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)

Phorbol ester (TPA) is generally considered to be a negative regulator of PtdIns-PLC activity. Here we show, for the first time, that the combination of TPA+ vanadate is a positive regulator (activator) of PtdIns-PLC in mouse elicited peritoneal macrophages. Vanadate or TPA on their own had no effect on PtdIns-PLC activity. In addition, TPA+ vanadate enhanced reactive oxygen species formation and protein tyrosine phosphorylation. PtdIns-PLC activation was suppressed by down regulation or inhibition of PKC, by inhibition of NADPH oxidase activity and scavenging of its product, and by inhibitors of protein tyrosine kinase activity. We conclude that PKC activation by TPA in the presence of vanadate activates the formation of reactive oxygen species, which are essential for the enhancement of protein tyrosine phosphorylation and eventually to PtdIns-PLC activation.
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PMID:Activation of macrophage PtdIns-PLC by phorbol ester and vanadate: involvement of reactive oxygen species and tyrosine phosphorylation. 751 Jan 6

Tumor necrosis factor (TNF) triggers cell spreading, release of granule constituents, and production of toxic oxygen derivatives in human neutrophils adherent to fibrinogen. This response requires cytoskeleton reorganization and is dependent on expression of beta 2 integrins. We analyzed distribution of distinct proteins in Triton X-100-soluble and insoluble fractions in neutrophils adherent to fibrinogen. We found that stimulation of adherent neutrophils with TNF causes the redistribution to a Triton-insoluble fraction of alpha-actinin, beta 2 integrins, and the four components whose assembly constitutes an active NADPH oxidase: the gp91-phox, p22-phox, p47-phox, and p67-phox proteins. Redistribution of these different proteins to a Triton-insoluble fraction took relatively long times and was maximal after about 30 min of stimulation with TNF. Prevention of actin polymerization with cytochalasin B hampered the TNF-induced redistribution of these proteins from a Triton-soluble to an insoluble fraction. In addition, tyrosine phosphorylated proteins and the protein tyrosine kinase p58fgr were recovered in this Triton-insoluble fraction. These findings show that stimulated, beta 2 integrin-dependent adhesion of neutrophils to fibrinogen is accompanied by redistribution to cytoskeletal structures of (1) beta 2 integrins, that is, neutrophil receptors for fibrinogen; (2) proteins involved in neutrophil effector functions, that is, components of NADPH oxidase; and (3) tyrosine phosphorylated proteins and the protein tyrosine kinase p58fgr, molecules that are potentially involved in the formation of a submembranous signaling complex.
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PMID:Tumor necrosis factor triggers redistribution to a Triton X-100-insoluble, cytoskeletal fraction of beta 2 integrins, NADPH oxidase components, tyrosine phosphorylated proteins, and the protein tyrosine kinase p58fgr in human neutrophils adherent to fibrinogen. 759 62

We have previously shown that vanadate potentiates the activating effect of phorbol ester (TPA) on cellular phospholipase A2 (PLA2) in a pathway dependent on the formation of reactive oxygen species (ROS). Here we evaluate the chain of enzymes (protein kinases and phosphatases) that participate in this process. Treatment of macrophages with vanadate plus TPA led to activation of protein kinase C (PKC) and NADPH oxidase (O2- generation in intact cells), massive cellular protein tyrosine phosphorylation, suppression of protein tyrosine phosphatase (PTP) activity and a sustained activation of protein tyrosine kinase (PTK) and myelin basic protein kinase activity (the latter three enzyme activities were assessed in cell lysates). Inhibition of ROS formation by diphenyleneiodonium (DPI) prevented PTP inhibition, PTK activation and protein tyrosine phosphorylation by vanadate plus TPA. Vanadate plus H2O2 mimicked the effect of vanadate plus TPA on PKC activation, cellular protein tyrosine phosphorylation, PTP and PTK, but their effects were resistant to DPI. Suppression of PKC activity (down-regulation; selective inhibitors) prevented the above-mentioned effects of vanadate plus TPA, but not of vanadate plus H2O2. Collectively, the results show that ROS formation induced by TPA in association with vanadate is essential in the modulation of protein tyrosine phosphorylation and PLA2 activity.
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PMID:Reactive oxygen species mediate phorbol ester-regulated tyrosine phosphorylation and phospholipase A2 activation: potentiation by vanadate. 769 72

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

The aim of this study was to examine the effects of serum iminodipeptides and prednisolone on superoxide generation and tyrosyl phosphorylation of proteins in neutrophils from a patient with prolidase deficiency, and also to find the causative effects of superoxide on inflammatory skin lesions. When the neutrophils from a patient with prolidase deficiency (PDPPMN) were preincubated with prolyl-proline (Pro-Pro), which is one of the iminodipeptides found at high concentration in the serum of patients with prolidase deficiency, the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation was enhanced in a concentration-dependent manner, although the extent of enhancing effect was lower than that in neutrophils from healthy humans (HPPMN). Pro-Pro also enhanced superoxide generation induced by opsonized zymosan (OZ) in PDPPMN but not that induced by arachidonic acid or phorbol 12-myristate 13-acetate. Herbimycin A and genistein decreased the fMLP- and OZ-induced superoxide generations after priming by Pro-Pro. 1-(5-isoquinoline-sulfonyl)-2-methyl-piperazine (H-7) and staurosporine did not decrease, but rather enhanced, the superoxide generation in a low concentration range. When PDPPMN were prepared, tyrosyl phosphorylation of 45 kDa protein in PDPPMN had already occurred. The phosphorylation was scarcely increased by incubation of the cells with Pro-Pro, in contrast to that in HPPMN. Genistein decreased the phosphorylation of 45 kDa protein in both PDPPMN and HPPMN. These results suggest that the priming effect of iminodipeptides on superoxide generation in PDPPMN is coupled with phosphorylation of 45 kDa protein by protein tyrosine kinase. Protein tyrosine kinase may play a critical role(s) in the regulatory mechanism of priming by iminodipeptides and activation of NADPH oxidase in the patient's neutrophils. In prolidase deficiency, the characteristic skin manifestations are inflammatory indurations and chronic leg ulcers. Prednisolone improves the ulcers, and this compound decreased the fMLP- and OZ-induced superoxide generation and tyrosyl phosphorylation of 45 kDa protein in the patient's neutrophils after priming by Pro-Pro. When inflammatory skin lesions were present, the levels of iminodipeptides in the patient's serum were elevated and the superoxide generation by neutrophils was up-regulated. When skin lesions were healing or absent, the levels of iminodipeptides in the patient's serum and superoxide generation by neutrophils were higher than those of healthy controls but lower than those in the inflammatory stages. Thus, the enhancement of superoxide generation by neutrophils via serum iminodipeptides would be one of the inducers of inflammatory skin lesions. Corticosteroid administration might be a therapeutic modality of choice for skin lesions.
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PMID:The effects of serum iminodipeptides and prednisolone on superoxide generation and tyrosyl phosphorylation of proteins in neutrophils from a patient with prolidase deficiency. 958 97

Periodontal disease, a frequent complication of diabetes mellitus, is the major cause of tooth loss. However, studies on neutrophil function in patients with this condition have yielded contradictory findings. The NADPH oxidase activity of 40 diabetic patients with periodontosis who were on metabolic control was evaluated and compared with that in 40 healthy subjects. Superoxide anion production was measured by a photometric method, with NBT reduction at 490 nm in a microplate reader and by a microscopic method, with a percentage of positive PMNs with granules of formazan in the cytoplasm. When the PMN respiratory burst was activated by phorbol myristate acetate (PMA), a protein kinase C (PKC) soluble activator, superoxide production of diabetics (4.31 +/- 1.67 A x 10(-3)/min) and normal subjects (4.25 +/- 1.25 A x 10(-3)/min) was comparable by photometric method, whereas a significantly defective response to opsonized zymosan was observed when the microscopic method was used (58 +/- 17% in diabetics and 66 +/- 18% in controls; p = 0.05). Therefore in patients with diabetes the impact on PMN function is of multifactorial origin, and is probably correlated to the glucose level and to glycation of PMN protein, such as NADPH oxidase or myeloperoxidase. Alternatively, glucose in PMN may be reduced by aldose reductase to polyols, and this pathway requires NADPH, the coenzyme for the respiratory burst. Moreover, we found that superoxide production in response to opsonized zymosan was reduced in diabetic patients. The activation of protein tyrosine kinase (PTK) is an important mechanism underlying transmembrane signaling and, moreover, protein tyrosine phosphorylations, stimulated by zymosan receptor-mediated activation, might be caused by the activation of specific PTK, whereas activation by PMA is probably mediated through another PKC type.
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PMID:Respiratory burst of neutrophils in diabetic patients with periodontal disease. 970 64

Reactive oxygen species (ROS) have been proposed to mediate vascular hypertrophy induced by angiotensin II (Ang II). Recently, we and others have shown that growth-promoting signals by Ang II involve protein tyrosine kinase (PTK) and extracellular signal-regulated kinase (ERK). However, whether ROS contribute to the Ang II-induced PTK and/or ERK activation in vascular smooth muscle cells (VSMCs) remains largely unclear. Here, we have investigated the possible involvement of ROS in Ang II-induced PTK and ERK activation. In the presence of a NADH/NADPH oxidase inhibitor, diphenyleneiodonium (DPI) or an antioxidant, alpha-tocopherol, Ang II-induced protein tyrosine phosphorylation of two major proteins (p120, p70) and ERK activation were markedly reduced, whereas ERK activation by epidermal growth factor was unaffected. DPI also inhibited Ang II-induced H2O2 production and PTK activation. In this regard, H2O2 and a membrane permeable thiol-oxidizing agent, diamide, stimulated protein tyrosine phosphorylation of p120 and p70, and ERK activation in VSMCs. H2O2 also enhanced PTK activity. From these data, we conclude that ROS play a critical role in the Ang II-induced PTK and ERK activation in VSMCs, thereby contributing to vascular growth associated with enhanced Ang II activity.
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PMID:Involvement of reactive oxygen species in the activation of tyrosine kinase and extracellular signal-regulated kinase by angiotensin II. 1096 82

We have previously demonstrated that thrombin upregulation of insulin-like growth factor-1 receptor (IGF-1R) is essential for thrombin-induced mitogenic signaling. To characterize the mechanisms involved, we studied transcription of the IGF-1R gene in rat aortic smooth muscle cells. Thrombin markedly increased IGF-1R mRNA levels, peaking at 3 hours (112+/-7% above control). This effect was mimicked by the hexapeptide SFFLRN (that functions as a tethered ligand) and was blocked by the thrombin inhibitor hirudin. Nuclear run-on assays indicated that thrombin stimulated IGF-1R gene transcription by 2.1-fold, and this was confirmed with the use of actinomycin D. Thrombin-mediated upregulation of IGF-1R mRNA and protein levels was protein kinase C independent but was completely inhibited by the protein tyrosine kinase inhibitor genistein and by the antioxidants N-acetyl-L-cysteine and pyrrolidinedithiocarbamate, suggesting the involvement of reactive oxygen species. The thrombin-induced increase in IGF-1R mRNA was inhibitable by diphenyleneiodonium chloride but not by other inhibitors of cellular oxidase systems, suggesting that NAD(P)H oxidase was necessary for the increase. Furthermore, inhibitors of the epidermal growth factor receptor kinase, Janus kinase-2 kinase, and Src kinase did not block the effect. Thus, thrombin transcriptionally regulates the IGF-1R gene via a redox-sensitive protein tyrosine kinase-dependent pathway that does not require protein kinase C activation. In view of our prior data indicating that IGF-1R density is a critical determinant of vascular smooth muscle cell growth, our findings have particular relevance to understanding mechanisms whereby growth factors such as thrombin regulate vascular proliferation in vivo.
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PMID:Thrombin regulates insulin-like growth factor-1 receptor transcription in vascular smooth muscle: characterization of the signaling pathway. 1137 74

The c-fps/fes proto-oncogene encodes a 92-kDa protein tyrosine kinase that is preferentially expressed in myeloid and endothelial cells. Fes is believed to play a role in vascular development and myelopoiesis and in the inflammatory responses of granulocytes and macrophages. To help define the biological role of this kinase and identify its downstream targets, we have developed a gain-of-function allele of Fes that has potent biological activity in myeloid cell progenitors. Introduction of constitutively active Fes into bipotential U937 cells induced the appearance of fully differentiated macrophages within 6 to 12 days. The Fes-expressing differentiated cells became adherent, had distinctive macrophage morphology, and exhibited increased expression of myelomonocytic differentiation markers, including CD11b, CD11c, CD18, CD14, and the macrophage colony-stimulating factor receptor. These cells acquired phagocytic properties and exhibited NADPH oxidase and nonspecific esterase activities, confirming that they were functionally active macrophages. Concomitantly, there was downregulation of the granulocytic marker granulocyte colony-stimulating factor receptor, indicating that the biological activity of Fes was coordinated in a lineage-specific manner. A constitutively active Src did not induce macrophage morphology or upregulation of myelomonocytic markers in U937 cells, suggesting that the biological activity we observed was not a general consequence of expression of an activated nonreceptor tyrosine kinase. Analysis of possible downstream targets of Fes revealed that this kinase activated the ets family transcription factor PU.1, which is essential for macrophage development. Our results strongly implicate Fes as a key regulator of terminal macrophage differentiation and identify PU.1 as a transcription factor that may mediate some of its biological activities in myeloid cells.
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PMID:Activated Fes protein tyrosine kinase induces terminal macrophage differentiation of myeloid progenitors (U937 cells) and activation of the transcription factor PU.1. 1186 67

The human IgA Fc receptor (FcalphaR, CD89) triggers several important physiological functions, including phagocytosis, NADPH oxidase activation and antigen presentation. Efforts are underway to delineate FcalphaR signal-transduction pathways that control these functions. In a previous study, we demonstrated that cross-linking of FcalphaR increased its partitioning into membrane glycolipid rafts and was accompanied by gamma-chain-dependent recruitment and phosphorylation of the tyrosine kinases Lck/Yes-related novel protein tyrosine kinase (Lyn) and Bruton's tyrosine kinase (Btk). Here we have performed a more extensive characterization of signalling effectors recruited to rafts on FcalphaR cross-linking. We demonstrate that in addition to tyrosine kinases Lyn and Btk, FcalphaR cross-linking also recruits B-lymphocyte kinase (Blk) and spleen tyrosine kinase (Syk) to rafts. We show recruitment of phosphoinositide kinases, including 3-phosphoinositide 3-kinase and phospholipase Cgamma2, and serine/threonine kinases such as protein kinase C (PKC) alpha, PKCepsilon, and protein kinase B (PKB) alpha. This suggests that lipid rafts serve as sites for FcalphaR-triggered recruitment of multiple classes of signalling effectors. We further demonstrate that tyrosine kinases and PKCalpha have a sustained association with rafts, whereas phosphoinositide 3-kinase and its downstream effectors have a transient association with rafts. This is consistent with temporally regulated divergence of FcalphaR signalling pathways in rafts. Furthermore, we suggest the spatial separation of signalling effectors by transport of phosphoinositide 3-kinase, phosphoinositide-dependent kinase 1, PKBalpha and PKCepsilon to endocytic compartments containing internalized FcalphaR.
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PMID:IgA Fc receptor (FcalphaR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts. 1202 95


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