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PMID:18606138

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Citation

Yamamoto, S, Nishimura, O, Misaki, K, Nishita, M, Minami, Y, Yonemura, S, Tarui, H and Sasaki, H (2008) Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev. Cell 15:23-36

Abstract

Vertebrate Wnt proteins activate several distinct pathways. Intrinsic differences among Wnt ligands and Frizzled (Fzd) receptors, and the availability of pathway-specific coreceptors, LRP5/6, and Ror2, affect pathway selection. Here, we show that a secreted glycoprotein, Cthrc1, is involved in selective activation of the planar cell polarity (PCP) pathway by Wnt proteins. Although Cthrc1 null mutant mice appeared normal, the introduction of a heterozygous mutation of a PCP gene, Vangl2, resulted in abnormalities characteristic of PCP mutants. In HEK293T cells, Cthrc1 activated the PCP pathway but suppressed the canonical pathway. Cell-surface-anchored Cthrc1 bound to Wnt proteins, Fzd proteins, and Ror2 and enhanced the interaction of Wnt proteins and Fzd/Ror2 by forming the Cthrc1-Wnt-Fzd/Ror2 complex. Consistent with this, Ror2 mutant mice also showed PCP-related abnormalities in the inner ear. These results suggest that Cthrc1 is a Wnt cofactor protein that selectively activates the Wnt/PCP pathway by stabilizing ligand-receptor interaction.

Links

PubMed Online version:10.1016/j.devcel.2008.05.007

Keywords

Animals; Cell Line; Cell Polarity; Embryo, Mammalian; Embryonic Stem Cells/cytology; Embryonic Stem Cells/metabolism; Extracellular Matrix Proteins/genetics; Extracellular Matrix Proteins/metabolism; Frizzled Receptors/genetics; Frizzled Receptors/metabolism; Glycoproteins/genetics; Glycoproteins/metabolism; Hair Cells, Auditory, Inner/cytology; Humans; Kidney/cytology; Lac Operon/genetics; Ligands; Mice; Mice, Knockout; Mutation; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Receptor Tyrosine Kinase-like Orphan Receptors; Recombination, Genetic; Signal Transduction; Tissue Distribution; Wnt Proteins/genetics; Wnt Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LRP6

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P27467

F

Seeded From UniProt

complete

MOUSE:WNT5A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6
PR:Q9Z138

F

Seeded From UniProt

complete

MOUSE:WNT3A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O88572
PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:WNT3A

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61089

F

Seeded From UniProt

complete

MOUSE:WNT11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:DVL2

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:FZD6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:FZD6

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P27467

F

Seeded From UniProt

complete

MOUSE:FZD6

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:VANG2

acts_upstream_of_or_within

GO:0060122: inner ear receptor cell stereocilium organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857642

P

Seeded From UniProt

complete

MOUSE:VANG2

acts_upstream_of_or_within

GO:0090177: establishment of planar polarity involved in neural tube closure

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857642

P

Seeded From UniProt

complete

MOUSE:VANG2

acts_upstream_of_or_within

GO:0090103: cochlea morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857642

P

Seeded From UniProt

complete

MOUSE:CTHR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9Z138

F

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CTHR1

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P22725
PR:P27467
PR:P48615

F

Seeded From UniProt

complete

MOUSE:CTHR1

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61086
PR:Q61089
PR:Q9EQD0

F

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0060122: inner ear receptor cell stereocilium organization

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1915838

P

  • occurs_in:(EMAPA:16194)

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3815067

P

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0090177: establishment of planar polarity involved in neural tube closure

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1915838

P

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1915838

P

Seeded From UniProt

complete

MOUSE:CTHR1

acts_upstream_of_or_within

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:FZD5

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P27467

F

Seeded From UniProt

complete

MOUSE:ROR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9D1D6

F

Seeded From UniProt

complete

MOUSE:ROR2

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P22725

F

Seeded From UniProt

complete

MOUSE:ROR2

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61089

F

Seeded From UniProt

complete

MOUSE:ROR2

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183225

P

Seeded From UniProt

complete

MOUSE:ROR2

acts_upstream_of_or_within

GO:0042472: inner ear morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183225

P

Seeded From UniProt

complete

MOUSE:FZD5

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P27467

F

Seeded From UniProt

complete

MOUSE:WNT3A

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61089

F

Seeded From UniProt

complete

MOUSE:WNT3A

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DVL2

acts_upstream_of_or_within

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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