The catenin p120 (p120ctn) is an armadillo repeat domain protein that binds to cadherins and has been shown to facilitate strong cell-cell adhesion. We have investigated a possible link between heterotrimeric G proteins and p120ctn, and found that both Galpha12 and Galpha13 can completely and selectively abrogate the p120ctn-induced branching phenotype in different cell types. Consistent with these observations, the expression of Galpha12 or Galpha13 compensates for the reduction of Rho activity induced by p120ctn. On the other hand, p120ctn can be selectively coimmunoprecipitated with Galpha12, and the coimmunoprecipitation was favored by activation of the G protein. A specific interaction between p120ctn and Galpha12Q231L was also observed in in vitro binding experiments. In addition, p120ctn can be immunoprecipitated along with Galpha12Q231L in L cells in absence of E-cadherin. Interestingly, the expression of Galpha12Q231L increases the amount of p120ctn associated with E-cadherin. These findings demonstrate that Galpha12 and p120ctn are binding partners, and they also suggest a role for Galpha12 in regulating p120ctn activity and its interaction with cadherins. We propose that the Galpha12-p120ctn interaction acts as a molecular switch, which regulates cadherin-mediated cell-cell adhesion.