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PMID:17804805

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Citation

Binnerts, ME, Kim, KA, Bright, JM, Patel, SM, Tran, K, Zhou, M, Leung, JM, Liu, Y, Lomas, WE 3rd, Dixon, M, Hazell, SA, Wagle, M, Nie, WS, Tomasevic, N, Williams, J, Zhan, X, Levy, MD, Funk, WD and Abo, A (2007) R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc. Natl. Acad. Sci. U.S.A. 104:14700-5

Abstract

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/beta-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.

Links

PubMed PMC1965484 Online version:10.1073/pnas.0702305104

Keywords

Animals; Cell Line; Drosophila/cytology; Drosophila/metabolism; Gene Expression Regulation; Genes, Reporter; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Kidney/cytology; LDL-Receptor Related Proteins/antagonists & inhibitors; LDL-Receptor Related Proteins/metabolism; Ligands; Low Density Lipoprotein Receptor-Related Protein-6; Luciferases/metabolism; Membrane Proteins/metabolism; Models, Biological; Phosphorylation; Precipitin Tests; Protein Binding; RNA, Small Interfering/metabolism; Recombinant Proteins/metabolism; Signal Transduction; Thrombospondins/genetics; Thrombospondins/metabolism; Transfection; 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

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96MU8

F

Seeded From UniProt

complete

HUMAN:DKK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96MU8

F

Seeded From UniProt

complete

HUMAN:RSPO1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96MU8

F

Seeded From UniProt

complete

HUMAN:RSPO1

involved_in

GO:0002090: regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RSPO1

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WLS

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KREM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O94907

F

Seeded From UniProt

complete

HUMAN:KREM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q2MKA7

F

Seeded From UniProt

complete

HUMAN:KREM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75581

F

Seeded From UniProt

complete

HUMAN:KREM1

involved_in

GO:0060828: regulation of canonical Wnt signaling pathway

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DKK1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DKK1

involved_in

GO:0002090: regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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