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Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector β-catenin (β-cat). The multiprotein destruction complex binds and phosphorylates β-cat and transfers it to the...

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Autores principales: Schaefer, Kristina N., Pronobis, Mira I., Williams, Clara E., Zhang, Shiping, Bauer, Lauren, Goldfarb, Dennis, Yan, Feng, Major, M. Ben, Peifer, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346726/
https://www.ncbi.nlm.nih.gov/pubmed/32129710
http://dx.doi.org/10.1091/mbc.E19-11-0647
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author Schaefer, Kristina N.
Pronobis, Mira I.
Williams, Clara E.
Zhang, Shiping
Bauer, Lauren
Goldfarb, Dennis
Yan, Feng
Major, M. Ben
Peifer, Mark
author_facet Schaefer, Kristina N.
Pronobis, Mira I.
Williams, Clara E.
Zhang, Shiping
Bauer, Lauren
Goldfarb, Dennis
Yan, Feng
Major, M. Ben
Peifer, Mark
author_sort Schaefer, Kristina N.
collection PubMed
description Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector β-catenin (β-cat). The multiprotein destruction complex binds and phosphorylates β-cat and transfers it to the SCF-TrCP E3-ubiquitin ligase for ubiquitination and destruction. Wnt signals act though Dishevelled to turn down the destruction complex, stabilizing β-cat. Recent work clarified underlying mechanisms, but important questions remain. We explore β-cat transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin. We find that Slimb/TrCP is a dynamic component of the destruction complex biomolecular condensate, while other E3 proteins are not. Recruitment requires Axin and not APC, and Axin’s RGS domain plays an important role. We find that elevating Dishevelled levels in Drosophila embryos has paradoxical effects, promoting the ability of limiting levels of Axin to turn off Wnt signaling. When we elevate Dishevelled levels, it forms its own cytoplasmic puncta, but these do not recruit Axin. Superresolution imaging in mammalian cells raises the possibility that this may result by promoting Dishevelled:Dishevelled interactions at the expense of Dishevelled: Axin interactions when Dishevelled levels are high.
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spelling pubmed-73467262020-07-16 Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex Schaefer, Kristina N. Pronobis, Mira I. Williams, Clara E. Zhang, Shiping Bauer, Lauren Goldfarb, Dennis Yan, Feng Major, M. Ben Peifer, Mark Mol Biol Cell Articles Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector β-catenin (β-cat). The multiprotein destruction complex binds and phosphorylates β-cat and transfers it to the SCF-TrCP E3-ubiquitin ligase for ubiquitination and destruction. Wnt signals act though Dishevelled to turn down the destruction complex, stabilizing β-cat. Recent work clarified underlying mechanisms, but important questions remain. We explore β-cat transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin. We find that Slimb/TrCP is a dynamic component of the destruction complex biomolecular condensate, while other E3 proteins are not. Recruitment requires Axin and not APC, and Axin’s RGS domain plays an important role. We find that elevating Dishevelled levels in Drosophila embryos has paradoxical effects, promoting the ability of limiting levels of Axin to turn off Wnt signaling. When we elevate Dishevelled levels, it forms its own cytoplasmic puncta, but these do not recruit Axin. Superresolution imaging in mammalian cells raises the possibility that this may result by promoting Dishevelled:Dishevelled interactions at the expense of Dishevelled: Axin interactions when Dishevelled levels are high. The American Society for Cell Biology 2020-05-01 /pmc/articles/PMC7346726/ /pubmed/32129710 http://dx.doi.org/10.1091/mbc.E19-11-0647 Text en © 2020 Schaefer et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Schaefer, Kristina N.
Pronobis, Mira I.
Williams, Clara E.
Zhang, Shiping
Bauer, Lauren
Goldfarb, Dennis
Yan, Feng
Major, M. Ben
Peifer, Mark
Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title_full Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title_fullStr Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title_full_unstemmed Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title_short Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex
title_sort wnt regulation: exploring axin-disheveled interactions and defining mechanisms by which the scf e3 ubiquitin ligase is recruited to the destruction complex
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346726/
https://www.ncbi.nlm.nih.gov/pubmed/32129710
http://dx.doi.org/10.1091/mbc.E19-11-0647
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