Exploring the role of protein lipidation as a new therapeutic target in cancer and other disorders

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Cell growth, division and differentiation are essential processes for life. However, these pathways must be tightly regulated to prevent developmental abnormalities or cancer. Cell growth and proliferation are regulated by a range of different growth factors that bind to cell surface receptors and activate intracellular signalling processes that induce gene expression changes or modify the activity of existing proteins in the cell. Mutations or gene expression changes in key components of growth factor signalling pathways can drive tumour development. There is growing interest in targeting post-translational modifications of cancer-related proteins as a therapeutic approach.The aim of this project is to explore the role of S-acylation in regulating proteins linked to cancer, including Ras proteins, Sprouty/SPRED proteins and cell surface receptors. S-acylation is a post-translational modification involving the attachment of fatty acids (predominantly palmitate) onto cysteine residues in proteins. We will employ techniques including gene editing (e.g. CRISPR), trap and release imaging approaches (e.g. retention using selective hooks system) and functional assays to determine how S-acylation regulates the localisation and activity of these proteins in cell growth pathways. We will also use chemical biology methods to examine how the localisation and function of these proteins are affected by different lipid types to determine if metabolic changes (as seen in cancer) could impact protein function and growth factor signalling through differential lipidation. Collectively, this project will provide new insight into the regulation of fundamental cell biology processes by a poorly-studied lipid modification and potentially uncover new therapeutic strategies that can be developed in future studies.