Abstract
Vascular endothelial growth factors (VEGFs) and their receptors play key roles in angiogenesis and lymphangiogenesis. VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3. We have created a library of VEGF/VEGF-C mosaic molecules that contains factors with novel receptor binding profiles, notably proteins binding to all three VEGF receptors ("super-VEGFs"). The analyzed super-VEGFs show both angiogenic and lymphangiogenic effects in vivo, although weaker than the parental molecules. The composition of the VEGFR-3 binding molecules and scanning mutagenesis revealed determinants of receptor binding and specificity. VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Aorta / cytology
-
Aorta / metabolism
-
B-Lymphocytes / cytology
-
B-Lymphocytes / metabolism
-
Cell Line
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / metabolism
-
Humans
-
Ligands
-
Mice
-
Mutagenesis
-
Neovascularization, Physiologic / physiology*
-
Phosphorylation
-
Protein Binding
-
Protein Conformation
-
Substrate Specificity
-
Surface Plasmon Resonance
-
Swine
-
Vascular Endothelial Growth Factor A / metabolism*
-
Vascular Endothelial Growth Factor C / metabolism*
-
Vascular Endothelial Growth Factor Receptor-1 / metabolism*
-
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
-
Vascular Endothelial Growth Factor Receptor-3 / metabolism*
Substances
-
Ligands
-
VEGFA protein, human
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factor C
-
Vascular Endothelial Growth Factor Receptor-1
-
Vascular Endothelial Growth Factor Receptor-2
-
Vascular Endothelial Growth Factor Receptor-3