Ph.D., University of Dundee, 1985
Posttranslational modification; phosphorylation; phosphatases; signal transduction; protein structure and function
Cells respond to environmental stimuli by initiating integrated networks of signal transduction pathways that are governed by reversible protein phosphorylation. We focus on protein tyrosine phosphorylation, aberrant regulation of which has been shown to underlie the etiology of major human diseases. We study this from the perspective of characterizing the structure, regulation and function of the Protein Tyrosine Phosphatase (PTP) family of enzymes. Overall, the objective of the lab is to develop strategies and tools for analysis of PTP regulation and function and integrate them with state of the art cell and animal models, to define critical tyrosine phosphorylation-dependent signaling events in human disease and thereby identify novel therapeutic targets.
Areas of research in the lab include functional analysis of members of the PTP family, using RNA interference in cell and animal models of disease. This is integrated with development of novel approaches to therapeutic intervention in PTP function, including identification and characterization of small molecule inhibitors, members of the PTP family.
A major emphasis involves characterization of the regulation of PTP function by reversible oxidation. Hydrogen peroxide, produced in response to a wide variety of physiological stimuli, fine-tunes tyrosine phosphorylation-dependent signaling by transient oxidation and inactivation of those PTPs that normally down-regulate the signaling response. We are exploiting redox regulation to establish functional links between individual PTPs and the control of specific signaling pathways and to modify the cellular response to such pathways.
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Krishnan, N., Koveal, D., Miller, D.H., Xue, B., Akshinthala, S.D., Kragelj, J., Jensen, M. R., Gauss, C.-M., Page, R., Blackledge, M., Muthuswamy, S.K., Peti, W. and Tonks, N.K. 2014. Targeting the disordered C-terminus of PTP1B with an allosteric inhibitor. Nature Chemical Biology. doi:10.1038/nchembio.1528
Tonks, N. K. 2013. Protein Tyrosine Phosphatases: from housekeeping enzymes to master-regulators of signal transduction. FEBS J. 280: 346–378.
Lin, G., Aranda, V., Muthuswamy, S.K. and Tonks, N.K. 2011. Identification of PTPN23 as novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the “PTP-ome.” Genes Dev. 25: 1412–1425.
Haque, A., Andersen, J.A., Salmeen, A., Barford, D. and Tonks, N.K. 2011. Conformation-Sensing Antibodies Stabilize the Oxidized Form of PTP1B and Inhibit its Phosphatase Activity. Cell 147: 185–198.
Krishnan, N., Fu, C., Pappin, D.J. and Tonks, N.K. 2011. H2S-induced sulfhydration of PTP1B and its role in the endoplasmic reticulum stress response. Sci. Signal. 4: ra86.