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NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor
The intestinal stem cell (ISC) marker LGR5 is a receptor for R‐spondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self‐renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in h...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996568/ https://www.ncbi.nlm.nih.gov/pubmed/31867777 http://dx.doi.org/10.15252/embj.2019102771 |
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author | Novellasdemunt, Laura Kucharska, Anna Jamieson, Cara Prange‐Barczynska, Maria Baulies, Anna Antas, Pedro van der Vaart, Jelte Gehart, Helmuth Maurice, Madelon M Li, Vivian SW |
author_facet | Novellasdemunt, Laura Kucharska, Anna Jamieson, Cara Prange‐Barczynska, Maria Baulies, Anna Antas, Pedro van der Vaart, Jelte Gehart, Helmuth Maurice, Madelon M Li, Vivian SW |
author_sort | Novellasdemunt, Laura |
collection | PubMed |
description | The intestinal stem cell (ISC) marker LGR5 is a receptor for R‐spondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self‐renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post‐translational regulation of LGR5. Here, we show that the HECT‐domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apc(min) mice with increased numbers of high‐grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/β‐catenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post‐translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression. |
format | Online Article Text |
id | pubmed-6996568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69965682020-02-05 NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor Novellasdemunt, Laura Kucharska, Anna Jamieson, Cara Prange‐Barczynska, Maria Baulies, Anna Antas, Pedro van der Vaart, Jelte Gehart, Helmuth Maurice, Madelon M Li, Vivian SW EMBO J Articles The intestinal stem cell (ISC) marker LGR5 is a receptor for R‐spondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self‐renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post‐translational regulation of LGR5. Here, we show that the HECT‐domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apc(min) mice with increased numbers of high‐grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/β‐catenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post‐translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression. John Wiley and Sons Inc. 2019-12-23 2020-02-03 /pmc/articles/PMC6996568/ /pubmed/31867777 http://dx.doi.org/10.15252/embj.2019102771 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Novellasdemunt, Laura Kucharska, Anna Jamieson, Cara Prange‐Barczynska, Maria Baulies, Anna Antas, Pedro van der Vaart, Jelte Gehart, Helmuth Maurice, Madelon M Li, Vivian SW NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title | NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title_full | NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title_fullStr | NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title_full_unstemmed | NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title_short | NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor |
title_sort | nedd4 and nedd4l regulate wnt signalling and intestinal stem cell priming by degrading lgr5 receptor |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996568/ https://www.ncbi.nlm.nih.gov/pubmed/31867777 http://dx.doi.org/10.15252/embj.2019102771 |
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