Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells.
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.
Kuba
K
K
Division of Biochemistry, Department of Oncology, Biomedical Research Center, Suita, Osaka, 565-0871, Japan.
Matsumoto
K
K
Ohnishi
K
K
Shiratsuchi
T
T
Tanaka
M
M
Nakamura
T
T
D020533:Angiogenesis Inhibitors; D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D006224:Cricetinae; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018082:Kringles; D008222:Lymphokines / Q000502:physiology; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met