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J. Biol. Chem., Vol. 280, Issue 43, 36326-36333, October 28, 2005

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The Homophilic Binding of Junctional Adhesion Molecule-C Mediates Tumor Cell-Endothelial Cell Interactions^*

Sentot Santoso, Valeria V. Orlova, Kaimei Song, Ulrich J. Sachs, Cornelia L. Andrei-Selmer, and Triantafyllos Chavakis1

From the Experimental Immunology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892 and the Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, D-35392 Giessen, Germany

The junctional adhesion molecule C (JAM-C) was recently shown to undergo a heterophilic interaction with the leukocyte 2 integrin Mac-1, thereby mediating interactions between vascular cells in inflammatory cell recruitment. Here, the homophilic interaction of JAM-C is presented and functionally characterized to mediate tumor cell-endothelial cell interactions. Recombinant soluble JAM-C in fluid phase bound to immobilized JAM-C as assessed in a purified system; moreover, JAM-C-transfected Chinese hamster ovary (CHO) cells adhered to immobilized JAM-C. The homophilic interaction of JAM-C was mediated by the isolated amino-terminal Ig domain (D1), but not the carboxyl-terminal Ig domain (D2), of the molecule. Dimerization of JAM-A is dependent on the sequence RVE in the amino-terminal Ig domain. This motif is conserved in JAM-C (Arg⁶⁴-Ile⁶⁵-Glu⁶⁶), and a single amino acid mutation in this motif (E66R) abolished the homophilic interaction of JAM-C. The lung carcinoma cell line NCI-H522 was found to express JAM-C. NCI-H522 cells adhered to immobilized JAM-C, as well as to JAM-C-transfected CHO cells, but not to mock-transfected CHO cells or to CHO cells transfected with the JAM-C mutant (E66R). Adhesion of NCI-H522 cells to JAM-C protein or JAM-C-transfected CHO cells was abolished in the presence of soluble JAM-C or the isolated D1. Furthermore, the adhesion of NCI-H522 cells to endothelial cells was significantly blocked by soluble JAM-C or the isolated D1. Thus, JAM-C undergoes a homophilic interaction via the Arg⁶⁴-Ile⁶⁵-Glu⁶⁶ motif on the membrane-distal Ig domain of the molecule. The homophilic interaction of JAM-C can mediate tumor cell-endothelial cell interactions and may thereby be involved in the process of tumor cell metastasis.

Received for publication, May 9, 2005 , and in revised form, July 29, 2005.

^* This work was supported by the Intramural Research Program of NCI, National Institutes of Health (to T. C.) and by the Deutsche Forschungsgemeinschaft (to S. S.). 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: Experimental Immunology Branch, NCI, National Institutes of Health, 10 Center Dr., Rm. 4B17, Bethesda, MD 20892. Tel.: 301-451-2104; Fax: 301-496-0887; E-mail: chavakist{at}mail.nih.gov.

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