The regulation and cellular activities of the Arl2 GTPase

Arl2 GTPase 的调节和细胞活性

• 批准号: 7987019
• 负责人: Richard A Kahn
• 金额: $ 29.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987019
• 关键词: Adenine Nucleotide Translocase; Adenine Nucleotides; Agonist; Arginine; Attenuated; Binding; Biological; Cell Death; Cell Nucleus; Cell division; Cell physiology; Cells; Cellular biology; Centrosome; Chemicals; Chronic Disease; Complex; Coupling; Cultured Cells; Cytoskeleton; Cytosol; Data; Diabetes Mellitus; Energy Metabolism; Eukaryota; Eukaryotic Cell; Family; GTPase-Activating Proteins; Generations; Genetic Transcription; Golgi Apparatus; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Hormones; In Vitro; Inner mitochondrial membrane; Laboratories; Lead; Link; Location; Maintenance; Malignant Neoplasms; Mediating; Membrane Protein Traffic; Microtubules; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Chaperones; Molecular Models; Morphology; Neurodegenerative Disorders; Orthologous Gene; Oxygen Consumption; Paclitaxel; Phenotype; Play; Production; Prokaryotic Cells; Property; Proteins; Recruitment Activity; Regulation; Role; SLC25A4 gene; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Specificity; Stress; Tertiary Protein Structure; Testing; Tubulin; cell growth regulation; cell motility; chemotherapeutic agent; cofactor; cytokine; energy balance; member; mitochondrion intermembrane space; molecular modeling; novel; protein complex; public health relevance; response; tumorigenesis

DESCRIPTION (provided by applicant): The Arf family of regulatory GTPases, within the Ras superfamily, emerged in prokaryotes and members of the Arf family, Arfs and Arl2, have been implicated as critical components in the endosymbiotic origins of eukaryotes. As such they are predicted to have essential roles in the regulation of cell biology in all eukaryotes. We and others have previously provided evidence for a role for Arl2 in microtubule growth in cells but more recently we have discovered an obligate role for Arl2 in maintenance of energy (ATP) levels that is predicted to be its fundamental role in eukaryotes. In this application I propose to develop molecular models of Arl2 regulation of ATP levels, as well as for the newly identified Arl2 GAPs/effectors in the ELMO (Engulfment and cell motility) family, that regulate mitochondria and Golgi morphology. This application has three specific aims. (1) Determine the role of Arl2 in maintenance of ATP levels. (2) Characterize the GAP domain of ELMOD2 and its actions in mitochondria including specifically its role in mitochondrial morphology. (3) Determine the specificity and functions of ELMOD1. I hypothesize that ELMOD1 acts in cells as an ArfGAP that can attenuate Arf signaling at the Golgi and impact membrane traffic also at the TGN, where it has effector properties. Together these aims will provide detailed molecular models of an ancient means of regulating energy metabolism in perhaps all eukaryotic cells, with ties to cell division, the cytoskeleton, and the regulation of gene transcription in the nucleus. These studies have the potential to fundamentally alter our understanding of essential cellular processes with ties to energy metabolism, cancer, sensitivity to cancer chemotherapeutics, and gene transcription. PUBLIC HEALTH RELEVANCE: Maintenance of proper energy balance is essential to the health and function of all cells and is the primary responsibility of mitochondria, the site of chemical energy (ATP) generation and oxygen consumption. Dramatic changes in energy utilization are known to accompany chronic diseases including cancer, neurodegenerative diseases, and diabetes. We have discovered novel signaling pathways that are involved in regulating cellular ATP levels and the morphology of the mitochondria and Golgi compartments that are tied to the ancient and highly conserved regulatory GTPase Arl2. In this application I propose three specific aims that will elucidate molecular mechanisms of Arl2 and Arl2 GTPase activating protein actions as regulators of ATP production, mitochondria morphology, and Golgi integrity with predicted links to cell division and the cell cytoskeleton.

描述(申请人提供)：在原核生物中出现的Ras超家族中的调节GTP酶Arf家族和Arf家族的成员Arf和Arl2被认为是真核生物内共生起源的关键成分。因此，它们被预测在所有真核生物的细胞生物学调控中具有重要作用。我们和其他人之前已经提供了Arl2在细胞微管生长中的作用的证据，但最近我们发现Arl2在维持能量(ATP)水平方面发挥了不可或缺的作用，这被预测是它在真核生物中的基础作用。在这个应用中，我建议建立Arl2调节ATP水平的分子模型，以及新发现的Elmo(吞噬和细胞运动)家族中调节线粒体和高尔基体形态的Arl2间隙/效应器。这个应用程序有三个具体目标。(1)确定Arl2在维持ATP水平中的作用。(2)研究ELMOD2的GAP结构域及其在线粒体中的作用，特别是其在线粒体形态中的作用。(3)确定ELMOD1的特异性和功能。我推测ELMOD1在细胞中作为ArfGAP发挥作用，可以减弱高尔基体的Arf信号，并影响TGN的膜交通，在TGN具有效应器特性。这些目标将共同提供一种古老的调控真核细胞能量新陈代谢的方法的详细分子模型，与细胞分裂、细胞骨架和核内基因转录调控有关。这些研究有可能从根本上改变我们对与能量代谢、癌症、对癌症化疗药物的敏感性和基因转录有关的基本细胞过程的理解。 与公众健康相关：维持适当的能量平衡对所有细胞的健康和功能至关重要，也是线粒体、产生化学能量(ATP)和消耗氧气的场所的主要责任。众所周知，能源利用的巨大变化会伴随着癌症、神经退行性疾病和糖尿病等慢性疾病。我们发现了新的信号通路，参与调节细胞ATP水平以及线粒体和高尔基体的形态，这些都与古老且高度保守的调节GTP酶Arl2有关。在这项应用中，我提出了三个特定的目标，以阐明Arl2和Arl2 GTP酶激活蛋白作为调节ATP产生、线粒体形态和高尔基体完整性的分子机制，并预测与细胞分裂和细胞骨架的联系。