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© The Rockefeller University Press, 0021-9525/1998//1083 $5.00
The Journal of Cell Biology, Volume 141, Number 4, , 1998 1083-1093

Articles

NF-{kappa}B Mediates {alpha}vβ3 Integrin-induced Endothelial Cell Survival



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

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

The {alpha}vβ3 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 β3 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 β1-integrin ligand) did not induce NF-{kappa}B activity. The {alpha}vβ3 integrin was most important for osteopontin-mediated NF-{kappa}B induction and survival, since adding a neutralizing anti-β3 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 I{kappa}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}vβ3 integrin-mediated endothelial cell survival.

Abbreviations used in this paper: cIAP, baculovirus inhibitors of apoptosis mammalian homologs; ECM, extracellular matrix; EMSA, electrophoretic mobility shift assay; FAK, focal adhesion kinase; NF-{kappa}B, nuclear factor-kappa B; PARP, poly(ADP-ribose) polymerase; PI3, phosphotidylinositol 3; RAEC, rat aortic endothelial cells.

Address all correspondence to Marta Scatena, Department of Pathology, University of Washington, Box 357335, Seattle, WA. Tel.: 206 685 4288; Fax: 206 685 3662; E-mail: mscatena{at}u.washington.edu


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