Systematic molecular and cell biological analysis of MST kinase signalling in cell death cell cycle and centrosome biology

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The human body is composed of diverse cell types with specialised tasks. Much research has been carried out to gain a better understanding of how cells decide where to be and what to do. Recent research has also shown that it is crucial to comprehend how cell number and tissue architecture is controlled under normal physiological conditions such as development or organ regeneration. Normally, to ensure that each tissue is patterned not only to a specific architecture but also to a defined size, multicellular organisms govern the coordination of cell death and multiplication by strict control mechanisms. Therefore, one very important aspect of ongoing research is to define key factors that are essential for this coordination. Interestingly, proteins that modify other proteins by a specific tag (through a molecular mechanism called by specialists phosphorylation) are sometimes central in the coordination of these activities. These modifiers (also termed kinases) represent the field of my interest. Significantly, the tagging of proteins by phosphorylation can change various properties of the tagged protein. For example, enzymatic activities can be increased or decreased, the localisation within the cell might be altered, or binding partners might be lost or gained. Therefore, it is very important that we understand how the activity of kinases is strictly regulated. Equally important, we also must comprehend the importance of (or sometimes also the lack thereof) certain kinase activities. With this study, I will investigate the yet unidentified complexities of an entire family of kinases. Members of this family have already been shown to function as tumour suppressor protein, but I strongly believe that we are yet to unveil important functions of these proteins in healthy normal human cells. By identifying roles of these kinases in the control of how cells die (programmed cell death, also termed apoptosis) and multiplicate (a process termed proliferation), I will decipher the biological significance of the entire kinase family. The studies will involve performing selective manipulation of kinase activities as well as their level of abundance, and the use of additional molecular and cell biological techniques to define which tagging (phosphorylation) events are the most important. Altogether, I strongly feel that the main objectives of this proposal will help to improve our understanding of this essential kinase family. Given that these kinases function in the immune and cardiovascular system, as well as in tumour suppression, discoveries from this proposal could serve as a foundation for improvements regarding lifelong health and wellbeing. On the long-term, understanding these kinases might help to establish how far these proteins can be used as read-outs in the prevention, detection, prognosis and treatment of various human diseases.