Functional interplay of ciliary trafficking complexes and motor proteins.

初级纤毛从几乎所有人类细胞的表面伸出，作为信号平台。它们对人类和动物的发育至关重要，并且在整个生命过程中都需要它们来控制与骨骼形成和维持、肾脏功能、大脑信号传导和许多其他身体功能相关的途径。这些纤毛是由一系列大的多蛋白复合物构建和维持的。我们在英国和日本的两个实验室对我们对所涉及的关键机器的理解做出了重大贡献。最近，我们分别定义了两种微管运动蛋白复合物，纤毛中的动力蛋白-2和动力蛋白-2的功能。它们不仅需要建立纤毛，还需要维护纤毛，并沿着这个结构驱动运输。我们的工作已经达到了一个阶段，我们认为结合我们的努力来更好地了解这些复合物是如何工作的是非常有益的，不仅仅是在孤立的情况下，而是在纤毛功能所需的其他大型多蛋白机器的背景下。dynein-2和kinesin-2微管马达在微管运动功能、蛋白质运输和纤毛功能之间提供了一个基本的联系，因为它在纤毛内驱动鞭毛内运输（IFT）。斯蒂芬斯实验室是第一个确定人类动力蛋白-2马达亚基组成的实验室。中山实验室在了解激酶-2如何与IFT机制整合方面取得了重大进展。这个雄心勃勃的项目旨在结合我们在蛋白质相互作用分析和细胞成像方面的专业知识，以确定动力蛋白-2和动力蛋白-2如何与其他主要的纤毛细胞IFT-A、IFT-B和BBSome相互作用并协同工作。我们的目标是提供一个完整的分子相互作用的动力蛋白-2复合物与系统的其他关键组成部分，动力蛋白-2马达，BBSome和IFT颗粒，IFT- a和IFT- b，使用分子细胞生物学方法的组合，包括先进的显微镜和蛋白质组学。我们目前的工作已经开发出蛋白质组学方法，已经确定了关键的相互作用蛋白，这些蛋白似乎指导了动力蛋白-2的组装和功能。这是一个前沿生物科学项目，旨在了解细胞生物学的基本过程。也就是说，纤毛的形成、对基于纤毛的信号通路的严格控制以及对细胞周期进入和退出的控制是正常健康的基础，也对人类和动物的健康具有潜在的长期影响。纤毛信号包括控制人类早期发育的纤毛信号，以及在整个生命过程中控制新陈代谢的纤毛信号。针对常见癌症的关键药物也针对纤毛信号通路。对纤毛的结构和功能的充分了解是许多领域的关键，从人类发育的最初阶段到整个生命都具有相关性。

Primary cilia project from the surface of nearly all human cells to serve as signalling platforms. They are essential for human and animal development and are also required throughout life to control pathways that relate to the formation and maintenance of bone, kidney function, signalling in the brain and many more body functions. These cilia are built and maintained by a series of large multi-protein complexes. Our two labs in the UK and Japan have made significant contributions to our understanding of the key machines involved. Most recently we have each defined the function of two microtubule motor protein complexes, dynein-2 and kinesin-2 in cilia. They are both required not only to build the cilium but to maintain it and drive transport along this structure. Our work has reached a point where we consider it hugely beneficial to combine our efforts to better understand how these complexes work, not just in isolation, but in the context of the other large multi-protein machines that are required for cilia function. The dynein-2 and kinesin-2 microtubule motors provides a fundamental link between microtubule motor function, protein trafficking, and cilia function because of its function in driving intraflagellar transport (IFT) within cilia. The Stephens lab was the first to define the subunit composition of the dynein-2 motor in humans. The Nakayama lab have made major advances in our understanding of how kinesin-2 integrates with the IFT machinery. This ambitious project seeks to combine our expertise in protein interaction analysis and cell imaging to define how dynein-2 and kinesin-2 interact with, and work in concert with, the other major ciliary machines called IFT-A, IFT-B and the BBSome. We aim to provide a complete picture of the molecular interactions of the dynein-2 complex with other critical components of the system, the kinesin-2 motor, the BBSome and the IFT particles, IFT-A and IFT-B, using a combination of molecular cell biology approaches including advanced microscopy and proteomics. Our current BBSRC-funded work has developed proteomics approaches that have identified key interacting proteins that seem to direct the assembly and function of dynein-2. This is a frontier bioscience project that seeks to understand fundamental processes in cell biology. That said, the formation of cilia, tight control of cilia-based signalling pathways, and the control of entry to and exit from the cell cycle are fundamental to normal health as well as having potential long-term impact on human and animal health. Ciliary signals include those that control early human development as well as others that occur throughout life to control metabolism. Key pharmaceuticals targeting common cancers are also directed against ciliary signalling pathway. A full understanding of the structure and function of cilia is key to a diverse array of fields and has relevance from the earliest stages of human development and throughout life.