Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Mol Cell Biol. 2012 Jun;32(11):2145-59. doi: 10.1128/MCB.06580-11. Epub 2012 Apr 2.
The DLC1 (for deleted in liver cancer 1) tumor suppressor gene encodes a RhoGAP protein that inactivates Rho GTPases, which are implicated in regulation of the cytoskeleton and adherens junctions (AJs), a cell-cell adhesion protein complex associated with the actin cytoskeleton. Malignant transformation and tumor progression to metastasis are often associated with changes in cytoskeletal organization and cell-cell adhesion. Here we have established in human cells that the AJ-associated protein α-catenin is a new binding partner of DLC1. Their binding was mediated by the N-terminal amino acids 340 to 435 of DLC1 and the N-terminal amino acids 117 to 161 of α-catenin. These proteins colocalized in the cytosol and in the plasma membrane, where together they associated with E-cadherin and β-catenin, constitutive AJ proteins. Binding of DLC1 to α-catenin led to their accumulation at the plasma membrane and required DLC1 GAP activity. Knocking down α-catenin in DLC1-positive cells diminished DLC1 localization at the membrane. The DLC1-α-catenin complex reduced the Rho GTP level at the plasma membrane, increased E-cadherin's mobility, affected actin organization, and stabilized AJs. This process eventually contributed to a robust oncosuppressive effect of DLC1 in metastatic prostate carcinoma cells. Together, these results unravel a new mechanism through which DLC1 exerts its strong oncosuppressive function by positively influencing AJ stability.
DLC1（肝癌缺失 1）肿瘤抑制基因编码一种 RhoGAP 蛋白，可使 Rho GTPases 失活，后者参与细胞骨架和黏着连接（AJs）的调节，AJs 是一种与肌动蛋白细胞骨架相关的细胞-细胞黏附蛋白复合物。恶性转化和肿瘤进展为转移通常与细胞骨架组织和细胞-细胞黏附的变化有关。在这里，我们在人细胞中建立了 AJ 相关蛋白α-连环蛋白是 DLC1 的一个新的结合伙伴。它们的结合由 DLC1 的 N 端氨基酸 340 到 435 和α-连环蛋白的 N 端氨基酸 117 到 161 介导。这些蛋白质在细胞质和质膜中共定位，在质膜中它们与 E-钙黏蛋白和β-连环蛋白（组成性 AJ 蛋白）一起结合。DLC1 与α-连环蛋白的结合导致它们在质膜中的积累，并需要 DLC1 GAP 活性。在 DLC1 阳性细胞中敲低α-连环蛋白会减少 DLC1 在膜上的定位。DLC1-α-连环蛋白复合物降低了质膜上的 Rho GTP 水平，增加了 E-钙黏蛋白的迁移率，影响了肌动蛋白的组织，并稳定了 AJs。这个过程最终导致 DLC1 在转移性前列腺癌细胞中具有强大的肿瘤抑制作用。总之，这些结果揭示了一种新的机制，通过该机制，DLC1 通过积极影响 AJ 的稳定性发挥其强大的肿瘤抑制功能。
