibility that endogenously generated reactive oxygen intermediates (ROI) may alter phosphotyrosine formation and thereby function as intra- or intercellular messengers in neutrophils. Exposure of human neutrophils to exogenous oxidants such as diamide induced marked tyrosine phosphorylation of several cellular proteins. More importantly, activation of the NADPH oxidase in permeabilized neutrophils, by direct stimulation of GTP-binding proteins, also resulted in enhanced tyrosine phosphorylation. The latter was NADPH-dependent, paralleled by production of superoxide, and was inhibited by diphenylene iodonium, an inhibitor of the flavoprotein component of the oxidase. Neutrophils, from a patient with chronic granulomatous disease, which are deficient in the production of ROI, demonstrated no such phosphotyrosine accumulation. We conclude that ROI produced by the NADPH oxidase can regulate tyrosine phosphorylation in granulocytes, possibly by effects of oxidation-sensitive tyrosine kinases and/or phosphatases.
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PMID:Regulation of tyrosine phosphorylation in neutrophils by the NADPH oxidase. Role of reactive oxygen intermediates. 834 2

The activation of human neutrophils by monosodium urate and calcium pyrophosphate dihydrate crystals is believed to play a critical role in the pathogenesis of arthritides such as acute gout and pseudogout, respectively. In this study, we investigated the potential involvement of tyrosine phosphorylation in microcrystal-mediated activation of human neutrophils. Immunoblot analysis with antiphosphotyrosine antibodies demonstrated that triclinic monosodium urate and calcium pyrophosphate dihydrate crystals stimulated a time- and concentration-dependent tyrosine phosphorylation of at least five proteins (pp130, 118, 80, 70, and 60). While phosphoprotein (pp) 118 and pp70 were the major phosphorylated substrates, pp70 was the dominant one in reactivity with antiphosphotyrosine antibodies. When the temporal patterns, as well as the levels of tyrosine phosphorylation for both types of crystals were compared, monosodium urate crystals were found to be more potent activators than calcium pyrophosphate dihydrate crystals. The tyrosine phosphorylation patterns induced by microcrystals differed from those stimulated by other soluble (FMLP, C5a, or leukotriene B4) or particulate (unopsonized latex beads or zymosan) agonists which stimulated preferentially the tyrosine phosphorylation of pp118. The ratio of the intensities of pp118 and pp70 were specific of the stimulation with microcrystals when compared to those observed with the other soluble or particulate agonists. Colchicine, a drug used specifically in the treatment of gout and pseudogout, inhibited microcrystal-induced tyrosine phosphorylation, while beta- and gamma-lumicolchicine were without effect. On the other hand, colchicine failed to inhibit FMLP-induced tyrosine phosphorylation. Furthermore, while colchicine inhibited the activation of the NADPH oxidase by microcrystals, it, on the other hand, enhanced the production of superoxide anions by FMLP. Taken together, these results (a) demonstrate that tyrosine phosphorylation is involved in the mechanism of activation of human neutrophils induced by microcrystals; and (b) suggest, on the basis of the characteristics of the observed patterns of tyrosine phosphorylation, that this response may be specific to the microcrystals and relevant to their phlogistic properties.
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PMID:Crystal-induced neutrophil activation. III. Inflammatory microcrystals induce a distinct pattern of tyrosine phosphorylation in human neutrophils. 838 91

In response to invading microorganisms, neutrophils produce large amounts of superoxide and other reactive oxygen intermediates (ROI) by assembly and activation of a multicomponent enzyme complex, the NADPH oxidase. While fulfilling a microbicidal role, ROI have also been postulated to serve as signaling molecules, because activation of the NADPH oxidase was found to be associated with increased tyrosine phosphorylation (Fialkow, L., Chan, C. K., Grinstein, S., and Downey, G.P. (1993) J. Biol. Chem. 268, 17131-17137). The mechanism whereby ROI induces phosphotyrosine accumulation was investigated using electroporated neutrophils stimulated with guanosine 5'-O-3-thiotriphosphate in order to bypass membrane receptors. In vitro immune complex assays and immunoblotting were used to identify five tyrosine kinases present in human neutrophils. Of these, p56/59hck, p72syk, and p77btk were activated during production of ROI. Interestingly, the in vitro autophosphorylation activities of p53/56lyn and p59fgr were found to decline with ROI production. The mode of regulation of p56/59hck was explored in detail. Oxidizing agents were unable to activate p56/59hck in vitro and, once activated in situ, reducing agents failed to inactivate it, suggesting that the effects of ROI are indirect. Tyrosine phosphorylation of p56/59hck paralleled its activation, and dephosphorylation in vitro reversed the stimulation. We therefore conclude that tyrosine phosphorylation is central to the regulation of p56/59hck and likely also of p72syk, which is similarly phosphorylated upon activation of the oxidase. Because ROI have been shown to reduce the activity of tyrosine phosphatases, we suggest that this inhibition allows constitutively active kinases to auto/transphosphorylate on stimulatory tyrosine residues, leading to an increase in their catalytic activity. Enhanced phosphotyrosine accumulation would then result from the combined effects of increased phosphorylation with decreased dephosphorylation.
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PMID:Endogenous reactive oxygen intermediates activate tyrosine kinases in human neutrophils. 857 38

Addition of GTPgammaS to saponin-permeabilised human neutrophils activated both the NADPH oxidase and phospholipase D (PLD). This PLD activation was hardly affected by staurosporine or Ro31-8220 (at concentrations which inhibited PMA stimulated PLD activity), indicating that it was largely independent of protein kinase C (PKC). This GTPgammaS stimulated PLD activity was enhanced by 1 mM ATP, but this ATP-enhanced activity was blocked by inhibitors of PKC. Addition of GTPgammaS resulted in very low levels of phosphorylation on tyrosine residues, but higher levels of phosphorylation on serine/threonine residues. Addition of pervanadate hydroperoxides stimulated phosphorylation on tyrosine residues and activated PLD which was blocked by addition of inhibitors of tyrosine kinases. Thus, GTPgammaS can stimulate PKC-dependent and -independent pathways of PLD activation. Whilst phosphorylation on tyrosine residues can result in activation of PLD, this is regulated independently of activation via G-proteins.
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PMID:GTPgammaS-stimulated phospholipase D activation in human neutrophils occurs by protein kinase C-dependent and -independent pathways but not tyrosine kinases. 860 92

Neutrophil activation by chemotactic factors and by inflammatory microcrystals is accompanied by increases in protein tyrosine phosphorylation and by the activation of the NADPH oxidase. The addition of colchicine inhibited both responses induced by triclinic monosodium urate or calcium pyrophosphate crystals. On the other hand, colchicine enhanced the tyrosine phosphorylation of specific protein in neutrophils stimulated by chemotactic factor and augmented the production of superoxide anions induced by these same agonists. The effects of colchicine were shared by other anti-microtubule agents (nocodazole and vinblastine) but not by its inactive analogue beta-lumicolchicine, trimethylcolchicinic acid, indomethacin, or phenylbutazone. Furthermore, the (enhancing as well as inhibitory) effects of colchicine on tyrosine phosphorylation and superoxide anion production were reversed by taxol. Finally, in human cytoplasts colchicine again inhibited microcrystal-stimulated tyrosine phosphorylation but did not change chemotactic factor-stimulated phosphorylation. These data strongly support the hypothesis that microtubule-related mechanisms are involved in the modulation of the tyrosine phosphorylation response in human neutrophils, and suggest that a relationship may exist between the augmentation of tyrosine phosphorylation and of the stimulation of the NADPH oxidase induced by chemotactic factors.
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PMID:Paradoxical effects of colchicine on the activation of human neutrophilis by chemotactic factors and inflammatory microcrystal. 869 Oct 72

Src family tyrosine kinases have been implicated in the adhesion-dependent activation of neutrophil functions (Yan, S. R., Fumagalli, L., and Berton, G. (1995) J. Inflamm. 45, 297-312; Lowell, C. A., Fumagalli, L., and Berton, G. (1996) J. Cell Biol. 133, 895-910). Because the activity of tyrosine kinases can be affected by oxidants, we investigated whether reactive oxygen intermediates (ROI) produced by adherent neutrophils regulate Src family kinase activities. Inhibition of ROI production by diphenylene iodonium, an inhibitor of NADPH oxidase, or degradation of H2O2 by exogenously added catalase inhibited the adhesion-stimulated activities of p58(c-fgr) and p53/56(lyn). In addition, adhesion-stimulated p58(c-fgr) and p53/56(lyn) activities were greatly reduced in neutrophils from patients with chronic granulomatous disease (CGD) that are deficient in the production of ROI. Exogenously added H2O2 increased p58(c-fgr) and p53/56(lyn) activities in nonadherent neutrophils. Although ROI regulated the activities of p58(c-fgr) and p53/56(lyn), they did not affect the redistribution of the two kinases to a Triton X-100-insoluble, cytoskeletal fraction that occurs in adherent neutrophils. Tyrosine phosphorylation of proteins in adherent, CGD neutrophils was only partially inhibited, suggesting that the full activation of p58(c-fgr) and p53/56(lyn), which depends on endogenously produced ROI, does not represent an absolute requirement for protein tyrosine phosphorylation. The adhesion-stimulated activity of the tyrosine kinase p72(syk) was not affected by catalase in normal neutrophils, and it was comparable in normal and CGD neutrophils. These findings suggest that ROI endogenously produced by adherent neutrophils regulate Src family kinases activity selectively and establish the existence of a cross-talk between reorganization of the cytoskeleton, production of ROI, and Src family tyrosine kinase activities in signaling by adhesion.
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PMID:Regulation of Src family tyrosine kinase activities in adherent human neutrophils. Evidence that reactive oxygen intermediates produced by adherent neutrophils increase the activity of the p58c-fgr and p53/56lyn tyrosine kinases. 879 54

This study concerns the controversial problem of whether the TNF-alpha (TNF) induces a respiratory burst in human neutrophils in suspension. The results have shown that in these cells TNF induces a classical respiratory burst. In fact, the production of oxygen free radicals 1) is linked to the translocation of NADPH oxidase components from cytosol to the plasma membrane, 2) does not take place in neutrophils from a patient lacking the cytochrome b558, and 3) does not involve other sources such as mitochondrial respiratory chain or xanthine oxidase. Signal transduction studies have demonstrated that this respiratory burst 1) is not accompanied by calcium transients, stimulation of phosphoinositide turnover, and phospholipase D activity (moreover, this burst is associated with the stimulation of the activity of phospholipase A2, but not of sphingomyelinase); 2) is strictly dependent on activation of tyrosine kinases, which is functional to the translocation to the plasma membrane of the cytosolic NADPH oxidase component rac; and 3) is dependent on the integrity of the cytoskeleton because it is completely suppressed by cytochalasin B. The integrity of the cytoskeleton is required for a full translocation of all the NADPH oxidase components and for an optimal activation of tyrosine kinases, but not for phospholipase A2 activation. Taken together, these findings demonstrate that TNF activates the NADPH oxidase through stimulation of tyrosine kinases, whose function is cytoskeleton-dependent, and raise the problem of whether the activation of this respiratory burst involves signals arising from TNF-activated beta2 integrins.
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PMID:Mechanisms of stimulation of the respiratory burst by TNF in nonadherent neutrophils: its independence of lipidic transmembrane signaling and dependence on protein tyrosine phosphorylation and cytoskeleton. 890 41

This review examines the functional role of phospholipase D in the neutrophil. Phospholipase D is emerging as an important component in the signal transduction pathways leading to granulocyte activation. Through the second messenger it produces, phosphatidic acid, phospholipase D plays an active role in the regulation of granulocyte NADPH oxidase activation and granular secretion. Many factors from both the cytosol and the membrane are necessary for maximal phospholipase D activation. This paper will focus on the regulation of phospholipase D by low molecular weight GTP-binding proteins, tyrosine kinases, and protein kinase C.
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PMID:Small GTPase-regulated phospholipase D in granulocytes. 896 Mar 52


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