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J. Biol. Chem., Vol. 278, Issue 47, 46750-46759, November 21, 2003

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Thrombomodulin-mediated Cell Adhesion

INVOLVEMENT OF ITS LECTIN-LIKE DOMAIN^*

Huey-Chun Huang¶, Guey-Yueh Shi, Shinn-Jong Jiang, Chung-Sheng Shi, Chun-Mei Wu, Hsi-Yuan Yang||, and Hua-Lin Wu**

From the Department of Biochemistry and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan 701, Republic of China, the ^¶Department of Medical Technology, China Medical College, Taichung, Taiwan 404, Republic of China, and ^||Institute of Molecular and Cell Biology, National Taiwan University, Taipei, Taiwan 107, Republic of China

Thrombomodulin (TM) is an integral membrane glycoprotein that is a potent anticoagulant factor. TM may also possess functions distinct from its anticoagulant activity. Here the influence of TM on cell adhesion was studied in TM-negative melanoma A2058 cells transfected with green fluorescent protein-tagged TM (TMG) or lectin domain-deleted TM (TMG(L)). Confocal microscopy demonstrated that both TMG and TMG(L) were distributed in the plasma membrane. TMG-expressed cells grew as closely clustered colonies, with TM localized prominently in the intercellular boundaries. TMG(L)-expressed cells grew singly. Overexpression of TMG, but not TMG(L), decreased monolayer permeability in vitro and tumor growth in vivo. The cell-to-cell adhesion in TMG-expressed cells was Ca²⁺-dependent and was inhibited by monoclonal antibody against the lectin-like domain of TM. The effects of TM-mediated cell adhesion were abolished by the addition of mannose, chondroitin sulfate A, or chondroitin sulfate C. In addition, anti-lectin-like domain antibody disrupted the close clustering of the endogenous TM-expressed keratinocyte HaCaT cell line derived from normal human epidermis. Double-labeling immunofluorescence staining revealed similar distributions of TM and actin filament in the cortex region of the TMG-expressed cells. Thus, TM can function as a Ca²⁺-dependent cell-to-cell adhesion molecule. Binding of specific carbohydrates to the lectin-like domain is essential for this specific function.

Received for publication, May 19, 2003 , and in revised form, August 27, 2003.

^* This work was supported by Ministry of Education Program for Promoting Academic Excellence of Universities Grant 91-B-FA09-2-4 and National Science Council, Republic of China, Grants NSC-89-2320-B006-151 and NSC-89-2316-B006-009-M42. 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.

^** To whom correspondence should be addressed. Tel.: 886-6-2353535-5541; Fax: 886-6-3028037; E-mail: halnwu{at}mail.ncku.edu.tw.

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