Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization

Kizil, C., Küchler, B., Yan, J.J., Özhan, G., Moro, E., Argenton, F., Brand, M., Weidinger, G., Antos, C.L.
Development (Cambridge, England)   141: 3529-39 (Journal)
Registered Authors
Antos, Christopher, Argenton, Francesco, Brand, Michael, Kizil, Caghan, Moro, Enrico, Özhan, Günes, Weidinger, Gilbert
Embryogenesis, Nuclear localization, Simplet/Fam53b, Wnt signaling, Zebrafish, β-Catenin
MeSH Terms
  • Animals
  • Blotting, Western
  • Cell Nucleus/metabolism*
  • Gene Expression Regulation, Developmental/physiology*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • Luciferases
  • Mice
  • Mice, Transgenic
  • RNA Interference
  • RNA, Small Interfering/genetics
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism*
  • Wnt Signaling Pathway/physiology*
  • beta Catenin/metabolism*
25183871 Full text @ Development
Canonical β-catenin-dependent Wnt signal transduction is important for several biological phenomena, such as cell fate determination, cell proliferation, stem cell maintenance and anterior-posterior axis formation. The hallmark of canonical Wnt signaling is the translocation of β-catenin into the nucleus where it activates gene transcription. However, the mechanisms regulating β-catenin nuclear localization are poorly understood. We show that Simplet/Fam53B (Smp) is required for Wnt signaling by positively regulating β-catenin nuclear localization. In the zebrafish embryo, the loss of smp blocks the activity of two β-catenin-dependent reporters and the expression of Wnt target genes, and prevents nuclear accumulation of β-catenin. Conversely, overexpression of smp increases β-catenin nuclear localization and transcriptional activity in vitro and in vivo. Expression of mutant Smp proteins lacking either the nuclear localization signal or the β-catenin interaction domain reveal that the translocation of Smp into the nucleus is essential for β-catenin nuclear localization and Wnt signaling in vivo. We also provide evidence that mammalian Smp is involved in regulating β-catenin nuclear localization: the protein colocalizes with β-catenin-dependent gene expression in mouse intestinal crypts; siRNA knockdown of Smp reduces β-catenin nuclear localization and transcriptional activity; human SMP mediates β-catenin transcriptional activity in a dose-dependent manner; and the human SMP protein interacts with human β-catenin primarily in the nucleus. Thus, our findings identify the evolutionary conserved SMP protein as a regulator of β-catenin-dependent Wnt signal transduction.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes