Regulation of ROS signal transduction by NADPH oxidase 4 localization

Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 07/2008; 181(7):1129-39. DOI: 10.1083/jcb.200709049
Source: PubMed

ABSTRACT 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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    ABSTRACT: In the nervous system, ROS have been implicated in several physiological and pathological events. It has been suggested that the members of the family of the NADPH-oxidases (NOX) could be a source of ROS involved in many of these processes. In hippocampus, ROS produced by NOX are required for the NMDA receptor-dependent long-term potentiation (LTP), thereby regulating hippocampal synaptic plasticity and memory formation. In developing neurons, ROS regulate the dynamics of the axonal growth cone during the establishment of neuronal networks and, in neurons from Aplysia, ROS produced by NOX promote axonal growth. In addition, ROS produced by NOX critically influence the neuronal proliferation and neurogenesis and they have been implicated in the progression of the programmed cell death of neurons during cerebellar development. Most of the physiological and pathological actions of ROS are mediated by modification of the redox state of several proteins. The oxidation of these proteins occurs in specific amino acid residues such as cysteine, tyrosine and tryptophan. In particular, the oxidation of cysteine residues is a major mechanism for the control of several protein. These molecules include channels, enzymes and proteins from the cytoskeleton. For example, in the striatum, the hydrogen peroxide modulates dopamine release by the oxidation of the ATP-sensitive K+ channels and, in dorsal root ganglion neurons, ROS induce the growth cone collapse by the oxidation of CRMP2. It has been proposed that ROS also alter the redox state of the proteins of the signaling pathways. For example, ROS produced in response to growth factors control the proliferation and neurogenesis of neural precursor cells through the redox regulation of PI3K/Akt pathway. On the other hand, the oxidation of thioredoxins (Trx) and glutaredoxins (Grx1) leads to their dissociation from ASK1 that dephosphorylates and promotes its activation and the consequent stimulation of JNK and p38, which are involved in several physiological processes such as apoptosis. Other proteins such as thioredoxin-interacting protein (TXNIP) negatively regulates Trx1 and controls the cellular redox state. Finally, Akt has also been reported to be inactivated by direct oxidation, but it can also be activated by the oxidation of PTEN. In this chapter, we review the experimental evidences supporting a role for ROS in cell signaling in the nervous system and we discuss the interactions of ROS with several proteins as part of the mechanisms that regulates neuronal physiology.
    Reactive Oxygen Species, Lipid Peroxidation and Protein Oxidation, Edited by Angel Catalá, 09/2014: chapter Role of Reactive Oxygen Species As Signaling Molecules in the Regulation of Physiological Processes of the Nervous System: pages 169-204; Nova Science Publishers., ISBN: 978-1-63321-886-4
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    ABSTRACT: NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidase in retinal endothelial cells. Our previous study suggests that upregulation of Nox4 in retinal endothelial cells contributes to retinal vascular leakage in diabetes. In the current study, we investigated the role and mechanism of Nox4 in regulation of retinal neovascularization (NV), a hallmark of proliferative diabetic retinopathy (PDR), using a mouse model of oxygen-induced retinopathy (OIR). Our results confirmed that Nox4 was expressed predominantly in retinal vasculature of mouse retina. Retinal expression of Nox4 was markedly increased in OIR, in parallel with enhanced phosphorylation of ERK. In human retinal microvascular endothelial cells (HRECs), overexpression of Nox4 by adenovirus significantly increased extracellular H2O2 generation, resulting in intensified VEGFR2 activation and exacerbated angiogenesis upon VEGF stimulation. In contrast, silencing Nox4 expression or scavenging H2O2 by polyethylene glycol- (PEG-) conjugated catalase inhibited endothelial migration, tube formation, and VEGF-induced activation of VEGFR2 signaling. Importantly, knockdown of retinal Nox4 by adenovirus-delivered siRNA significantly reduced ERK activation and attenuated retinal NV formation in OIR. Taken together, our data indicate that Nox4 promotes retinal NV formation through H2O2/VEGFR2/ERK signaling pathway. Reducing retinal Nox4 expression may represent a promising therapeutic approach for neovascular retinal diseases such as PDR.
    Journal of Diabetes Research 01/2015; 2015:963289. DOI:10.1155/2015/963289 · 3.54 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) primarily produced via NADPH oxidase play an important role for killing microorganisms in neutrophils. In this study we examined if ROS production in Human promyelocytic leukemia cells (HL60) differentiated into neutrophil-like cells (dHL60) induces ER stress and activates the unfolded protein response (UPR). To cause ROS production cells were treated with PMA or by chronic hyperglycemia. Chronic hyperglycemia failed to induce ROS production and did not cause activation of the UPR in dHL60 cells. PMA, a pharmacologic NADPH oxidase activator, induced ER stress in dHL60 cells as monitored by IRE-1 and PERK pathway activation, and this was independent of calcium signaling. The NADPH oxidase inhibitor, DPI, abolished both ROS production and UPR activation. These results show that ROS produced by NADPH oxidase induces ER stress and suggests a close association between the redox state of the cell and the activation of the UPR in neutrophil-like HL60 cells.
    PLoS ONE 02/2015; 10(2):e0116410. DOI:10.1371/journal.pone.0116410 · 3.53 Impact Factor

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