Life Sciences Research for Lifelong Health

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.

We are currently advertising for a PhD Studentship entitled 'Exploring the role of the Protein Tyrosine Phosphatase Receptor-Type F (PTPRF) in focal adhesion dynamics' - more details are available at:  www.babraham.ac.uk/vacancies-training/phd-programme/phd-opportunities

Latest Publications

Vismodegib resistant mutations are not selected in multifocal relapses of locally advanced basal cell carcinoma after vismodegib discontinuation.
Ighilahriz M, Benfodda M, Sharpe H, Soufir N, Mourah S, Dumaz N, Battistella M, Savina A, Bouquet F, Nikolaev S, Basset-Seguin N

Hedgehog pathway inhibitors (HPI) inactivating SMO , have become first line treatment for patients with locally advanced BCC (laBCC). HPI safety and efficacy have been shown in clinical trials . Nevertheless, common adverse events lead to treatment discontinuation. This article is protected by copyright. All rights reserved.

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Journal of the European Academy of Dermatology and Venereology : JEADV, , 1468-3083, , 2019

PMID: 31187903

The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion.
Fearnley GW, Young KA, Edgar JR, Antrobus R, Hay IM, Liang WC, Martinez-Martin N, Lin W, Deane JE, Sharpe HJ

Cell-cell communication in multicellular organisms depends on the dynamic and reversible phosphorylation of protein tyrosine residues. The receptor-linked protein tyrosine phosphatases (RPTPs) receive cues from the extracellular environment and are well placed to influence cell signaling. However, the direct events downstream of these receptors have been challenging to resolve. We report here that the homophilic receptor PTPRK is stabilized at cell-cell contacts in epithelial cells. By combining interaction studies, quantitative tyrosine phosphoproteomics, proximity labeling and dephosphorylation assays we identify high confidence PTPRK substrates. PTPRK directly and selectively dephosphorylates at least five substrates, including Afadin, PARD3 and ╬┤-catenin family members, which are all important cell-cell adhesion regulators. In line with this, loss of PTPRK phosphatase activity leads to disrupted cell junctions and increased invasive characteristics. Thus, identifying PTPRK substrates provides insight into its downstream signaling and a potential molecular explanation for its proposed tumor suppressor function.

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eLife, 8, 2050-084X, , 2019

PMID: 30924770

Grking the Smoothened signal.
Sharpe HJ, de Sauvage FJ

The kinase GRK2 has been linked to the clinically important Hedgehog (HH) signaling pathway, where it is paradoxically required for signal transduction yet also promotes internalization and degradation of the critical HH signal transducer Smoothened. Two reports by Li and Pusapati in this issue of provide new insights into the role of GRK2 in HH signaling.

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Science signaling, 11, 1937-9145, , 2018

PMID: 29438011

Group Members

Latest Publications

Vismodegib resistant mutations are not selected in multifocal relapses of locally advanced basal cell carcinoma after vismodegib discontinuation.

Ighilahriz M, Benfodda M, Sharpe H

Journal of the European Academy of Dermatology and Venereology : JEADV
1468-3083: (2019)

PMID: 31187903

Grking the Smoothened signal.

Sharpe HJ, de Sauvage FJ

Science signaling
11 1937-9145: (2018)

PMID: 29438011

A new trick for an old lipid.

Sharpe H

eLife
5 2050-084X: (2016)

PMID: 27885984

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Bonilla X, Parmentier L, King B

Nature genetics
48 1546-1718:398-406 (2016)

PMID: 26950094

Regulation of the oncoprotein Smoothened by small molecules.

Sharpe HJ, Wang W, Hannoush RN

Nature chemical biology
11 1552-4469:246-55 (2015)

PMID: 25785427

Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.

Sharpe HJ, Pau G, Dijkgraaf GJ

Cancer cell
27 1878-3686:327-41 (2015)

PMID: 25759019

Efficacy of Hedgehog pathway inhibitors in Basal cell carcinoma.

Basset-Seguin N, Sharpe HJ, de Sauvage FJ

Molecular cancer therapeutics
14 1538-8514:633-41 (2015)

PMID: 25585509

Signaling: An oxysterol ligand for Smoothened.

Sharpe HJ, de Sauvage FJ

Nature chemical biology
8 1552-4469:139-40 (2012)

PMID: 22257852

A comprehensive comparison of transmembrane domains reveals organelle-specific properties.

Sharpe HJ, Stevens TJ, Munro S

Cell
142 1097-4172:158-69 (2010)

PMID: 20603021

Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates.

Strisovsky K, Sharpe HJ, Freeman M

Molecular cell
36 1097-4164:1048-59 (2009)

PMID: 20064469