ARL2: Regulator of Cytoskeleton and Mitochondria

ARL2：细胞骨架和线粒体的调节因子

• 批准号: 7001332
• 负责人: Richard A Kahn
• 金额: $ 26.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-02 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001332
• 关键词: SDS polyacrylamide gel electrophoresis; actins; biological signal transduction; chromatography; complementary DNA; cytoskeleton; guanosinetriphosphatases; microtubules; mitochondria; molecular cloning; phosphorylation; polymerase chain reaction; protein localization; radiography; recombinant proteins; tubulin

DESCRIPTION (provided by applicant): Signal transduction research today encompasses all aspects of cell regulation and metabolism. While dissecting the complexities inherent in the detailed mechanisms of each cellular pathway there is a growing appreciation for the need to understand how different pathways are connected within each cell. Such connections are required for cells to respond in a coordinated fashion to changes in environment, cell cycle or developmental stage. At the heart of these integrated circuits are the regulatory GTPases in the Ras superfamily. While most families within the Ras superfamily have fairly well defined functions (e.g., Ras as regulator of proliferation, Rho as regulators of cytoskeleton) the Arf family is more divergent in both structures and functions. Though Arfs regulate vesicle traffic in all eukaryotes, they also regulate aspects of lipid metabolism. Models that integrate these two principal functions into a general view of cell regulation by Arfs remain controversial but correctly identify what is needed in modeling Arf functions - a vision of a higher order integration of cell regulation. In this proposal we focus on mammalian Arl2, and its novel locations and functions in cells. Evidence from a number of organisms reveals that Arl2 orthologs regulate microtubule dynamics. Studies in my laboratory have revealed a unique assortment of cellular locations for mammalian Arl2 (including mitochondria, cytosol, and plasma membrane) that argue for cellular roles distinct from microtubule Idynamics. Understanding the role of Arl2 in each of these locations is predicted to add to our understanding of the integration of tubulin dynamics with other cellular processes. Insight into why and how these activities are linked by a common regulatory protein will provide a higher level of understanding of cell regulation and the interplay between these essential processes. Because Arl2 and Arl3 share a number of structural, biochemical, and biological similarities I also propose to study aspects of Arl3 function, originally in comparison to Arl2 but also in its own right as a putative regulator of actin dynamics. And finally, relating these functions and mechanisms to those of the Arfs should also reveal important similarities and differences within the Arf family.

描述（由申请人提供）： 当今的信号转导研究涵盖了细胞调节和新陈代谢的各个方面。在剖析每个细胞通路的详细机制所固有的复杂性的同时，人们越来越认识到需要了解每个细胞内不同通路如何连接。细胞需要这种连接才能以协调的方式对环境、细胞周期或发育阶段的变化作出反应。这些集成电路的核心是 Ras 超家族中的调节 GTP 酶。虽然 Ras 超家族中的大多数家族具有相当明确的功能（例如，Ras 作为增殖调节剂，Rho 作为细胞骨架调节剂），但 Arf 家族在结构和功能上差异更大。尽管 Arfs 调节所有真核生物中的囊泡运输，但它们也调节脂质代谢的各个方面。将这两个主要功能整合到 Arf 细胞调节的一般视图中的模型仍然存在争议，但正确地确定了 Arf 功能建模所需的内容 - 细胞调节的更高阶整合的愿景。在本提案中，我们重点关注哺乳动物 Arl2 及其在细胞中的新位置和功能。来自许多生物体的证据表明，Arl2 直系同源物调节微管动力学。我实验室的研究揭示了哺乳动物 Arl2 独特的细胞位置分类（包括线粒体、细胞质和质膜），这些位置主张与微管动力学不同的细胞作用。了解 Arl2 在每个位置中的作用预计将有助于我们了解微管蛋白动力学与其他细胞过程的整合。深入了解这些活动为何以及如何通过共同的调节蛋白联系起来，将有助于更好地理解细胞调节以及这些基本过程之间的相互作用。由于 Arl2 和 Arl3 在结构、生化和生物学方面有许多相似之处，我还建议研究 Arl3 功能的各个方面，最初是为了与 Arl2 进行比较，但也以其本身作为肌动蛋白动力学的假定调节因子。最后，将这些功能和机制与 Arf 的功能和机制联系起来也应该揭示 Arf 家族内部的重要相似之处和不同之处。