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Cell Growth & Differentiation, Vol 7, Issue 2 213-221, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor

A Sawano, T Takahashi, S Yamaguchi, M Aonuma and M Shibuya
Department of Genetics, University of Tokyo, Japan.

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.


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T. Oyama, S. Ran, T. Ishida, S. Nadaf, L. Kerr, D. P. Carbone, and D. I. Gabrilovich
Vascular Endothelial Growth Factor Affects Dendritic Cell Maturation Through the Inhibition of Nuclear Factor-{kappa}B Activation in Hemopoietic Progenitor Cells
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T. Murohara, J. R. Horowitz, M. Silver, Y. Tsurumi, D. Chen, A. Sullivan, and J. M. Isner
Vascular Endothelial Growth Factor/Vascular Permeability Factor Enhances Vascular Permeability Via Nitric Oxide and Prostacyclin
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B. Barleon, F. Totzke, C. Herzog, S. Blanke, E. Kremmer, G. Siemeister, D. Marme, and G. Martiny-Baron
Mapping of the Sites for Ligand Binding and Receptor Dimerization at the Extracellular Domain of the Vascular Endothelial Growth Factor Receptor FLT-1
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N. Rahimi, V. Dayanir, and K. Lashkari
Receptor Chimeras Indicate That the Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Modulates Mitogenic Activity of VEGFR-2 in Endothelial Cells
J. Biol. Chem., June 2, 2000; 275(22): 16986 - 16992.
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D. Wang, D. B. Donner, and R. S. Warren
Homeostatic Modulation of Cell Surface KDR and Flt1 Expression and Expression of the Vascular Endothelial Cell Growth Factor (VEGF) Receptor mRNAs by VEGF
J. Biol. Chem., May 26, 2000; 275(21): 15905 - 15911.
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B. Li, G. Fuh, G. Meng, X. Xin, M. E. Gerritsen, B. Cunningham, and A. M. de Vos
Receptor-selective Variants of Human Vascular Endothelial Growth Factor: GENERATION AND CHARACTERIZATION
J. Biol. Chem., September 22, 2000; 275(38): 29823 - 29828.
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K. Suzuma, K. Naruse, I. Suzuma, N. Takahara, K. Ueki, L. P. Aiello, and G. L. King
Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR, Flt1, and Phosphatidylinositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells
J. Biol. Chem., December 29, 2000; 275(52): 40725 - 40731.
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B.-Q. Shen, D. Y. Lee, K. M. Cortopassi, L. A. Damico, and T. F. Zioncheck
Vascular Endothelial Growth Factor KDR Receptor Signaling Potentiates Tumor Necrosis Factor-induced Tissue Factor Expression in Endothelial Cells
J. Biol. Chem., February 16, 2001; 276(7): 5281 - 5286.
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S. Iyer, D. D. Leonidas, G. J. Swaminathan, D. Maglione, M. Battisti, M. Tucci, M. G. Persico, and K. R. Acharya
The Crystal Structure of Human Placenta Growth Factor-1 (PlGF-1), an Angiogenic Protein, at 2.0 A Resolution
J. Biol. Chem., April 13, 2001; 276(15): 12153 - 12161.
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M. Orlandini and S. Oliviero
In Fibroblasts Vegf-D Expression Is Induced by Cell-Cell Contact Mediated by Cadherin-11
J. Biol. Chem., March 2, 2001; 276(9): 6576 - 6581.
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L. D. Mayo, K. M. Kessler, R. Pincheira, R. S. Warren, and D. B. Donner
Vascular Endothelial Cell Growth Factor Activates CRE-binding Protein by Signaling through the KDR Receptor Tyrosine Kinase
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