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

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.

• Authors: Chenguang Fan, Qiang Li, Dan Ross, John F Engelhardt
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 3 Pg. 2072-80 (Jan 17 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12429743 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• I-kappa B Proteins
• NF-kappa B
• NF-KappaB Inhibitor alpha
• Tyrosine
• Proto-Oncogene Proteins pp60(c-src)

Topics

• Hypoxia (metabolism)
• I-kappa B Proteins (metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins pp60(c-src) (metabolism)
• Transcriptional Activation
• Tyrosine (metabolism)