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Sharpe Group

Sharpe Group
Sharpe Group

Research Summary

We are interested in understanding how the cells that make up our tissues and organs communicate. Our cells are decorated with proteins, or receptors, that can sense alterations in their local environment and promote signalling pathways leading to changes in behaviour such as growth, movement or attachment. We focus on receptors that communicate to the cell interior through an enzyme known as a protein phosphatase. These receptor tyrosine phosphatases can change the function of other proteins by catalysing the removal of phosphate groups. The principles of how these receptors contribute to signalling remain poorly understood.

The receptor tyrosine phosphatases are linked to diverse areas of biology from immune cell signalling to blood vessel development to cell-cell adhesion, with some implicated in disease processes such as spinal cord injury, wound healing and cancer. Importantly, protein tyrosine phosphatases are targets of reactive oxygen species, which serve as critical signalling molecules that can be dysregulated in ageing and disease.

Our recent work has led us to focus on how protein tyrosine phosphatases are influenced by the cellular microenvironment. First by the presence of the chemical second messenger hydrogen peroxide, and secondly by mechanical cues, which are known to influence cellular protein tyrosine phosphorylation. To understand the normal and pathological functions of phosphatases we use biochemistry, proteomics, primary and cancer cell lines, as well as mouse models. 

 

Latest Publications

Open Access
Young KA, Mulholland KE, Wojdyla K, Casanova SA, Lai T, Fearnley GW, Antrobus R, Barton PR, Anderson KR, Biggins L, Andrews SR, Mahler-Araujo B, Sharpe HJ Signalling , Bioinformatics

PTPRK is a receptor tyrosine phosphatase linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. It regulates cell-cell adhesion, but is also reported to regulate numerous cancer-associated signalling pathways. However, its signalling mechanism remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

+view abstract Journal of cell science, PMID: 38904097

Open Access
van der Klaauw AA, Horner EC, Pereyra-Gerber P, Agrawal U, Foster WS, Spencer S, Vergese B, Smith M, Henning E, Ramsay ID, Smith JA, Guillaume SM, Sharpe HJ, Hay IM, Thompson S, Innocentin S, Booth LH, Robertson C, McCowan C, Kerr S, Mulroney TE, O'Reilly MJ, Gurugama TP, Gurugama LP, Rust MA, Ferreira A, Ebrahimi S, Ceron-Gutierrez L, Scotucci J, Kronsteiner B, Dunachie SJ, Klenerman P, , Park AJ, Rubino F, Lamikanra AA, Stark H, Kingston N, Estcourt L, Harvala H, Roberts DJ, Doffinger R, Linterman MA, Matheson NJ, Sheikh A, Farooqi IS, Thaventhiran JED Signalling , Immunology

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI鈥>鈥40鈥塳g/m) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9鈥塳g/m). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P鈥=鈥0.0003) 6鈥塵onths after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.

+view abstract Nature medicine, PMID: 37169862

Foster WS, Newman J, Thakur N, Spencer AJ, Davies S, Woods D, Godfrey L, Ross SH, Sharpe HJ, Richard AC, Bailey D, Lambe T, Linterman MA Immunology

Effective vaccines have reduced SARS-CoV-2 morbidity and mortality; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity, and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8 T cells are important for killing virally infected cells, and vaccines that induce antigen specific CD8 T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titres are sub-optimal, as can occur in older individuals. Here, we show that in aged mice, spike-epitope specific CD8 T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV-19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV-19 elicits a good CD8 T cell response in older bodies, but that typical age-associated features are evident on these vaccine reactive T cells.

+view abstract Immunology and cell biology, PMID: 36975169

Group Members

Hayley Sharpe

Group Leader

Silvia Aldaz-Casanova

Laboratory Manager

Roksana Dutkiewicz

PhD Student

Tiffany Lai

PhD Student

Katie Mulholland

Postdoc Research Scientist

Oisharja Rahman

PhD Student

Katarzyna Wojdyla

Postdoc Research Scientist