Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells.
Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells.
复制标题
DOI：
10.1158/1541-7786.mcr-11-0616
复制
发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Tran NL
中科院分区：
文献类型：
--
作者：
Fortin SP;Ennis MJ;Schumacher CA;Zylstra-Diegel CR;Williams BO;Ross JT;Winkles JA;Loftus JC;Symons MH;Tran NL
恶性胶质母细胞瘤的特征在于它们能够浸润到正常脑中。我们以前报道过，结合的多功能细胞因子TNF样弱诱导凋亡（TWEAK），其受体成纤维细胞生长因子诱导14（Fn 14）诱导胶质母细胞瘤细胞侵袭通过Rac 1激活。在这里，我们发现Cdc 42在Fn 14介导的Rac 1激活中起着至关重要的作用。TWEAK处理的神经胶质瘤细胞显示Cdc 42的活化增加，并且使用siRNA耗尽Cdc 42废除了TWEAK诱导的Rac 1活化并废除了神经胶质瘤细胞的迁移和侵袭。相反，Rac 1耗竭不影响Cdc 42通过Fn 14的激活，表明Cdc 42介导TWEAK刺激的Rac 1激活。此外，我们确定了两个鸟嘌呤核苷酸交换因子（GEF），Ect 2和Trio，分别参与TWEAK诱导的Cdc 42和Rac 1的激活。Ect 2的耗尽消除了TWEAK诱导的Cdc 42和Rac 1活化，以及随后的TWEAK-Fn 14指导的胶质瘤细胞迁移和侵袭。相反，Trio耗竭抑制TWEAK诱导的Rac 1活化，但不抑制TWEAK诱导的Cdc 42活化。最后，在G-tva转基因小鼠中使用用于胶质细胞特异性基因转移的RCAS载体系统在体内小鼠星形胶质细胞中Fn 14或Ect 2的不适当表达诱导星形胶质细胞在脑内迁移，证实了TWEAK-Fn 14信号级联在胶质母细胞瘤侵袭中的体外重要性。我们的研究结果表明，TWEAK-Fn 14信号轴刺激胶质瘤细胞的迁移和侵袭通过两个GEF-GTf 3信号单元，Ect 2-Cdc 42和Trio-Rac 1。Fn 14-Rho GEF-Rho GTd 3信号通路的组分为神经胶质瘤治疗提供了创新的药物靶点。
Malignant glioblastomas are characterized by their ability to infiltrate into normal brain. We previously reported that binding of the multifunctional cytokine TNF-like weak inducer of apoptosis (TWEAK) to its receptor fibroblast growth factor–inducible 14 (Fn14) induces glioblastoma cell invasion via Rac1 activation. Here, we show that Cdc42 plays an essential role in Fn14-mediated activation of Rac1. TWEAK-treated glioma cells display an increased activation of Cdc42, and depletion of Cdc42 using siRNA abolishes TWEAK-induced Rac1 activation and abrogates glioma cell migration and invasion. In contrast, Rac1 depletion does not affect Cdc42 activation by Fn14, showing that Cdc42 mediates TWEAK-stimulated Rac1 activation. Furthermore, we identified two guanine nucleotide exchange factors (GEF), Ect2 and Trio, involved in TWEAK-induced activation of Cdc42 and Rac1, respectively. Depletion of Ect2 abrogates both TWEAK-induced Cdc42 and Rac1 activation, as well as subsequent TWEAK-Fn14–directed glioma cell migration and invasion. In contrast, Trio depletion inhibits TWEAK-induced Rac1 activation but not TWEAK-induced Cdc42 activation. Finally, inappropriate expression of Fn14 or Ect2 in mouse astrocytes in vivo using an RCAS vector system for glial-specific gene transfer in G-tva transgenic mice induces astrocyte migration within the brain, corroborating the in vitro importance of the TWEAK-Fn14 signaling cascade in glioblastoma invasion. Our results suggest that the TWEAK-Fn14 signaling axis stimulates glioma cell migration and invasion through two GEF-GTPase signaling units, Ect2-Cdc42 and Trio-Rac1. Components of the Fn14-Rho GEF-Rho GTPase signaling pathway present innovative drug targets for glioma therapy.