VEGF receptor subtypes KDR and FLT1 show different sensitivities to heparin and placenta growth factor.
Vascular endothelial growth factor (VEGF) is an angiogenic growth factor which binds to two structurally related tyrosine kinase receptors denoted KDR and FLT1. To compare the interaction of VEGF with each receptor, cell lines which express individual receptor subtypes were identified using Northern blot hybridization. Bovine aortic endothelial (ABAE) cells and WM35 melanoma cells were found to express KDR, while FLT1 was primarily expressed on SK-MEL-37. Both receptor subtypes were detected on another melanoma cell line (WM9). Heparin augmented VEGF binding to KDR-expressing cells (ABAE and WM35), but inhibited VEGF binding to FLT1-expressing cells (SK-MEL-37 and WM9). The concentration of heparin required for half maximal stimulation of VEGF binding to KDR-expressing cells (500 ng/ml) was 25 times greater than that required for half maximal inhibition of binding to FLT1-expressing cells (20 ng/ml). In WM9 cells, the effect of heparin was bimodal; low concentration inhibited, while higher concentrations stimulated binding of 125I-VEGF. Placenta growth factor (PIGF-1) is a recently described growth factor structurally similar to VEGF. PIGF-1 had a negligible or no effect on 125I-VEGF binding to KDR-expressing cells (ABAE, WM35), but did complete for binding to FLT1-expressing cells (SK-MEL-37 and WM9). Addition of heparin had no effect on its ability to compete for binding with 125I-VEGF. The data indicate differential regulation of the two VEGF receptors by heparin and extended specificity of FLT1 receptor, but not KDR, for binding PIGF-1 growth factor.
Terman
B
B
Lederle Laboratories, Medical Research Division, Pearl River, New York 10965, USA.
Khandke
L
L
Dougher-Vermazan
M
M
Maglione
D
D
Lassam
N J
NJ
Gospodarowicz
D
D
Persico
M G
MG
Böhlen
P
P
Eisinger
M
M
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D015870:Gene Expression; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011869:Radioligand Assay; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1
C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D000072483:Placenta Growth Factor; D006493:Heparin; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1