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Published 2 September 2003. doi:10.1083/jcb.200304105
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© The Rockefeller University Press, 0021-9525/2003/9/933 $5.00
The Journal of Cell Biology, Volume 162, Number 5, 933-943

Article

Differential {alpha}v integrin–mediated Ras-ERK signaling during two pathways of angiogenesis



John D. Hood, Ricardo Frausto, William B. Kiosses, Martin A. Schwartz and David A. Cheresh

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to David Cheresh, The Scripps Research Institute, Dept. of Immunology, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-8281. Fax: (858) 784-8926. email: cheresh{at}scripps.edu

Antagonists of {alpha}vß3 and {alpha}vß5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these {alpha}v integrins differentially contribute to sustained Ras-extracellular signal–related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or {alpha}vß5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin {alpha}vß3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-{alpha}vß5 blocked upstream of Ras, whereas anti-{alpha}vß3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/{alpha}vß3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins {alpha}vß3 and {alpha}vß5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.

Key Words: integrin alphaV; FGF receptor; VEGF receptor; c-Raf protein; MAP-ERK kinase

J.D. Hood's present address is TargeGen, Inc., 9393 Towne Centre Drive, Suite 120, San Diego, CA 92121.

M.A. Schwartz's present address is Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908.

Abbreviations used in this paper: CAM, chick chorioallantoic membrane; EC, endothelial cell; ERK, extracellular signal–related kinase; FRNK, FAK-related nonkinase; PAK, p21-activated kinase; PAK83-149, PAK-1 auto-inhibitory domain.


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