14‐3‐3σ synergizes Wnt and Akt to promote embryonic stem cell proliferation via regulating GSK‐3β/β‐catenin

Abstract

Pluripotent embryonic stem (ES) cells are considered to be an unlimited cell source for tissue regeneration and cell‐based therapy. Investigating the molecular mechanism underlying the regulation of ES 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 ES cell proliferation is unknown. In this study, we show that retinoid acid (RA) suppressed selectively the expression of 14‐3‐3σ isoform. Knockdown of 14‐3‐3σ with siRNA reduced mESC proliferation, while 14‐3‐3σ transfection increased mESC growth and rescued RA‐induced growth arrest. The growth‐enhancing action of 14‐3‐ 3σ was abrogated by β‐catenin knockdown. 14‐3‐3σ bound GSK‐ 3β and increased GSK‐3β phosphorylation in a PI‐3K/Akt‐dependent manner. Furthermore, 14‐3‐3σ enhanced Wnt3ainduced β‐catenin level and GSK‐3β phosphorylation. DKK abolished Wnt3a‐induced effect but did not interfere GSK‐3β/14‐ 3‐3σ binding. These findings show for the first time that 14‐3‐3σ plays an important role in regulating mESC proliferation by binding and sequestering phosphorylated GSK‐3β and enhancing Wnt‐signaled GSK‐3β inactivation. 14‐3‐3σ is a novel target for ES cell expansion.