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 main objectives are to understand mechanisms of cell signalling that are mediated by the membrane-associated receptor PTPs (RPTPs) by identifying their physiological roles, substrates and principles of regulation.
One of our research focuses is PTPRK, a receptor tyrosine phosphatase previously implicated in cell adhesion, tumour suppression and Transforming Growth Factor beta signalling. We have evidence that PTPRK regulates gastrointestinal homeostasis and hope to exploit this to gain a molecular understanding of its signaling through dephosphorylation of specific substrates. We will use proteomics, cell biology, imaging and in vivo approaches to identify relevant substrates and physiological functions of PTPRK. Specifically, we will use in situ proximity labelling techniques and phosphoproteomics to identify candidate substrates. By using imaging and mouse models we will identify key cell types where PTPRK functions to facilitate the characterization and validation of substrates in a physiologically relevant system.
In addition to understanding its role in homeostasis, cancer genomics studies suggest PTPRK is mutated and deleted in several human cancers. Importantly, PTPRK is a recurrent gene fusion partner with the oncogene RSPO3. Perturbation of PTPRK might influence tumour behavior, as well as drug responses. By identifying cell-based assays for PTPRK function, we will investigate the impact of these disease-associated alterations. These studies will not only provide important insights into PTPRK function, but could ultimately reveal strategies for manipulating RPTP signalling in disease.
Ximena Bonilla, Laurent Parmentier, Bryan King, Fedor Bezrukov, Gürkan Kaya, Vincent Zoete, Vladimir B. Seplyarskiy, Hayley J. Sharpe … Frederic J. de Sauvage, Stylianos E. Antonarakis* & Sergey I. Nikolaev*. 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 H.J., Pau G., Dijkgraaf G.J., Basset-Seguin N., Modrusan Z., Januario T., Tsui V., Durham A.B., Dlugosz A.A., Haverty P.M., Bourgon R., Tang J.Y., Sarin K.Y., Dirix L., Fisher D.C., Rudin C.M., Sofen H., Migden M.R., Yauch R.L., de Sauvage F.J. Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 27, 327 (2015)
Herzig Y.*, Sharpe H.J.*, 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 H.J., Stevens T.J., Munro S. Organelle-specific constraints on the composition of transmembrane domains. Cell. 142, 158 (2010)