The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Abstract

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 mesenchymal transition (EMT) by maintaining E-cadherin and β-catenin at the cell membrane in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrated that NDRG1 inhibited the phosphorylation of β-catenin at Ser33/37, Thr41 and increased non-phosphorylated β-catenin levels on the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting β-catenin phosphorylation involved the NDRG1-mediated up-regulation of the GSK3β-binding protein, FRAT1, which prevents the association of GSK3β with the Axin1/APC/CK1 destruction complex and subsequent phosphorylation of β-catenin. Additionally, NDRG1 was shown to modulate the WNT/β-catenin pathway by inhibiting β-catenin nuclear translocation. This was mediated through its effect of reducing 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 regulation of β-catenin phosphorylation and distribution by NDRG1.