Hayley Sharpe

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

Mutations in phospholipase C eta-1 () are associated with holoprosencephaly.
Drissi I, Fletcher E, Shaheen R, Nahorski M, Alhashem AM, Lisgo S, Fernández-Jaén A, Schon K, Tlili-Graiess K, Smithson SF, Lindsay S, J Sharpe H, Alkuraya FS, Woods G

Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities.

+ View Abstract

Journal of medical genetics, `, `, 05 Apr 2021

PMID: 33820834

Protein tyrosine phosphatases in cell adhesion.
Young KA, Biggins L, Sharpe HJ

Adhesive structures between cells and with the surrounding matrix are essential for the development of multicellular organisms. In addition to providing mechanical integrity, they are key signalling centres providing feedback on the extracellular environment to the cell interior, and vice versa. During development, mitosis and repair, cell adhesions must undergo extensive remodelling. Post-translational modifications of proteins within these complexes serve as switches for activity. Tyrosine phosphorylation is an important modification in cell adhesion that is dynamically regulated by the protein tyrosine phosphatases (PTPs) and protein tyrosine kinases. Several PTPs are implicated in the assembly and maintenance of cell adhesions, however, their signalling functions remain poorly defined. The PTPs can act by directly dephosphorylating adhesive complex components or function as scaffolds. In this review, we will focus on human PTPs and discuss their individual roles in major adhesion complexes, as well as Hippo signalling. We have collated PTP interactome and cell adhesome datasets, which reveal extensive connections between PTPs and cell adhesions that are relatively unexplored. Finally, we reflect on the dysregulation of PTPs and cell adhesions in disease.

+ View Abstract

The Biochemical journal, 478, 5, 12 Mar 2021

PMID: 33710332

The receptor PTPRU is a redox sensitive pseudophosphatase.
Hay IM, Fearnley GW, Rios P, Köhn M, Sharpe HJ, Deane JE

The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal "backdoor" cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.

+ View Abstract

Nature communications, 11, 1, 26 Jun 2020

PMID: 32591542