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Project 11: Information flow through growth factor receptor kinases: unraveling the crosstalk between the inside to the outside of the cell
Promotor: Peter Carmeliet, VIB Vesalius Research Center, K.U.Leuven
Co-promotor: Joost Schymkowitz & Frederic Rousseau, VIB Switch Laboratory, Vrije Universiteit Brussel
Keywords: Receptor Tyrosine Kinases, Inflammation, Cancer, Angiogenesis, Protein Structure
Host University: K.U.Leuven
Receptor tyrosine kinases (RTK's) are transmembrane proteins with an extracellular receptor domain with a high affinity for a particular ligand, such as a polypeptide growth factor, a cytokine or a hormone. Ligand binding triggers the activation of an intracellular tyrosine kinase domain, which in turn triggers upregulation of specific pathways leading to particular functional outcomes such as proliferation or growth. In other words, information about an extracellular binding event is effectively transferred to the cell interior and the RTK is acting as the channel. Given their strategic position at the cellular interface and their involvement in cancer and inflammation, RTK's constitute excellent drug targets. Existing drugs target act either by complete inhibition of the tyrosine kinase domain via small organic compounds or by inhibition of the extracellular binding event via monoclonal antibodies. Our laboratories have recently uncovered an exciting new paradigm to modify RTK activity, by directly interfering with the flow of information from the outside to the inside of the cell. In particular, we have shown that small compounds can act as allosteric modulators that alter downstream signaling pathways. Allosteric drugs have received a lot of attention recently because they significant advantages over competitive inhibitors, since they often achieve partial antagonism, eliminating undesired activities while leaving others intact, and thus decreasing unwanted side-effects. We were able to identify the region in the extracellular domain of the protein that is crucial for signal transduction and we have shown to alter the signaling capability of the receptor by site directed mutagenesis. Given these two important tools (compounds plus mutations), the project aims to further investigate (allosteric) regulatory mechanisms of important RTKs (i.e. VEGFRs, PDGFRs, etc), and - more specifically - the crosstalk between the extracellular, growth factor binding domain of the receptor, and the activity of the intracellular kinase domain. To achieve this goal, we will combine in silico modeling, biophysical analysis, mutagenesis and cell biology to further unravel novel regulatory mechanisms of signal transduction, which will, most likely, lead to novel concepts for therapy-design. Since 15 years, the Vesalius Research Center (VRC) has focused its research interests on unraveling the molecular basis of angiogenesis (i.e. the formation of blood vessels) and translating these genetic insights in therapeutic concepts - and, if possible, novel treatments. In addition, the Switch laboratory has extensive expertise in the study of protein folding & stability and recently developed a theoretical framework for studying the relation between conformational flexibility of a molecule and its signal transduction capacity.
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