Understanding the mechanisms of cross-talk between posttranslational modifications during growth factor signalling

细胞行为由复杂的细胞信号事件系统控制，包括改变蛋白质功能、活性或稳定性的翻译后修饰（PTM）。已知两种这样的PTM（磷酸化和泛素化）之间的串扰在确定特定的细胞结果中起重要作用，然而在某些细胞条件下关于这些修饰的相互作用仍有很多需要了解。蛋白质组学技术的进步使得能够在全球范围内对磷酸化和泛素化事件进行大规模分析。结合定量技术，如在细胞培养物中用氨基酸稳定同位素标记（SILAC），可以研究在特定细胞条件下大量修饰肽的丰度变化。可以使用磷酸化和泛素化肽的并行富集策略来鉴定肽的共修饰，从而了解这两种修饰是如何交叉调节的。生长因子调节的信号传导途径依赖于翻译后修饰来控制生物反应的持续时间。成纤维细胞生长因子（FGF）信号通路是介导许多细胞过程如细胞增殖、分化和存活的一种这样的通路。已知泛素化事件在反馈回路中起作用以衰减信号，尽管这些事件尚未在全球范围内进行研究。该项目的目的是研究响应FGF的磷酸化和泛素化之间的串扰，并了解这些修饰如何动态地共同作用以微调相关的生物反应。

Cell behaviour is controlled by a complex system of cell signalling events that include post-translational modifications (PTMs) that alter the functionality, activity or stability of a protein. Cross talk between two such PTMs, phosphorylation and ubiquitination, is known to play an important role in determining specific cellular outcomes, however there is still much to learn about the interplay of these modification under certain cellular conditions. Advances in proteomics techniques have enabled large scale analysis of both phosphorylation and ubiquitination events on a global scale. Combined with quantitative techniques such as stable isotope labelling with amino acids in cell culture (SILAC), changes in the abundance of large numbers of modified peptides under specific cellular conditions can be investigated. Co-modification of peptides can be identified using concurrent enrichment strategies for both phosphorylated and ubiquitinated peptides, leading to an understanding of how these two modifications are cross-regulated. Growth factor regulated signalling pathways are reliant on post-translational modifications to control the duration of a biological response. The fibroblast growth factor (FGF) signalling pathway is one such pathway that mediates many cellular processes such as cell proliferation, differentiation and survival. Ubiquitination events are known to act in feedback loops to attenuate the signal, although these events have not been studied in a global context. The aim of this project is to study the cross talk between phosphorylation and ubiquitination in response to FGF and gain an understanding of how these modifications dynamically act together to finely tune the associated biological responses.