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J. Biol. Chem., Vol. 282, Issue 12, 8741-8748, March 23, 2007

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Des--carboxyl Prothrombin-promoted Vascular Endothelial Cell Proliferation and Migration^*

From the Department of Medicine and Medical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan

Des--carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C- and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.

Received for publication, October 3, 2006 , and in revised form, January 25, 2007.

^* This work was supported by Grant 16390210 from the Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-86-235-7219; Fax: 81-86-225-5991; E-mail: hshiraha{at}md.okayama-u.ac.jp.

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