Direct and regulated interaction of integrin α(E)β7 with E-cadherin

Abstract

The cadherins are a family of homophilic adhesion molecules that play a vital role in the formation of cellular junctions and in tissue morphogenesis. Members of the integrin family are also involved in cell to cell adhesion, but bind heterophilically to immunoglobulin superfamily molecules such an intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, or mucosal addressin cell adhesion molecule (MadCAM)-1. Recently, an interaction between epithelial (E-) cadherin and the mucosal lymphocyte integrin, α(E)β7, has been proposed. Here, we demonstrate that a human E-cadherin-Fc fusion protein binds directly to soluble recombinant α(E)β7, and to α(E)β7 solubilized from intraepithelial T lymphocytes. Furthermore, intraepithelial lymphocytes or transfected JY' cells expressing the α(E)β7 integrin adhere strongly to purified e-cadherin-Fc coated on plastic, and the adhesion can be inhibited by antibodies to α(E)β7 or e-cadherin. The binding of α(E)β7 integrin to cadherins is selective since cell adhesion to P-cadherin-Fc through α(E)E7 requires >100-fold more fusion protein than to E-cadherin-Fc. Although the structure of the α(E)-chain is unique among integrins, the avidity of α(E)β7 for e-cadherin can be regulated by divalent cations or phorbol myristate acetate. Cross-linking of the T cell receptor complex on intraepithelial lymphocytes increases the avidity of α(E)β7 for E- cadherin, and may provide a mechanism for the adherence and activation of lymphocytes within the epithelium in the presence of specific foreign antigen. Thus, despite its dissimilarity to known integrin ligands, the specific molecular interaction demonstrated here indicates that E-cadherin is a direct counter receptor for the α(E)β7 integrin.