MRC DiMeN Doctoral Training Partnership: Proteomics approaches to discover new roles for non-canonical signalling in cancer

Supervisor team
Prof. Claire E. Eyers (Department of Biochemistry, Institute of Integrative Biology, University of Liverpool)
https://www.liverpool.ac.uk/integrative-biology/staff/claire-eyers/
Prof. Andy Jones (Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool)
https://www.liverpool.ac.uk/integrative-biology/staff/andrew-jones/

Key dates:
Deadline for application: 21st January 2019
Start date: 1st October 2019

Project description
Abnormal protein phosphorylation is strongly associated with cancer aetiology. Considerable efforts have been undertaken to profile phosphorylation networks via serine, threonine and tyrosine residues and the responsible kinases/phosphatases. There is growing evidence, including much recent work in the groups of the supervisory team, that other amino acids, such as histidine, aspartate, glutamate, lysine and arginine, can be phosphorylated. However, to date, the study of so-called ‘non-canonical’ phosphorylation (i.e. on residues other than S, T and Y) has been severely limited due to lack of experimental tools. We have recently developed a method for unbiased phosphorylation site identification by mass spectrometry (MS), leading to the discovery of widespread phosphorylation (many 100s of sites) on non-canonical (pX) residues. We are now exploring the complete phosphoproteome in key tumour cell models, such as breast cancer, and as a function of cell cycle progression. In addition, there is a wealth of publicly available data on gene expression in various breast cancer sub-types and throughout the cell cycle. At present, it is largely unknown how the coherent system signals through canonical and non-canonical kinase functions, and crucially why particular breast cancer sub-types respond poorly to therapy.
In this project, you will be generating new MS data sets to understand the regulation of non-canonical phosphorylation by classic therapeutic protein kinase inhibitors. You will analyse these data in tandem with existing MS and gene expression data sets from public repositories. You will be trained into how to use bioinformatics techniques to improve predictions of the responsible kinases, and to determine new biomarkers for patient stratification.

This studentship will complement collaborative activities already ongoing in the research groups of the supervisors. Consequently, you will be supported by an active team of both phosphoproteomics ‘data-generating’ scientists working to define changes in non-canonical protein phosphorylation in cancer sub-types and across the cell cycle, and data analysts/bioinformaticians.

The key objectives of this PhD studentship project are:
1. Generate and collate datasets (transcriptomic/proteomic) on canonical and non-canonical phosphoproteome changes across the cell cycle and in different breast cancer sub-types to predict kinase-substrate relationships using bioinformatics techniques.
2. Use derived network information to predict key pathways/enzymes regulating non-canonical phosphorylation, which will be targeted for cellular perturbation (small molecule inhibitors, siRNA and/or site specific CRIPSR/cas9 knock-in) and pathway validation.
3. Define the regulatory mechanisms of phosphorylation-driven biomarkers for one or more breast cancer sub-types with a view to pursuing future avenues for therapeutic intervention

In terms of training, key outcomes for the student include:
• Understanding and application of state-of-the art phosphoproteomics strategies to elucidate the role and regulation of these novel non-canonical phosphorylation events in cancer
• Data science / bioinformatics (coding, data visualisation, statistics and machine learning)
• A portfolio of training in critical and highly transferable skill sets including cell biology, quantitative phosphoproteomics and data science (coding, data visualisation, statistics and machine learning)

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/