p120 catenin (p120^ctn) regulates cadherin stability, and thus facilitates strong cell-cell adhesion. Previously, we demonstrated that Gα₁₂ interacts with p120^ctn. In the present study, we have delineated a region of p120^ctn that binds to Gα₁₂. We report that the N-terminal region of p120^ctn (amino acids 1-346) is necessary and sufficient for the interaction. While the coiled-coiled domain and a charged region, comprising a.a 102-120, were found to be dispensable, amino acids 121-323 were required for p120^ctn binding to Gα₁₂. This region harbors the phosphorylation domain of p120^ctn and has been postulated as important for RhoA regulation. Downregulation of Src family kinase-induced tyrosine phosphorylation of p120^ctn was observed in the presence of activated Gα₁₂. This down-regulation was triggered by three different Gα₁₂ mutants uncoupled from RhoA signalling. Furthermore, a dominant active form of RhoA did not reduce Src-induced phosphoryaltion of p120^ctn. In summary, our results suggest that Gα₁₂ binds to p120^ctn and modulates its phosphorylation status through a Rho-independent mechanism. Gα₁₂ emerges as an important regulator of p120^ctn function, and possibly of cadherin-mediated adhesion and/or cell motility.