Akademik Veri Yönetim Sistemi
DEVELOPMENT, cilt.141, sa.18, ss.3529-3539, 2014 (SCI-Expanded)
Canonical beta-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 beta-catenin into the nucleus where it activates gene transcription. However, the mechanisms regulating beta-catenin nuclear localization are poorly understood. We show that Simplet/Fam53B (Smp) is required forWnt signaling by positively regulating beta-catenin nuclear localization. In the zebrafish embryo, the loss of smp blocks the activity of two beta-catenin-dependent reporters and the expression of Wnt target genes, and prevents nuclear accumulation of beta-catenin. Conversely, overexpression of smp increases beta-catenin nuclear localization and transcriptional activity in vitro and in vivo. Expression of mutant Smp proteins lacking either the nuclear localization signal or the beta-catenin interaction domain reveal that the translocation of Smp into the nucleus is essential for beta-catenin nuclear localization and Wnt signaling in vivo. We also provide evidence that mammalian Smp is involved in regulating beta-catenin nuclear localization: the protein colocalizes with beta-catenin-dependent gene expression in mouse intestinal crypts; siRNA knockdown of Smp reduces beta-catenin nuclear localization and transcriptional activity; human SMP mediates beta-catenin transcriptional activity in a dose-dependent manner; and the human SMP protein interacts with human beta-catenin primarily in the nucleus. Thus, our findings identify the evolutionary conserved SMP protein as a regulator of beta-catenin-dependent Wnt signal transduction.