Gα12 and Gα13 Negatively Regulate the Adhesive Functions of Cadherin

• Published in: The Journal of biological chemistry Vol. 277; no. 27; pp. 24594 - 24600
• Main Authors: Meigs, Thomas E., Fedor-Chaiken, Mary, Kaplan, Daniel D., Brackenbury, Robert, Casey, Patrick J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.07.2002
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M201984200

Cadherins function to promote adhesion between adjacent cells and play critical roles in such cellular processes as development, tissue maintenance, and tumor suppression. We previously demonstrated that heterotrimeric G proteins of the G12 subfamily comprised of Gα12 and Gα13 interact with the cytoplasmic domain of cadherins and cause the release of the transcriptional activator β-catenin (Meigs, T. E., Fields, T. A., McKee, D. D., and Casey, P. J. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 519–524). Because of the importance of β-catenin in cadherin-mediated cell-cell adhesion, we examined whether G12 subfamily proteins could also regulate cadherin function. The introduction of mutationally activated G12proteins into K562 cells expressing E-cadherin blocked cadherin-mediated cell adhesion in steady-state assays. Also, in breast cancer cells, the introduction of activated G12 proteins blocked E-cadherin function in a fast aggregation assay. Aggregation mediated by a mutant cadherin that lacks G12 binding ability was not affected by activated G12 proteins, indicating a requirement for direct G12-cadherin interaction. Furthermore, in wound-filling assays in which ectopic expression of E-cadherin inhibits cell migration, the expression of activated G12 proteins reversed the inhibition via a mechanism that was independent of G12-mediated Rho activation. These results validate the G12-cadherin interaction as a potentially important event in cell biology and suggest novel roles for G12 proteins in the regulation of cadherin-mediated developmental events and in the loss of cadherin function that is characteristic of metastatic tumor progression.