Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury

Qiang Li; Yulong Zhang; Jennifer J Marden; Botond Banfi; John F Engelhardt

doi:10.1042/BJ20071534

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Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury

Journal article

Open access

Peer reviewed

Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury

Qiang Li, Yulong Zhang, Jennifer J Marden, Botond Banfi and John F Engelhardt

The Biochemical journal, Vol.411(3), pp.531-541

05/01/2008

DOI: 10.1042/BJ20071534

PMCID: PMC3597079

PMID: 18397177

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https://www.ncbi.nlm.nih.gov/pmc/articles/3597079View

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Abstract

c-Src has been shown to activate NF-kappaB (nuclear factor kappaB) following H/R (hypoxia/reoxygenation) by acting as a redox-dependent IkappaBalpha (inhibitory kappaB) 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 IkappaBalpha. 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.

Reactive Oxygen Species - metabolism

Humans

Cells, Cultured

NADPH Oxidases - metabolism

NF-kappa B - metabolism

Oxygen - metabolism

Phosphotyrosine - metabolism

Cell Hypoxia

Endocytosis

I-kappa B Kinase - metabolism

Proto-Oncogene Proteins pp60(c-src) - genetics

Proto-Oncogene Proteins pp60(c-src) - metabolism

Endosomes - enzymology

Enzyme Activation

rac1 GTP-Binding Protein - metabolism

Details

Title: Subtitle: Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury
Creators: Qiang Li - Department of Anatomy and Cell Biology and the Center for Gene Therapy, The College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yulong Zhang
Jennifer J Marden
Botond Banfi
John F Engelhardt
Resource Type: Journal article
Publication Details: The Biochemical journal, Vol.411(3), pp.531-541
DOI: 10.1042/BJ20071534
PMID: 18397177
PMCID: PMC3597079
NLM abbreviation: Biochem J
ISSN: 0264-6021
eISSN: 1470-8728
Publisher: England
Grant note: DK067928 / NIDDK NIH HHS DK51315 / NIDDK NIH HHS R01 DK067928 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS P30 DK54759 / NIDDK NIH HHS R01 DK051315 / NIDDK NIH HHS
Language: English
Date published: 05/01/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Otolaryngology; Internal Medicine
Record Identifier: 9984025443702771

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