期刊
EMBO REPORTS
卷 22, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/embr.202051415
关键词
colorectal cancer; deubiquitination; EMT; LGR4; 5; 6; mouse intestinal organoids
资金
- Deutsche Forschungsgemeinschaft (DFG) [PE 2674/1, SFB1324, SFB1335, 360372040]
- Humboldt Research Fellowship
- ProjektDEAL
The study reveals that USP42 protects ZNRF3/RNF43 from ubiquitin-dependent clearance and antagonizes R-spondin, leading to inhibition of Wnt signaling pathway.
The tumour suppressors RNF43 and ZNRF3 play a central role in development and tissue homeostasis by promoting the turnover of the Wnt receptors LRP6 and Frizzled (FZD). The stem cell growth factor R-spondin induces auto-ubiquitination and membrane clearance of ZNRF3/RNF43 to promote Wnt signalling. However, the deubiquitinase stabilising ZNRF3/RNF43 at the plasma membrane remains unknown. Here, we show that the USP42 antagonises R-spondin by protecting ZNRF3/RNF43 from ubiquitin-dependent clearance. USP42 binds to the Dishevelled interacting region (DIR) of ZNRF3 and stalls the R-spondin-LGR4-ZNRF3 ternary complex by deubiquitinating ZNRF3. Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling. Furthermore, we show that USP42 functions as a roadblock for paracrine Wnt signalling in colon cancer cells and mouse small intestinal organoids. We provide new mechanistic insights into the regulation R-spondin and conclude that USP42 is crucial for ZNRF3/RNF43 stabilisation at the cell surface.
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