32 research outputs found
Targeting Membrane Trafficking as a Strategy for Cancer Treatment
Membrane trafficking is emerging as an attractive therapeutic strategy for cancer. Recent reports have found a connection between Wnt signaling, receptor-mediated endocytosis, V-ATPase, lysosomal activity, and macropinocytosis through the canonical Wnt pathway. In macropinocytic cells, a massive internalization of the plasma membrane can lead to the loss of cell-surface cadherins, integrins, and other antigens that mediate cell–cell adhesion, favoring an invasive phenotype. V-ATPase is a key regulator in maintaining proper membrane trafficking, homeostasis, and the earliest developmental decisions in the Xenopus vertebrate development model system. Here, we review how the interference of membrane trafficking with membrane trafficking inhibitors might be clinically relevant in humans
Canonical Wnt signaling induces focal adhesion and Integrin beta-1 endocytosis
During canonical Wnt signaling, the Wnt receptor complex is sequestered
together with glycogen synthase kinase 3 (GSK3) and Axin inside late endosomes, known as multivesicular bodies (MVBs). Here, we present experiments
showing that Wnt causes the endocytosis of focal adhesion (FA) proteins and
depletion of Integrin b 1 (ITGb1) from the cell surface. FAs and integrins link
the cytoskeleton to the extracellular matrix. Wnt-induced endocytosis caused
ITGb1 depletion from the plasma membrane and was accompanied by striking
changes in the actin cytoskeleton. In situ protease protection assays in cultured
cells showed that ITGb1 was sequestered within membrane-bounded organelles
that corresponded to Wnt-induced MVBs containing GSK3 and FA-associated
proteins. An in vivo model using Xenopus embryos dorsalized by Wnt8 mRNA
showed that ITGb1 depletion decreased Wnt signaling. The finding of a crosstalk
between two major signaling pathways, canonical Wnt and focal adhesions,
should be relevant to human cancer and cell biology
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GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery
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