NF-κB Mediates αvβ3 Integrin-induced Endothelial Cell Survival

نویسندگان

  • Marta Scatena
  • Manuela Almeida
  • Michelle L. Chaisson
  • Nelson Fausto
  • Roberto F. Nicosia
  • Cecilia M. Giachelli
چکیده

The alphavbeta3 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-kappaB) activity. Different extracellular matrix molecules were able to protect rat aorta- derived endothelial cells from apoptosis induced by serum withdrawal. Osteopontin and beta3 integrin ligation rapidly increased NF-kappaB 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 beta1-integrin ligand) did not induce NF-kappaB activity. The alphavbeta3 integrin was most important for osteopontin-mediated NF-kappaB induction and survival, since adding a neutralizing anti-beta3 integrin antibody blocked NF-kappaB activity and induced endothelial cell death when cells were plated on osteopontin. NF-kappaB was required for osteopontin- and vitronectin-induced survival since inhibition of NF-kappaB activity with nonphosphorylatable IkappaB completely blocked the protective effect of osteopontin and vitronectin. In contrast, NF-kappaB was not required for fibronectin, laminin, and collagen type I-induced survival. Activation of NF-kappaB by osteopontin depended on the small GTP-binding protein Ras and the tyrosine kinase Src, since NF-kappaB 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-kappaB activation. These studies identify NF-kappaB as an important signaling molecule in alphavbeta3 integrin-mediated endothelial cell survival.

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عنوان ژورنال:
  • The Journal of Cell Biology

دوره 141  شماره 

صفحات  -

تاریخ انتشار 1998