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J. Cell Biol., Volume 141, Number 4, May 18, 1998 1083-1093

NF-kappa B Mediates alpha vbeta 3 Integrin-induced Endothelial Cell Survival

Marta Scatena,* Manuela Almeida,* Michelle L. Chaisson,* Nelson Fausto,* Roberto F. Nicosia,Dagger and Cecilia M. Giachelli*

* Department of Pathology, University of Washington, Seattle, Washington 98195; and Dagger  Department of Pathology, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19102

The alpha vbeta 3 integrin plays a fundamental role during the angiogenesis process by inhibiting endothelial cell apoptosis. However, the mechanism of inhibition is unknown. In this report, we show that integrin-mediated cell survival involves regulation of nuclear factor-kappa B (NF-kappa B) activity. Different extracellular matrix molecules were able to protect rat aorta- derived endothelial cells from apoptosis induced by serum withdrawal. Osteopontin and beta 3 integrin ligation rapidly increased NF-kappa B activity as measured by gel shift and reporter activity. The p65 and p50 subunits were present in the shifted complex. In contrast, collagen type I (a beta 1-integrin ligand) did not induce NF-kappa B activity. The alpha vbeta 3 integrin was most important for osteopontin-mediated NF-kappa B induction and survival, since adding a neutralizing anti-beta 3 integrin antibody blocked NF-kappa B activity and induced endothelial cell death when cells were plated on osteopontin. NF-kappa B was required for osteopontin- and vitronectin-induced survival since inhibition of NF-kappa B activity with nonphosphorylatable Ikappa B completely blocked the protective effect of osteopontin and vitronectin. In contrast, NF-kappa B was not required for fibronectin, laminin, and collagen type I-induced survival. Activation of NF-kappa B by osteopontin depended on the small GTP-binding protein Ras and the tyrosine kinase Src, since NF-kappa B reporter activity was inhibited by Ras and Src dominant-negative mutants. In contrast, inhibition of MEK and PI3-kinase did not affect osteopontin-induced NF-kappa B activation. These studies identify NF-kappa B as an important signaling molecule in alpha vbeta 3 integrin-mediated endothelial cell survival.


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