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代谢的各个方面。在剖析每个细胞途径的详细机制中固有的复杂性时，人们对需要了解每个细胞中不同途径如何连接的需要越来越多。细胞需要以协调的方式对环境，细胞周期或发育阶段的变化进行响应。这些综合电路的核心是RAS超家族中的调节GTPase。尽管RAS超家族中的大多数家庭具有相当明确的功能（例如，RAS作为增殖的调节剂，RHO作为细胞骨架的调节剂）ARF家族在结构和功能上都更加不同。尽管ARF调节所有真核生物的囊泡流量，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对细胞调节的一般视图中的模型仍然有争议，但正确地确定了建模ARF功能所需的内容 - 对细胞调节的高阶整合的愿景。在此提案中，我们专注于哺乳动物ARL2及其在细胞中的新位置和功能。来自许多生物的证据表明，ARL2直系同源物调节微管动力学。在我的实验室中的研究表明，哺乳动物ARL2（包括线粒体，细胞质和质膜）的细胞位置有独特的各种位置，这些细胞角色涉及与微动物学不同的细胞作用。预计了解ARL2在这些位置中的每个位置中的作用将增加我们对微管蛋白动力学与其他细胞过程的整合的理解。深入了解这些活动如何以及如何通过常见的调节蛋白联系在一起，将为细胞调节和这些基本过程之间的相互作用提供更高水平的了解。由于ARL2和ARL3共享许多结构，生化和生物学相似性，因此我也建议研究ARL3功能的各个方面，最初与ARL2相比，但本身也作为肌动蛋白动力学的推定调节剂。最后，将这些功能和机制与ARF的功能和机制联系起来，还应揭示ARF家族中重要的相似性和差异。