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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2017
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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. |
format | Online Article Text |
id | pubmed-5706997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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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