Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells

Keiji Kuba, Kunio Matsumoto, Kenji Ohnishi, Takayuki Shiratsuchi, Masao Tanaka, Toshikazu Nakamura

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

NK4 composed of the N-terminal hairpin and subsequent four-kringle domains of Hepatocyte growth factor (HGF) is bifunctional, acting as a competitive antagonist for HGF and an angiogenesis inhibitor. In this study, we determined whether or not four-kringle domains of HGF (K1-4) have anti-angiogenic activity. For this purpose, we prepared recombinant K1-4 and NK4, using the baculovirus expression system. Although NK4 antagonized HGF-induced DNA synthesis of rat hepatocytes, cell scattering of MDCK cells and the c-Met/HGF receptor tyrosine phosphorylation in endothelial cells, K1-4 failed to antagonize HGF-induced DNA synthesis, cell scattering and the c-Met/HGF receptor tyrosine phosphorylation in endothelial cells, thus, indicating that K1-4 lacks HGF-antagonist activity. However, endothelial proliferation and migration induced by HGF was inhibited by K1-4, similar to the case seen with NK4. Furthermore, K1-4 inhibited the proliferation and migration of human dermal microvascular endothelial cells induced by vascular endothelial growth factor or by basic fibroblast growth factor. We propose that kringle 1-4 of HGF inhibits angiogenic responses in endothelial cells, independently of HGF-c-Met signaling pathways.

Original languageEnglish
Pages (from-to)846-852
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume279
Issue number3
DOIs
Publication statusPublished - Dec 29 2000

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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