Ubiquitylation Dynamics in Adhesion Complexes: Impact on Cell Migration and the Transcriptional Landscape

黏附复合物是细胞用来解释和响应细胞外环境的动态结构。在多细胞生物中，粘附复合体信号传导几乎参与了所有的生物过程，并导致包括癌症在内的多种疾病的发生。粘附复合物中的整合素受体控制来自细胞外环境的机械力如何跨膜传递，从而控制细胞迁移和转录，这是细胞主要功能的基础。通过采用蛋白质组学方法，我们可以剖析整合素招募的蛋白质网络中的分子复杂性，被称为“粘附体”。我们的数据表明，许多调节泛素的分子被招募到粘附体中。泛素系统由一系列复杂的酶和多肽组成，这些酶和多肽调节蛋白质稳定性和信号传导以协调生物过程。该项目将研究“泛素密码”如何动态调节粘附复合物、细胞迁移和整合素依赖性转录。通过采用系统生物学方法；利用最先进的蛋白质组学分析，数据整合和活细胞成像，我们的目标是确定泛素系统如何动态控制整合素介导的功能。我们将首先定义粘附复合物的泛素化特征——“粘附体泛素代码”，并描述其在粘附转换过程中的动态变化。随后，我们将确定“粘附体泛素密码”对粘附动力学和细胞迁移的影响，并评估“粘附体泛素密码”如何协调机械力的传递以控制转录。最终，这些跨学科的研究将揭示泛素化的动态变化如何控制粘附动力学和力转导，从而调节细胞迁移和力依赖性转录。

Adhesion complexes are dynamic structures used by cells to interpret and respond to their extracellular environment. Adhesion complex signalling contributes to almost all biological processes in multicellular organisms and disruption drives a wide range of diseases, including cancer. Integrin receptors in adhesion complexes control how mechanical forces from the extracellular environment are transmitted across the membrane to control cell migration and transcription, which underpin major cellular functions. By employing proteomic approaches, we can dissect the molecular complexity within the network of proteins recruited to integrins, known as the "adhesome". Our data suggests that many molecules that regulate ubiquitin are recruited to the adhesome. The ubiquitin system comprises a complex range of enzymes and polypeptides that regulate protein stability and signalling to co-ordinate biological processes. This project will investigate how the "ubiquitin code" dynamically regulates adhesion complexes, cell migration and integrin-dependent transcription. By employing a systems-biology approach; using state-of-the-art proteomic analysis, data integration and live-cell imaging, we aim to determine how the ubiquitin system dynamically controls integrin-mediated functions. We will start by defining the ubiquitylation profile of adhesion complexes - the "adhesome ubiquitin code" and by characterising dynamic changes of this during adhesion turnover. Subsequently, we will determine the impact of the "adhesome ubiquitin code" on adhesion dynamics and cell migration and assess how the "adhesome ubiquitin code" co-ordinates transmission of mechanical forces to control transcription. Ultimately these inter-disciplinary studies will reveal how dynamic changes in ubiquitylation control adhesion dynamics and force transduction to regulate cell migration and force-dependent transcription.