Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

• Published in: Blood 2006-03, Vol.107 (5), p.1896-1902
• Main Authors: Faraone, Debora, Aguzzi, Maria S., Ragone, Gianluca, Russo, Katia, Capogrossi, Maurizio C., Facchiano, Antonio
• Format: Article
• Language: English
• Subjects: Becaplermin; Biological and medical sciences; Blood vessels and receptors; Cells, Cultured; Dimerization; Drug Antagonism; Endothelial Cells - cytology; Endothelial Cells - physiology; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Phosphorylation; Platelet-Derived Growth Factor - metabolism; Platelet-Derived Growth Factor - pharmacology; Protein Kinases - metabolism; Protein Processing, Post-Translational - drug effects; Protein Processing, Post-Translational - physiology; Proto-Oncogene Proteins c-sis; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Signal Transduction; Transfection; Umbilical Veins - cytology; Umbilical Veins - physiology; Vertebrates: cardiovascular system
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-04-1524

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-α (PDGF-Rα) 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-Rα 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-Rα heterodimerization may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control endothelial cell function.