14-3-3? regulates ?-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3?.

ABSTRACT: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear.In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3? isoform. Knockdown of 14-3-3? with siRNA reduced embryonic stem cell proliferation, while only 14-3-3? transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3? was abrogated by ?-catenin knockdown, we investigated the influence of 14-3-3? overexpression on ?-catenin/GSK-3?. 14-3-3? bound GSK-3? and increased GSK-3? phosphorylation in a PI-3K/Akt-dependent manner. It disrupted ?-catenin binding by the multiprotein destruction complex. 14-3-3? overexpression attenuated ?-catenin phosphorylation and rescued the decline of ?-catenin induced by retinoid acid. Furthermore, 14-3-3? enhanced Wnt3a-induced ?-catenin level and GSK-3? phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3?/14-3-3? binding.Our findings show for the first time that 14-3-3? plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3? and enhancing Wnt-signaled GSK-3? inactivation. 14-3-3? is a novel target for embryonic stem cell expansion.

SUBMITTER: Chang TC 

PROVIDER: S-EPMC3387134 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature