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


Faculty of Health and Life Science

Dr M Morgan , Prof M Trost Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Liverpool United Kingdom Biochemistry Cell Biology Molecular Biology

About the Project

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

 HOW TO APPLY

Applications should be made by emailing 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 , 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.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1) ** Targeted proteomic analysis reveals enrichment of atypical ubiquitin chains in contractile murine tissues. J Proteomics. 2020 Oct 30;229:103963. doi: 10.1016/j.jprot.2020.103963.
2) Self-Assembling Proteins as High-Performance Substrates for Embryonic Stem Cell Self-Renewal. Advanced Materials (Impact Factor: 25.81). 2019 Mar 13:e1807521
3) ** Integrin αVβ6-EGFR crosstalk regulates bidirectional force transmission and controls breast cancer invasion BioRxiv. 2018 doi: 10.1101/407908
4) ** Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages. EMBO J. 2019 Jun 3;38(11):e100299. doi: 10.15252/embj.2018100299.
5) ** Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated through an Eps8-dependent GTPase switch Journal of Pathology. 2017 Jun 13 10.1002/path.4923
6) ** USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature. 2017 Oct 26;550(7677) :534-538. doi: 10.1038/nature24006
7) PPFIA1 drives active α5β1 integrin recycling from the TGN to control fibronectin fibrillogenesis and vascular morphogenesis Nature Communications. 2016 Nov 7:13546
8) ** Emerging properties of adhesion complexes: What are they and what do they do? Trends Cell Biol. 2015 Jul; 25(7):388-97
9) ** Syndecan-4 phosphorylation is a control point for integrin recycling Developmental Cell. 2013 Mar 11;24(5):472-485
10) A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis Developmental Cell. 2012 Nov 13;23(5):1081-2.
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