Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice

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  • Sachie Hiratsuka
    Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan
  • Osamu Minowa
    Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan
  • Junko Kuno
    Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan
  • Tetsuo Noda
    Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan
  • Masabumi Shibuya
    Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan

書誌事項

公開日
1998-08-04
DOI
  • 10.1073/pnas.95.16.9349
公開者
Proceedings of the National Academy of Sciences

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<jats:p> Receptor tyrosine kinases Flt-1 and Flk-1/KDR, and their ligand, the vascular endothelial growth factor (VEGF), were shown to be essential for angiogenesis in the mouse embryo by gene targeting. Flk-1/KDR null mutant mice exhibited impaired endothelial and hematopoietic cell development. On the other hand, Flt-1 null mutation resulted in early embryonic death at embryonic day 8.5, showing disorganization of blood vessels, such as overgrowth of endothelial cells. Flt-1 differs from Flk-1 in that it displays a higher affinity for VEGF but lower kinase activity, suggesting the importance of its extracellular domain. To examine the biological role of Flt-1 in embryonic development and vascular formation, we deleted the kinase domain without affecting the ligand binding region. Flt-1 tyrosine kinase-deficient homozygous mice ( <jats:italic> flt-1 <jats:sup>TK−/−</jats:sup> </jats:italic> ) developed normal vessels and survived. However, VEGF-induced macrophage migration was strongly suppressed in <jats:italic> flt-1 <jats:sup>TK−/−</jats:sup> </jats:italic> mice. These results indicate that Flt-1 without tyrosine kinase domain is sufficient to allow embryonic development with normal angiogenesis, and that a receptor tyrosine kinase plays a main biological role as a ligand-binding molecule. </jats:p>

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