Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal

描述(申请人提供)：脑肿瘤治疗中的一个主要问题是其侵袭性生长和对周围正常脑组织的侵袭。不幸的是，我们对这些肿瘤侵袭行为背后的机制的了解非常有限。最近的证据表明，实体肿瘤的侵袭性涉及Rho GTP酶下游的信号事件。Rho家族的小分子GTP酶，特别是RhoA，通过对肌动蛋白细胞骨架和微管的作用，是细胞黏附、细胞极性、定向细胞迁移和不对称细胞分裂的关键调节因子。我们对细胞黏附和迁移机制的基础研究发现，Rho鸟嘌呤交换因子(Global)PLEKHG5通过与包括MUPP1、PATJ、PALS1和LIN7在内的一系列极性蛋白质的相互作用和激活RhoA信号，在促进细胞定向迁移方面发挥重要作用。有趣的是，我们的初步数据表明PLEKHG5及其细胞极性配对MUPP1在人脑胶质瘤中高表达。初步实验支持PLEKHG5参与了胶质瘤细胞体外迁移的增加。因此，我们推测，PLEKHG5在迁移的胶质瘤细胞前沿的募集和激活特异性地调节RhoA的活性，促进胶质瘤细胞的定向迁移和侵袭。我们的主要目的是确定PLEKHG5在胶质瘤细胞迁移和侵袭中的作用，并确定调节PLEKHG5亚细胞定位的机制及其对细胞定向迁移的影响。为了实现这些目标，我们建议：1.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力。2.确定相互作用的极性蛋白、PLEKHG5磷酸化和下游效应分子对PLEKHG5活性、亚细胞定位和定向细胞迁移的作用， 公共卫生相关性：恶性胶质瘤呈侵袭性生长，其向周围正常脑组织的扩散是其不良临床结果的主要因素，突显了对这些肿瘤的病因和治疗干预的新见解的必要性。我们的研究发现，PLEKHG5在诱导细胞极化和细胞迁移方面发挥着重要作用。在这项研究中，我们将确定PLEKHG5在胶质瘤生物学中的作用，并确定其促进人脑胶质瘤侵袭性侵袭行为的机制。

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.