Neuropilin-1 is a placenta growth factor-2 receptor.
Placenta growth factor (PlGF) belongs to the family of vascular endothelial growth factors (VEGFs). It binds to the flt-1 VEGF receptor but not to the KDR/flk-1 receptor which is thought to mediate most of the angiogenic and proliferative effects of VEGF. Three PlGF isoforms are produced by alternative splicing. PlGF-1 and PlGF-3 differ from PlGF-2 since they lack the exon 6 encoded peptide which bestows upon PlGF-2 its heparin binding properties. Cross-linking experiments revealed that 125I-PlGF-2 binds to two endothelial cell surface receptors in a heparin dependent fashion. The binding of 125I-PlGF-2 to these receptors was inhibited by an excess of PlGF-2 and by the 165-amino acid form of VEGF (VEGF165), but not at all by VEGF121 and very marginally if at all by PlGF-1. The apparent molecular weight and the binding characteristics of these receptors correspond to those of the recently identified VEGF165 specific receptor neuropilin-1, and we therefore conclude that neuropilin-1 is a receptor for PlGF-2. The binding of 125I-PlGF-2 as well as the binding of 125I-VEGF165 to these receptors was inhibited by a synthetic peptide derived from exon 6 of PlGF. Furthermore, the binding of 125I-PlGF-2, but not that of 125I-VEGF165, was also inhibited by a synthetic peptide derived from exon 7 of PlGF. These observations indicate that the peptides encoded by these exons probably participate in the formation of the domain which mediates the binding of PlGF-2 to these receptors. We have also determined, using chemically modified heparin species, that the presence of sulfate moieties on the glucosamine-O-6 and on the iduronic acid-O-2 groups of heparin was required for the potentiation of 125I-PlGF-2 binding to these receptors. To determine if PlGF-2 is able to induce biological responses that are not induced by PlGF-1, we compared the effects of PlGF-1 and PlGF-2 on the migration and proliferation of endothelial cells. Both PlGF forms induced migration of endothelial cells. However, there was no quantitative difference between the response to PlGF-2 and the response to PlGF-1. Furthermore, neither PlGF-1 nor PlGF-2 had any effect upon the proliferation of the endothelial cells.
Migdal
M
M
Department of Biology, Technion, Israel Institute of Technology, Haifa, 32000, Israel.
Huppertz
B
B
Tessler
S
S
Comforti
A
A
Shibuya
M
M
Reich
R
R
Baumann
H
H
Neufeld
G
G
D000818:Animals; D002417:Cattle; D002455:Cell Division; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005091:Exons; D005944:Glucosamine / Q000737:chemistry; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007067:Iduronic Acid / Q000737:chemistry; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039942:Neuropilin-1; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C098069:PIGF protein, human; D010455:Peptides; D011506:Proteins; D011956:Receptors, Cell Surface; D039942:Neuropilin-1; D007067:Iduronic Acid; D006493:Heparin; D005944:Glucosamine