Platelet Factor 4 Modulates Fibroblast Growth Factor 2 (FGF-2) Activity and Inhibits FGF-2 Dimerization
| Autor: | Andreas Bikfalvi, Catherine Savona, Zhongchao Han, Catherine Perollet, J. P. Caen |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
medicine.medical_specialty
Angiogenesis media_common.quotation_subject Basic fibroblast growth factor Immunology CHO Cells Biology Platelet Factor 4 Fibroblast growth factor Biochemistry Mice chemistry.chemical_compound Cricetinae Internal medicine medicine Animals Receptor Fibroblast Growth Factor Type 1 Internalization Cells Cultured media_common Chinese hamster ovary cell Receptor Protein-Tyrosine Kinases Cell Biology Hematology Receptors Fibroblast Growth Factor Endocytosis Cell biology Endothelial stem cell Endocrinology Mechanism of action chemistry Fibroblast growth factor receptor Fibroblast Growth Factor 2 Endothelium Vascular Heparitin Sulfate medicine.symptom Dimerization Cell Division |
| Zdroj: | Blood. 91:3289-3299 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v91.9.3289.3289_3289_3299 |
| Popis: | Platelet factor 4 (PF-4) inhibits angiogenesis in vitro and in vivo. The mechanism of inhibition is poorly understood. We have investigated the mechanism of inhibition by examining the interaction of PF-4 and the fibroblast growth factor-2 (FGF-2)/fibroblast growth factor receptor (FGFR) system. PF-4 inhibited the binding of FGF-2 to high-affinity and low-affinity binding sites in murine microvascular endothelial cells (LEII cells) and proliferation. Maximum inhibition of binding to endothelial FGF receptors was observed at PF-4 concentrations between 5 and 10 μg/mL (half maximum inhibition at 0.6 μg/mL), and proliferation was completely inhibited at 2 μg/mL. At this concentration, PF-4 reduced internalization of125I–FGF-2 by threefold and delayed degradation. To gain insight into the mechanism of inhibition, we have analyzed the interaction of PF-4 with FGF-2/FGFR by using mutant heparan sulfate–deficient Chinese hamster ovary (CHO) cells transfected with the FGFR-1 cDNA (CHOm–FGFR-1) and by examining the direct interaction with FGF-2. In the absence of heparin, PF-4 inhibited binding of 125I–FGF-2 to CHOm–FGFR-1 cells in a concentration-dependent manner, although not completely. In the presence of heparin, PF-4 abolished totally the stimulatory effect of heparin. Furthermore, PF-4 complexed to FGF-2 and inhibited endogenous or heparin-induced FGF-2 dimerization. These results indicate that PF-4 interacts with FGF-2 by complex formation, inhibiting FGF-2 dimerization, binding to FGF receptors, and internalization. This mechanism most likely contributes to the antiangiogenic properties of PF-4. |
| Databáze: | OpenAIRE |
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