Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal

描述（由申请人提供）：脑肿瘤治疗的一个主要问题是其侵袭性生长和侵入周围正常脑组织。不幸的是，我们对这些肿瘤侵袭性行为背后的机制的理解非常有限。最近的证据表明，实体肿瘤的侵袭性涉及Rho GTPases下游的信号事件。Rho家族的小gtpase，特别是RhoA，是细胞粘附、细胞极性、定向细胞迁移和不对称细胞分裂的关键调节剂，通过它们对肌动蛋白细胞骨架和微管的影响。我们对细胞粘附和迁移机制的基础研究发现，Rho鸟嘌呤交换因子（GEF） PLEKHG5通过与极性蛋白复合物（包括MUPP1、PATJ、PALS1和LIN7）的相互作用以及RhoA信号的激活，在促进定向细胞迁移中起重要作用。有趣的是，我们的初步数据表明PLEKHG5及其细胞极性伴侣MUPP1在人类胶质瘤中高度表达。初步实验支持PLEKHG5参与体外胶质瘤细胞迁移的增加。因此，我们假设迁移胶质瘤细胞边缘PLEKHG5的募集和激活特异性调节RhoA活性，促进胶质瘤细胞的定向迁移和侵袭性。我们的主要目标是确定PLEKHG5在胶质瘤细胞迁移和侵袭中的作用，并确定调节PLEKHG5亚细胞定位及其对定向细胞迁移的影响的机制。为实现这些目标，我们建议：评估plekhg5介导的RhoA激活是否促进胶质瘤细胞的定向迁移和增加侵袭性。2. 确定极性相互作用蛋白、PLEKHG5磷酸化和下游效应物对PLEKHG5活性、亚细胞定位和定向细胞迁移的作用；

DESCRIPTION (provided by applicant): A major issue in the management of brain tumors is their aggressive growth and invasion into surrounding normal brain tissue. Unfortunately, our understanding of the mechanisms that underlie the aggressive behavior of these tumors is very limited. Recent evidence indicates that the invasiveness of solid tumors involves signaling events downstream of Rho GTPases. The Rho family of small GTPases in general and RhoA in particular, are critical regulators of cell adhesion, cell polarity, directed cell migration and asymmetric cell division, through their effects on the actin cytoskeleton and microtubules. Our basic research findings on the mechanics of cell adhesion and migration have identified the Rho guanine exchange factor (GEF) PLEKHG5 as important in promoting directed cell migration, via its interaction with a complex of polarity proteins, including MUPP1, PATJ, PALS1, and LIN7, and activation of RhoA signaling. Interestingly, our preliminary data indicate that PLEKHG5 and its cell polarity partner MUPP1 are highly expressed in human gliomas. Preliminary experiments support the involvement of PLEKHG5 in the increased migration of glioma cells in vitro. Therefore, we postulate that that recruitment to and activation of PLEKHG5 at the leading edges of migrating glioma cells specifically regulates RhoA activity to promote the directional migration and invasiveness of glioma cells. Our main objectives are to define the involvement of PLEKHG5 in glioma cell migration and invasion, and to identify the mechanisms that regulate the sub-cellular localization of PLEKHG5 and its effects on directed cell migration. To achieve these objectives we propose to: 1. Assess whether PLEKHG5-mediated RhoA activation promotes the directed migration and increased invasiveness of glioma cells. 2. Determine the role of interacting polarity proteins, PLEKHG5 phosphorylation, and downstream effectors on PLEKHG5 activity, sub-cellular localization and directed cell migration, PUBLIC HEALTH RELEVANCE: Malignant gliomas grow aggressively, and their spread into surrounding normal brain tissue is a major factor in their poor clinical outcome, underscoring the need for new insights into the etiology and therapeutic intervention of these tumors. Our research findings have identified PLEKHG5 as an important player in inducing cell polarization and cell migration. In this study, we will define the role of PLEKHG5 in glioma biology, and identify mechanisms by which it promotes the aggressive invasive behavior of human gliomas.