The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK4.

N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and β-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 β-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated β-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting β-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3β-binding protein FRAT1, which prevents the association of GSK3β with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of β-catenin. Additionally, NDRG1 is shown to modulate the WNT-β-catenin pathway by inhibiting the nuclear translocation of β-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 β-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of β-catenin phosphorylation and distribution.