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Science 301 (5629): 94-96

Copyright © 2003 by the American Association for the Advancement of Science

Role of Raf in Vascular Protection from Distinct Apoptotic Stimuli

Alireza Alavi,* John D. Hood,* Ricardo Frausto, Dwayne G. Stupack, David A. Cheresh{dagger}

Abstract: Raf kinases have been linked to endothelial cell survival. Here, we show that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) differentially activate Raf, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. bFGF activated Raf-1 via p21-activated protein kinase–1 (PAK-1) phosphorylation of serines 338 and 339, resulting in Raf-1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase–1 (MEK1). In contrast, VEGF activated Raf-1 via Src kinase, leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. These findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis.

Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: cheresh{at}scripps.edu

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