Jin_2014_J.Cell.Sci_127_3116

N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor beta (TGF-beta)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and beta-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of beta-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated beta-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting beta-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3beta-binding protein FRAT1, which prevents the association of GSK3beta with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of beta-catenin. Additionally, NDRG1 is shown to modulate the WNT-beta-catenin pathway by inhibiting the nuclear translocation of beta-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for beta-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of beta-catenin phosphorylation and distribution.