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不同的通路在每个细胞内是如何连接的。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都有相当明确的功能(例如，RAS作为增殖调节因子，Rho作为细胞骨架调节因子)，但Arf家族在结构和功能上更具差异性。虽然ARF调节所有真核生物的囊泡运输，但它们也调节脂类代谢的各个方面。将这两个主要功能集成到ARF对细胞调节的一般视图中的模型仍然存在争议，但正确地识别了建模ARF功能所需的内容-细胞调节的更高阶整合的愿景。在这项建议中，我们关注哺乳动物的Arl2，以及它在细胞中的新位置和功能。来自许多生物体的证据表明，Arl2同源基因调节微管动力学。我实验室的研究揭示了哺乳动物Arl2(包括线粒体、胞浆和质膜)的一种独特的细胞位置，这证明了细胞的作用不同于微管IDynamic。了解Arl2在这些位置中的每一个位置的作用预计将有助于我们理解微管蛋白动力学与其他细胞过程的整合。深入了解为什么以及如何通过共同的调节蛋白将这些活动联系在一起，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Arl2和Arl3在结构、生化和生物学上有许多相似之处，我还建议研究Arl3功能的各个方面，最初是与Arl2比较，但也是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家族内部重要的相似和不同之处。

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.