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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, and they underpin a metazoan (multicellular) existence. By studying how adhesion receptors signal, it will be possible to understand how cell fate is controlled.

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 methodology for employing mass spectrometric analyses of isolated complexes to define the adhesion receptor-associated proteome (ref. 1). This technique allows an unbiased approach to studying adhesion signalling. This project will use this method to identify candidate proteins that mediate signalling. 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).

How does adhesion control diverse cell behaviours? The bioinformatic analyses that we have carried out of adhesion complexes so far suggest that they not only contain factors that link receptors to the cytoskeleton, but that they also contain factors involved in regulating protein synthesis and controlling cell division. It will be interesting to identify the mechanisms that link adhesion to these global cell functions.

Associated skills: Mass spectrometry, RNA interference, DNA manipulation, PCR, Mammalian cell culture, Transfection/Immunoprecipitation, Western blotting, Immunofluorescence microscopy, Bioinformatics.

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.

Funding Notes

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). Informal enquiries may be made directly to the primary supervisor.

References

1. Humphries, J.D., Byron, A., Bass, M.D., Craig, S.E., Pinney, J.W., Knight, D. and Humphries, M.J. (2009) Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science Sig. 2: ra51
2. 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
3. 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
4. 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
5. Humphries, J.D., Paul, N.R., Humphries, M.J. and Morgan, M.R. (2015) Emerging properties of adhesion complexes: What are they and what do they do? Trends Cell Biol. 25: 388-397
6. 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
7. 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
8. Horton, E.R., Astudillo, P., Humphries, M.J. and Humphries, J.D. (2016) Mechanosensitivity of integrin adhesion complexes: role of the consensus adhesome. Exp. Cell Res. 343: 7-13

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