Abstract
Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Axin Protein
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Cell Line
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Dishevelled Proteins
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Embryo, Nonmammalian / cytology
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Embryo, Nonmammalian / drug effects
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Embryo, Nonmammalian / metabolism
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Enzyme Inhibitors / pharmacology
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Frizzled Receptors / chemistry
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Frizzled Receptors / metabolism*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Humans
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Low Density Lipoprotein Receptor-Related Protein-6
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Mice
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Models, Biological
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Structure, Tertiary
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Receptors, LDL / metabolism*
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Repressor Proteins / metabolism*
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Signal Transduction* / drug effects
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Wnt Proteins / metabolism*
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Xenopus
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Xenopus Proteins
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Axin Protein
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DVL1 protein, Xenopus
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Dishevelled Proteins
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Enzyme Inhibitors
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Frizzled Receptors
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-6
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Lrp6 protein, mouse
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Phosphoproteins
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Receptors, LDL
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Repressor Proteins
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Wnt Proteins
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Xenopus Proteins
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axin1 protein, Xenopus
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beta Catenin
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Glycogen Synthase Kinase 3