R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/β-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 resp...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-09, Vol.104 (37), p.14700-14705
Main Authors: Binnerts, Minke E, Kim, Kyung-Ah, Bright, Jessica M, Patel, Sejal M, Tran, Karolyn, Zhou, Mei, Leung, John M, Liu, Yi, Lomas, Woodrow E. III, Dixon, Melissa, Hazell, Sophie A, Wagle, Marie, Nie, Wen-Sheng, Tomasevic, Nenad, Williams, Jason, Zhan, Xiaoming, Levy, Michael D, Funk, Walter D, Abo, Arie
Format: Article
Language:English
Subjects:
Animals
beta Catenin - genetics
beta Catenin - metabolism
Biochemistry
Biological Sciences
Cell Line
Cells
Digestive system
Drosophila - cytology
Drosophila - metabolism
Gene Expression Regulation
Genes, Reporter
Humans
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Internalization
Journalism
Kidney - cytology
L cells
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
Physiological regulation
Plasmids
Precipitin Tests
Protein Binding
Proteins
Receptors
Recombinant Proteins - metabolism
RNA, Small Interfering - metabolism
Rodents
Signal Transduction
Small interfering RNA
Thrombospondins - genetics
Thrombospondins - metabolism
Transfection
Wnt Proteins - metabolism
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Summary:The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/β-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0702305104