PMID:22575959

Citation	Hao, HX, Xie, Y, Zhang, Y, Charlat, O, Oster, E, Avello, M, Lei, H, Mickanin, C, Liu, D, Ruffner, H, Mao, X, Ma, Q, Zamponi, R, Bouwmeester, T, Finan, PM, Kirschner, MW, Porter, JA, Serluca, FC and Cong, F (2012) ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485:195-200
Abstract	R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/β-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.
Links	PubMed Online version:10.1038/nature11019
Keywords	Animals; Cell Polarity/physiology; Colorectal Neoplasms/genetics; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Feedback, Physiological; Female; Frizzled Receptors/metabolism; HEK293 Cells; Humans; Low Density Lipoprotein Receptor-Related Protein-6/metabolism; Male; Mice; Mice, Knockout; Oncogene Proteins/deficiency; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; Protein Stability; Protein Structure, Tertiary; Receptors, G-Protein-Coupled/deficiency; Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism; Receptors, Wnt/metabolism; Thrombospondins/metabolism; Ubiquitin-Protein Ligases/chemistry; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination; Wnt Signaling Pathway; Xenopus; Zebrafish; beta Catenin/metabolism
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:FZD6	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:LRP6	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
MOUSE:WNT3A	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q61091	F		Seeded From UniProt	complete
HUMAN:RSPO1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:RSPO1	involved_in	GO:0030177: positive regulation of Wnt signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ZNRF3	involved_in	GO:0060828: regulation of canonical Wnt signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ZNRF3	involved_in	GO:2000095: regulation of Wnt signaling pathway, planar cell polarity pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:FZD8	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P27467	F		Seeded From UniProt	complete
HUMAN:RNF43	involved_in	GO:0030178: negative regulation of Wnt signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RNF43	involved_in	GO:0016567: protein ubiquitination	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RNF43	located_in	GO:0005887: integral component of plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:RNF43	enables	GO:0004842: ubiquitin-protein transferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:LGR4	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q2MKA7	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O75581	F		Seeded From UniProt	complete
HUMAN:ZNRF3	involved_in	GO:0016567: protein ubiquitination	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ZNRF3	located_in	GO:0005887: integral component of plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:ZNRF3	involved_in	GO:0006511: ubiquitin-dependent protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0004842: ubiquitin-protein transferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005109: frizzled binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9H461	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005109: frizzled binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O60353	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005109: frizzled binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q13467	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005109: frizzled binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULV1	F		Seeded From UniProt	complete
HUMAN:ZNRF3	involved_in	GO:0090090: negative regulation of canonical Wnt signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ZNRF3	involved_in	GO:2000051: negative regulation of non-canonical Wnt signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ZNRF3	involved_in	GO:0038018: Wnt receptor catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O60353	F		Seeded From UniProt	complete
HUMAN:ZNRF3	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9BXB1	F		Seeded From UniProt	complete
HUMAN:FZD4	enables	GO:0031625: ubiquitin protein ligase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:FZD5	enables	GO:0031625: ubiquitin protein ligase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:FZD6	enables	GO:0031625: ubiquitin protein ligase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete
HUMAN:FZD8	enables	GO:0031625: ubiquitin protein ligase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9ULT6	F		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.