title: The role of c-Fes in vascular endothelial growth factor-A-mediated signaling by endothelial cells.
abstract: c-Fes plays pivotal roles in angiogenic cellular responses of endothelial cells. Here we examined the role of c-Fes in vascular endothelial growth factor-A (VEGF-A)-mediated signaling pathways in endothelial cells. We introduced either wild-type or kinase-inactive c-Fes in porcine aortic endothelial (PAE) cell lines, which endogenously express VEGF receptor (VEGFR)-1, and PAE cells ectopically expressing VEGFR-2 (denoted KDR/PAE cells) and generated stable cell lines. VEGF-A induced autophosphorylation of c-Fes only in KDR/PAE cells, suggesting that VEGFR-2 was required for its activation. Expression of kinase-inactive c-Fes failed to demonstrate dominant negative effect on VEGF-A-induced chemotaxis and capillary morphogenesis. Phosphoinositide 3-kinase (PI3-kinase) was activated in KDR/PAE cells and c-Fes contributed to this process in a kinase activity-dependent manner. However, VEGFR-2, insulin receptor substrate-1, and c-Src were also involved in VEGF-A-induced activation of PI3-kinase, resulting in the compensation in cells expressing kinase-inactive c-Fes. Interestingly, overexpression of wild-type c-Fes in PAE cells induced VEGF-A-independent capillary morphogenesis. Considered collectively, VEGF-A activated PI3-kinase partly through c-Fes and increase in c-Fes kinase activity enhanced capillary morphogenesis by yet unknown signaling pathways.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. shigeruk@net.nagasaki-u.ac.jp
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kanda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Miyata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanetake
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002196:Capillaries / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051578:Proto-Oncogene Proteins c-fes; D015398:Signal Transduction; D013552:Swine; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D008024:Ligands; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C496645:FES protein, human; D051578:Proto-Oncogene Proteins c-fes; D019061:src-Family Kinases