The regulation and cellular activities of the Arl2 GTPase

Arl2 GTPase 的调节和细胞活性

• 批准号: 8330939
• 负责人: Richard A Kahn
• 金额: $ 48.45万
• 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/8330939
• 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（由申请人提供）：调节性 GTP 酶的 Arf 家族属于 Ras 超家族，出现在原核生物中，而 Arf 家族的成员 Arfs 和 Arl2 已被认为是真核生物内共生起源中的关键成分。因此，预计它们在所有真核生物的细胞生物学调节中发挥重要作用。我们和其他人之前已经提供了 Arl2 在细胞微管生长中发挥作用的证据，但最近我们发现 Arl2 在维持能量 (ATP) 水平方面发挥着必然作用，预计这将是其在真核生物中的基本作用。在此应用中，我建议开发 Arl2 ATP 水平调节的分子模型，以及 ELMO（吞噬和细胞运动）家族中新发现的 Arl2 GAP/效应器，调节线粒体和高尔基体形态。该应用程序具有三个具体目标。 (1)确定Arl2在维持ATP水平中的作用。 (2) 表征 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。我假设 ELMOD1 在细胞中作为 ArfGAP 发挥作用，可以减弱高尔基体的 Arf 信号传导，并影响 TGN 的膜交通，它在 TGN 具有效应器特性。这些目标共同将为调节可能在所有真核细胞中的能量代谢的古老手段提供详细的分子模型，该模型与细胞分裂、细胞骨架和细胞核中基因转录的调节有关。这些研究有可能从根本上改变我们对与能量代谢、癌症、癌症化疗敏感性和基因转录相关的重要细胞过程的理解。 公共健康相关性：维持适当的能量平衡对于所有细胞的健康和功能至关重要，并且是线粒体（化学能 (ATP) 生成和氧气消耗的场所）的主要责任。众所周知，能源利用的巨大变化会伴随癌症、神经退行性疾病和糖尿病等慢性疾病。我们发现了参与调节细胞 ATP 水平以及线粒体和高尔基体形态的新信号通路，这些信号通路与古老且高度保守的调节性 GTP 酶 Arl2 相关。在本申请中，我提出了三个具体目标，以阐明 Arl2 和 Arl2 GTPase 激活蛋白作为 ATP 产生、线粒体形态和高尔基体完整性调节剂的分子机制，并预测与细胞分裂和细胞骨架的联系。