Abstract
An XWnt8-Fz5 fusion protein synergizes with LRP6 to potently activate beta-catenin-dependent signaling. Here, we generated a fusion in which XWnt8 was fused to the N-terminus of LRP6 and show it synergizes with both Fz4 and Fz5 to potently transactivate beta-catenin-dependent Wnt signaling. Based on this, we hypothesized that the main function of Wnt is to nucleate the formation of a physical complex between LRP6 and a Frizzled. Dkk1, but not the related Dkk3, binds LRP6 and inhibits canonical Wnt signaling by blocking the interaction of Wnt and LRP6. Therefore, we reasoned that a covalent fusion of Dkk1 to Fz5 (Dkk1-Fz5) would mimic Wnt ligand by nucleating the formation of a complex containing Fz5 and LRP6, while Dkk3 (Dkk3-Fz5) would not. We found that Dkk1-Fz5, but not Dkk3-Fz5, potently synergized with LRP6 to activate signaling in a dishevelled-dependent manner.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Cytoskeletal Proteins / metabolism*
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Frizzled Receptors
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Gene Expression Regulation / physiology
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism*
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Kidney / embryology
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Kidney / metabolism*
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Proteins / genetics
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Proteins / metabolism*
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Receptors, G-Protein-Coupled
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Receptors, LDL / metabolism
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Receptors, Neurotransmitter / genetics
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Receptors, Neurotransmitter / metabolism*
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology*
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Trans-Activators / metabolism*
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Wnt Proteins
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beta Catenin
Substances
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CTNNB1 protein, human
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Cytoskeletal Proteins
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DKK1 protein, human
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Dkk1 protein, mouse
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FZD5 protein, human
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Frizzled Receptors
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Intercellular Signaling Peptides and Proteins
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LDL-Receptor Related Proteins
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LRP5 protein, human
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Low Density Lipoprotein Receptor-Related Protein-5
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Lrp5 protein, mouse
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Proteins
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Receptors, G-Protein-Coupled
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Receptors, LDL
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Receptors, Neurotransmitter
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Recombinant Fusion Proteins
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Trans-Activators
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Wnt Proteins
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beta Catenin