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Hayley Sharpe

Receptor tyrosine phosphatase signalling in physiology and disease

The reversible phosphorylation of tyrosine residues on proteins serves as a critical switch in the regulation of fundamental cellular processes and is controlled by the antagonistic actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Dysregulation of this balance is associated with numerous diseases as well as developmental abnormalities. Our understanding of phosphatases lags way behind that of kinases, particularly in terms of their cellular substrates. We focus on the membrane-associated receptor PTPs (RPTPs), which have the potential to sense the extracellular environment and transmit intracellular signals through tyrosine dephosphorylation. Our main objectives are to understand mechanisms of cell signalling by RPTPs by identifying their physiological roles, substrates and principles of regulation. To this end, we use proteomics, cell biology, imaging and in vivo approaches to identify relevant substrates and physiological functions of receptors.

Currently, we are focused on the receptor PTPRK, which has been implicated in growth factor signalling and cell adhesion. We will use a combination of proteomics approaches to identify putative substrates for this receptor in order to better understand its role in the cell. An understanding of the normal function of PTPRK might also reveal how it contributes to tumorigenesis since cancer genome studies show PTPRK is mutated and deleted in several human cancers. Perturbation of PTPRK might influence tumour behaviour, as well as drug responses. Importantly, PTPRK is also a recurrent gene fusion partner with the oncogene RSPO3. By identifying cell-based assays for PTPRK function, we will investigate the impact of these disease-associated alterations. Our studies will not only provide important insights into PTPRK function, but could ultimately reveal strategies for manipulating RPTP signalling in disease.

 

Sharpe lab website

 

Sharpe lab

Key publications:

Sharpe HJ & de Sauvage FJ. Grking the Smoothened signal. Science Signalling 11, eaar6377 (2018).

Sharpe H. Signalling: a new trick for an old lipid. eLife 5:e22492 (2016).

Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, Seplyarskiy VB, Sharpe HJ … de Sauvage FJ, Antonarakis SE* & Nikolaev SI*. Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma. Nature Genetics 48, 398-406 (2016).

Sharpe HJ, Wang W, Hannoush RN & de Sauvage FJ. Regulation of the Smoothened oncoprotein by small molecules. [Review] Nature Chem. Biol. 11, 246–255 (2015).

Sharpe HJ, Pau G, Dijkgraaf GJ, Basset-Seguin N, Modrusan Z, Januario T, Tsui V, Durham AB, Dlugosz AA, Haverty PM, Bourgon R, Tang JY, Sarin KY, Dirix L, Fisher DC, Rudin CM, Sofen H, Migden MR, Yauch RL & de Sauvage FJ. Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 27, 327 (2015)

Herzig Y*, Sharpe HJ*, Elbaz Y, Munro S & Schuldiner M. A systematic approach to pair secretory cargo receptors with their cargo suggests a mechanism for cargo selection by erv14. PLoS Biol. 10, e1001329 (2012) (*Equal contribution)

Sharpe HJ, Stevens TJ & Munro S. Organelle-specific constraints on the composition of transmembrane domains. Cell 142, 158 (2010)


 

Hayley Sharpe

Dr Hayley Sharpe

contact: hjs49@cam.ac.uk

Department: Clinical Biochemistry

Group members

Gareth Fearnley · Iain Hay · Katie Young

Funding

Wellcome Trust

Royal Society

CRUK Cambridge Centre