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MBC in Press, published online ahead of print October 10, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0004

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Submitted on January 5, 2007
Revised on September 28, 2007
Accepted on October 2, 2007

Transactivation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Melissa L. Petreaca,*{dagger} Min Yao,{dagger} Yan Liu,{dagger} Kathryn DeFea,*{ddagger} and Manuela Martins-Green*{dagger}

*Graduate Program in Cell, Molecular, and Developmental Biology, {dagger}Department of Cell Biology and Neuroscience, and {ddagger}Division of Biomedical Sciences, University of California, Riverside, CA 92521

Monitoring Editor: Mark Ginsberg

Interleukin-8 (IL-8/CXCL8) is a chemokine that increases endothelial permeability during early stages of angiogenesis. However, the mechanisms involved in IL-8/CXCL8-induced permeability are poorly understood. Here, we show that permeability induced by this chemokine requires the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2/Flk-1/KDR). IL-8/CXCL8 stimulates VEGFR2 phosphorylation in a VEGF-independent manner suggesting VEGFR2 transactivation. We investigated the possible contribution of physical interactions between VEGFR2 and the IL-8/CXCL8 receptors leading to VEGFR2 transactivation. Both IL-8 receptors interact with VEGFR2 following IL-8/CXCL8 treatment, and the time course of complex formation is comparable to that of VEGFR2 phosphorylation. Src kinases are involved upstream of receptor complex formation and VEGFR2 transactivation during IL-8/CXCL8-induced permeability. An inhibitor of Src kinases blocked IL-8/CXCL8-induced VEGFR2 phosphorylation, receptor complex formation, and endothelial permeability. Furthermore, inhibition of the VEGFR abolishes RhoA activation by IL-8/CXCL8, as well as gap formation, suggesting a mechanism whereby VEGFR2 transactivation mediates IL-8/CXCL8-induced permeability. These studies point to VEGFR2 transactivation as an important signaling pathway utilized by chemokines such as IL-8/CXCL8, and may lead to the development of new therapies that can be used in conditions involving increases in endothelial permeability or angiogenesis, particularly in pathological situations associated with both IL-8/CXCL8 and VEGF.

Address correspondence to: Manuela Martins-Green (manuela.martins{at}ucr.edu)




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