title: Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns.
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.
authors.affiliation: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, P.O. Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Terhi
authors.initials: T
authors.lastname: Karpanen
authors.forename: Tomas
authors.initials: T
authors.lastname: Strandin
authors.forename: Kukka
authors.initials: K
authors.lastname: Aho
authors.forename: Hilkka
authors.initials: H
authors.lastname: Lankinen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D016296:Mutagenesis; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D008024:Ligands; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3