Distinct regions of the cadherin cytoplasmic domain are essential for functional interaction with Gα12 and β-catenin

Heterotrimeric G proteins of the G(12) subfamily mediate cellular signals leading to events such as cytoskeletal rearrangements, cell proliferation, and oncogenic transformation. Several recent studies have revealed direct effector 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 cytoplasmic domains of several members of the cadherin family of cell adhesion molecules (Meigs, T. E., Fields, T. A., McKee, D. D., and Casey, P. J. (2001) Proc. Natl. Acad. Sei. U. S. A. 98, 519-524). This interaction causes beta -catenin to release from cadherin and relocalize to the cytoplasm and nucleus, where it participates in transcriptional activation. Here we report that two distinct regions of the epithelial cadherin (E-cadherin) tail are required for interaction with beta -catenin and G alpha (12), respectively. Deletion of an acidic, 19-amino acid region of E-cadherin abolishes its ability to bind beta -catenin in vitro, to inhibit beta -catenin-mediated transactivation, or to stabilize beta -catenin; causes subcellular mislocalization of beta -catenin; and disrupts cadherin-mediated cell adhesion. On the other hand, deletion of a distinct 11-amino acid region of E-cadherin dramatically attenuates interaction with G alpha (12); furthermore, G alpha (12) is ineffective in stimulating beta -catenin release from an E-cadherin cytoplasmic domain lacking this putative G alpha (12)-binding region. These findings indicate that G alpha (12) and beta -catenin do not compete for the same binding site on cadherin and provide molecular targets for selectively disrupting the interaction of these proteins with cadherin.