Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol

Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 07/2008; 181(7):1129-39. DOI: 10.1083/jcb.200709049
Source: PubMed


Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.

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    • "NOX4-derived ROS can also inactivate PTEN [16,29], which is a well-known negative regulator of PI3K/Akt activity. Besides, NOX4 has been shown to promote the phosphorylation of EGFR [30,31], whose activation results in stimulation of PI3K/Akt pathway, and this effect may be, at least partly dependent on redox regulation of PTP1B [32]. These findings suggest that the mechanisms for NOX4-stimulated PI3K/Akt pathway are complicated and there may be crosstalk with other signals, like EGFR signaling, to further activate PI3K/Akt signaling. "
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    ABSTRACT: NADPH oxidase 4 (NOX4) is deregulated in various cancers and involved in cancer proliferation and metastasis. However, what the role of NOX4 plays during malignant progression of non-small cell lung cancer (NSCLC) remains unknown. Our results show that NOX4 was upregulated in NSCLC cell lines and samples from patients, compared with controls; NOX4 protein levels were closely correlated with clinical disease stage and survival time. Overexpression of NOX4 in A549 and H460 NSCLC cells enhanced cell proliferation and invasion in vitro, and produced larger tumors, shorter survival time, and more lung metastasis in nude mice than control cells. On the contrary, NOX4 depletion inhibited NSCLC cell aggressiveness. Inhibition of PI3K/Akt pathway could sufficiently block the cellular effects of NOX4 overexpression in NSCLC cells both in vitro and in vivo. Specifically, we demonstrated that PI3K/Akt pathway also positively regulated NOX4 expression via NF-κB-mediated manner. Therefore, there existed a mutual positive regulation between NOX4 and PI3K/Akt signaling in NSCLC cells, and NOX4 was confirmed to functionally interplay with PI3K/Akt signaling to promote NSCLC cell proliferation and invasion. In conclusion, the positive feedback loop between NOX4 and PI3K/Akt signaling contributes to NSCLC progression.
    Oncotarget 05/2014; 5(12). DOI:10.18632/oncotarget.2025 · 6.36 Impact Factor
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    • "Unlike the majority of Nox proteins, which produce superoxide, Nox4 appears to primarily produce hydrogen peroxide (H 2 O 2 ) [26] [27] [28]. In response to physiological stimuli, Nox4 generates H 2 O 2 and activates signaling pathways, such as insulin [29] and epidermal growth factor signaling [30], through the oxidation of specific protein thiols. Protein thiols can undergo oxidation to various oxidation products, including S-glutathionylated thiols, i.e., mixed disulfide bonds between protein thiols and glutathione [31]. "
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    ABSTRACT: Aims Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and Results Metabolic stress sensitizes or “primes” human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.
    01/2014; 2(1). DOI:10.1016/j.redox.2014.01.003
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    • "This leads to oxidative inactivation of protein tyrosine phosphatases (PTPs), which prolongs RTK signaling until cytosolic ROS scavengers such as Prxs have cleared H2O2 [56–60] (Figure 1(a)). At least in certain contexts, such H2O2-dependent signal amplification is mediated by ER-resident NOX4 and PTP1B [31] (Figure 1(b)). Thus, activated EGFR is internalized into endosomes and transported close to the ER [61] where its PTP1B-dependent dephosphorylation is negatively regulated by NOX4-derived H2O2 [31]. "
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    ABSTRACT: Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and-possibly-lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.
    International Journal of Cell Biology 10/2013; 2013(47):180906. DOI:10.1155/2013/180906
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