IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms12887.html
   My bibliography  Save this article

Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

Author

Listed:
  • Ippei Kikuchi

    (Graduate School of Medicine, The University of Tokyo)

  • Atsushi Takahashi-Kanemitsu

    (Graduate School of Medicine, The University of Tokyo)

  • Natsuki Sakiyama

    (Graduate School of Medicine, The University of Tokyo)

  • Chao Tang

    (Graduate School of Medicine, The University of Tokyo)

  • Pei-Jung Tang

    (Graduate School of Medicine, The University of Tokyo)

  • Saori Noda

    (Graduate School of Medicine, The University of Tokyo)

  • Kazuki Nakao

    (Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo)

  • Hidetoshi Kassai

    (Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo)

  • Toshiro Sato

    (Keio University School of Medicine)

  • Atsu Aiba

    (Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo)

  • Masanori Hatakeyama

    (Graduate School of Medicine, The University of Tokyo
    Max Planck-The University of Tokyo Center for Integrative Inflammology
    CREST, Japan Science and Technology Agency)

Abstract

Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.

Suggested Citation

  • Ippei Kikuchi & Atsushi Takahashi-Kanemitsu & Natsuki Sakiyama & Chao Tang & Pei-Jung Tang & Saori Noda & Kazuki Nakao & Hidetoshi Kassai & Toshiro Sato & Atsu Aiba & Masanori Hatakeyama, 2016. "Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12887
    DOI: 10.1038/ncomms12887
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms12887
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms12887?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12887. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.