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A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin

Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits...

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Detalles Bibliográficos
Autores principales: Aznar, Nicolas, Sun, Nina, Dunkel, Ying, Ear, Jason, Buschman, Matthew D., Ghosh, Pradipta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706997/
https://www.ncbi.nlm.nih.gov/pubmed/29021338
http://dx.doi.org/10.1091/mbc.E17-06-0405
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author Aznar, Nicolas
Sun, Nina
Dunkel, Ying
Ear, Jason
Buschman, Matthew D.
Ghosh, Pradipta
author_facet Aznar, Nicolas
Sun, Nina
Dunkel, Ying
Ear, Jason
Buschman, Matthew D.
Ghosh, Pradipta
author_sort Aznar, Nicolas
collection PubMed
description Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits canonical Wnt responses. Here we demonstrate that the PI3-K→Akt pathway serves as a positive feedback loop that further enhances noncanonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide- (PI) binding domain of Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell–cell contact sites, enhances noncanonical Wnt signals, and thereby suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression.
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spelling pubmed-57069972018-02-16 A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin Aznar, Nicolas Sun, Nina Dunkel, Ying Ear, Jason Buschman, Matthew D. Ghosh, Pradipta Mol Biol Cell Articles Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits canonical Wnt responses. Here we demonstrate that the PI3-K→Akt pathway serves as a positive feedback loop that further enhances noncanonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide- (PI) binding domain of Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell–cell contact sites, enhances noncanonical Wnt signals, and thereby suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression. The American Society for Cell Biology 2017-12-01 /pmc/articles/PMC5706997/ /pubmed/29021338 http://dx.doi.org/10.1091/mbc.E17-06-0405 Text en © 2017 Aznar et al. 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 (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Aznar, Nicolas
Sun, Nina
Dunkel, Ying
Ear, Jason
Buschman, Matthew D.
Ghosh, Pradipta
A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title_full A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title_fullStr A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title_full_unstemmed A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title_short A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
title_sort daple-akt feed-forward loop enhances noncanonical wnt signals by compartmentalizing β-catenin
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706997/
https://www.ncbi.nlm.nih.gov/pubmed/29021338
http://dx.doi.org/10.1091/mbc.E17-06-0405
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