Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells.
The vascular endothelial growth factor (VEGF) family has recently expanded by the identification and cloning of three additional members, namely VEGF-B, VEGF-C, and VEGF-D. In this study we demonstrate that VEGF-B binds selectively to VEGF receptor-1/Flt-1. This binding can be blocked by excess VEGF, indicating that the interaction sites on the receptor are at least partially overlapping. Mutating the putative VEGF receptor-1/Flt-1 binding determinants Asp63, Asp64, and Glu67 to alanine residues in VEGF-B reduced the affinity to VEGF receptor-1 but did not abolish binding. Mutational analysis of conserved cysteines contributing to VEGF-B dimer formation suggest a structural conservation with VEGF and platelet-derived growth factor. Proteolytic processing of the 60-kDa VEGF-B186 dimer results in a 34-kDa dimer containing the receptor-binding epitopes. The binding of VEGF-B to its receptor on endothelial cells leads to increased expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1, suggesting a role for VEGF-B in the regulation of extracellular matrix degradation, cell adhesion, and migration.
Olofsson
B
B
Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, S-171 77 Stockholm, Sweden.
Korpelainen
E
E
Pepper
M S
MS
Mandriota
S J
SJ
Aase
K
K
Kumar
V
V
Gunji
Y
Y
Jeltsch
M M
MM
Shibuya
M
M
Alitalo
K
K
Eriksson
U
U
D016475:3T3 Cells; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002417:Cattle; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D010960:Plasminogen Activators / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018411:Spodoptera; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis; D042561:Vascular Endothelial Growth Factor B; D040281:Vascular Endothelial Growth Factor Receptor-1
D017931:DNA Primers; D016228:Endothelial Growth Factors; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D042561:Vascular Endothelial Growth Factor B; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D003545:Cysteine