1] Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
1] Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Science, Kunming, China [3] Graduate School, Chinese Academy of Sciences, Beijing, China.
Oncogene. 2014 Mar 20;33(12):1558-69. doi: 10.1038/onc.2013.97. Epub 2013 Apr 8.
PDZ domains represent one group of the major structural units that mediate protein interactions in intercellular contact, signal transduction and assembly of biological machineries. Tax-interacting protein (TIP)-1 protein is composed of a single PDZ domain that distinguishes TIP-1 from other PDZ domain proteins that more often contain multiple protein domains and function as scaffolds for protein complex assembly. However, the biological functions of TIP-1, especially in cell transformation and tumor progression, are still controversial as observed in a variety of cell types. In this study, we have identified ARHGEF7, a guanine nucleotide exchange factor for Rho GTPases, as one novel TIP-1-interacting protein in human glioblastoma cells. We found that the presence of TIP-1 protein is essential to the intracellular redistribution of ARHGEF7 and rhotekin, one Rho effector and the spatiotemporally coordinated activation of Rho GTPases (RhoA, Cdc42 and Rac1) in migrating glioblastoma cells. TIP-1 knockdown resulted in both aberrant localization of ARHGEF7 and rhotekin, as well as abnormal activation of Rho GTPases that was accompanied with impaired motility of glioblastoma cells. Furthermore, TIP-1 knockdown suppressed tumor cell dispersal in orthotopic glioblastoma murine models. We also observed high levels of TIP-1 expression in human glioblastoma specimens, and the elevated TIP-1 levels are associated with advanced staging and poor prognosis in glioma patients. Although more studies are needed to further dissect the mechanism(s) by which TIP-1 modulates the intracellular redistribution and activation of Rho GTPases, this study suggests that TIP-1 holds potential as both a prognostic biomarker and a therapeutic target of malignant gliomas.
PDZ 结构域是介导细胞间相互作用、信号转导和生物机器组装的主要结构单元之一。Tax 相互作用蛋白 (TIP)-1 蛋白由一个 PDZ 结构域组成，这将 TIP-1 与其他 PDZ 结构域蛋白区分开来，后者通常包含多个蛋白质结构域，并作为蛋白质复合物组装的支架。然而，TIP-1 的生物学功能，尤其是在细胞转化和肿瘤进展中的作用，在各种细胞类型中观察到的结果仍然存在争议。在这项研究中，我们已经鉴定出 ARHGEF7，一种 Rho GTPases 的鸟嘌呤核苷酸交换因子，是人类神经胶质瘤细胞中 TIP-1 的一种新的相互作用蛋白。我们发现 TIP-1 蛋白的存在对于 ARHGEF7 和 rho 效应物 rotekin 的细胞内重新分布以及迁移的神经胶质瘤细胞中 Rho GTPases（RhoA、Cdc42 和 Rac1）的时空协调激活是必不可少的。TIP-1 敲低导致 ARHGEF7 和 rotekin 的定位异常，以及 Rho GTPases 的异常激活，伴随神经胶质瘤细胞的运动能力受损。此外，TIP-1 敲低抑制了神经胶质瘤细胞在原位神经胶质瘤小鼠模型中的扩散。我们还观察到人类神经胶质瘤标本中 TIP-1 的高表达水平，并且 TIP-1 水平的升高与胶质瘤患者的晚期分期和预后不良相关。尽管需要进一步研究以进一步剖析 TIP-1 调节 Rho GTPases 的细胞内重分布和激活的机制，但这项研究表明 TIP-1 可能成为恶性神经胶质瘤的预后生物标志物和治疗靶点。
