c-Src has been shown to activate NF-κB (nuclear factor κB) following H/R (hypoxia/reoxygenation) by acting as a redox-dependent IκBα (inhibitory κB) tyrosine kinase. In the present study, we have investigated the redox-dependent mechanism of c-Src activation following H/R injury and found that ROS (reactive oxygen species) generated by endosomal Noxs (NADPH oxidases) are critical for this process. Endocytosis following H/R was required for the activation of endosomal Noxs, c-Src activation, and the ability of c-Src to tyrosine-phosphorylate IκBα. Quenching intra-endosomal ROS during reoxygenation inhibited c-Src activation without affecting c-Src recruitment from the plasma membrane to endosomes. However, siRNA (small interfering RNA)-mediated knockdown of Rac1 prevented c-Src recruitment into the endosomal compartment following H/R. Given that Rac1 is a known activator of Nox1 and Nox2, we investigated whether these two proteins were required for c-Src activation in Nox-deficient primary fibroblasts. Findings from these studies suggest that both Nox1 and Nox2 participate in the initial redox activation of c-Src following H/R. In summary, our results suggest that Rac1-dependent Noxs play a critical role in activating c-Src following H/R injury. This signalling pathway may be a useful therapeutic target for ischaemia/reperfusion-related diseases.
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Research Article|
April 14 2008
Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury
Qiang Li;
Qiang Li
1Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A.
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Yulong Zhang;
Yulong Zhang
1Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A.
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Jennifer J. Marden;
Jennifer J. Marden
1Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A.
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Botond Banfi;
Botond Banfi
1Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A.
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John F. Engelhardt
John F. Engelhardt
1
1Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A.
1To whom correspondence should be addressed, at Room 1-111 BSB, Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242, U.S.A. (email john-engelhardt@uiowa.edu).
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Publisher: Portland Press Ltd
Received:
November 07 2007
Revision Received:
December 05 2007
Accepted:
December 11 2007
Accepted Manuscript online:
April 14 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (3): 531–541.
Article history
Received:
November 07 2007
Revision Received:
December 05 2007
Accepted:
December 11 2007
Accepted Manuscript online:
April 14 2008
Citation
Qiang Li, Yulong Zhang, Jennifer J. Marden, Botond Banfi, John F. Engelhardt; Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury. Biochem J 1 May 2008; 411 (3): 531–541. doi: https://doi.org/10.1042/BJ20071534
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