A p120-catenin-CK1epsilon complex regulates Wnt signaling

Abstract

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 CK1ε 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 CK1ε binding to LRP5/6 and prevents CK1ε activation upon Wnt3a stimulation. Elimination of p120-catenin also inhibits early responses to Wnt, such as LRP5/6 and Dvl-2 phosphorylation and axin recruitment to the signalosome, as well as later effects, such as β-catenin stabilization. Moreover, since CK1ε is also required for E-cadherin phosphorylation, a modification that decreases the affinity for β-catenin, p120-catenin depletion prevents the increase in β-catenin transcriptional activity even in the absence of β-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 β-catenin transcriptional activity different of β-catenin stability.

This study was supported by grants awarded by the Ministerio de Ciencia e Innovación: BFU2006-03203 and BFU2009-07578 to M.D. and SAF2006-00339 to A.G.H. Partial support from the Instituto Carlos III (RD06/0020/0040) and the Generalitat de Catalunya (2009SGR867 and 2009SGR585) is also appreciated. D.C. and G.V. were supported by predoctoral fellowships from the Ministerio de Educación and E.L., from the UAB.