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VEGF and VEGFR2 bind to similar pH-sensitive sites on fibronectin, exposed by heparin-mediated conformational changes
- Source :
- Journal of Biological Chemistry, 296
- Publication Year :
- 2020
-
Abstract
- Physical interactions between vascular endothelial growth factor (VEGF), a central player in blood endothelial cell biology, and fibronectin, a major fibrillar protein of the extracellular matrix, are important determinants of angiogenic activity in health and disease. Conditions signaling the need for new blood vessel growth, such as hypoxia and low extracellular pH, increase VEGF–fibronectin interactions. These interactions can be further fine-tuned through changes in the availability of the VEGF-binding sites on fibronectin, regulated by conformational changes induced by heparin and heparan sulfate chains within the extracellular matrix. These interactions may alter VEGF bioavailability, generate gradients, or alter the way VEGF is recognized by and activates its cell-surface receptors. Here, using equilibrium and kinetic studies, we discovered that fibronectin can also interact with the extracellular domain of the VEGF receptor 2 (VEGFR2). The VEGFR2-binding sites on fibronectin show great similarity to the VEGF-binding sites, as they were also exposed upon heparin-induced conformational changes in fibronectin, and the interaction was enhanced at acidic pH. Kinetic parameters and affinities for VEGF and VEGFR2 binding to fibronectin were determined by surface plasmon resonance measurements, revealing two populations of fibronectin-binding sites for each molecule. Our data also suggest that a VEGF/VEGFR2/fibronectin triple complex may be formed by VEGF or VEGFR2 first binding to fibronectin and subsequently recruiting the third binding partner. The formation of such a complex may lead to the activation of distinct angiogenic signaling pathways, offering new possibilities for clinical applications that target angiogenesis.<br />Journal of Biological Chemistry, 296<br />ISSN:0021-9258<br />ISSN:1083-351X
- Subjects :
- 0301 basic medicine
Vascular Endothelial Growth Factor A
Angiogenesis
Biochemistry
Extracellular matrix
03 medical and health sciences
chemistry.chemical_compound
Protein Domains
Extracellular
Humans
Receptor
Molecular Biology
Binding Sites
030102 biochemistry & molecular biology
biology
Chemistry
Heparin
Computational Biology
Cell Biology
Heparan sulfate
Hydrogen-Ion Concentration
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Fibronectins
Vascular endothelial growth factor
Fibronectin
Kinetics
030104 developmental biology
biology.protein
Signal transduction
Protein Binding
Subjects
Details
- ISSN :
- 1083351X and 00219258
- Volume :
- 296
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....acb1cd991b2938d706a7af55b2223034