Heterodimerization of FGF-receptor 1 and PDGF-receptor-alpha: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells.
Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2-induced events, such as proliferation of human umbilical vein endothelial cells (HUVECs), FGF-2 cellular internalization, phosphorylation of intracellular signaling factors including p38, rac1/cdc42, MKK4, and MKK3/6, and phosphorylation of FGF-receptor 1 (FGF-R1). PDGF-receptor-alpha (PDGF-Ralpha) was found to mediate PDGF-BB inhibitory effects because its neutralization fully restored FGF-2 mitogenic activity and internalization. Additional biochemical analyses, coimmunoprecipitation experiments, and FRET analysis showed that FGF-R1 and PDGF-Ralpha directly interact in vitro and in vivo and that this interaction is somehow increased in the presence of the corresponding ligands FGF-2 and PDGF-BB. These results suggest that FGF-R1/PDGF-Ralpha heterodimerization may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control endothelial cell function.
Faraone
Debora
D
Laboratorio di Patologia Vascolare, Istituto Dermopatico della Immacolata, IDI-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
Aguzzi
Maria S
MS
Ragone
Gianluca
G
Russo
Katia
K
Capogrossi
Maurizio C
MC
Facchiano
Antonio
A
D000077214:Becaplermin; D002478:Cells, Cultured; D019281:Dimerization; D004336:Drug Antagonism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology / Q000502:physiology*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D011494:Protein Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha