NEDD4 and NEDD4L Regulate Wnt Signaling and Intestinal Stem Cell Priming by Degrading LGR5 Receptor

The study demonstrated that the E3 ligases NEDD4 and NEDD4L played a crucial role in regulating intestinal stem cell (ISC) priming by degrading the LGR5 receptor, which is essential for Wnt signaling. The loss of NEDD4 and NEDD4L led to increased ISC proliferation, heightened sensitivity to R-spondin stimulation, and accelerated tumor development in Apcmin mice, resulting in more high-grade adenomas. Mechanistically, NEDD4 and NEDD4L negatively regulated Wnt/β-catenin signaling by targeting LGR5 and DVL2 for degradation. This post-translational regulation of LGR5 by NEDD4/NEDD4L was significant for ISC priming, and their inactivation increased Wnt activation and ISC numbers, enhancing tumor predisposition and progression.