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The Journal of Immunology, 2005, 175: 1014-1021.
Copyright © 2005 by The American Association of Immunologists

Critical Role of the Fifth Domain of E-Cadherin for Heterophilic Adhesion with {alpha}E{beta}7, But Not for Homophilic Adhesion

Kiyono Shiraishi1,*,{dagger}, Kensei Tsuzaka*,{dagger}, Keiko Yoshimoto{dagger}, Chika Kumazawa*,{dagger}, Kyoko Nozaki*,{dagger}, Tohru Abe{dagger}, Kazuo Tsubota{ddagger} and Tsutomu Takeuchi*,{dagger}

* Project Research Laboratory, Research Center for Genomic Medicine and{dagger} Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, Saitama, Japan; and{ddagger} Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan

The integrin {alpha}E{beta}7 is expressed on intestinal intraepithelial T lymphocytes and CD8+ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between {alpha}E{beta}7+ T and epithelial cells is mediated by the adhesive interaction of {alpha}E{beta}7 and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and {alpha}E{beta}7, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When {alpha}E{beta}7+ K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of {alpha}E{beta}7+ K562 cells. In contrast, the binding of {alpha}E{beta}7+ K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with {alpha}E{beta}7+ K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with {alpha}E{beta}7, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to {alpha}E{beta}7 and may be a potential target for treatments altering the adhesion of {alpha}E{beta}7+ T cells to epithelial cells in inflammatory epithelial diseases.




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