Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β–Catenin/Armadillo

Gagliardi, Maria; Hernandez, Ana; McGough, Ian J.; Vincent, Jean‐Paul

doi:10.1242/jcs.155424

Cited by 30 publications

(31 citation statements)

References 51 publications

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“…Consistent with Clathrin's reported role in mitotic spindle organization (29), knockdown of Clathrin HC led to reduced cell proliferation. In addition, Gagliardi and colleagues reported a decrease in levels of multiple Wnt pathway proteins with or without Wnt stimulation in the presence of endocytosis inhibitors and suggested that inhibition of endocytosis may trigger degradation of multiple proteins through an unknown mechanism (39). Finally, disruption of Dynamin, which has been employed to inhibit endocytosis, could lead to pleiotropic effects and confound study conclusions.…”

Section: Discussionmentioning

confidence: 99%

β-catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism

Rim

Kinney

Nusse

2020

Preprint

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The Wnt pathway is a key intercellular signaling cascade that regulates development, tissue homeostasis, and regeneration. However, gaps remain in our understanding of the molecular events that take place between ligand-receptor binding and target gene transcription. Here we used a novel tool for quantitative, real-time assessment of endogenous pathway activation, measured in single cells, to answer an unresolved question in the field – whether receptor endocytosis is required for Wnt signal transduction. We combined knockdown or knockout of essential components of Clathrin-mediated endocytosis with quantitative assessment of Wnt signal transduction in mouse embryonic stem cells (mESCs). Disruption of Clathrin-mediated endocytosis did not affect accumulation and nuclear translocation of β-catenin, as measured by single-cell live imaging of endogenous β-catenin, and subsequent target gene transcription. Disruption of another receptor endocytosis pathway, Caveolin-mediated endocytosis, did not affect Wnt pathway activation either. These results, confirmed in multiple cell lines, suggest that endocytosis is not a general requirement for Wnt signal transduction. We show that off-target effects of a drug used to inhibit endocytosis may be one source of the discrepancy among reports on the role of endocytosis in Wnt signaling.

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Section: Discussionmentioning

confidence: 99%

β-catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism

Rim

Kinney

Nusse

2020

Preprint

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“…Previous work indicated that Axin is sequestered in multivesicular bodies (MVBs) that form following Wnt stimulation [48]; however a subsequent study revealed that MVB formation is not required for Wnt pathway activation in Drosophila [49]. The membrane-proximal Axin puncta we have observed are unlikely to represent MVBs, since these puncta are found in the absence of Wnt exposure; however, the presence of these puncta may suggest that Axin associates with other types of vesicles juxtaposed with the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling

et al. 2016

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Deregulation of the Wnt signal transduction pathway underlies numerous congenital disorders and cancers. Axin, a concentration-limiting scaffold protein, facilitates assembly of a “destruction complex” that prevents signaling in the unstimulated state and a plasma membrane-associated “signalosome” that activates signaling following Wnt stimulation. In the classical model, Axin is cytoplasmic under basal conditions, but relocates to the cell membrane after Wnt exposure; however, due to the very low levels of endogenous Axin, this model is based largely on examination of Axin at supraphysiological levels. Here, we analyze the subcellular distribution of endogenous Drosophila Axin in vivo and find that a pool of Axin localizes to cell membrane proximal puncta even in the absence of Wnt stimulation. Axin localization in these puncta is dependent on the destruction complex component Adenomatous polyposis coli (Apc). In the unstimulated state, the membrane association of Axin increases its Tankyrase-dependent ADP-ribosylation and consequent proteasomal degradation to control its basal levels. Furthermore, Wnt stimulation does not result in a bulk redistribution of Axin from cytoplasmic to membrane pools, but causes an initial increase of Axin in both of these pools, with concomitant changes in two post-translational modifications, followed by Axin proteolysis hours later. Finally, the ADP-ribosylated Axin that increases rapidly following Wnt stimulation is membrane associated. We conclude that even in the unstimulated state, a pool of Axin forms membrane-proximal puncta that are dependent on Apc, and that membrane association regulates both Axin levels and Axin’s role in the rapid activation of signaling that follows Wnt exposure.

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“…Lastly, evidence that endocytosis appears to be an obligate step for Wnt signal transduction (Bilic et al, 2007; Blitzer & Nusse, 2006), as is known for many other signaling pathways (Goh & Sorkin, 2013; Haglund & Dikic, 2012), raises the possibility that cadherins may impact Wnt signaling by controlling Wnt receptor complex internalization into signalosomes (Bilic et al, 2007). In this regard, recent studies show that Wnt receptor complex activation can promote the sequestration of GSK3 into multivesicular bodies (Taelman et al, 2010) (although perhaps not in flies; Gagliardi, Hernandez, McGough, & Vincent, 2014), leading to β-catenin stabilization and signaling, where the cadherin and p120 ctn appear required for this process (Vinyoles et al, 2014). Given that the cadherin/catenin complex is fundamental not only for cell–cell adhesion but for basic membrane dynamics (Abreu-Blanco, Verboon, Liu, Watts, & Parkhurst, 2012; Schepis, Sepich, & Nelson, 2012), it may not be surprising to find these examples of the cadherin/catenin complex being both required for and inhibitory to Wnt/β-catenin signaling.…”

Section: The Cadherin–catenin Complex As Both a Potentiator And Anmentioning

confidence: 99%

Nuclear Signaling from Cadherin Adhesion Complexes

McCrea

Maher

Gottardi

2015

Current Topics in Developmental Biology

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The arrival of multicellularity in evolution facilitated cell–cell signaling in conjunction with adhesion. As the ectodomains of cadherins interact with each other directly in trans (as well as in cis), spanning the plasma membrane and associating with multiple other entities, cadherins enable the transduction of “outside-in” or “inside-out” signals. We focus this review on signals that originate from the larger family of cadherins that are inwardly directed to the nucleus, and thus have roles in gene control or nuclear structure–function. The nature of cadherin complexes varies considerably depending on the type of cadherin and its context, and we will address some of these variables for classical cadherins versus other family members. Substantial but still fragmentary progress has been made in understanding the signaling mediators used by varied cadherin complexes to coordinate the state of cell–cell adhesion with gene expression. Evidence that cadherin intracellular binding partners also localize to the nucleus is a major point of interest. In some models, catenins show reduced binding to cadherin cytoplasmic tails favoring their engagement in gene control. When bound, cadherins may serve as stoichiometric competitors of nuclear signals. Cadherins also directly or indirectly affect numerous signaling pathways (e.g., Wnt, receptor tyrosine kinase, Hippo, NFκB, and JAK/STAT), enabling cell–cell contacts to touch upon multiple biological outcomes in embryonic development and tissue homeostasis.

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Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β–Catenin/Armadillo

Cited by 30 publications

References 51 publications

β-catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism

β-catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism

Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling

Nuclear Signaling from Cadherin Adhesion Complexes

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