Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6

Mol Cell. 2014 Feb 6;53(3):444-57. doi: 10.1016/j.molcel.2013.12.010. Epub 2014 Jan 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cadherins / physiology*
  • Catenins / metabolism
  • Catenins / physiology*
  • Caveolins / metabolism
  • Glycogen Synthase Kinase 3 / metabolism*
  • HEK293 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-5 / analysis
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-6 / analysis
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Mice
  • Multivesicular Bodies / metabolism*
  • Phosphorylation
  • Wnt Signaling Pathway*
  • Wnt3A Protein / metabolism
  • Wnt3A Protein / physiology

Substances

  • Cadherins
  • Catenins
  • Caveolins
  • LRP5 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Wnt3A Protein
  • delta catenin
  • Glycogen Synthase Kinase 3