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.
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia.
Runsen
R
Jin
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia.
Wensheng
W
Liu
Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia.
Sharleen
S
Menezes
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
Fei
F
Yue
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Department of General Surgery, Shanghai Minhang District Central Hospital (Minhang District Central Hospital of Shanghai Ruijin Hospital Group), Shanghai 201100, P.R. China zmhtiger@yeah.net d.richardson@med.usyd.edu.au zaklina.kovacevic@sydney.edu.au.
Minhua
M
Zheng
Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia zmhtiger@yeah.net d.richardson@med.usyd.edu.au zaklina.kovacevic@sydney.edu.au.
Zaklina
Z
Kovacevic
Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia zmhtiger@yeah.net d.richardson@med.usyd.edu.au zaklina.kovacevic@sydney.edu.au.
Des R
DR
Richardson
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D020868:Gene Silencing; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D054462:p21-Activated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C495270:CTNNB1 protein, human; C491819:FRAT1 protein, human; C116367:PAK4 protein, human
FRAT1; Metastasis suppressor; NDRG1; PAK4; β-catenin