Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor.
Placenta Growth Factor (PIGF) is a new member of vascular endothelial growth factor (VEGF) family. Although VEGF binds Flt family Flt-1 and KDR/Flk-1 tyrosine kinases at high affinity for signal transduction, biological activities and the receptors of PIGF have not been extensively studied. Reverse transcription-PCR showed that PIGF-2, a subtype of PIGF-1 that bears a basic amino acid-rich domain, is more abundant than PIGF-1 and thus is the major subtype in human placenta. Using antibodies specific to PIGF-1 or -2 as markers, we obtained large amounts of PIGFs in the baculovirus expression system. PIGF-2 had growth-stimulatory activity on human umbilical vein endothelial cells and vascular permeability activity in the Miles assay at levels about 10-fold lower than those of VEGF. All PIGF-1 activities were lower than those of PIGF-2. Both PIGFs competed for the binding of 125I-labeled VEGF to Flt-1 receptor but not to KDR/Flk-1 expressed on NIH3T3 cells. Furthermore, 125I-labeled PIGF bound to Flt-1 at high affinity but not to KDR/Flk-1. Supporting the notion that PIGF can use only Flt-1 as a receptor, PIGF activated Flt-1 to autophosphorylate, whereas PIGF could not generate signals from KDR/Flk-1. These results indicate that Flt-1, but not KDR/Flk-1, is a receptor for PIGF, suggesting that the weak biological activities of PIGF are due to its use of only part of the available VEGF signaling. These mild characteristics of PIGF may be important for the appropriate development and maintenance of normal placental tissue.
Sawano
A
A
Department of Genetics, University of Tokyo, Japan.
Takahashi
T
T
Yamaguchi
S
S
Aonuma
M
M
Shibuya
M
M
D016475:3T3 Cells / Q000201:enzymology / Q000648:ultrastructure; D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001483:Base Sequence; D001667:Binding, Competitive / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology; D018076:DNA, Complementary / Q000502:physiology; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism / Q000648:ultrastructure; D005070:Evans Blue / Q000493:pharmacokinetics*; D015870:Gene Expression / Q000502:physiology; D006133:Growth Substances / Q000378:metabolism*; D006168:Guinea Pigs; D006493:Heparin; D006801:Humans; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D005070:Evans Blue; D006493:Heparin; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1