Addition of exogenous diacylglycerol enhances Wnt/β-catenin signaling through stimulation of macropinocytosis

Azbazdar, Yagmur; Tejeda-Munoz, Nydia; Monka, Julia C.; Dayrit, Alex; Binder, Grace; Ozhan, Gunes; De Robertis, Edward M.

doi:10.1016/j.isci.2023.108075

Cited by 5 publications

(5 citation statements)

References 44 publications

(76 reference statements)

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“…Recent findings have uncovered important links between Wnt signal transduction and membrane trafficking ( Albrecht et al, 2021 ). It was discovered that the dorsalization phenotype by LiCl is blocked by the macropinocytosis inhibitor EIPA ( Tejeda-Muñoz and De Robertis, 2022a ; Tejeda-Muñoz et al, 2023 ; Azbazdar et al, 2023 ), suggesting that dorsal development requires macropinocytosis. Lysosomal inhibition during early development with the V-ATPase inhibitors Bafilomycin, or Concanamycin A ( Tejeda-Muñoz and De Robertis, 2022a ), and in the present study with Ouabain, highlights membrane trafficking as an emerging critical target for Wnt inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Lysosomal inhibition during early development with the V-ATPase inhibitors Bafilomycin, or Concanamycin A ( Tejeda-Muñoz and De Robertis, 2022a ), and in the present study with Ouabain, highlights membrane trafficking as an emerging critical target for Wnt inhibition. Inhibitors of macropinocytosis or lysosomes can inhibit Wnt signaling; the opposite effect can be achieved by using Phorbol 12-myristate 13-acetate (PMA) or the second messenger lipid diacylglycerol (DAG), both of which can enhance Wnt signaling ( Tejeda-Muñoz et al, 2023 ; Azbazdar et al, 2023 ). The latter observations may have important implications in understanding the activity of tumor promoters which have a powerful role in cancer progression without directly mutating DNA ( Hanahan and Weinberg, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

Tejeda-Muñoz,

Azbazdar,

Sosa

et al. 2024

Biology Open

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Recent research has shown that membrane trafficking plays an important role in canonical Wnt signaling through sequestration of the β-catenin destruction complex inside multivesicular bodies (MVBs) and lysosomes. In this study, we introduce Ouabain, an inhibitor of the Na,K-ATPase pump that establishes electric potentials across membranes, as a potent inhibitor of Wnt signaling. We find that Na,K-ATPase levels are elevated in advanced colon carcinoma, that this enzyme is elevated in cancer cells with constitutively activated Wnt pathway and is activated by GSK3 inhibitors that increase macropinocytosis. Ouabain blocks macropinocytosis, which is an essential step in Wnt signaling, probably explaining the strong effects of Ouabain on this pathway. In Xenopus embryos, brief Ouabain treatment at the 32-cell stage critical for the earliest Wnt signal in development inhibited brain development and could be reversed by Lithium chloride, a Wnt mimic. Inhibiting membrane trafficking may provide a way of targeting Wnt-driven cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

Tejeda-Muñoz,

Azbazdar,

Sosa

et al. 2024

Biology Open

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“…It seems likely that PMA may facilitate Wnt/β-catenin signaling by mimicking the DAG lipid in macropinosomes. We have tested this hypothesis by direct addition of DAG to cells and found cooperation with Wnt signaling ( Azbazdar et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

The PMA phorbol ester tumor promoter increases canonical Wnt signaling via macropinocytosis

Tejeda-Munoz,

Azbazdar,

Monka

et al. 2023

eLife

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Activation of the Wnt pathway lies at the core of many human cancers. Interestingly, Wnt, cell adhesion, and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here we show that a macropinocytosis activator, the tumor promoter Phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the Xenopus embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. The crosstalk between canonical Wnt, the Protein Kinase C (PKC) pathway, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.

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“…[51] As was the case with PMA, addition of DAG also induced macropinocytosis in cultured cells and increased the effects of LiCl in microinjected embryos. [56] In human colorectal carcinoma biopsies, the degree of malignancy correlated with the accumulation of β-catenin, MVB and lysosome markers, and the decrease in GSK3 levels, suggesting that endolysosomal trafficking is important in human cancer progression. [51] These results indicate that tumor promoters act by increasing the response to β-catenin signaling by stimulating membrane trafficking.…”

Section: Phorbol Ester Tumor Promoters Potentiate the Early Dorsal Ax...mentioning

confidence: 95%

The early dorsal signal in vertebrate embryos requires endolysosomal membrane trafficking

Azbazdar,

De Robertis

2023

BioEssays

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Fertilization triggers cytoplasmic movements in the frog egg that lead in mysterious ways to the stabilization of β‐catenin on the dorsal side of the embryo. The novel Huluwa (Hwa) transmembrane protein, identified in China, is translated specifically in the dorsal side, acting as an egg cytoplasmic determinant essential for β‐catenin stabilization. The Wnt signaling pathway requires macropinocytosis and the sequestration inside multivesicular bodies (MVBs, the precursors of endolysosomes) of Axin1 and Glycogen Synthase Kinase 3 (GSK3) that normally destroy β‐catenin. In Xenopus, the Wnt‐like activity of GSK3 inhibitors and of Hwa mRNA can be blocked by brief treatment with inhibitors of membrane trafficking or lysosomes at the 32‐cell stage. In dorsal blastomeres, lysosomal cathepsin is activated and intriguing MVBs surrounded by electron dense vesicles are formed at the 64‐cell stage. We conclude that membrane trafficking and lysosomal activity are critically important for the earliest asymmetries in vertebrate embryonic development.

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Addition of exogenous diacylglycerol enhances Wnt/β-catenin signaling through stimulation of macropinocytosis

Cited by 5 publications

References 44 publications

Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

The PMA phorbol ester tumor promoter increases canonical Wnt signaling via macropinocytosis

The early dorsal signal in vertebrate embryos requires endolysosomal membrane trafficking

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