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Research ArticleArticle

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Chengchun Min, Dong-Im Cho, Kyoung-Ja Kwon, Kwon-Sup Kim, Chan Young Shin and Kyeong-Man Kim
Molecular Pharmacology July 2011, 80 (1) 68-78; DOI: https://doi.org/10.1124/mol.111.071340
Chengchun Min
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Dong-Im Cho
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Kyoung-Ja Kwon
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Kwon-Sup Kim
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Chan Young Shin
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Kyeong-Man Kim
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Abstract

Classical G protein-coupled receptors (GPCRs) and canonical Wnt pathways were believed to use distinct signaling pathways. However, recent studies have shown that these two pathways interact each other by sharing several intermediate signaling components. Recent in vivo studies showed that antipsychotic drugs, which block dopamine D2-like receptors, increase the cellular levels of downstream signaling components of canonical Wnt pathways, such as dishevelled (Dvl), glycogen synthase kinase 3β (GSK3β), and β-catenin. These results suggest that some functional interactions might exist between Wnt pathway and D2-like receptors. In this study, we show that among five different dopamine receptor subtypes, D2 receptor (D2R) selectively inhibited the Wnt signaling, which was measured by lymphoid enhancing factor-1 (LEF-1)-dependent transcriptional activities. D2R-mediated inhibition of Wnt signaling was agonist- and G protein-independent and did not require receptor phosphorylation or endocytosis. D2R inhibited the LEF-1-dependent transcriptional activities, and this inhibitory activity was not affected by the inhibition of GSK-3β, suggesting that D2R inhibited the Wnt signaling by acting on the downstream of GSK3β. D2R directly interacted with β-catenin through the second and third loops, leading to a reduction of β-catenin distribution in the nucleus, resulting in an inhibition of LEF-1-dependent transcription. This is a novel mechanism for the regulation of canonical Wnt signaling by GPCRs, in which receptor proteins recruit β-catenin from cytosol to the plasma membrane, resulting in the decrement of the β-catenin/LEF-1-dependent transcription in the nucleus.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Korean Research Foundation [Grants KRF-2008-E00747, KRF-2010-0005355].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071340.

  • ABBREVIATIONS:

    FZD
    Frizzled
    Wnt
    Wingless/int
    GRK
    G protein-coupled receptor kinase
    LRP
    lipoprotein receptor-related protein
    GSK
    glycogen synthase kinase
    CKI
    casein kinase I
    LRP
    low-density lipoprotein receptor-related protein
    LEF
    lymphoid-enhancing factor
    GFP
    green fluorescent protein
    HEK
    human embryonic kidney
    DMEM
    Dulbecco's modified Eagle's medium
    RNAi
    RNA interference
    CMV
    vytomegalovirus
    PAGE
    polyacrylamide gel electrophoresis
    GST
    glutathione transferase
    CM
    conditioned medium
    GPCR
    G protein-coupled receptor
    Dvl
    disheveled
    I3D2
    third intracellular loop of D2.

  • Received January 20, 2011.
  • Accepted April 14, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Chengchun Min, Dong-Im Cho, Kyoung-Ja Kwon, Kwon-Sup Kim, Chan Young Shin and Kyeong-Man Kim
Molecular Pharmacology July 1, 2011, 80 (1) 68-78; DOI: https://doi.org/10.1124/mol.111.071340

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Research ArticleArticle

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Chengchun Min, Dong-Im Cho, Kyoung-Ja Kwon, Kwon-Sup Kim, Chan Young Shin and Kyeong-Man Kim
Molecular Pharmacology July 1, 2011, 80 (1) 68-78; DOI: https://doi.org/10.1124/mol.111.071340
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