title: Alternatively spliced FGFR-1 isoform signaling differentially modulates endothelial cell responses to peroxynitrite.
abstract: Mounting experimental evidence has suggested that the trophic environment of cells in culture is an important determinant of their vulnerability to the cytotoxic effects of reactive oxidants such as peroxynitrite (ONOO(-)). However, acidic fibroblast growth factor (FGF-1)-induced signaling renders some cells more sensitive and others resistant to the cytotoxic effects of ONOO(-). To determine whether alternatively spliced fibroblast growth factor receptor (FGFR-1) isoforms are responsible for this differential response, we have stably transfected FGFR-negative rat brain-derived resistant vessel endothelial cells (RVEC) with human cDNA sequences encoding either FGFR-1 alpha or FGFR-1 beta. FGF-1 treatment of RVEC(R-1 alpha) transfectants enhanced ONOO(-)-mediated cell death in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and p38 MAP kinase activities and independent of Src-family kinase (SFK) activity. FGF-1 treatment of RVEC(R-1 beta) transfectants inhibited the cytotoxic effects of ONOO(-) in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and SFK activities and independent of p38 MAP kinase activity. FGF-1-induced preactivation of both FGFR-1 tyrosine and Erk 1/2 kinases was detected in both RVEC(R-1 alpha) and RVEC(R-1 beta) transfectants. FGF-1-induced preactivation of p38 MAPK was restricted to RVEC(R-1 alpha) transfectants, whereas, ligand-induced preactivation of SFK was limited to RVEC(R-1 beta) transfectants. Collectively, these results both reemphasize the role of extracellular trophic factors and their receptor-mediated signaling pathways during cellular responses to oxidant stress and provide a first indication that the alternatively spliced FGFR-1 isoforms induce differential signal transduction pathways.
authors.affiliation: Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Greendorfer
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
authors.forename: Clement A
authors.initials: CA
authors.lastname: Diglio
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D005822:Genetic Vectors; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018076:DNA, Complementary; D008024:Ligands; D016877:Oxidants; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D030421:Peroxynitrous Acid; D006493:Heparin; C496348:FGFR1 protein, human; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases