Sharpe Group

Sharpe Group
Sharpe Group
Hayley Sharpe
Tenure Track Group Leader
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. 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

Hay IM, Mulholland KE, Lai T, Graham SC, Sharpe HJ, Deane JE Signalling

Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively dephosphorylating several cell junction regulators including the protein Afadin (Fearnley et al, 2019). Here, we demonstrate that Afadin is recruited for dephosphorylation by directly binding to the PTPRK D2 pseudophosphatase domain. We mapped this interaction to a putative coiled coil (CC) domain in Afadin that is separated by more than 100 amino acids from the substrate pTyr residue. We identify the residues that define PTP specificity, explaining how Afadin is selectively dephosphorylated by PTPRK yet not by the closely related receptor tyrosine phosphatase PTPRM. Our work demonstrates that PTP substrate specificity can be determined by protein-protein interactions distal to the active site. This explains how PTPRK and other PTPs achieve substrate specificity despite a lack of specific sequence context at the substrate pTyr. Furthermore, by demonstrating that these interactions are phosphorylation-independent and mediated via binding to a non-catalytic domain, we highlight how receptor PTPs could function as intracellular scaffolds in addition to catalyzing protein dephosphorylation.

+view abstract eLife, PMID: 36264065 20 10 2022

Hay IM, Mulholland KE, Lai T, Graham SC, Sharpe HJ, Deane JE Signalling

Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively dephosphorylating several cell junction regulators including the protein Afadin (Fearnley et al., 2019). Here we demonstrate that Afadin is recruited for dephosphorylation by directly binding to the PTPRK D2 pseudophosphatase domain. We mapped this interaction to a putative coiled coil (CC) domain in Afadin that is separated by more than 100 amino acids from the substrate pTyr residue. We identify the residues that define PTP specificity, explaining how Afadin is selectively dephosphorylated by PTPRK yet not by the closely related receptor tyrosine phosphatase PTPRM. Our work demonstrates that PTP substrate specificity can be determined by protein-protein interactions distal to the active site. This explains how PTPRK and other PTPs achieve substrate specificity despite a lack of specific sequence context at the substrate pTyr. Furthermore, by demonstrating that these interactions are phosphorylation-independent and mediated via binding to a non-catalytic domain, we highlight how receptor PTPs could function as intracellular scaffolds in addition to catalyzing protein dephosphorylation.

+view abstract eLife, PMID: 36264065 20 Oct 2022

Yurchenko AA, Pop OT, Ighilahriz M, Padioleau I, Rajabi F, Sharpe HJ, Poulalhon N, Dreno B, Khammari A, Delord M, Alberdi A, Soufir N, Battistella M, Mourah S, Bouquet F, Savina A, Besse A, Mendez-Lopez M, Grange F, Monestier S, Mortier L, Meyer N, Dutriaux C, Robert C, Saïag P, Herms F, Lambert J, de Sauvage F, Dumaz N, Flatz L, Basset-Seguin N, Nikolaev SI Signalling

Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms.

+view abstract Clinical Cancer Research, PMID: 35078858 25 Jan 2022

Group Members

Hayley Sharpe

Tenure Track Group Leader

Roksana Dutkiewicz

PhD Student

Tiffany Lai

PhD Student

Lauren Maggs

PhD Student

Katie Mulholland

Postdoc Research Scientist

Oisharja Rahman

Research Assistant

Katarzyna Wojdyla

Postdoc Research Scientist

Leah Wynn

Visiting Student

Katherine Young

PhD Student