Protein kinases mediate most of the signal transduction events in cells by phosphorylation of specific substrates – modifying their activity, cellular location, and/or association with other proteins. The extremely critical role of kinases for critical cellular decisions came evident when an unexpectedly large number of kinases (120/518) were found to be mutationally activated activated or their expression increased due to gene-amplification or translocation in many types of human cancer, suggesting that either a large number of kinase-pathways can contribute to cancer, or that many kinases can regulate the same pathways when activated unphysiologically. These observations point towards a model where cancer can be caused by combinations of multiple different alterations within the cellular systems that control cell and tissue growth, and cancer can thus be clearly described as a complex and multifactorial disease. To date, cancer causing mechanism have been primarily studied using the methods of cell biology, biochemistry and/or genetics, methods which typically reduce complex cellular responses into (often linear) sequences of signaling events. While these efforts have accumulated enormous amounts of detailed information, the heterogeneity of the experimental approaches makes integration of this information into a comprehensive quantitative model a daunting if not impossible task. The critical information about the connectivity of concurrently active signaling pathways, their dynamics and the emergence of physiological responses from molecular events has remained elusive. The main goal of this proposed project is to use systems biology methods to characterize and decipher the cancer linked kinase signalling networks at a molecular and quantitative level to provide the basis for predictive mathematical models for cancer onset. This knowledge of wiring diagram of cancer related kinases will be fundamental in developing therapeutic strategies for cancer.
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