title: Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases.
abstract: Tumor suppressors ZNRF3 and RNF43 inhibit Wnt signaling through promoting degradation of Wnt coreceptors Frizzled (FZD) and LRP6, and this activity is counteracted by stem cell growth factor R-spondin. The mechanism by which ZNRF3 and RNF43 recognize Wnt receptors remains unclear. Here we uncover an unexpected role of Dishevelled (DVL), a positive Wnt regulator, in promoting Wnt receptor degradation. DVL knockout cells have significantly increased cell surface levels of FZD and LRP6. DVL is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. Physical interaction with DVL is essential for the Wnt inhibitory activity of ZNRF3/RNF43. Binding of FZD through the DEP domain of DVL is required for DVL-mediated downregulation of FZD. Fusion of the DEP domain to ZNRF3/RNF43 overcomes their DVL dependency to downregulate FZD. Our study reveals DVL as a dual function adaptor to recruit negative regulators ZNRF3/RNF43 to Wnt receptors to ensure proper control of pathway activity.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xiaomo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Charlat
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Zamponi
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: feng.cong@novartis.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000072261:Dishevelled Proteins; D005434:Flow Cytometry; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D060490:Receptors, Wnt / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015513:Oncogene Proteins; D010750:Phosphoproteins; D060490:Receptors, Wnt; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C572950:ZNRF3 protein, human