Journal
CELL REPORTS
Volume 32, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107973
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Funding
- NIH [F32 GM123622, R01 CA215185]
- University of California Institute for Mexico and the United States (UC MEXUS)
- Consejo Nacional de Ciencia y Tecnologia (CONACYT) [FE-17-65]
- UCLA Clinical and Translational Institute undergraduate fellowship [CTSI UL1TR000124]
- Fondazione AIRC under 5 per Mille 2019 [22759]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (DENOVOSTEM grant) [670126]
- Norman Sprague Endowment for Molecular Oncology
- Howard Hughes Medical Institute
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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 beta-catenin destruction complex. We find that mutation of Axial, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCI), 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, beta-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.
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