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Cell Rep January 1, 2020; 32 (4): 107973.
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GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery.

Albrecht LV , Tejeda-Muñoz N , Bui MH , Cicchetto AC , Di Biagio D , Colozza G , Schmid E , Piccolo S , Christofk HR , De Robertis EM .

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.

PubMed ID: 32726636
PMC ID: PMC7666578
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: axin1 cd63 ctnnb1 dnai1 gsk3b hccs mrc1 pak1 wnt3a wnt8a
GO keywords: lysosomal membrane [+]
Antibodies: Pak1 Ab2 Pak1 Pak2 Pak3 Ab3

Article Images: [+] show captions
References [+] :
Acebron, Mitotic wnt signaling promotes protein stabilization and regulates cell size. 2014, Pubmed