ARL2: Regulator of Cytoskeleton and Mitochondria

描述（由申请人提供）： 今天的信号转导研究涵盖了细胞调节和代谢的各个方面。在剖析每个细胞通路的详细机制中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的通路是如何连接的。这种连接是细胞以协调的方式对环境，细胞周期或发育阶段的变化做出反应所必需的。这些集成电路的核心是Ras超家族中的调节性GTP酶。虽然Ras超家族中的大多数家族具有相当好定义的功能（例如，Ras作为细胞增殖的调节因子，Rho作为细胞骨架的调节因子）Arf家族在结构和功能上都更加不同。虽然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Arfs细胞调控的一般观点中的模型仍然存在争议，但正确识别了Arf功能建模所需的内容-细胞调控的高阶整合的愿景。在这个建议中，我们专注于哺乳动物Arl 2，和它的新的位置和功能在细胞中。来自许多生物体的证据揭示Arl 2直系同源物调节微管动力学。在我的实验室的研究已经揭示了一个独特的分类哺乳动物Arl 2（包括线粒体，胞质溶胶和质膜）的细胞位置，认为细胞的作用不同于微管Idynamics。了解Arl 2在这些位置中的每一个中的作用预计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。深入了解这些活动为什么以及如何通过一个共同的调节蛋白联系起来，将提供对细胞调节和这些基本过程之间相互作用的更高水平的理解。由于Arl 2和Arl 3有许多结构，生物化学和生物学上的相似性，我还建议研究Arl 3功能的各个方面，最初与Arl 2相比，但也以其自身的权利作为肌动蛋白动力学的假定调节器。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家族中重要的相似性和差异性。

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.