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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Drosophila / cytology
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Drosophila / metabolism
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Gene Expression Regulation
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Genes, Reporter
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Kidney / cytology
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LDL-Receptor Related Proteins / antagonists & inhibitors*
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LDL-Receptor Related Proteins / metabolism
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Ligands
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Low Density Lipoprotein Receptor-Related Protein-6
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Luciferases / metabolism
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Membrane Proteins / metabolism
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Models, Biological
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Phosphorylation
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Precipitin Tests
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Protein Binding
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RNA, Small Interfering / metabolism
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Recombinant Proteins / metabolism
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Signal Transduction*
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Thrombospondins / genetics
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Thrombospondins / metabolism*
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Transfection
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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DKK1 protein, human
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Intercellular Signaling Peptides and Proteins
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KREMEN1 protein, human
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LDL-Receptor Related Proteins
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LRP6 protein, human
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Ligands
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Low Density Lipoprotein Receptor-Related Protein-6
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Lrp6 protein, mouse
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Membrane Proteins
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RNA, Small Interfering
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RSPO1 protein, human
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Recombinant Proteins
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Thrombospondins
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Wnt Proteins
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beta Catenin
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Luciferases