The ubiquitin-dependent activation of kinases

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Cells respond and adapt to various internal and external stimuli through a variety of detectors, which receive the signal. The signal orchestrates the cell response through a signal transduction pathway. Signal transduction pathways involve numerous components all woven together in what seems like an impossible meshwork of interconnecting components, much like inside a telephone exchange. Therefore, to ensure that a correct signal is propagated and transmitted, key decision making hubs that interpret the incoming signal and define the output are required. These hubs are switched on at defined moments by a protein called ubiquitin. Ubiquitin can be assembled into long polymers, just like beads on a string, and the different ways in which ubiquitin can be self-assembled, results in defined codes.I will determine how certain signalling hubs are regulated by ubiquitin and know how to transmit an appropriate response. The signalling hubs that I am interested in reside in crucial cellular pathways that are vital for cells to respond to infection by a pathogen or to external signals. Interpretation of these signals is vital for cellular survival: several human diseases ranging from inflammatory diseases, certain cancers and neurological disorders all arise from defects within these signalling hubs. My approach to understanding the regulation of these signalling hubs involves reconstitution and analysis of the separate components followed by building the complex together. Taking such an approach ensures that the function of each component can be carefully analysed and the function of it can be understood. I will use a toolkit of biochemical and biophysical techniques to understand how the ubiquitin code is able to regulate a defined subset of signalling hubs and I will obtain molecular snap-shots that will provide the three-dimensional structure of the activated signalling hub bound to ubiquitin. Understanding the structure of these activated hubs will, for the first time, provide a glimpse into how the entire complex is regulated. Furthermore, the structure will provide an explanation of how particular genetic mutations in these hubs leads to certain diseases. For example, Crohn's disease and amyotrophic lateral sclerosis. In addition, the structures will serve as a guide for the development of new compounds that disrupt the ubiquitin-dependent activation of these signalling hubs and therefore may offer new alternative treatments for these diseases. Therefore, my research will progress the knowledge of how and why these signalling events can go astray in a number of human diseases.