Infection, Immunology and Translational Medicine - 'Investigating the mechanism of non-catalytic tyrosine phosphorylated receptor triggering' (360G-Wellcome-097108_Z_11_Z)

The central goal of this project is to investigate the mechanism of non-catalytic tyrosine phosphorylated receptor (NTR) triggering. These receptors share a number of features. For example, they contain, or associate with adaptor molecules that contain, tyrosine residues that are phosphorylated by extrinsic kinases, and have comparatively small extracellular domains which bind surface-associated ligands. Our hypothesis is that the kinetic-segregation model, initially proposed to explain T cell receptor triggering, applies to all othermembers of the NTR family. A number of recent reports including work with natural killer cell receptors have provided evidence to support this notion. This project aims to develop and validate a number of generic techniques for systemically investigating the mechanism of NTR triggering and testing the KS model. Imaging, biochemical studies and functional assays will all be utilisedto aid in this. In parallel, a more in-depth analysis of a small subset of NTRs from various subgroups of the family, including leukocyte-associated immunoglobulin-like receptor 1 will be conducted. These experiments will complement the artificial system developed for large-scale systemic investigations of numerous NTRs, by utilising more physiological settings, including the use of natural ligands and primary cells that normally express the NTR.