Vascular regulation by kringles of HGF and molecular cloning of a novel kringle-containing protein

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Various proteins containing kringle domains play diverse roles in tissue regeneration, blood coagulation/fibrinolysis, neural development, and blood vessel regulation. Identification of a novel kringle-containing molecule is likely to lead to further understanding of blood vessel regulation, including angiogenesis and anti-angiogenesis. In the present study, to study regulatory mechanisms by which kringle domains exhibit angio-regulatory functions, we analyzed angiostatic action of NK4, previously identified as HGF-antagonist. Likewise, we succeeded in molecular cloning of a novel kringle-containg molecule, Kremen.1) NK4 as angiogenesis inhibitor : NK4, a four kringles-cpontaining HGF-antagonist, inhibited proliferation and migration of vascular endothelial cells in culture. Likewise, NK4 inhibited angiogenesis in CAM and cornea assays in vivo. Together with a previously characterized biological action of NK4 as HGF-antagonist, therapeutic potential of NK4 for treatment of metastatic c … More ancers were tested. NK4 administered into mice potently suppressed metastasis, tumor angiogenesis, and tumor growth of cancers, including lung, breast, and pancreatic cancers. NK4 will become a potent anti-cancer agent, targeting malignant behavior of cancer.2) Using a newly established cloning strategy for kringle-containg proteins, 'Kringle-SAGE', we cloned cDNA for Kremen. Kremen is composed of 473 amino acids and is type-I transmembrane protein. Kremen contains unique domains, kringle domain and CUB domain in its extracellular region, while it has no specific conserved functional motif in its intracellular region. Kremen mRNA is expressed in diverse tissues, while it is up-regulated during muscular and neural differentiation. Kringle domain of Although Kremen may have some roles in vascular regulation and differentiation of muscular and neural cells, its roles remain to be further addressed. A newly established method for comprehensive cloning of kringle-proteins, Kringle-SAGE is powerful in molecular cloning of kringle proteins. Less