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

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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.