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Published online June 23, 2008
doi:10.1083/jcb.200709049
The Journal of Cell Biology, Vol. 181, No. 7, 1129-1139
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Chen et al.
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Article

 Regulation of ROS signal transduction by NADPH oxidase 4 localization

Kai Chen, Michael T. Kirber, Hui Xiao, Yu Yang, and John F. Keaney, Jr.

Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605

Correspondence to Kai Chen: kai.chen{at}umassmed.edu

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.

Abbreviations used in this paper: EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; HAEC, human aortic endothelial cell; MEF, mouse embryonic fibroblast; MSP, mitochondrial signal peptide; NO, nitric oxide; NOS, NO synthase; Nox, NADPH oxidase; PTP, protein tyrosine phosphatase; ROS, reactive oxygen species; VE, vascular endothelial.

© 2008 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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