Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal

描述（由申请人提供）：脑肿瘤管理中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行为的机制的理解非常有限。最近的证据表明，实体瘤的侵袭性涉及Rho GTP酶下游的信号传导事件。一般而言，Rho家族的小GTP酶和特别是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作用。我们对细胞粘附和迁移机制的基础研究结果已经确定了Rho鸟嘌呤交换因子（GEF）PLEKHG 5在促进定向细胞迁移中的重要性，通过其与极性蛋白质的复合物的相互作用，包括MUPP1，PATJ，PALS1和LIN 7，以及RhoA信号的激活。有趣的是，我们的初步数据表明，PLEKHG 5和它的细胞极性伙伴MUPP1在人类胶质瘤中高度表达。初步实验支持PLEKHG 5参与胶质瘤细胞体外迁移增加。因此，我们推测，在迁移的神经胶质瘤细胞的前缘，PLEKHG 5的募集和激活特异性调节RhoA活性，以促进神经胶质瘤细胞的定向迁移和侵袭。我们的主要目标是确定PLEKHG 5参与胶质瘤细胞的迁移和侵袭，并确定调节PLEKHG 5的亚细胞定位及其对定向细胞迁移的影响的机制。为了实现这些目标，我们建议：1。评估PLEKHG 5介导的RhoA活化是否促进胶质瘤细胞的定向迁移和增加的侵袭力。 2.确定相互作用的极性蛋白、PLEKHG 5磷酸化和下游效应物对PLEKHG 5活性、亚细胞定位和定向细胞迁移的作用， 公共卫生相关性：恶性胶质瘤生长积极，他们的扩散到周围正常脑组织是一个主要因素，在其不良的临床结果，强调需要新的见解，这些肿瘤的病因和治疗干预。我们的研究结果已经确定PLEKHG 5是诱导细胞极化和细胞迁移的重要参与者。在这项研究中，我们将确定PLEKHG 5在胶质瘤生物学中的作用，并确定其促进人类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.