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Nat Commun. 2016 Sep 21;7:12887. doi: 10.1038/ncomms12887.

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

Author information

1
Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
2
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
3
Division of Gastroenterology, Keio University School of Medicine, Tokyo 108-8345, Japan.
4
Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
5
CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.

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.

PMID:
27650679
PMCID:
PMC5036006
DOI:
10.1038/ncomms12887
[Indexed for MEDLINE]
Free PMC Article

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