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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.
Afiliación
  • Novellasdemunt L; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • Kucharska A; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • Jamieson C; Oncode Institute and Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Prange-Barczynska M; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • Baulies A; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • Antas P; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • van der Vaart J; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands.
  • Gehart H; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands.
  • Maurice MM; Oncode Institute and Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Li VS; Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
EMBO J ; 39(3): e102771, 2020 02 03.
Article en En | MEDLINE | ID: mdl-31867777
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 Apcmin mice with increased numbers of high-grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G / Ubiquitina-Proteína Ligasas Nedd4 / Intestinos Límite: Animals / Female / Humans / Male Idioma: En Revista: EMBO J Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G / Ubiquitina-Proteína Ligasas Nedd4 / Intestinos Límite: Animals / Female / Humans / Male Idioma: En Revista: EMBO J Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido