Distinct regions of the cadherin cytoplasmic domain are essential for functional interaction with G alpha(12) and beta-catenin

Heterotrimeric G proteins of the G(12) subfamily mediate cellular signals l eading to events such as cytoskeletal rearrangements, cell proliferation, a nd oncogenic transformation. Several recent studies have revealed direct ef fector proteins through which G(12) subfamily members may transmit signals leading to various cellular responses. Our laboratory recently demonstrated that G alpha (12) and G alpha (13) specifically interact with the cytoplas mic domains of several members of the cadherin family of cell adhesion mole cules (Meigs, T. E., Fields, T. A., McKee, D. D., and Casey, P. J. (2001) P roc. Natl. Acad. Sei. U. S. A. 98, 519-524). This interaction causes beta - catenin to release from cadherin and relocalize to the cytoplasm and nucleu s, where it participates in transcriptional activation. Here we report that two distinct regions of the epithelial cadherin (E-cadherin) tail are requ ired for interaction with beta -catenin and G alpha (12), respectively. Del etion of an acidic, 19-amino acid region of E-cadherin abolishes its abilit y to bind beta -catenin in vitro, to inhibit beta -catenin-mediated transac tivation, or to stabilize beta -catenin; causes subcellular mislocalization of beta -catenin; and disrupts cadherin-mediated cell adhesion. On the oth er hand, deletion of a distinct 11-amino acid region of E-cadherin dramatic ally attenuates interaction with G alpha (12); furthermore, G alpha (12) is ineffective in stimulating beta -catenin release from an E-cadherin cytopl asmic domain lacking this putative G alpha (12)-binding region. These findi ngs indicate that G alpha (12) and beta -catenin do not compete for the sam e binding site on cadherin and provide molecular targets for selectively di srupting the interaction of these proteins with cadherin.