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GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery

Lauren V Albrecht1, Nydia Tejeda-Muñoz1, Maggie H Bui1

  • 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.

Cell Reports
|July 30, 2020
PubMed

Insights

Canonical Wnt signaling regulates endocytosis via GSK3 and the β-catenin destruction complex. Inhibition of GSK3 or Axin1 mutation activates macropinocytosis and lysosomal activity, impacting cellular membrane trafficking.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Endocytosis Research

Background:

  • Canonical Wnt signaling is increasingly recognized as a key regulator of cellular endocytosis.
  • The β-catenin destruction complex, including Axin1 and GSK3, plays a crucial role in Wnt pathway regulation.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex in Wnt-induced macropinocytosis.
  • To elucidate the impact of Axin1 mutation and GSK3 inhibition on endolysosomal activity and membrane trafficking.

Main Methods:

  • Investigated Wnt signaling effects on macropinocytosis using GSK3 inhibitors (LiCl, CHIR99021) and Axin1 mutation.
  • Assessed endolysosomal activity via tracers for cathepsin D, β-glucosidase, and ovalbumin degradation.
  • Utilized Xenopus embryos for in vivo macropinocytosis studies and employed macropinocytosis inhibitors (EIPA, IPA-3).

Main Results:

  • Mutation of Axin1, a tumor suppressor, activates macropinocytosis.
  • Inhibition of GSK3 by various agents triggers macropinocytosis and increases acidic endolysosomes.
  • GSK3 inhibition or Axin1 mutation enhances lysosomal activity and protein degradation, dependent on membrane trafficking.

Conclusions:

  • GSK3 and the β-catenin destruction complex are critical regulators of Wnt-induced macropinocytosis.
  • Increased lysosomal activity following GSK3 inhibition or Axin1 mutation is driven by enhanced membrane trafficking.
  • This study reveals a novel link between Wnt signaling, GSK3, and macropinocytosis-mediated lysosomal function.
Keywords:
Axin1Pak1cathepsin Dcolorectal carcinomahepatocellular carcinomalysosomemembrane traffickingmultivesicular bodiesnutrient acquisitionβ-glucosidase

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