Cadherin sequences that inhibit beta-catenin signaling: A study in yeast and mammalian cells

Drosophila Armadillo and its mammalian homologue beta -catenin are scaffold ing proteins involved in the assembly of multiprotein complexes with divers e biological roles. They mediate adherens junction assembly, thus determini ng tissue architecture, and also transduce Wnt/Wingless intercellular signa ls, which regulate embryonic cell fates and, if inappropriately activated, contribute to tumorigenesis. To learn more about Armadillo/beta -catenin's scaffolding function, we examined in detail its interaction with one of its protein targets, cadherin. We utilized two assay systems: the yeast two-hy brid system to study cadherin binding in the absence of Armadillo/beta -cat enin's other protein partners, and mammalian cells where interactions were assessed in their presence. We found that segments of the cadherin cytoplas mic tail as small as 23 amino acids bind Armadillo or beta -catenin in yeas t, whereas a slightly longer region is required for binding in mammalian ce lls. We used mutagenesis to identify critical amino acids required for cadh erin interaction with Armadillo/beta -catenin, Expression of such short cad herin sequences in mammalian cells did not affect adherens junctions but ef fectively inhibited beta -catenin-mediated signaling. This suggests that th e interaction between beta -catenin and T cell factor family transcription factors is a sensitive target for disruption, making the use of analogues o f these cadherin derivatives a potentially useful means to suppress tumor p rogression.