Microtubule motors in health and disease
Our research centres on microtubule motor proteins: their regulation, diversity and function, both in healthy cells and how their misfunction may contribute to disease.
Microtubules and their associated motor proteins play a variety of vital roles in orchestrating many processes within higher eukaryotes, such as membrane traffic and cell division. A major challenge is to understand how the cell co-ordinates and regulates all aspects of microtubule-based movement, both temporally and spatially. A number of diseases have been linked malfunction of motor proteins, particularly within the nervous system, and it is certain that more examples will be identified. In addition, our research has shown that the motor protein cytoplasmic dynein is an early target for destruction during programmed cell death, and that disrupting cytoplasmic dynein function in otherwise normal cells can itself trigger apoptosis. Taken together with the essential function of motors in cell division and in transporting tumour suppressors such as Adenomatous Polyposis Coli, this raises the possibility that abnormal motor function could play a part in the development of cancer.
The reconstitution of microtubule-based movement in cell-free systems provides a powerful approach for analysing the components involved. We use cell-free extracts as a rich source of motors, microtubules and membranes. High resolution video-enhanced light microscopy is then used to follow the movement of organelles along microtubules in real time. We also track the movement of green fluorescent protein-tagged cargoes within living cells using timelapse fluorescence microscopy. We combine these motility assays with a wide range of cell and molecular biological techniques to ask the following interconnected questions:
- how are membrane-associated motors regulated during the cell cycle?
- how are membrane movement and membrane traffic integrated within space and time?
- how does one motor bind to many different cargoes?
We have recently made progress on the third topic, as we have shown that different isoforms of kinesin light chain are important in targeting kinesin-1 to distinct membranes (Wozniak & Allan, 2006)(Open access manuscript version : PDF 10.2Mb)