title: Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways.
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.
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Kikuchi
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi-Kanemitsu
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Sakiyama
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Tang
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Noda
authors.affiliation: Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kassai
authors.affiliation: Division of Gastroenterology, Keio University School of Medicine, Tokyo 108-8345, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010957:Plasmids; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C454900:CDC73 protein, human; C529591:HRPT2 protein, mouse; D053823:Hedgehog Proteins; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins