title: Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin.
abstract: 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 Galpha12 and Galpha13 interact with the cytoplasmic domain of cadherins and cause the release of the transcriptional activator beta-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 beta-catenin in cadherin-mediated cell-cell adhesion, we examined whether G12 subfamily proteins could also regulate cadherin function. The introduction of mutationally activated G12 proteins 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Meigs
authors.forename: Mary
authors.initials: M
authors.lastname: Fedor-Chaiken
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Kaplan
authors.forename: Robert
authors.initials: R
authors.lastname: Brackenbury
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
mesh_terms: D001943:Breast Neoplasms; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002449:Cell Aggregation; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020962:Heterotrimeric GTP-Binding Proteins