title: Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization.
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.
authors.affiliation: DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
authors.forename: Caghan
authors.initials: C
authors.lastname: Kizil
authors.affiliation: DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Küchler
authors.affiliation: DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
authors.forename: Jia-Jiun
authors.initials: JJ
authors.lastname: Yan
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, Dresden 01307, Germany.
authors.forename: Günes
authors.initials: G
authors.lastname: Özhan
authors.affiliation: Department of Molecular Medicine, University of Padua, Via U. Bassi 58/B, Padua 25131, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.affiliation: Department of Biology, University of Padua, Via U. Bassi 58/B, Padua 35131, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Brand
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Weidinger
authors.affiliation: DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany christopher.antos@crt-dresden.de.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Antos
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C000592647:Fam53b protein, mouse; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases
keywords: Embryogenesis; Nuclear localization; Simplet/Fam53b; Wnt signaling; Zebrafish; β-Catenin