The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK4
The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK4
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DOI：
10.1242/jcs.147835
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发表时间：
2014-07-15
影响因子：
4
通讯作者：
Richardson, Des R.
中科院分区：
文献类型：
--
作者：
Jin, Runsen;Liu, Wensheng;Richardson, Des R.
N-myc下游调控基因1 （NDRG1）是一种有效的转移抑制因子，已被证明可以通过维持前列腺和结肠癌细胞中E-cadherin和β -catenin的细胞膜定位来抑制转化生长因子β (tgf - β)诱导的上皮-间质转化（EMT）。然而，确切的分子机制尚不清楚。在这项研究中，我们发现NDRG1抑制了β -catenin在Ser33/37和Thr41位点的磷酸化，并增加了DU145前列腺癌细胞和HT29结肠癌细胞质膜上非磷酸化的β -catenin水平。抑制β -catenin磷酸化的机制涉及ndrg1介导的GSK3 β结合蛋白FRAT1的上调，这可以阻止GSK3 β与Axin1-APC-CK1破坏复合物的关联以及随后的β -catenin磷酸化。此外，NDRG1通过抑制β -catenin的核易位来调节wnt - β -catenin通路。这是通过p21活化激酶4 （PAK4）核定位的ndrg1依赖性减少介导的，PAK4被认为是β -连环蛋白核易位的转运体。目前的研究首次阐明了ndrg1依赖性调节β -连环蛋白磷酸化和分布的独特分子机制。
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 GSK3 beta-binding protein FRAT1, which prevents the association of GSK3 beta 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.