The Regulation and Cellular Activities of the ARL2 GTPase

ARL2 GTPase 的调节和细胞活性

• 批准号: 8964313
• 负责人: Richard A Kahn
• 金额: $ 32.84万
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964313
• 关键词: Address; Affect; Binding; Biological; Biology; Cell division; Cell physiology; Cells; Cellular biology; Centrosome; Complex; Crista ampullaris; Cytoskeleton; Cytosol; Disease; Dissection; Embryo; Energy Metabolism; Equilibrium; Essential Genes; Eukaryota; Eukaryotic Cell; Family; Fibroblasts; Functional disorder; Funding; Generations; Grant; Guanine Nucleotide Dissociation Inhibitors; Guanosine Triphosphate Phosphohydrolases; Hamman-Rich syndrome; Health; Heart Diseases; Human Pathology; Intervention; Knockout Mice; Link; Malignant Neoplasms; Mediating; Membrane; Membrane Protein Traffic; Microtubules; Mitochondria; Modeling; Molecular; Molecular Chaperones; Molecular Models; Morphology; Mus; Nerve Degeneration; Pathway interactions; Phenocopy; Point Mutation; Preparation; Process; Production; Proteins; Reagent; Regulation; Retinal Degeneration; Role; Series; Signal Transduction; Site; Small Interfering RNA; System; Testing; Tubulin; Work; base; cell growth regulation; cell motility; cofactor; deafness; density; dimer; human disease; insight; member; molecular modeling; mutant; novel; polymerization; protein complex; public health relevance

 DESCRIPTION (provided by applicant): Members of the ARF family of regulatory GTPases function as nodes in cell signaling to coordinate essential cell processes; including membrane traffic, energy metabolism, and the cytoskeleton. The focus of this application is one of those GTPases, ARL2, and its binding partners. An understanding of the molecular mechanisms of ARL2 action to carry out or regulate essential cell processes will reveal novel insights into fundamental aspects of cell biology as well as providing potential targets for intervention to alte the course of human diseases; including but not limited to cancer, heart disease, neurodegeneration, retinal degeneration, and deafness. During the previous four years of funding we have provided rigorous tests of several models for ARL2 actions in different parts of eukaryotic cells, discarding some and refining others. We have also generated many key reagents, including the first purified protein preparations of mg levels of four different proteins and a series of point mutations in ARL2 that allow dissection of its different essential roles in eukaryotic cells. Thus, we are poised to make much more rapid progress in our understanding of the molecular mechanisms of regulation of tubulin folding and polymerization, ATP generation in mitochondria, and mitochondrial fission and motility. In the next funding period we propose three new, specific aims that are logical extensions of our previous work but which promise to have a far broader impact on several fields of cell signaling and regulation. In aim 1 we will test the model that ARL2 acts with the tubulin-specific co-chaperone cofactor D (TBCD) to regulate tubulin folding, microtubule density or polymerization, and less directly cell division. In aim 2 w will test the hypothesis that ARL2 regulates ATP production in mitochondria via changes in cristae remodeling and mitochondrial fusion. And in aim 3 we examine how mitochondrial fusion and motility are regulated by the ARL2 effector and GAP, ELMOD2.

 描述（由申请人提供）：调节 GTP 酶 ARF 家族的成员在细胞信号传导中充当节点，以协调重要的细胞过程；包括膜运输、能量代谢和细胞骨架。该应用的重点是 GTPases 之一、ARL2 及其结合伙伴。了解 ARL2 执行或调节重要细胞过程的分子机制将揭示细胞生物学基本方面的新见解，并为改变人类疾病进程的干预提供潜在目标；包括但不限于癌症、心脏病、神经变性、视网膜变性和耳聋。在过去四年的资助期间，我们对真核细胞不同部位的 ARL2 作用的多个模型进行了严格的测试，丢弃了一些模型并改进了其他模型。我们还生产了许多关键试剂，包括四种不同蛋白质毫克级的第一个纯化蛋白质制剂，以及 ARL2 中的一系列点突变，从而可以剖析其在真核细胞中的不同基本作用。因此，我们准备在对微管蛋白折叠和聚合、线粒体中 ATP 生成以及线粒体裂变和运动调节的分子机制的理解方面取得更快的进展。在下一个资助期内，我们提出了三个新的具体目标，它们是我们之前工作的逻辑延伸，但有望对细胞信号传导和调控的多个领域产生更广泛的影响。在目标 1 中我们将测试 该模型认为，ARL2 与微管蛋白特异性辅助伴侣辅助因子 D (TBCD) 一起作用，调节微管蛋白折叠、微管密度或聚合，以及不太直接的细胞分裂。在目标 2 中，我们将检验 ARL2 通过嵴重塑和线粒体融合的变化来调节线粒体中 ATP 产生的假设。在目标 3 中，我们研究了 ARL2 效应器和 GAP、ELMOD2 如何调节线粒体融合和运动。