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Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.

Wnt/β-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, β-catenin is targeted continuously for protea-somal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 1, 2011, Vol.108(5), pp.1937-1942
Main Author: Fiedler, Marc
Other Authors: Mendoza-Topaz, Carolina , Rutherford, Trevor J , Mieszczanek, Juliusz , Bienz, Mariann
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1017063108
Link: http://search.proquest.com/docview/849012592/?pq-origsite=primo
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title: Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.
format: Article
creator:
  • Fiedler, Marc
  • Mendoza-Topaz, Carolina
  • Rutherford, Trevor J
  • Mieszczanek, Juliusz
  • Bienz, Mariann
subjects:
  • Adaptor Proteins, Signal Transducing–Chemistry
  • Amino Acid Sequence–Metabolism
  • Animals–Metabolism
  • Axin Protein–Chemistry
  • Biopolymers–Metabolism
  • Dishevelled Proteins–Metabolism
  • Down-Regulation–Metabolism
  • Drosophila–Metabolism
  • Drosophila Proteins–Metabolism
  • Humans–Metabolism
  • Models, Molecular–Metabolism
  • Molecular Sequence Data–Metabolism
  • Nuclear Magnetic Resonance, Biomolecular–Metabolism
  • Phosphoproteins–Metabolism
  • Point Mutation–Metabolism
  • Protein Binding–Metabolism
  • Sequence Homology, Amino Acid–Metabolism
  • Beta Catenin–Metabolism
  • Adaptor Proteins, Signal Transducing
  • Axin Protein
  • Biopolymers
  • Dishevelled Proteins
  • Drosophila Proteins
  • Phosphoproteins
  • Axin Protein, Drosophila
  • Beta Catenin
  • Dsh Protein, Drosophila
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 1, 2011, Vol.108(5), pp.1937-1942
description: Wnt/β-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, β-catenin is targeted continuously for protea-somal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation by Dishevelled, which recruits Axin to the plasma membrane and assembles it into a signalosome. This key event during Wnt signal transduction depends on dynamic head-to-tail polymerization by the DIX domain of Dishevelled. Here, we use rescue assays in Drosophila tissues and functional assays in human cells to show that polymerization-blocking mutations in the DIX domain of Axin disable its effector function in down-regulating Armadillo/β-catenin and its response to Dishevelled during Wnt signaling. Intriguingly, NMR spectroscopy revealed that the purified DIX domains of the two proteins interact with each other directly through their polymerization interfaces, whereby the same residues mediate both homo- and heterotypic interactions. This result implies that Dishevelled has the potential to act as a "natural" dominant-negative, binding to the polymerization interface of Axin's DIX domain to interfere with its self-assembly, thereby blocking its effector function.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1017063108
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleDishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.
creatorFiedler, Marc ; Mendoza-Topaz, Carolina ; Rutherford, Trevor J ; Mieszczanek, Juliusz ; Bienz, Mariann
contributorFiedler, Marc (correspondence author) ; Fiedler, Marc (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, February 1, 2011, Vol.108(5), pp.1937-1942
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1017063108
subjectAdaptor Proteins, Signal Transducing–Chemistry ; Amino Acid Sequence–Metabolism ; Animals–Metabolism ; Axin Protein–Chemistry ; Biopolymers–Metabolism ; Dishevelled Proteins–Metabolism ; Down-Regulation–Metabolism ; Drosophila–Metabolism ; Drosophila Proteins–Metabolism ; Humans–Metabolism ; Models, Molecular–Metabolism ; Molecular Sequence Data–Metabolism ; Nuclear Magnetic Resonance, Biomolecular–Metabolism ; Phosphoproteins–Metabolism ; Point Mutation–Metabolism ; Protein Binding–Metabolism ; Sequence Homology, Amino Acid–Metabolism ; Beta Catenin–Metabolism ; Adaptor Proteins, Signal Transducing ; Axin Protein ; Biopolymers ; Dishevelled Proteins ; Drosophila Proteins ; Phosphoproteins ; Axin Protein, Drosophila ; Beta Catenin ; Dsh Protein, Drosophila
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Wnt/β-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, β-catenin is targeted continuously for protea-somal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation by Dishevelled, which recruits Axin to the plasma membrane and assembles it into a signalosome. This key event during Wnt signal transduction depends on dynamic head-to-tail polymerization by the DIX domain of Dishevelled. Here, we use rescue assays in Drosophila tissues and functional assays in human cells to show that polymerization-blocking mutations in the DIX domain of Axin disable its effector function in down-regulating Armadillo/β-catenin and its response to Dishevelled during Wnt signaling. Intriguingly, NMR spectroscopy revealed that the purified DIX domains of the two proteins interact with each other directly through their polymerization interfaces, whereby the same residues mediate both homo- and heterotypic interactions. This result implies that Dishevelled has the potential to act as a "natural" dominant-negative, binding to the polymerization interface of Axin's DIX domain to interfere with its self-assembly, thereby blocking its effector function.

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titleDishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.
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0Adaptor Proteins, Signal Transducing–Chemistry
1Amino Acid Sequence–Metabolism
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6Down-Regulation–Metabolism
7Drosophila–Metabolism
8Drosophila Proteins–Metabolism
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10Models, Molecular–Metabolism
11Molecular Sequence Data–Metabolism
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16Sequence Homology, Amino Acid–Metabolism
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titleDishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.
authorFiedler, Marc ; Mendoza-Topaz, Carolina ; Rutherford, Trevor J ; Mieszczanek, Juliusz ; Bienz, Mariann
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8Drosophila Proteins–Metabolism
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15Protein Binding–Metabolism
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