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PMID:16543246

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Citation

Nam, JS, Turcotte, TJ, Smith, PF, Choi, S and Yoon, JK (2006) Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J. Biol. Chem. 281:13247-57

Abstract

Wnt signaling plays critical biological roles during normal embryonic development and homeostasis in adults. In the canonical pathway, binding of Wnt ligands to the Frizzled (Fzd) receptor and the low density lipoprotein-related receptor (LRP) 5 or LRP6 coreceptor initiates downstream signaling events leading to gene activation by beta-catenin and the T-cell factor (TCF)-lymphoid enhancer factor (LEF) family transcription factor complex. In this study, we provide several lines of evidence that the mouse Cristin/R-spondin family proteins function as Fzd8 and LRP6 receptor ligands and induce the canonical Wnt/beta-catenin signaling pathway, leading to TCF-dependent gene activation. First, conditioned medium containing Cristin/R-spondin proteins effectively induced reporter activity in a TCF-binding site-dependent manner. Second, stimulation of cells with Cristin/R-spondin was accompanied by stabilization of endogenous beta-catenin proteins and induction of canonical Wnt target genes. Third, Cristin/R-spondin proteins physically interacted with the extracellular domains of the LRP6 and Fzd8 receptors in vivo and in vitro. Interestingly, unlike canonical Wnt ligands, Cristin/R-spondin failed to form a ternary complex with both LRP6 and Fzd8 receptors, suggesting that R-spondin may activate the canonical Wnt signaling pathway by different mechanisms. Furthermore, Cristin/R-spondin proteins possess an intriguing positive modulatory activity on Wnt ligands, possibly through a direct interaction. Our findings expand the repertoire of ligands that induce beta-catenin/TCF-dependent gene activation and implicate the presence of active beta-catenin-dependent gene activation in a Wnt-free biological context.

Links

PubMed Online version:10.1074/jbc.M508324200

Keywords

Amino Acid Sequence; Animals; Cell Line; Gene Expression Regulation, Developmental; Heparin/metabolism; Humans; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Molecular Sequence Data; Multigene Family; Phylogeny; Protein Binding; Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism; Receptors, LDL/genetics; Receptors, LDL/metabolism; Signal Transduction; Thrombospondins/genetics; Thrombospondins/metabolism; Transcriptional Activation; Wnt Proteins/metabolism; beta Catenin/genetics; beta Catenin/metabolism

Significance

Annotations

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

HUMAN:LRP6

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

MOUSE:RSPO3

located_in

GO:0005576: extracellular region

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RSPO3

enables

GO:0008201: heparin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RSPO3

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75581

F

Seeded From UniProt

complete

MOUSE:RSPO3

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61091

F

Seeded From UniProt

complete

MOUSE:RSPO3

acts_upstream_of_or_within

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay 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

PR:Q2TJ95
PR:Q9Z132

F

Seeded From UniProt

complete

MOUSE:RSPO2

located_in

GO:0005576: extracellular region

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RSPO2

enables

GO:0008201: heparin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RSPO1

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RSPO1

enables

GO:0008201: heparin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RSPO1

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14114

F

Seeded From UniProt

complete

MOUSE:RSPO1

acts_upstream_of_or_within

GO:0060070: canonical Wnt signaling pathway

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61091

P

Seeded From UniProt

complete

MOUSE:WNT1

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

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:FZD8

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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