Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal

极性 RhoGEF PLEKHG5 对脑肿瘤扩散的作用

基本信息

批准号：
7873359
负责人：
Panagiotis Z. Anastasiadis
金额：
$ 22.95万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7873359
关键词：
14-3-3 Proteins Actins Aggressive behavior Basic Science Behavior Biology Brain Neoplasms Cell Adhesion Cell Polarity Cell division Cell physiology Cells Central Nervous System Neoplasms Clinical Complex Cytoskeleton Data Diffuse Effectiveness Endocytosis Endothelial Cells Epithelial Epithelial Cells Etiology Event Excision Exhibits Extracellular Matrix Family Glioma Growth Guanine Guanine Nucleotide Exchange Factors Hippocampus (Brain)Homologous Gene Human In Vitro Malignant Glioma Malignant Neoplasms Mechanics Mediating Membrane Microtubule Stabilization Microtubules Monomeric GTP-Binding Proteins Mutate Myosin ATPase N-terminal Nature Neurons Normal Cell Oncogene Proteins Outcome Phosphorylation Process Protein Tyrosine Kinase Proteins Proteomics Radiation Regulation Research Role Signal Transduction Solid Neoplasm Takeda brand of pioglitazone hydrochloride Testing Therapeutic Intervention Tumor Cell Line Tumor Suppressor Proteins Tyrosine Phosphorylation angiogenesis brain tissue cancer cell cell motility insight migration mortality novel protein protein interaction public health relevance rapid growth research study rho rho GTP-Binding Proteins tumor tumor progression

项目摘要

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.

描述（由申请人提供）：脑肿瘤治疗中的一个主要问题是它们的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背后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 GTPases 下游的信号转导事件。小 GTP 酶的 Rho 家族，特别是 RhoA，通过对肌动蛋白细胞骨架和微管的影响，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因子。我们关于细胞粘附和迁移机制的基础研究结果表明，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）相互作用，对于促进定向细胞迁移非常重要，以及 RhoA 信号传导的激活。有趣的是，我们的初步数据表明 PLEKHG5 及其细胞极性伙伴 MUPP1 在人类神经胶质瘤中高度表达。初步实验支持 PLEKHG5 参与体外神经胶质瘤细胞迁移的增加。因此，我们假设迁移神经胶质瘤细胞前缘的 PLEKHG5 的招募和激活特异性调节 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 PLEKHG5 在神经胶质瘤细胞迁移和侵袭中的参与，并确定调节 PLEKHG5 亚细胞定位的机制及其对定向细胞迁移的影响。为了实现这些目标，我们建议： 1. 评估 PLEKHG5 介导的 RhoA 激活是否促进神经胶质瘤细胞的定向迁移和增加侵袭性。 2. 确定相互作用的极性蛋白、PLEKHG5 磷酸化和下游效应子对 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：恶性神经胶质瘤生长迅速，扩散到周围正常脑组织是其临床结果不佳的一个主要因素，这强调需要对这些肿瘤的病因学和治疗干预有新的认识。我们的研究结果已确定 PLEKHG5 在诱导细胞极化和细胞迁移中发挥着重要作用。在这项研究中，我们将定义 PLEKHG5 在神经胶质瘤生物学中的作用，并确定其促进人类神经胶质瘤侵袭性侵袭行为的机制。