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

Ippei Kikuchi, Atsushi Takahashi-Kanemitsu, Natsuki Sakiyama, Chao Tang, Pei-Jung Tang, Saori Noda, Kazuki Nakao, Hidetoshi Kassai, Toshiro Sato, Atsu Aiba and Masanori Hatakeyama ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12887

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