@article{34a6654e75b1462e8a5ad13b81d73852,
title = "NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor",
abstract = "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/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.",
keywords = "Lgr5, NEDD4, Wnt, colorectal cancer, intestinal stem cell",
author = "Laura Novellasdemunt and Anna Kucharska and Cara Jamieson and Maria Prange-Barczynska and Anna Baulies and Pedro Antas and {van der Vaart}, Jelte and Helmuth Gehart and Maurice, {Madelon M} and Li, {Vivian Sw}",
note = "Funding Information: We thank H. Kawabe for providing the Nedd4‐floxed and Nedd4l‐floxed animals and Andr{\'e}s M{\'e}ndez Lucas for assistance with animal experiments. We thank the Francis Crick Institute's Experimental Histopathology, Flow Cytometry and Biological Research Facilities. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK) (FC001105), the UK Medical Research Council (FC001105) and the Wellcome Trust (FC001105). Work in the V.S.W.L laboratory was also supported by the European Union's Horizon 2020 research and innovation programme (668294). The work of M.M.M. is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society, and is supported by the Netherlands Organization for Scientific Research (NWO VICI Grant 91815604; ZonMW‐TOP grant 91218050). Funding Information: We thank H. Kawabe for providing the Nedd4-floxed and Nedd4l-floxed animals and Andr?s M?ndez Lucas for assistance with animal experiments. We thank the Francis Crick Institute's Experimental Histopathology, Flow Cytometry and Biological Research Facilities. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK) (FC001105), the UK Medical Research Council (FC001105) and the Wellcome Trust (FC001105). Work in the V.S.W.L laboratory was also supported by the European Union's Horizon 2020 research and innovation programme (668294). The work of M.M.M. is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society, and is supported by the Netherlands Organization for Scientific Research (NWO VICI Grant 91815604; ZonMW-TOP grant 91218050). Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = feb,
day = "3",
doi = "10.15252/embj.2019102771",
language = "English",
volume = "39",
pages = "1--15",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "3",
}