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

细胞生长、分裂和分化是生命的基本过程。然而，这些途径必须严格调控，以防止发育异常或癌症。细胞生长和增殖由一系列不同的生长因子调节，这些生长因子与细胞表面受体结合并激活细胞内信号传导过程，从而诱导基因表达变化或改变细胞中现有蛋白质的活性。生长因子信号通路关键成分的突变或基因表达变化可驱动肿瘤发展。本项目的目的是探索S-酰化在调节与癌症相关的蛋白质（包括Ras蛋白、Sprouty/SPRED蛋白和细胞表面受体）中的作用。S-酰化是一种翻译后修饰，涉及脂肪酸（主要是棕榈酸）连接到蛋白质中的半胱氨酸残基上。我们将采用包括基因编辑（例如CRISPR），捕获和释放成像方法（例如使用选择性钩系统的保留）和功能测定在内的技术来确定S-酰化如何调节这些蛋白质在细胞生长途径中的定位和活性。我们还将使用化学生物学方法来研究这些蛋白质的定位和功能如何受到不同脂质类型的影响，以确定代谢变化（如癌症中所见）是否会通过差异脂质化影响蛋白质功能和生长因子信号传导。总的来说，该项目将为研究不足的脂质修饰对基本细胞生物学过程的调节提供新的见解，并可能发现可在未来研究中开发的新治疗策略。

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.