Critical role of the fifth domain of E-cadherin for heterophilic adhesion with alpha E beta 7, but not for homophilic adhesion.
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.
Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical Center, Saitama Medical School, 1397-1 Yamane, Hidaka, Saitama 350-1241, Japan. kiyono@saitama-med.ac.jp
Kiyono
K
Shiraishi
Kensei
K
Tsuzaka
Keiko
K
Yoshimoto
Chika
C
Kumazawa
Kyoko
K
Nozaki
Tohru
T
Abe
Kazuo
K
Tsubota
Tsutomu
T
Takeuchi
D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics; D002449:Cell Aggregation / Q000235:genetics; D002450:Cell Communication / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020014:K562 Cells; D007739:L Cells; D051379:Mice; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014162:Transfection
D015820:Cadherins; D016023:Integrins; D011993:Recombinant Fusion Proteins; C070709:integrin alphaEbeta7; D005982:Glutathione Transferase