期刊
EMBO JOURNAL
卷 39, 期 3, 页码 -出版社
WILEY
DOI: 10.15252/embj.2019102771
关键词
colorectal cancer; intestinal stem cell; Lgr5; NEDD4; Wnt
资金
- Francis Crick Institute from Cancer Research UK (CRUK) [FC001105]
- UK Medical Research Council [FC001105]
- Wellcome Trust [FC001105]
- European Union's Horizon 2020 research and innovation programme [668294]
- Dutch Cancer Society
- Netherlands Organization for Scientific Research (NWO VICI Grant) [91815604]
- Netherlands Organization for Scientific Research (ZonMW-TOP grant) [91218050]
- H2020 Societal Challenges Programme [668294] Funding Source: H2020 Societal Challenges Programme
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/beta-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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