Cargando…
Glycogen synthase kinase 3β inhibition enhances Notch1 recycling
The Notch signaling pathway is essential throughout development and remains active into adulthood, where it performs a critical role in tissue homeostasis. The fact that defects in signaling can lead to malignancy illustrates the need to control Notch activity tightly. GSK3β is an established regula...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014177/ https://www.ncbi.nlm.nih.gov/pubmed/29237816 http://dx.doi.org/10.1091/mbc.E17-07-0474 |
_version_ | 1783334180411670528 |
---|---|
author | Zheng, Li Conner, Sean D. |
author_facet | Zheng, Li Conner, Sean D. |
author_sort | Zheng, Li |
collection | PubMed |
description | The Notch signaling pathway is essential throughout development and remains active into adulthood, where it performs a critical role in tissue homeostasis. The fact that defects in signaling can lead to malignancy illustrates the need to control Notch activity tightly. GSK3β is an established regulator of the Notch signaling pathway, although its mechanism of action remains unclear. Given the emerging role for GSK3β in receptor trafficking, we tested the idea that GSK3β controls signaling by regulating Notch transport. Consistent with published reports, we find that GSK3β inhibition enhances Notch1 signaling activity. Immunolocalization analysis reveals that Notch1 localization within a tubulovesicular compartment is altered when GSK3β activity is disrupted. We also find that receptor cell surface levels increase following acute GSK3β inhibition. This is followed by elevated Notch intracellular domain (NICD) production and a corresponding increase in signaling activity. Moreover, Notch transport assays reveal that receptor recycling rates increase when GSK3β activity is inhibited. Collectively, results presented here support a model where GSK3β regulates signaling by controlling postendocytic transport of Notch1. Given that GSK3β activity is suppressed following stimulation by multiple signal transduction pathways, our findings also suggest that cells can modulate Notch1 activity in response to extracellular signals by mobilizing Notch1 from endosomal stores. |
format | Online Article Text |
id | pubmed-6014177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-60141772018-06-22 Glycogen synthase kinase 3β inhibition enhances Notch1 recycling Zheng, Li Conner, Sean D. Mol Biol Cell Brief Reports The Notch signaling pathway is essential throughout development and remains active into adulthood, where it performs a critical role in tissue homeostasis. The fact that defects in signaling can lead to malignancy illustrates the need to control Notch activity tightly. GSK3β is an established regulator of the Notch signaling pathway, although its mechanism of action remains unclear. Given the emerging role for GSK3β in receptor trafficking, we tested the idea that GSK3β controls signaling by regulating Notch transport. Consistent with published reports, we find that GSK3β inhibition enhances Notch1 signaling activity. Immunolocalization analysis reveals that Notch1 localization within a tubulovesicular compartment is altered when GSK3β activity is disrupted. We also find that receptor cell surface levels increase following acute GSK3β inhibition. This is followed by elevated Notch intracellular domain (NICD) production and a corresponding increase in signaling activity. Moreover, Notch transport assays reveal that receptor recycling rates increase when GSK3β activity is inhibited. Collectively, results presented here support a model where GSK3β regulates signaling by controlling postendocytic transport of Notch1. Given that GSK3β activity is suppressed following stimulation by multiple signal transduction pathways, our findings also suggest that cells can modulate Notch1 activity in response to extracellular signals by mobilizing Notch1 from endosomal stores. The American Society for Cell Biology 2018-02-15 /pmc/articles/PMC6014177/ /pubmed/29237816 http://dx.doi.org/10.1091/mbc.E17-07-0474 Text en © 2018 Zheng and Conner. “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 | Brief Reports Zheng, Li Conner, Sean D. Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title | Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title_full | Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title_fullStr | Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title_full_unstemmed | Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title_short | Glycogen synthase kinase 3β inhibition enhances Notch1 recycling |
title_sort | glycogen synthase kinase 3β inhibition enhances notch1 recycling |
topic | Brief Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014177/ https://www.ncbi.nlm.nih.gov/pubmed/29237816 http://dx.doi.org/10.1091/mbc.E17-07-0474 |
work_keys_str_mv | AT zhengli glycogensynthasekinase3binhibitionenhancesnotch1recycling AT connerseand glycogensynthasekinase3binhibitionenhancesnotch1recycling |