Postgrad LIVE! Study Fairs

Birmingham | Edinburgh | Liverpool | Sheffield | Southampton | Bristol

University of Birmingham Featured PhD Programmes
University of Hong Kong Featured PhD Programmes
University College London Featured PhD Programmes
University of Kent Featured PhD Programmes
Birkbeck, University of London Featured PhD Programmes

Cleavage of receptor protein tyrosine phosphatases: mechanisms and consequences


Project Description

This project aims to establish a new paradigm in cell signalling by showing how cell surface-anchored phosphatases can be converted into distinct cytoplasmic phosphatases by a cleavage event, thus effectively doubling a cell’s phosphatase repertoire.
Protein phosphorylation is a common mode of regulation of protein function and enzyme activity and plays vitally important roles in key cellular processes such as cell growth, cell division, protein synthesis, and signal transduction. The addition and removal of phosphate groups is controlled by kinases and phosphatases. For a long time, phosphatases were regarded as house-keeping proteins whose de-phosphorylation activity was unspecific and unregulated. However, over the last decade it has become clear that this group of enzymes are highly selective and regulate important cellular functions.
One group of phosphatases, known as receptor protein tyrosine phosphatases (RPTPs), are localised at the plasma membrane and consist of variable extracellular domains that are homologous to adhesion molecules, a transmembrane domain, and intracellular phosphatase domains capable of removing phosphates from their substrates. It has recently emerged that these proteins undergo proteolytic processing by ‘molecular scissor’ proteins: first, the extracellular domain is shed via the action of ADAM metalloproteinases, and then the intracellular phosphatase domain is cleaved by a γ-secretase complex. Release of the intracellular domain essentially creates a distinct signalling molecule. The intracellular phosphatase domain can re-localise, allowing it access to subcellular localisations and substrates that its membrane counterpart does not encounter. It is also possible that it undergoes a conformational change that may affect catalytic activity. Thus, processing of receptor protein tyrosine phosphatases is likely to be a mechanism used by the cell to control phosphatase activity and the resultant signalling consequences. The impact of shedding the extracellular domain can also have significant impact on cell behaviour. Many of the extracellular domains play roles in cell-cell adhesion and cell-matrix adhesion and loss of these interactions could promote a more migratory phenotype.
Cleavage of receptor phosphatases is a concept that remains largely under-studied, we still have much to discover about the mechanisms involved in regulating receptor phosphatase processing and the extent of the biological consequences. The aim of this project is to identify the mechanisms controlling cleavage and explore the impact of cleavage on biological processes such as cell signalling and migration. A range of cell lines, including cancer cells, will be used to highlight changes in the regulatory mechanism that may be associated with disease. Biochemical methods used will include western blotting and immunoprecipitation, phosphoproteomics to identify changes in the phosphorylation status of proteins upon cleavage, and advanced imaging techniques to visualise protein localisation within the cell.

Funding Notes

Midlands Integrative Biosciences Training Partnership View Website

References

Sarhan, A.R., Patel, T.R., Creese, A.J., Tomlinson, M.G., Hellberg, C., Heath, J.K., Hotchin, N.A., and Cunningham, D.L. (2016) Regulation of Platelet Derived Growth Factor Signalling by LAR Protein Tyrosine Phosphatase: A Quantitative Phosphoproteomics Study Mol Cell Proteomics 15(6), 1823-1836
Sarhan, A.R., Patel, T.R., Cowell, A.R., Tomlinson, M.G., Hellberg, C., Heath, J.K., Cunningham, D.L., and Hotchin, N.A. (2016) LAR Protein Tyrosine Phosphatase Regulates Focal Adhesions via CDK1 J Cell Sci 129(15), 2962-1971
Matthews A.L., Koo C.Z., Szyroka J., Harrison N., Kanhere A., and Tomlinson M.G. (2018) Regulation of Leukocytes by TspanC8 Tetraspanins and the "Molecular Scissor" ADAM10. Front Immunol. 9: 1451

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2018
All rights reserved.