Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity.
VEGFR-3 is essential for vascular development and maintenance of lymphatic vessel's integrity. Little is known about its cooperative effect with other receptors of the same family. Contrary to VEGFR-2, stimulation of VEGFR-3 by VEGF-C and -D failed to enhance its phosphorylation either in HEK293T or in PAE cells. These ligands were unable to induce angiogenesis of PAEC expressing VEGFR-3 alone. In the presence of VEGFR-2, VEGF-C and -D induced heterodimerization of VEGFR-3 with VEGFR-2. This heterodimerization was associated with enhanced VEGFR-3 phosphorylation and subsequent cellular responses as evidenced by the formation of capillary-like structures in PAE cells and proliferation of primary human endothelial cells expressing both receptors. Taken together, these results show for the first time that VEGFR-3 needs to be associated to VEGFR-2 to induce ligand-dependent cellular responses.
Sanofi-Synthélabo Research, Cardiovascular Department, Toulouse, France.
Antoine
A
Alam
Jean-Pascal
JP
Herault
Pauline
P
Barron
Benoit
B
Favier
Pierre
P
Fons
Nathalie
N
Delesque-Touchard
Isabelle
I
Senegas
Patricia
P
Laboudie
Jacques
J
Bonnin
Cecile
C
Cassan
Pierre
P
Savi
Bruce
B
Ruggeri
Peter
P
Carmeliet
Françoise
F
Bono
Jean-Marc
JM
Herbert
D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D019281:Dimerization; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000737:chemistry; D042643:Vascular Endothelial Growth Factor D / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000737:chemistry*
C479233:3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propanol; D002227:Carbazoles; D008024:Ligands; D010455:Peptides; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3