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)

Insulin caused a transient increase in H2O2 accumulation in human fat cell suspensions that was observed only in the presence of an inhibitor of catalase and heme-containing peroxidases, such as azide, and reached peak levels of 30 microM within 5 min. The cells contained a plasma membrane-bound NADPH oxidase, producing 1 mol H2O2/mol of NADPH oxidation, that was activated on exposure of intact cells to insulin at contrations that are physiologically relevant (0.1-10 nM). The hormone effect was rapid and was due to a selective increase in substrate affinity. The enzyme was magnesium dependent, required a flavine nucleotide for optimal activity, and was most active at pH 5.0-6.5. In contrast to all other hormone- or cytokine-sensitive NADPH oxidases that have been characterized in sufficient detail, the human fat cell oxidase retained its hormone responsiveness after cell disruption, and only Mn2+, but no ATP, was required for a ligand-induced activation in crude plasma membranes. The results demonstrate that insulin utilizes tyrosine kinase-independent pathways for receptor signaling and strongly support the view that H2O2 contributes to the intracellular propagation of the insulin signal.
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PMID:Human fat cells possess a plasma membrane-bound H2O2-generating system that is activated by insulin via a mechanism bypassing the receptor kinase. 131 14

Protein kinase C (PKC) appears to have a central role in the O2- response of neutrophils following stimulation of membrane receptors. The second messenger, diacylglycerol (DG), that activates PKC is derived from membrane phospholipids via activation of phosphatidylinositol 4,5-bisphosphate (PIP2)-phospholipase C (PLC) and phospholipase D (PLD), with the latter pathway being more prominent in primed cells. In resting cells receptor coupling to PLD is through a G-protein. Priming brings a cytoplasmic tyrosine kinase into the transducer sequence which, through protein phosphorylation, increases the efficiency of coupling between membrane receptors and PLD. Phosphatidic acid (PA), the initial product of the PLD pathway, also appears to act as a second messenger by directly activating the NADPH oxidase responsible for generating O2-. Interconversion of PA and DG by phosphatidate phosphohydrolase and DG kinase determines which of these second messengers has the dominant role.
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PMID:New pathways of phagocyte activation: the coupling of receptor-linked phospholipase D and the role of tyrosine kinase in primed neutrophils. 133 78

To determine the role of protein tyrosine phosphorylation in the activation of phospholipase D (PLD), electropermeabilized HL-60 cells labeled in [3H]alkyl-phosphatidylcholine were treated with vanadate derivatives. Micromolar concentrations of vanadyl hydroperoxide (V(4+)-OOH) induced accumulation of tyrosine-phosphorylated proteins. Concomitantly, V(4+)-OOH or a combination of vanadate and NADPH elicited a concentration- and time-dependent accumulation of phosphatidic acid (PtdOH). In the presence of ethanol a sustained formation of phosphatidylethanol was observed, indicating that a type D phospholipase was activated. A good correlation was found to exist between the accumulation of tyrosine-phosphorylated proteins and activation of PLD. The V(4+)-OOH concentration dependence of the two responses was nearly identical, and the time course of activation was similar, with tyrosine phosphorylation preceding PLD activation by approximately 1 min. The ability of V(4+)-OOH to induce both responses was found to be strictly dependent on the presence of ATP and/or Mg2+, suggesting that PLD activation involves phosphotransferase reactions. Accordingly, ST638, a tyrosine kinase inhibitor, reduced concomitantly tyrosine phosphorylation and PLD activation elicited by V(4+)-OOH. The mechanism of action of V(4+)-OOH was investigated. The diacylglycerol kinase inhibitors, dioctanoylethylene glycol and R59022 potentiated PLD stimulation by exogenous diacylglycerol but not by V(4+)-OOH. Moreover, stimulation by V(4+)-OOH and by phorbol esters was synergystic. Therefore, diacylglycerol-induced activation of protein kinase C is unlikely to mediate the effects of V(4+)-OOH. The response of PLD to V(4+)-OOH was larger than that to guanosine 5'-(gamma-thio)triphosphate. Moreover, the effects of GTP gamma S and V(4+)-OOH were additive. Hence, activation of G proteins cannot account for the stimulation of PLD by V(4+)-OOH. V(4+)-OOH also triggers a burst of O2 consumption by the NADPH oxidase. Inhibition of PtdOH accumulation by addition of ethanol or by ST638 abolished this respiratory burst. Together, the results establish a strong correlation between tyrosine phosphorylation, PLD activation, and stimulation of the NADPH oxidase in HL-60 cells, suggesting a causal relationship.
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PMID:Peroxides of vanadate induce activation of phospholipase D in HL-60 cells. Role of tyrosine phosphorylation. 160 60

A comprehensive model of cellular activation and proliferation is developed. The model has arachidonic acid (ARA) produced mainly from PLA2 on both sides of the membrane, and superoxide and other activated oxygen species (AOS) formed from O2 by electrons passing out through membrane NANPH and NADH oxidases, as the immediate stimulants of solute permeability. Both ARA and AOS interact with the various solute channel proteins especially their external thiols and disulfides, to increase influx of metabolic substrates, Na, Ca and O2. PLA2 and NADPH oxidase are turned on by growth factors at their receptors acting through tyrosine kinase phosphorylations of messenger proteins GP and ras p-21, stimulated proteases, and by Ca-calmodulin. The adenylate cyclase system has opposite, deactivating character as it increases efflux of Ca and desensitizes growth factor receptors by phosphorylation to shut down the increased solute permeability. Most cancer types are due to carcinogen binding to cell membrane channel and mitochondrial sites for increased solute influx with excessive AOS production inside the cell from mitochondria and other vesicles. High Ca, Na and AOS stimulate proliferation with extra high levels causing transformation to the autogenic, more embryonic-type cancer cell.
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PMID:Unitary model of cell activation, growth control, cancer and other diseases: 1. Activated oxygen species and arachidonic acid modulation of solute permeabilities, internal Ca, Na and AOS levels and DNA transcription and synthesis. 192 75

Activation of the NADPH oxidase was examined in electrically permeabilized human neutrophils exposed to non-hydrolysable guanine nucleotides. Guanosine 5'-[gamma-thio]triphosphate (GTP[S]) induced a marked increase in the rate of O2 consumption, which was partially resistant to staurosporine, an inhibitor of protein kinase C, under conditions where the response to diacylglycerol was virtually abolished. The respiratory burst elicited by GTP[S] was dependent on the presence of ATP and Mg2+, suggesting involvement of phosphorylation reactions. Accordingly, phosphoprotein formation was greatly stimulated by the guanine nucleotide. The polypeptide phosphorylation pattern induced by GTP[S] was similar to, but not identical with, that observed with diacylglycerol, indicating the activation of kinases other than protein kinase C by the guanine nucleotide. The possible involvement of tyrosine kinases was assessed by immunoblotting using anti-phosphotyrosine antibodies. Treatment of electroporated cells with GTP[S] stimulated the accumulation of tyrosine-phosphorylated proteins. This effect was not induced by diacylglycerol, indicating that tyrosine phosphorylation is not secondary to stimulation of protein kinase C. The results indicate that, in neutrophils, activated G-proteins can stimulate tyrosine kinase and/or inhibit tyrosine phosphatase activity. Changes in the amounts of tyrosine-phosphorylated proteins may signal activation of the respiratory burst.
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PMID:Guanine nucleotides induce tyrosine phosphorylation and activation of the respiratory burst in neutrophils. 293 Apr 92

We previously reported that phorbol 12-myristate 13-acetate (PMA)-induced superoxide (O2.-) generation of neutrophils was inhibited by hypericin, a photosensitizing pigment found in St. Johnswort (herb Hypericin triquetrifolium Turra), via a mechanism involving protein kinase C (PKC). To obtain further insights into the mechanism of inhibition, the effects of hypericin on stimulation-dependent O2.- generation and related enzymes of neutrophils were investigated. Hypericin inhibited O2.- generation of neutrophils induced by PKC-dependent and -independent stimuli in a light- and concentration-dependent manner. Oxygen was required for the light-dependent inhibition by hypericin. NADPH oxidase activity in a cell-free system and TNF-alpha-induced tyrosyl phosphorylation of neutrophil proteins were also inhibited by hypericin in a concentration- and light-dependent manner. However, tyrosine kinase of p60src, an enzyme not bound to a membrane, was not inhibited either in the light or in the dark. Oxygen uptake of neutrophils by photosensitization with hypericin resulted in the formation of singlet oxygen (1O2), O2.-, and hydroxyl radical (.OH) and enhanced lipid peroxidation. The formation of 1O2 was inhibited by azide, a quencher of 1O2, but not by desferrioxamine (DSF), a ferric ion chelator. By contrast, both generation of .OH and lipid peroxidation were inhibited by DSF but not by azide. Furthermore, PMA-induced O2.- generation inhibited by hypericin partially recovered in the presence of azide but not DSF. These results suggested that the light-dependent inhibition of O2.- generation by hypericin might be due to inhibition of tyrosine kinase, PKC, and NADPH oxidase via an oxygen-dependent mechanism, possibly through both Type I and II photosensitization mechanisms.
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PMID:Inhibition of neutrophil superoxide generation by hypericin, an antiretroviral agent. 748 96

We studied involvement of tyrosine-phosphorylated proteins in activation of NADPH oxidase in guinea pig neutrophils. Pervanadate, which is the oxidized form of orthovanadate, induced O2- production and protein tyrosine phosphorylation in neutrophils. O2- production induced by pervanadate was more sensitive to the tyrosine kinase-specific inhibitor, ST-638, as compared with the production induced by PMA. On the other hand, staurosporine more selectively inhibited PMA-induced O2- production than pervanadate-induced production. These results indicate that tyrosine kinase, not protein kinase C, is involved in pervanadate-induced O2- production. The tyrosine-phosphorylated proteins were detected in both the cytosol and membrane fractions prepared from pervanadate-induced neutrophils. In order to examine if tyrosine residues of some components of NADPH oxidase were directly phosphorylated, tyrosine-phosphorylated proteins were removed from solubilized membranes prepared from the pervanadate-stimulated neutrophils by immunoprecipitation with an anti-phosphotyrosine anti-body. NADPH oxidase activity in the solubilized membranes was not decreased by the treatment. These findings suggest that the components of NADPH oxidase are not tyrosine-phosphorylated by pervanadate treatment, that tyrosine phosphorylation may be involved in the signal transduction pathway of NADPH oxidase activation by pervanadate, and that this pathway is independent of the activation by protein kinase C.
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PMID:Respiratory burst and tyrosine phosphorylation by vanadate. 748 2

Cytosolic components of the phagocyte NADPH oxidase (p47phox, p67phox, and Rac2) translocate to the plasma membrane on cell activation where they interact with a membrane-bound cytochrome b to generate superoxide anion. Phosphorylation reactions are known to be important for activity of NADPH oxidase. Translocation of Rac2, p47phox, and p67phox were all enhanced in formyl-Met-Leu-Phe-stimulated neutrophils treated with 50 nM of the protein phosphatase 1/2A inhibitor calyculin A. Rac translocation was blocked by the tyrosine kinase inhibitors genistein (50 microM) and herbimycin (17 microM), whereas movement of p47phox and p67phox were not inhibited. Cell-free analysis of Rac translocation also demonstrated that translocation of p47phox and p67phox were not linked to the movement or availability of Rac2. Thus, Rac2 does not appear to regulate NADPH oxidase by controlling movements of the cytosolic components to the membrane-associated enzyme but may exert its effect at the level of the assembled complex. Tyrosine kinase activity is required for translocation of Rac in the chemoattractant-stimulated human neutrophil.
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PMID:Dissociation of Rac translocation from p47phox/p67phox movements in human neutrophils by tyrosine kinase inhibitors. 761 2

Receptors for chemoattractants that direct the migration of phagocytic leukocytes to sites of injury/infection also modulate many other leukocyte functions that are critical to the inflammatory response. These chemoattractant receptors, members of the G protein-coupled heptahelical receptor family, have been classically linked to cell activation via phospholipase C, calcium, and protein kinase C. We show here that activation of the N-formyl peptide chemoattractant receptor stimulates an additional protein kinase C-independent pathway through the Src-related tyrosine kinase, Lyn, in human neutrophils. We demonstrate that activation of Lyn is associated with binding to the Shc adapter protein, which becomes phosphorylated on tyrosine residues. This interaction appears to be mediated via the Shc SH2 domain. Complexes of phosphorylated Lyn and Shc with phosphatidylinositol 3-kinase are rapidly formed in stimulated neutrophils, correlating with phosphatidylinositol 3,4,5-trisphosphate [corrected] formation and cell activation. This signaling pathway involving a Src-related kinase and the Shc adapter protein provides a potential mechanism linking chemoattractant receptors to downstream events involving Rac activation and NADPH oxidase. Regulation of Shc by G protein-coupled receptors may also allow these receptors to modulate the activity of the Ras/mitogen-activated protein kinase cascade.
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PMID:G protein-coupled chemoattractant receptors regulate Lyn tyrosine kinase.Shc adapter protein signaling complexes. 765 13

We studied a step where tyrosine phosphorylation is involved in a signaling pathway for the activation of the superoxide (O2-)-generating NADPH oxidase using electropermeabilized human neutrophils. The permeabilized cells produced O2- by the addition of a protein tyrosine phosphatase inhibitor, vanadate, as well as N-formyl-methionyl-leucyl-phenylalanine (fMLP) and protein kinase C (PKC) activators such as phorbol myristate acetate (PMA) and L-alpha-1-oleoyl-2-acetoyl-sn-3-glycerol (OAG). The O2- production by the stimulants was completely inhibited by PKC inhibitors such as calphostin C and staurosporine and was not affected by 1% ethanol, a metabolic modulator of phospholipase D (PLD). Furthermore, the O2- production by vanadate and fMLP, but not by OAG and PMA, was inhibited by both an inhibitor of phospholipase C (PLC), neomycin, and an inhibitor of tyrosine kinase, ST-638. These findings suggest that tyrosine phosphorylation is involved in the activation of the oxidase at a step before diacylglycerol formation by PLC, and that PLD may not be involved in the signaling pathway in permeabilized cells.
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PMID:Tyrosine phosphorylation is involved in the respiratory burst of electropermeabilized human neutrophils at a step before diacylglycerol formation by phospholipase C. 768 14


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