Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation

Chenguang Fan; Qiang Li; Dan Ross; John F Engelhardt

doi:10.1074/jbc.M206718200

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Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation

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Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation

Chenguang Fan, Qiang Li, Dan Ross and John F Engelhardt

The Journal of biological chemistry, Vol.278(3), pp.2072-2080

01/17/2003

DOI: 10.1074/jbc.M206718200

PMID: 12429743

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Abstract

NF kappa B is a critical transcription factor involved in modulating cellular responses to environmental injuries. Tyrosine 42 phosphorylation of I kappa B alpha has been shown to mediate NF kappa B activation following hypoxia/reoxygenation (H/R) or pervanadate treatment. This pathway differs from the canonical proinflammatory pathways, which mediate NF kappa B activation through serine phosphorylation of I kappa B alpha by the IKK complex. In the present study, we investigated the involvement of c-Src in the redox activation of NFkappaB following H/R or pervanadate treatment. Our results demonstrate that pervanadate or H/R treatment leads to tyrosine phosphorylation of I kappa B alpha and NF kappa B transcriptional activation independent of the IKK pathway. In contrast, inhibition of c-Src by pp2 treatment or in c-Src (-/-) knockout cell lines, demonstrated a significant reduction in I kappa B alpha tyrosine phosphorylation and NF kappa B activation following pervanadate or H/R treatment. Overexpression of glutathione peroxidase-1 or catalase, but not Mn-SOD or Cu,Zn-SOD, significantly reduced both NF kappa B activation and tyrosine phosphorylation of I kappa B alpha. In vitro kinase assays further demonstrated that immunoprecipitated c-Src has the capacity to directly phosphorylate GST-I kappa B alpha and that this I kappa B alpha kinase activity is significantly reduced by Gpx-1 overexpression. These results suggest that c-Src-dependent tyrosine phosphorylation of I kappa B alpha and subsequent activation of NF kappa B is controlled by intracellular H(2)O(2) and defines an important redox-regulated pathway for NF kappa B activation following H/R injury that is independent of the IKK complex.

Phosphorylation

NF-KappaB Inhibitor alpha

Tyrosine - metabolism

NF-kappa B - genetics

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

Transcriptional Activation

NF-kappa B - metabolism

I-kappa B Proteins - metabolism

Hypoxia - metabolism

Details

Title: Subtitle: Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation
Creators: Chenguang Fan - Molecular Biology Graduate Program, the Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242, USA
Qiang Li
Dan Ross
John F Engelhardt
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(3), pp.2072-2080
DOI: 10.1074/jbc.M206718200
PMID: 12429743
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: DK51315 / NIDDK NIH HHS P30 DK54759 / NIDDK NIH HHS P50 HL60316 / NHLBI NIH HHS
Language: English
Date published: 01/17/2003
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025424102771

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