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

Development. 2014 Sep;141(18):3529-39. doi: 10.1242/dev.108415.


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.

Keywords: Embryogenesis; Nuclear localization; Simplet/Fam53b; Wnt signaling; Zebrafish; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

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*


  • Fam53b protein, mouse
  • RNA, Small Interfering
  • Wnt Proteins
  • beta Catenin
  • Luciferases