Title: The structural biology of recognition and signalling at the cell surface.
Funder: Cancer Research UK

Abstract: We study the interactions at cell surfaces by which the cells of the human body communicate. Our goals are to produce, using structural biology, detailed æsnap-shotsÆ to reveal the mechanisms which determine what cells do and where, for example, whether a cell stays attached to its neighbours or migrates elsewhere. The Cancer Research UK Receptor Structure Research Group is focused on the structural biology of cell surface recognition and signalling complexes. During the current quinquennium we have combined structural (x-ray crystallographic), biophysical and functional analyses to dissect the features controlling complex formation, affinity and specificity for extracellular ligand-receptor interactions in a number of systems of relevance to cancer research. Through interdisciplinary collaborations with CR-UK funded researchers our results are guiding the development of synthetic NKT cell agonists for use as immune modulators, and strategies to inhibit tumour growth exploiting the natural antagonist IGF-II receptor (IGF2R). The proposed programme of basic research for the next quinquenium aims to break fresh ground in our understanding of single membrane span cell surface receptors by generating detailed insights into the mechanisms by which extracellular interactions trigger cytoplasmic signalling pathways. To do so, we will need to analyse full membrane spanning versions of our target systems and test our proposed hypotheses back in the context of multi-molecular assemblies at the cell surface. We will focus on four cell surface receptor systems of fundamental importance in tissue morphogenesis and homeostasis; these can be grouped into three inter-related project areas: 1. Guidance and adhesion. What are the mechanisms by which two cell guidance signalling systems (ephrins - Eph receptor tyrosine kinases, semaphorins - plexins) contribute to the balance between cell motility and adhesion? 2. Adhesion and signalling. How do extracellular interactions impact on the cytoplasmic phosphatase activity of receptor protein tyrosine phosphatases and their co-localization with cadherin substrates? 3. Signalling agonists and antagonists. How is Wnt signalling modulated at the cell surface? All of the above systems have been implicated as contributing to, or suppressing, the tumorigenic process, in particular the balance between cell adhesion and migration. I therefore expect that the reagents, data and insights we generate will ultimately underpin translational research and I will develop the necessary interdisciplinary collaborations as appropriate. During the current quinquennium we have developed the methodologies to allow us to address the challenges presented by large multi-molecular assemblies and membrane spanning receptors. These methods include efficient large scale expression of proteins in mammalian cells and manipulation of glycosylation. We will need to link x-ray crystallographic and/or electron microscopic analyses with the function of receptors in living cells and to achieve this we will exploit a variety of fluorescence microscopy techniques.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS