SPOTLIGHT ON DR HAYLEY SHARPE
Affiliations:
Group Leader, Babraham Institute
Research focus: My lab studies protein tyrosine phosphatases, which are understudied enzymes that are key components of cellular signalling pathways. Our insights from the last 8 years have directed our focus towards investigating phosphatases and kinases as redox sensors – proteins that can respond to changes in cellular oxidants to control cell behaviour. Reactive oxygen species, such as hydrogen peroxide, are increasingly viewed as key signalling molecules and these systems are often perturbed in disease. We’re particularly interested in how signalling in response to oxidants changes with age.
Hayley Sharpe
Recent advance from the lab: We have characterised phosphatase-substrate interactions (e.g. Hay et al. ELIfe (2022) that reveal the basis of selectivity, enabling us to generate tools to further dissect the catalytic functions of these enzymes. However, our data also supports protein tyrosine phosphatases having roles beyond catalysis in key signalling pathways, which we think could reveal new rationales or mechanisms to target them therapeutically.
An area where protein tyrosine phosphatases play a key role is in T cell signalling. Our lab was recently awarded ERC funding to explore the mystery of how antigen binding to receptors on the surface of T cells triggers the signalling cascades that result in the T cell taking action. This can be to summon other immune cells, proliferate or kill an infected cell.
Key challenge for the field: Overcoming the “undruggability” of phosphatases. Due to their highly charged and similar active sites, a major challenge has been the development of selective, bioavailable inhibitors. This has not only limited clinical development but also impacts the tools available for basic research. We’re trying to understand both non-catalytic and catalytic functions of protein tyrosine phosphatases that can then be controlled by the redox environment (the level of reactive oxygen species in the cell), with a view to identifying new ways to target them beyond the enzyme active site.
Most exciting basic or clinical breakthrough in the past few years: The advent of allosteric SHP2 (PTPN11) inhibitors for cancer (in trials) and a selective, bioavailable active site inhibitor of PTPN1/2. This suggests targeting the active sites of other family members in the future could be possible, overcoming a key challenge in the field.
https://www.babraham.ac.uk/our-research/signalling/hayley-sharpe
Published March 2024