Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44
Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44
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DOI：
10.1016/j.chembiol.2006.07.011
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发表时间：
2006-09-01
影响因子：
--
通讯作者：
Fenteany, Gabriel
中科院分区：
文献类型：
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作者：
Kahsai, Alem W.;Zhu, Shoutian;Fenteany, Gabriel
在筛选新的小分子细胞运动调节剂的过程中，我们发现奎诺卡霉素（也称为奎诺卡辛）类似物DX-52-1是上皮细胞迁移的抑制剂。虽然已经假设DX-52-1的主要靶点是DNA，但我们鉴定并证实了根毒素是DX-52-1在细胞中的相关分子靶点。Radixin是也参与信号转导途径的膜-肌动蛋白细胞骨架连接蛋白的ezrin/radixin/膜突蛋白家族的成员。DX-52-1特异性地共价结合到radixin的C-末端区域，该区域包含与肌动蛋白丝相互作用的结构域。细胞中radixin的过表达消除了它们对DX-52-1的抗迁移活性的敏感性。小干扰RNA介导的Radixin表达沉默降低了细胞迁移速率。最后，我们发现DX-52-1破坏了radixin与肌动蛋白和细胞粘附分子CD 44相互作用的能力。
In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52-1 is DNA, we identified and confirmed radixin as the relevant molecular target of DX-52-1 in the cell. Radixin is a member of the ezrin/radixin/moesin family of membrane-actin cytoskeleton linker proteins that also participate in signal transduction pathways. DX-52-1 binds specifically and covalently to the C-terminal region of radixin, which contains the domain that interacts with actin filaments. Overexpression of radixin in cells abrogates their sensitivity to DX-52-1's antimigratory activity. Small interfering RNA-mediated silencing of radixin expression reduces the rate of cell migration. Finally, we found that DX-52-1 disrupts radixin's ability to interact with both actin and the cell adhesion molecule CD44.