A p120-catenin-CK1ε complex regulates Wnt signaling

p120-catenin is an E-cadherin-associated protein that modulates E-cadherin function and stability. We describe here that p120-catenin is required for Wnt pathway signaling. p120-catenin binds and is phosphorylated by CK1 epsilon in response to Wnt3a. p120-catenin also associates to the Wnt co-receptor LRP5/6, an interaction mediated by E-cadherin, showing an unexpected physical link between adherens junctions and a Wnt receptor. Depletion of p120-catenin abolishes CK1 epsilon binding to LRP5/6 and prevents CK1 epsilon activation upon Wnt3a stimulation. Elimination of p120-catenin also inhibits early responses to Wnt, such as LRP5/6 and Dv1-2 phosphorylation and axin recruitment to the signalosome, as well as later effects, such as beta-catenin stabilization. Moreover, since CK1 epsilon is also required for E-cadherin phosphorylation, a modification that decreases the affinity for beta-catenin, p120-catenin depletion prevents the increase in beta-catenin transcriptional activity even in the absence of beta-catenin degradation. Therefore, these results demonstrate a novel and crucial function of p120-catenin in Wnt signaling and unveil additional points of regulation by this factor of beta-catenin transcriptional activity different of beta-catenin stability.