Abstract
Activation of the Wnt signaling cascade provides key signals during development and in disease. Here we provide evidence, by designing a Wnt receptor with ligand-independent signaling activity, that physical proximity of Arrow (LRP) to the Wnt receptor Frizzled-2 triggers the intracellular signaling cascade. We have uncovered a branch of the Wnt pathway in which Armadillo activity is regulated concomitantly with the levels of Axin protein. The intracellular pathway bypasses Gsk3beta/Zw3, the kinase normally required for controlling beta-catenin/Armadillo levels, suggesting that modulated degradation of Armadillo is not required for Wnt signaling. We propose that Arrow (LRP) recruits Axin to the membrane, and that this interaction leads to Axin degradation. As a consequence, Armadillo is no longer bound by Axin, resulting in nuclear signaling by Armadillo.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Adaptor Proteins, Signal Transducing*
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Animals
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Armadillo Domain Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / cytology
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Drosophila melanogaster / embryology*
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Drosophila melanogaster / metabolism
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Embryo, Nonmammalian
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Female
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Frizzled Receptors
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Gene Expression Regulation, Developmental / genetics
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mutation / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, G-Protein-Coupled
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Receptors, LDL / genetics
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Receptors, LDL / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / genetics*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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Wnt1 Protein
Substances
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ARM protein, Drosophila
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Adaptor Proteins, Signal Transducing
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Armadillo Domain Proteins
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Carrier Proteins
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Drosophila Proteins
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Frizzled Receptors
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Lrp5 protein, rat
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Membrane Proteins
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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Receptors, LDL
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Recombinant Fusion Proteins
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Senp2 protein, rat
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Trans-Activators
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Transcription Factors
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Wnt1 Protein
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fz protein, Drosophila
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wg protein, Drosophila
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Sgg protein, Drosophila
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Glycogen Synthase Kinase 3