title: The nonreceptor protein-tyrosine kinase c-Fes is involved in fibroblast growth factor-2-induced chemotaxis of murine brain capillary endothelial cells.
abstract: Fibroblast growth factor-2 (FGF-2)-induced migration of endothelial cells is involved in angiogenesis in vivo. However, signal transduction pathways leading to FGF-2-induced chemotaxis of endothelial cells are largely unknown. Previous studies have shown that the cytoplasmic protein-tyrosine kinase c-Fes is expressed in vascular endothelial cells and may influence angiogenesis in vivo. To investigate the contribution of c-Fes to FGF-2 signaling, we expressed wild-type or kinase-inactive human c-Fes in the murine brain capillary endothelial cell line, IBE (Immortomouse brain endothelial cells). Wild-type c-Fes was tyrosine-phosphorylated upon FGF-2-stimulation in transfected cells, whereas kinase-inactive c-Fes was not. Overexpression of wild-type c-Fes promoted FGF-2-independent tube formation of IBE cells. Tube formation was not observed with endothelial cells expressing kinase-inactive c-Fes, indicating a requirement for c-Fes kinase activity in this biological response. Expression of kinase-defective c-Fes suppressed endothelial cell migration following FGF-2 treatment, suggesting that activation of endogenous c-Fes may be required for the chemotactic response. Expression of either wild-type c-Fes or the kinase-inactive mutant did not affect the tyrosine phosphorylation FRS2, Shc, or phospholipase C-gamma, nor did it influence the kinetics of mitogen-activated protein kinase activation. These results implicate c-Fes in FGF-2-induced chemotaxis of endothelial cells through signaling pathways not linked to mitogenesis.
authors.affiliation: Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. shigeruk@net.nagasaki-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Kanda
authors.forename: E C
authors.initials: EC
authors.lastname: Lerner
authors.forename: S
authors.initials: S
authors.lastname: Tsuda
authors.forename: T
authors.initials: T
authors.lastname: Shono
authors.forename: H
authors.initials: H
authors.lastname: Kanetake
authors.forename: T E
authors.initials: TE
authors.lastname: Smithgall
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply; D002196:Capillaries; D002455:Cell Division; D002460:Cell Line; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010960:Plasminogen Activators / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051578:Proto-Oncogene Proteins c-fes; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D011505:Protein-Tyrosine Kinases; C496645:FES protein, human; C496646:Fes protein, mouse; D051578:Proto-Oncogene Proteins c-fes; D010960:Plasminogen Activators