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Proteomic analyses of adhesion signalling in cancer


Project Description

Why adhesion? Cell surface adhesion receptors play key roles in the control of cell movement, survival, division and differentiation. By studying how adhesion receptors signal, it will be possible to understand how cell fate is controlled. The main research interests of the lab are in the signals that link cell adhesion to the cell cycle and in the mechanisms that cancer cells use to subvert this control. Although it has been known for many decades that proliferation is anchorage-dependent, and that tumour cells often lose this property, the mechanisms are unclear. We now aim to determine how cells sense the adhesive microenvironment and how this either prevents or encourages proliferation.

What don’t we understand? Following binding to extracellular matrix ligands, adhesion receptors trigger the assembly of multi-protein complexes on the cytoplasmic face of the plasma membrane. These complexes contain signalling molecules and cytoskeletal proteins, and their role is to control the location of signalling pathways and provide a physical link to the contractile actomyosin polymer network. The identity of the molecules that transduce signals, the mechanisms of complex assembly and disassembly, the stoichiometry of complex components, the key control points, and the extent of variation between complexes in different cells are not known.

How to get answers to these questions? Recently, we have developed the first methodologies for employing mass spectrometric analyses (both proteins and phosphoproteins) of isolated adhesion complexes to define the adhesion receptor-associated proteome. These techniques allow an unbiased approach to studying adhesion signalling. This project will therefore explore one of the following areas: (a) the identity of the links between adhesion receptors and the cell cycle machinery that are responsible for cell rounding during mitosis, (b) the cell cycle-dependent changes that take place in adhesion complexes [both using proteomic, bioinformatic, biochemical (e.g. IP-blotting and phosphorylation analysis) and/or cell biological approaches (e.g. fluorescence imaging)], and (c) the mechanisms whereby extracellular matrix rigidity is converted into signals that control cell proliferation and tumour evolution. Candidates will then be validated by a combination of biochemical (e.g. using IP-blotting and phosphorylation analysis) and/or cell biological approaches (e.g. using fluorescence imaging).

Entry Requirements:
Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in biological sciences, such as biochemistry and molecular biology. A Masters qualification in a similar area would be a significant advantage.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Byron, A., Askari, J.A., Humphries, J.D., Jacquemet, G., Koper, E.J., Warwood, S., Choi, C.K., Stroud, M.J., Chen, C.S., Knight, D. and Humphries, M.J. (2015) A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting. Nature Comm. 6: 6135
2. Robertson, J., Jacquemet, G., Byron, A., Jones, M.C., Warwood, S., Selley, J.N., Knight, D., Humphries, J.D. and Humphries, M.J. (2015) Defining the phospho-adhesome: phosphoproteomic analysis of integrin signalling. Nature Comm. 6: 6265
3. Jones, M.C., Humphries, J.D., Byron, A., Millon-Frémillon, A., Robertson, J., Paul, N.R., Ng, D.H.J., Askari, J.A. and Humphries, M.J. (2015) Isolation of integrin-based adhesion complexes. Curr. Protocols 9.8.1-9.8.15
4. Horton, E.R., Byron, A., Askari, J.A., Ng, D.H.J., Millon-Frémillon, A., Robertson, J., Koper, E.J., Paul, N.R., Warwood, S., Knight, D., Humphries, J.D. and Humphries, M.J. (2015) Definition of a consensus integrin adhesome and analysis of its dynamics during adhesion complex assembly and disassembly. Nature Cell Biol. 17: 1577-1587
5. Horton, E.R., Humphries, J.D., Stutchbury, B., Jacquemet, G., Ballestrem, C., Barry, S.T. and Humphries, M.J. (2016) Modulation of FAK and Src adhesion signalling occurs independently of adhesion complex composition. J. Cell Biol. 212: 349-364
6. Jones, M.C., Askari, J.A., Humphries, J.D. and Humphries, M.J. (2018) Cell adhesion is regulated by CDK1 during the cell cycle. J. Cell Biol. 217: 3203-3218
7. Lock, J.G., Jones, M.C., Askari, J.A., Gong, X., Oddone, A., Olofsson, H., Göransson, S., Lakadamyali, M., Humphries, M.J. and Strömblad, S. (2018) Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis. Nature Cell Biol. 20: 1290-1302

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