Analysis of the regulation and function of the mitotic kinase Citron kinase in cell division

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Cells are the building blocks of many organisms, including humans. Growth, development and reproduction in all these organisms depend on the accurate and fascinating process of cell division, which faithfully partitions the genetic information between the two dividing cells. Proper cell division is also crucial for determining cell fate and tissue organization. Errors during this process are responsible for many genetic diseases, including Down's syndrome, microcephaly, sterility, and cancer. Thus, a thorough understanding of the mechanisms that control cell division may lead to the development of novel therapeutic treatments for these genetic diseases. Moreover, recent evidence also indicates a clear link between cell division and ageing and therefore a knowledge of the cell division process can help understand both the natural process of ageing and the origin of early ageing-related diseases. Complex control and surveillance mechanisms have evolved to ensure the fidelity and robustness of cell division. The genetic material - DNA - is compacted into chromosomes during cell division and is not accessible for the production of new factors. Therefore, the mechanisms that control cell division rely in large part on the regulation of the function and activity of proteins that have been generated before cells begin dividing. One class of proteins that play a key role in controlling the accuracy and fidelity of cell division are the serine/threonine kinases. These kinases can regulate the function, dynamics and activity of numerous other cell division proteins, known as substrates, by adding phosphate groups - a process know as phosphorylation - that alter the mechanical and structural properties of their targets. The goal of this project is to dissect the role of one of this kinase, Citron kinase (CIT-K), which controls different aspects of cell division. We propose to use cutting edge post-genomic technologies to identify all the substrates of CIT-K throughout cell division and to understand how CIT-K is itself regulated through phosphorylation by other kinases. As CIT-K has been linked to human primary microcephaly and proposed as a potential target in anti-cancer therapy, our research will not only help understand key mechanisms that control cell division and proliferation, but will also lay the foundation for the development of future therapies for the treatment of these human pathologies.