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

Meritxell Vinyoles1, Beatriz Del Valle-Pérez1, Josué Curto1

  • 1Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.

Molecular Cell
|January 14, 2014
PubMed

Insights

Wnt signaling stabilizes beta-catenin by inhibiting GSK3. This study reveals that GSK3 sequestration into multivesicular bodies (MVBs) requires p120-catenin/cadherin dissociation, a key step for Wnt pathway activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Canonical Wnt ligands activate beta-catenin transcriptional activity.
  • GSK3 inhibition is crucial for beta-catenin stabilization.
  • Two proposed mechanisms for GSK3 inhibition involve LRP5/6 binding or MVB sequestration.

Purpose of the Study:

  • To investigate the mechanism of GSK3 sequestration into MVBs.
  • To elucidate the role of p120-catenin and cadherin in GSK3 sequestration.
  • To understand how these interactions affect Wnt-mediated beta-catenin stabilization.

Main Methods:

  • Utilized Wnt signaling pathway research.
  • Employed p120-catenin and cadherin mutants.
  • Analyzed GSK3 sequestration into MVBs.
  • Assessed beta-catenin upregulation via Wnt3a stimulation.

Main Results:

  • GSK3 complex internalization into MVBs depends on p120-catenin/cadherin dissociation.
  • Cadherin phosphorylation and p120-catenin separation control cadherin-LRP5/6 interaction.
  • Mutants preventing dissociation block GSK3 sequestration, partially inhibiting beta-catenin upregulation.

Conclusions:

  • GSK3 sequestration into MVBs is dependent on p120-catenin/cadherin complex dissociation.
  • This sequestration mechanism contributes to Wnt-induced beta-catenin stabilization.
  • The findings clarify a critical step in Wnt/beta-catenin pathway regulation.

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