GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery

Albrecht, Lauren V.; Tejeda-Muñoz, Nydia; Bui, Maggie H.; Cicchetto, Andrew; Biagio, Daniele Di; Colozza, Gabriele; Schmid, E.; Piccolo, Stefano; Christofk, Heather R.; Robertis, E. M. De

doi:10.1016/j.celrep.2020.107973

Cited by 61 publications

(111 citation statements)

References 59 publications

(101 reference statements)

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“…The strong link between the Wnt and ALP pathways we observed suggests the existence of a bi-directional feedback loop, so that alterations in one pathway may affect the other. This idea is in line with other reports on the ability of the endo-lysosomal system to modulate Wnt signaling and in turn, the Wnt pathway regulating the lysosomal compartment [35,61,63,[72][73][74][75]. Albrecht et al reported an increase in both endocytosis and the lysosomal degradation of extracellular proteins within minutes of the addition of Wnt3a in NIH-3T3 fibroblasts.…”

Section: Discussionsupporting

confidence: 89%

“…Albrecht et al reported an increase in both endocytosis and the lysosomal degradation of extracellular proteins within minutes of the addition of Wnt3a in NIH-3T3 fibroblasts. Additionally, Wnt3a treatment or inhibition of GSK3β in HeLa and HCC Alexander cells increased Lysotracker staining, and Cathepsin D and GCase activity [75]. A neuroprotective effect of Wnt ligands in vivo has also been reported [76][77][78][79][80].…”

Section: Discussionmentioning

confidence: 99%

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Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease

Srikanth

Feldman

2020

Biomolecules

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Gaucher Disease (GD), which is the most common lysosomal storage disorder, is caused by bi-allelic mutations in GBA1—a gene that encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The neuronopathic forms of GD (nGD) are characterized by severe neurological abnormalities that arise during gestation or early in infancy. Using GD-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs), we have previously reported that neuronal cells have neurodevelopmental defects associated with the downregulation of canonical Wnt signaling. In this study, we report that GD NPCs display elevated levels of Dkk1, which is a secreted Wnt antagonist that prevents receptor activation. Dkk1 upregulation in mutant NPCs resulted in an increased degradation of β-catenin, and there was a concomitant reduction in lysosomal numbers. Consistent with these results, incubation of the mutant NPCs with recombinant Wnt3a (rWnt3a) was able to outcompete the excess Dkk1, increasing β-catenin levels and rescuing lysosomal numbers. Furthermore, the incubation of WT NPCs with recombinant Dkk1 (rDkk1) phenocopied the mutant phenotype, recapitulating the decrease in β-catenin levels and lysosomal depletion seen in nGD NPCs. This study provides evidence that downregulation of the Wnt/β-catenin pathway in nGD neuronal cells involves the upregulation of Dkk1. As Dkk1 is an extracellular Wnt antagonist, our results suggest that the deleterious effects of Wnt/β-catenin downregulation in nGD may be ameliorated by the prevention of Dkk1 binding to the Wnt co-receptor LRP6, pointing to Dkk1 as a potential therapeutic target for GBA1-associated neurodegeneration.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease

Srikanth

Feldman

2020

Biomolecules

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“…Hence, an important function of Wnt signaling in this context seems to be a constant down-regulation of a sub-pool of Wnt-controlled basal GSK3β activity. It is interesting that fine-tuned regulation of Wnt associated GSK3β activity seems not only be important for mitotic regulation, but also, for example, for macropinocytosis and metabolite changes as demonstrated recently (38). Importantly, down-regulation of basal GSK3β required for proper mitosis is mediated by basal Wnt signaling that requires ongoing secretion of Wnt ligands.…”

Section: Discussionmentioning

confidence: 92%

Wnt10b-GSK3β–dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells

et al. 2020

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Wnt signaling is crucial for proper development, tissue homeostasis and cell cycle regulation. A key role of Wnt signaling is the GSK3β-mediated stabilization of β-catenin, which mediates many of the critical roles of Wnt signaling. In addition, it was recently revealed that Wnt signaling can also act independently of β-catenin. In fact, Wnt mediated stabilization of proteins (Wnt/STOP) that involves an LRP6-DVL–dependent signaling cascade is required for proper regulation of mitosis and for faithful chromosome segregation in human somatic cells. We show that inhibition of Wnt/LRP6 signaling causes whole chromosome missegregation and aneuploidy by triggering abnormally increased microtubule growth rates in mitotic spindles, and this is mediated by increased GSK3β activity. We demonstrate that proper mitosis and maintenance of numerical chromosome stability requires continuous basal autocrine Wnt signaling that involves secretion of Wnts. Importantly, we identified Wnt10b as a Wnt ligand required for the maintenance of normal mitotic microtubule dynamics and for proper chromosome segregation. Thus, a self-maintaining Wnt10b-GSK3β–driven cellular machinery ensures the proper execution of mitosis and karyotype stability in human somatic cells.

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“…These optimized protocols, applied in different cell types and pathophysiologic contexts, provide useful tools to study lysosome function in cultured living cells. For complete details on the use and execution of this protocol, please refer to Albrecht et al. (2020) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Albrecht et al. (2020) .…”

mentioning

confidence: 99%

Protocol for Probing Regulated Lysosomal Activity and Function in Living Cells

2020

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Summary Lysosomes are the catabolic center of the cell. Limitations of many lysosomal tracers include low specificity and lack of reliable physiological readouts for changes in growth factor-regulated lysosomal activity. The imaging-based protocols described here provide insights at the cellular level to quantify functions essential to lysosomal biology, including β-glucosidase enzymatic cleavage, active Cathepsin D, and pH regulation in real time. These optimized protocols, applied in different cell types and pathophysiologic contexts, provide useful tools to study lysosome function in cultured living cells. For complete details on the use and execution of this protocol, please refer to Albrecht et al. (2020) .

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GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery

Cited by 61 publications

References 59 publications

Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease

Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease

Wnt10b-GSK3β–dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells

Protocol for Probing Regulated Lysosomal Activity and Function in Living Cells

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