Department of Natural Sciences, The Lebanese American University, P.O. Box: 13-5053, Chouran, Beirut 1102 2801, Lebanon.
Department of Pharmacology, University of North Carolina School of Medicine, CB7365, Chapel Hill, NC27599, USA.
Exp Cell Res. 2014 Feb 15;321(2):109-22. doi: 10.1016/j.yexcr.2013.11.023. Epub 2013 Dec 10.
Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Rho GTPases are small monomeric G proteins that play important roles in cytoskeleton rearrangement, cell motility, and tumor invasion. In the present study, we show that the knock down of StarD13, a GTPase activating protein (GAP) for RhoA and Cdc42, inhibits astrocytoma cell migration through modulating focal adhesion dynamics and cell adhesion. This effect is mediated by the resulting constitutive activation of RhoA and the subsequent indirect inhibition of Rac. Using Total Internal Reflection Fluorescence (TIRF)-based Förster Resonance Energy Transfer (FRET), we show that RhoA activity localizes with focal adhesions at the basal surface of astrocytoma cells. Moreover, the knock down of StarD13 inhibits the cycling of RhoA activation at the rear edge of cells, which makes them defective in retracting their tail. This study highlights the importance of the regulation of RhoA activity in focal adhesions of astrocytoma cells and establishes StarD13 as a GAP playing a major role in this process.
恶性星形细胞瘤高度浸润正常脑的邻近和远处区域。Rho GTPases 是小的单体 G 蛋白,在细胞骨架重排、细胞迁移和肿瘤浸润中发挥重要作用。在本研究中,我们表明,RhoA 和 Cdc42 的 GTP 酶激活蛋白(GAP)StarD13 的敲低通过调节粘着斑动力学和细胞黏附来抑制星形细胞瘤细胞迁移。这种效应是通过 RhoA 的组成型激活和随后 Rac 的间接抑制介导的。使用全内反射荧光(TIRF)基础的Förster 共振能量转移(FRET),我们表明 RhoA 活性在星形细胞瘤细胞基底表面的粘着斑处定位。此外,StarD13 的敲低抑制了细胞后缘 RhoA 激活的循环,使它们在缩回尾部时出现缺陷。这项研究强调了调节星形细胞瘤细胞粘着斑中 RhoA 活性的重要性,并确立了 StarD13 作为在该过程中发挥主要作用的 GAP。