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PMID:22575959

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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

Significance

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


See also

References

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