title: Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.
abstract: 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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Hood
authors.forename: Ricardo
authors.initials: R
authors.lastname: Frausto
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: 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
chemical_list: 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