Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.
Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav 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 alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 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-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 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 alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.
Hood
John D
JD
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Frausto
Ricardo
R
Kiosses
William B
WB
Schwartz
Martin A
MA
Cheresh
David A
DA
D000818:Animals; D002642:Chick Embryo; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D054462:p21-Activated Kinases; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins