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

This project will enable us to understand mechanisms controlling cell migration and transcription, which underpin major cellular functions.

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 animals and disruption drives a wide range of diseases, particularly 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.

By employing proteomic approaches, we can dissect the molecular complexity within the network of proteins recruited to integrins (the “adhesome”). We have evidence 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. We now want to investigate how the “ubiquitin code” dynamically regulates adhesion complexes, cell migration and integrin-dependent transcription. 

Objectives

You will employ a systems-biology approach; using state-of-the-art proteomic analysis, data integration and live-cell imaging to determine how the ubiquitin system dynamically controls integrin-mediated functions. You will:

1) Define the ubiquitylation profile of adhesion complexes – the “adhesome ubiquitin code”

2) Characterise dynamic changes in “adhesome ubiquitin code” during adhesion turnover

3) Determine the impact of the “adhesome ubiquitin code” on adhesion dynamics and cell migration

4) Assess how the “adhesome ubiquitin code” co-ordinates transmission of mechanical forces to control transcription

These inter-disciplinary studies will reveal how dynamic changes in ubiquitylation control adhesion dynamics and force transduction in order to regulate cell migration and force-dependent transcription.

Supervision and training

You will join a multidisciplinary supervisory team with expertise in adhesion receptor signalling, mechanobiology, adhesome proteomics and bioimaging (Mark Morgan), ubiquitin biology, development of proteomic and ubiquitylomic analytical methods and high-throughput drug discovery pipelines (Matthias Trost), and integration of mechanical forces and chemical signalling to co-ordinate cell behaviour (Collaborator, IBEC, Barcelona).

The project incorporates advanced imaging techniques including super-resolution and live-cell imaging, 3D traction-force microscopy and FRET/FLIM. In parallel, the you will gain expertise in advanced proteomics, data analyses and computational modelling. You will also learn a wide range of cell biological, biochemical and molecular techniques. 

You will be based in the Morgan Lab in Liverpool, with opportunities to spend time at the the Trost Lab in Newcastle learning techniques to analyse ubiquitylation using mass spectrometry and in the Cellular & Molecular Mechanobiology Lab, IBEC, Barcelona, performing advanced traction-force microscopy.

Informal enquiries may be made to mark.morgan@liverpool.ac.uk

 HOW TO APPLY

Applications should be made by emailing bbsrcdtp@liverpool.ac.uk with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to bbsrcdtp@liverpool.ac.uk, noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.