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Originally published In Press as doi:10.1074/jbc.M212358200 on January 15, 2003

J. Biol. Chem., Vol. 278, Issue 13, 11449-11456, March 28, 2003
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Anti-angiogenic Activity of the Recombinant Kringle Domain of Urokinase and Its Specific Entry into Endothelial Cells*

Kwang Sei KimDagger §, Yong-Kil HongDagger §, Young Ae JoeDagger , Yoon LeeDagger , Joo-Young ShinDagger , Hyo-Eun ParkDagger , Il-Ha Lee||, Soo-Young Lee||, Dong-Ku Kang§**, Soo-Ik Chang**Dagger Dagger , and Soo Il Chung§§

From the Dagger  Cancer Research Institute, Catholic Research Institutes of Medical Sciences and the || Department of Natural Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, the ** Department of Biochemistry, College of Natural Science, Biotechnology Research Institute, Chungbuk National University, Cheongju 361-763, the Dagger Dagger  Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul 120-752, and the §§ Mogam Biotechnology Research Institute, Yongin 449-910, Korea

Urokinase plasminogen activator (uPA) belongs to a family of proteins that contains kringle domain and plays an important role in inflammation, tissue remodeling, angiogenesis, and tumor metastasis by pericellular plasminogen activation. Kringle domains of plasminogen have been shown to demonstrate anti-angiogenic and anti-tumor activities. Here, we report our investigation of the kringle domain of uPA for anti-angiogenic activity and a possible cellular mechanism of action. The recombinant kringle domain of uPA (Asp45-Lys135) (UK1) inhibited endothelial cell proliferation stimulated by basic fibroblast growth factor, vascular endothelial growth factor (VEGF), or epidermal growth factor. It also inhibited migration of endothelial cells induced by VEGF or uPA, and in vivo angiogenesis on the chick chorioallantoic membrane. It did not block plasminogen activation by activated uPA in clot lysis and chromogenic substrate assays. Neither binding of UK1 to immobilized uPA receptor nor competitive inhibition of uPA binding were confirmed by real-time interaction analysis. However, internalization of UK1 followed by translocation from cytosol to nucleus was determined to be specific to endothelial cells. It also elicited a transient increase of Ca2+ flux of more than 2-fold within 2 min of exposure in an endothelial cell-specific manner. These results suggest that the kringle domain of uPA exhibits anti-angiogenic activity and that its anti-angiogenic activity may occur through a different mechanism from inhibition of uPA-uPA receptor interaction or uPA proteolytic activity and may be associated with endothelial-cell specific internalization not mediated by the uPA receptor.

* This work was supported in part by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare (02-PJ1-PG10-20802-0007), the National Projects of the Korean Ministry of Science and Technology (98-G-08-03-A-26), and the Korea Science and Engineering Foundation through the Cancer Metastasis Research Center at Yonsei University and the Vascular System Research Center at Kangwon National University.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

To whom correspondence should be addressed: Cancer Research Institute, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Banpo-dong 505, Seocho-ku, Seoul 137-701, Korea. Tel.: 82-2-590-2404; Fax: 82-2-532-0575; E-mail: youngjoe@catholic.ac.kr.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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