Recognition of E-cadherin by integrin alpha(E)beta(7) - Requirement for cadherin dimerization and implications for cadherin and integrin function

We have investigated the importance of dimerization of E-cadherin in the he terophilic adhesive interaction between E-cadherin and integrin alpha (E)be ta (7). Dimerization of cadherin molecules in parallel alignment is known t o be essential for homophilic adhesion and has been attributed to Ca2+-depe ndent interactions in the domain 1-2 junction or to cross-intercalation of Trp2 from one molecule to the other. We have disrupted either or both of th ese proposed mechanisms by point mutations in E-cadherin-Fc and have tested the modified proteins for alpha (E)beta (7)-mediated cell adhesion. Preven tion of Trp2 intercalation had no adverse effect on integrin-mediated adhes ion, whereas disruption of Ca2+ binding permitted adhesion but with reduced efficiency. Both modifications in combination abolished recognition by alp ha (E)beta (7). In EGTA, alpha (E)beta (7) adhered to wild type E-cadherin but not to the Trp2 deletion mutant. Independent evidence that the mutation s prevented either or both mechanisms for dimerization is presented. The da ta show that dimerization is required for recognition by alpha (E)beta (7) and that it can take place by either of two mechanisms. Implications for th e roles of the alpha (E) and beta (7) integrin subunits in ligand binding a nd for Trp2 and Ca2+ in the assembly of cadherin complexes are discussed.