Cell Reports
Volume 32, Issue 4, 28 July 2020, 107973
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Article
GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery

https://doi.org/10.1016/j.celrep.2020.107973Get rights and content
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Highlights

  • GSK3 and Axin1 normally repress macropinocytosis in basal cellular conditions

  • GSK3 inhibition or Axin1 mutation triggers macropinocytosis and metabolite changes

  • Macropinocytosis induces acidification and catabolic activity of lysosomes

  • Lysosomal activation by Wnt signaling is independent of new protein synthesis

Summary

Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, β-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity.

Keywords

Axin1
lysosome
hepatocellular carcinoma
colorectal carcinoma
nutrient acquisition
multivesicular bodies
Pak1
membrane trafficking
β-glucosidase
cathepsin D

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