|ZFIN ID: ZDB-PUB-140904-4|
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.
|Source:||Development (Cambridge, England) 141: 3529-39 (Journal)|
|Registered Authors:||Antos, Christopher, Argenton, Francesco, Brand, Michael, Kizil, Caghan, Moro, Enrico, Özhan, Günes, Weidinger, Gilbert|
|Keywords:||Embryogenesis, Nuclear localization, Simplet/Fam53b, Wnt signaling, Zebrafish, β-Catenin|
|PubMed:||25183871 Full text @ Development|
Kizil, C., Küchler, B., Yan, J.J., Özhan, G., Moro, E., Argenton, F., Brand, M., Weidinger, G., Antos, C.L. (2014) Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization. Development (Cambridge, England). 141:3529-39.
ABSTRACTCanonical 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.