Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor:<i>In vivo</i>expression and antitumor activity

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  • Michael L. Gagnon
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Diane R. Bielenberg
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Ze'ev Gechtman
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Hua-Quan Miao
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Seiji Takashima
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Shay Soker
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan
  • Michael Klagsbrun
    Departments of Surgical Research, Pathology, and Urology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; and First Department of Medicine, Osaka University Hospital, Yamadaoka 2-2, Suita, Osaka 565, Japan

書誌事項

公開日
2000-02-25
DOI
  • 10.1073/pnas.040337597
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p>Neuropilin-1 (NRP1) is a 130-kDa transmembrane receptor for semaphorins, mediators of neuronal guidance, and for vascular endothelial growth factor 165 (VEGF<jats:sub>165</jats:sub>), an angiogenesis factor. A 2.2-kb truncated NRP1 cDNA was cloned that encodes a 644-aa soluble NRP1 (sNRP1) isoform containing just the a/CUB and b/coagulation factor homology extracellular domains of NRP1. sNRP1 is secreted by cells as a 90-kDa protein that binds VEGF<jats:sub>165</jats:sub>, but not VEGF<jats:sub>121</jats:sub>. It inhibits<jats:sup>125</jats:sup>I-VEGF<jats:sub>165</jats:sub>binding to endothelial and tumor cells and VEGF<jats:sub>165</jats:sub>-induced tyrosine phosphorylation of KDR in endothelial cells. The 3′ end of sNRP1 cDNA contains a unique, 28-bp intron-derived sequence that is absent in full-length NRP1 cDNA. Using a probe corresponding to this unique sequence, sNRP1 mRNA could be detected by<jats:italic>in situ</jats:italic>hybridization differentially from full-length NRP1 mRNA, for example, in cells of liver, kidney, skin, and breast. Analysis of blood vessels<jats:italic>in situ</jats:italic>showed that NRP1, but not sNRP1, was expressed. sNRP1 was functional<jats:italic>in vivo</jats:italic>. Unlike control tumors, tumors of rat prostate carcinoma cells expressing recombinant sNRP1 were characterized by extensive hemorrhage, damaged vessels, and apoptotic tumor cells. These results demonstrate the existence of a naturally occurring, soluble NRP1 that is expressed differently from intact NRP1 and that appears to be a VEGF<jats:sub>165</jats:sub>antagonist.</jats:p>

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