Gα12 binds to the N-terminal regulatory domain of p120ctn, and downregulates p120ctn tyrosine phosphorylation induced by Src family kinases via a RhoA independent mechanism

p120 catenin (p120ctn) regulates cadherin stability, and thus facilitates strong cell-cell adhesion. Previously, we demonstrated that Gα12 interacts with p120ctn. In the present study, we have delineated a region of p120ctn that binds to Gα12. We report that the N-terminal region of p120ctn (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 p120ctn binding to Gα12. This region harbors the phosphorylation domain of p120ctn and has been postulated as important for RhoA regulation. Downregulation of Src family kinase-induced tyrosine phosphorylation of p120ctn 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 p120ctn. In summary, our results suggest that Gα12 binds to p120ctn and modulates its phosphorylation status through a Rho-independent mechanism. Gα12 emerges as an important regulator of p120ctn function, and possibly of cadherin-mediated adhesion and/or cell motility.