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

粘附复合物是细胞用来解释和响应其细胞外环境的动态结构。粘附复合物信号传导有助于多细胞生物体中几乎所有的生物过程，并且破坏驱动了包括癌症在内的各种疾病。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以控制细胞迁移和转录，这是主要细胞功能的基础。通过采用蛋白质组学的方法，我们可以剖析分子的复杂性网络的蛋白质招募到整合素，称为“粘附体”。我们的数据表明，许多调节泛素的分子被募集到粘附体。泛素系统包括一系列复杂的酶和多肽，它们调节蛋白质稳定性和信号传导以协调生物过程。本计画将探讨“泛蛋白密码”如何动态地调控黏着复合物、细胞迁移及整合素依赖的转录。通过采用系统生物学方法;使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。我们将首先定义的泛素化概况的粘附复合物-“粘附体泛素代码”，并通过表征动态变化，这在粘附周转。随后，我们将确定“粘附体泛素代码”对粘附动力学和细胞迁移的影响，并评估“粘附体泛素代码”如何协调机械力的传输以控制转录。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，以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.