The Wnt canonical ligands elicit the activation of β-catenin transcriptional activity, a response dependent on, but not limited to, β-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs. These mutants substantially inhibit, but do not completely prevent, the β-catenin upregulation caused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of β-catenin stabilization by Wnt.

This work was funded by grants from the Ministerio de Economía (BFU2012-31554 to M.D. and SAF2010-16089 to A.G.H.) and Fundació La Marató de TV3 (120130) to M.D. and A.G.H. Support from Fundación Científica de la Asociación Española contra el Cáncer, ISCIII/FEDER (RD12/0036/005) and Generalitat de Catalunya (2009SGR867) is also appreciated. M.V. and L.A.-C. were recipients of predoctoral fellowships from FPI, and R.V.-C. was a recipient of a fellowship from ISCIII