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(BBSRC DTP) Definition of the force-sensitive mechanisms linking the plasma membrane to the nucleus using proximity biotinylation-based proteomics


Faculty of Biology, Medicine and Health

Manchester United Kingdom Biochemistry Bioinformatics Biomedical Engineering Biophysics Cancer Biology Cell Biology Medical Physics Molecular Biology

About the Project

The behaviour of cells is determined by how they interpret their genetic and epigenetic programming in the context of signals from their surroundings. These environmental cues are often chemical, but recent work has shown the importance of mechanical stimulation in driving responses to cell morphology, metabolism, motility, proliferation and commitment to lineage. Cells sense the mechanical properties of their environment through integrin adhesion receptors that bind and pull against components of the extracellular matrix (ECM). The modulated response to ECM stiffness, and its maintenance at the appropriate level, is essential for tissue health. In the context of development and repair, stem cells can be directed towards tissue-specific lineages. Mesenchymal stem cells (MSCs) can be directed towards adipogenesis in soft environments, or towards chondro- or osteogenesis in stiff environments, and have been widely studied due to their potential for applications in regenerative medicine. The ECM is also central to many disease processes, and the aberrantly stiff, fibrotic environment of many cancers has been shown to contribute to uncontrolled cellular proliferation and metastatic processes. In pancreatic cancer, for example, the ECM produced by pancreatic fibroblasts (PFs) is an order of magnitude stiffer than the healthy tissue.

Cells respond to physical stimuli, such as stiffness, through mechano-transduction pathways that convert mechanical to biochemical signals. Many of the proteins involved with these processes, such as components of the integrin adhesion complex (IAC) at the cell/ECM interface or the linker of nucleo- and cytoskeleton (LINC) complex at the nuclear membrane, have been identified and characterised. However, these complexes have generally been studied as discrete entities. We lack a holistic picture of how mechanical signals are carried from the ECM through to the nucleus, where distinct genetic programmes can be modulated. Here we propose to use proximity biotinylation mass spectrometry (BioID-MS) to systematically identify the protein linkages that enable communication between cellular regulatory machinery and cellular environments with distinct mechanical properties. BioID-MS enables protein interactions to be identified by selectively tagging proteins proximal to a ‘bait’. By engineering a library of bait constructs for structural and signalling components of IACs and LINC complexes, we will develop a quantitative, global picture of how MSCs and PFs respond to environmental stiffness. By determining how these two complexes are integrated, we intend to identify conserved mechano-transduction pathways, as well as those that may be affected by disease and thus be future targets for intervention.

https://www.wellcome-matrix.org/people/joe-swift/
https://www.wellcome-matrix.org/people/martin-humphries/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships 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.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

(1) Chastney MR, Lawless C, Humphries JD, Warwood S, Jones MC, Knight D, Jorgensen C, Humphries MJ. (2020) Topological features of integrin adhesion complexes revealed by multiplexed proximity biotinylation. J. Cell Biol. 219, e202003038.

(2) Randles MJ, Lausecker F, Humphries JD, Byron A, Clark SJ, Miner JH, Zent R, Humphries MJ, Lennon R. (2020) Basement membrane ligands initiate distinct signalling networks to direct cell shape. Matrix Biol. doi.org/10.1016/j.matbio.2020.02.005

(3) Ajeian JN, Horton ER, Astudillo P, Byron A, Askari JA, Millon-Frémillon A, Knight D, Kimber SJ, Humphries MJ, Humphries JD. (2016) Proteomic analysis of integrin-associated complexes from mesenchymal stem cells. Proteomics Clin. Appl. 10, 51-57.

(4) Horton ER, Astudillo P, Humphries MJ, Humphries JD (2016) Mechanosensitivity of integrin adhesion complexes: role of the consensus adhesome. Exp. Cell Res. 343, 7-13.

(5) Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PCDP, Pinter J, Pajerowski JD, Spinler KR, Shin J-W, Tewari M, Rehfeldt F, Speicher DW, Discher DE. (2013) Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 341, 1240104.

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