The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD.
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| Titel: | The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD. |
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| Autoren: | Lu B; Discovery Sciences, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA., Cong F; Discovery Sciences, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. |
| Quelle: | Science signaling [Sci Signal] 2025 Oct 14; Vol. 18 (908), pp. eadv1529. Date of Electronic Publication: 2025 Oct 14. |
| Publikationsart: | Journal Article |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Association for the Advancement of Science |
| MeSH-Schlagworte: | Ubiquitin-Protein Ligases*/metabolism , Ubiquitin-Protein Ligases*/genetics , Frizzled Receptors*/metabolism , Frizzled Receptors*/genetics , Proteolysis* , Wnt Signaling Pathway*/physiology , Wnt Proteins*/metabolism , Wnt Proteins*/genetics, Humans ; HEK293 Cells ; Ubiquitination ; beta Catenin/metabolism ; beta Catenin/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Dishevelled Proteins ; Phosphoproteins/metabolism ; Phosphoproteins/genetics |
| Abstract: | Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin-induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface. |
| Substance Nomenclature: | EC 2.3.2.27 (ZNRF3 protein, human) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (Frizzled Receptors) 0 (beta Catenin) EC 2.3.2.27 (RNF43 protein, human) 0 (Adaptor Proteins, Signal Transducing) 0 (Dishevelled Proteins) 0 (Phosphoproteins) 0 (Wnt Proteins) |
| Entry Date(s): | Date Created: 20251014 Date Completed: 20251014 Latest Revision: 20251014 |
| Update Code: | 20251015 |
| DOI: | 10.1126/scisignal.adv1529 |
| PMID: | 41086253 |
| Datenbank: | MEDLINE |
Nájsť tento článok vo Web of Science | Abstract: | Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin-induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface. |
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| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.adv1529 |