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Annual Review of Cell and Developmental Biology

Volume 37, 2021

Cell Biology of Canonical Wnt Signaling

Abstract

Wnt signaling has multiple functions beyond the transcriptional effects of β-catenin stabilization. We review recent investigations that uncover new cell physiological effects through the regulation of Wnt receptor endocytosis, Wnt-induced stabilization of proteins (Wnt-STOP), macropinocytosis, increase in lysosomal activity, and metabolic changes. Many of these growth-promoting effects of canonical Wnt occur within minutes and are independent of new protein synthesis. A key element is the sequestration of glycogen synthase kinase 3 (GSK3) inside multivesicular bodies and lysosomes. Twenty percent of human proteins contain consecutive GSK3 phosphorylation motifs, which in the absence of Wnt can form phosphodegrons for polyubiquitination and proteasomal degradation. Wnt signaling by either the pharmacological inhibition of GSK3 or the loss of tumor-suppressor proteins, such as adenomatous polyposis coli (APC) and Axin1, increases lysosomal acidification, anabolic metabolites, and macropinocytosis, which is normally repressed by the GSK3-Axin1-APC destruction complex. The combination of these cell physiological effects drives cell growth.

Keyword(s): endocytosis, GSK3, lysosome, macropinocytosis, receptor trafficking, Wnt-STOP
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2021-10-06
2025-04-24
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Cell Biology of Canonical Wnt Signaling
Annual Review of Cell and Developmental Biology 37, 369 (2021); https://doi.org/10.1146/annurev-cellbio-120319-023657
/content/journals/10.1146/annurev-cellbio-120319-023657
/content/journals/10.1146/annurev-cellbio-120319-023657
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Supplementary Data

  • Supplemental Movie 1: Alexander hepatocellular carcinoma (HCC) cells lacking Axin1 have dynamic remodeling and vesicle formation in the apical plasma membrane that is absent from the membranes between neighboring cells. In contrast, HCCs reconstituted with Axin1 have relatively low plasma membrane motility. Cells transfected with membrane-GFP were filmed by live cell microscopy for 30 minutes. Scale bars, 10 µm. Reproduced from Albrecht et al. 2020a, with permission from Cell Press.

  • Article Type: Review Article

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