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Molecular and Cellular Biology, April 2001, p. 2570-2580, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2570-2580.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Epidermal Growth Factor-Like Repeats Mediate Lateral and Reciprocal Interactions of Ep-CAM Molecules in Homophilic Adhesions

M. Balzar,1 I. H. Briaire-de Bruijn,1 H. A. M. Rees-Bakker,1 F. A. Prins,1 W. Helfrich,2 L. de Leij,2 G. Riethmüller,3 S. Alberti,4 S. O. Warnaar,1 G. J. Fleuren,1 and S. V. Litvinov1

Department of Pathology, Leiden University Medical Center, Leiden,1 and Department of Clinical Immunology, University Hospital Groningen, Groningen,2 The Netherlands; Institute for Immunology, University of Munich, Munich, Germany3; and Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy4

Received 6 July 2000/Returned for modification 2 August 2000/Accepted 2 January 2001

Ep-CAM is a new type of cell adhesion molecule (CAM) which does not structurally resemble the members of the four major families (cadherins, integrins, selectins, and CAMs of the immunoglobulin superfamily) and mediates Ca2+-independent, homophilic adhesions. The extracellular domain of Ep-CAM consists of a cysteine-rich region, containing two type II epidermal growth factor (EGF)-like repeats, followed by a cysteine-poor region. We generated mutated Ep-CAM forms with various deletions in the extracellular domain. These deletion mutants, together with monoclonal antibodies recognizing different epitopes in the extracellular domain, were used to investigate the role of the EGF-like repeats in the formation of intercellular contacts mediated by Ep-CAM molecules. We established that both EGF-like repeats are required for the formation of Ep-CAM-mediated homophilic adhesions, including the accumulation of Ep-CAM molecules at the cell-cell boundaries, and the anchorage of the Ep-CAM adhesion complex to F-actin via alpha -actinin. Deletion of either EGF-like repeat was sufficient to inhibit the adhesion properties of the molecule. The first EGF-like repeat of Ep-CAM is required for reciprocal interactions between Ep-CAM molecules on adjacent cells, as was demonstrated with blocking antibodies. The second EGF-like repeat was mainly required for lateral interactions between Ep-CAM molecules. Lateral interactions between Ep-CAM molecules result in the formation of tetramers, which might be the first and necessary step in the formation of Ep-CAM-mediated intercellular contacts.

Molecular and Cellular Biology, April 2001, p. 2570-2580, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2570-2580.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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