Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases

Xiaomo Jiang; Olga Charlat; Raffaella Zamponi; Yi Yang; Feng Cong

doi:10.1016/j.molcel.2015.03.015

Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases

Mol Cell. 2015 May 7;58(3):522-33. doi: 10.1016/j.molcel.2015.03.015. Epub 2015 Apr 16.

Authors

Xiaomo Jiang¹, Olga Charlat¹, Raffaella Zamponi¹, Yi Yang¹, Feng Cong²

Affiliations

¹ Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
² Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: [email protected].

PMID: 25891077
DOI: 10.1016/j.molcel.2015.03.015

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Dishevelled Proteins
Flow Cytometry
Frizzled Receptors / genetics
Frizzled Receptors / metabolism
HEK293 Cells
Humans
Immunoblotting
Low Density Lipoprotein Receptor-Related Protein-6 / genetics
Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
Microscopy, Fluorescence
Mutation
Oncogene Proteins / genetics
Oncogene Proteins / metabolism*
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Protein Binding
Proteolysis
RNA Interference
Receptors, Wnt / genetics
Receptors, Wnt / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Wnt Signaling Pathway / genetics

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Dishevelled Proteins
Frizzled Receptors
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Oncogene Proteins
Phosphoproteins
Receptors, Wnt
RNF43 protein, human
Ubiquitin-Protein Ligases
ZNRF3 protein, human