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PMID:17804805
| 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 |
| edit table |
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 | |
|
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 | ||
|
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 | |||
|
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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