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）：脑肿瘤管理的一个主要问题是它们的侵略性生长和侵袭周围正常的脑组织。不幸的是，我们对这些肿瘤侵略性行为的机制的理解非常有限。最近的证据表明，实体瘤的侵入性涉及Rho GTPases下游的信号事件。通常，小型GTPase的Rho家族，尤其是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，它们通过其对肌动蛋白细胞骨架和微管的影响。我们关于细胞粘附力和迁移力学的基础研究发现，已经确定了Rho Guanine交换因子（GEF）Plekhg5在促进定向细胞迁移的情况下与包括MUPP1，PATJ，PATJ，PALS1和LIN7以及RHOA信号的激活（包括MUPP1，PATJ，PALS1和LIN7）（包括MUPP1，PATJ，PALS1和LIN7）的相互作用。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，我们假设在迁移神经胶质瘤细胞的主要边缘募集和激活Plekhg5专门调节RhoA活性，以促进神经胶质瘤细胞的定向迁移和侵入性。我们的主要目的是定义Plekhg5参与神经胶质瘤细胞迁移和侵袭，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激活是否促进了胶质瘤细胞的定向迁移和增加的侵入性。 2。确定相互作用的极性蛋白，plekhg5磷酸化以及下游效应子对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：恶性神经胶质瘤积极生长，它们在正常的脑组织中的扩散是其临床不良结果的主要因素，强调了对这些肿瘤的病因学和治疗干预的新见解。我们的研究发现已将Plekhg5确定为诱导细胞极化和细胞迁移的重要参与者。在这项研究中，我们将定义plekhg5在神经胶质瘤生物学中的作用，并确定它促进人神经胶质瘤的侵略性行为的机制。