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

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

Author information

1
DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
2
Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, Dresden 01307, Germany.
3
Department of Molecular Medicine, University of Padua, Via U. Bassi 58/B, Padua 25131, Italy.
4
Department of Biology, University of Padua, Via U. Bassi 58/B, Padua 35131, Italy.
5
DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, Dresden 01307, Germany.
6
Institute for Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
7
DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany christopher.antos@crt-dresden.de.

Abstract

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

PMID:
25183871
DOI:
10.1242/dev.108415
[Indexed for MEDLINE]
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