Functional interplay of ciliary trafficking complexes and motor proteins.

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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.