Ph.D., University of Dundee, 1985
|Cells must constantly react to what is happening around them, adapting to changes in neighboring cells or the environment. I study the signals that cells use to exchange information with their surroundings. Our group is finding drugs that target these signals and thus can treat diabetes, obesity, cancer, and autism spectrum disorders.|
Nicholas Tonks and colleagues study a family of enzymes called protein tyrosine phosphatases, or PTPs, which remove phosphate groups from proteins and other signaling molecules, such as lipids, in cells. Disruption of PTP function is a cause of major human diseases, and several of the PTPs are potential therapeutic targets for such diseases. Tonks’ group seeks to fully characterize the PTP family, understanding how PTP activity is controlled and how PTPs modify signaling pathways. In addition, they are working to determine how those pathways are abrogated in serious illnesses, including cancer, diabetes, and Parkinson’s disease. The overall goal is to identify new targets and strategies for therapeutic intervention in human disease. Tonks and colleagues have defined new roles for PTPs in regulating signaling events in breast cancer, identifying three PTPs as novel potential tumor suppressors. They have characterized the regulation of PTP1B by reversible oxidation, demonstrating that it is regulated by covalent modification of the active site by hydrogen sulfide (H2S) under conditions of ER stress that are linked to protein-folding-related pathologies, such as Parkinson’s and Alzheimer’s. In addition, they have generated recombinant antibodies that selectively recognize the oxidized conformation of PTP1B; these antibodies display the ability to promote insulin signaling in cells and suggest novel approaches to therapy for diabetes. Finally, they have also discovered a novel mechanism for allosteric regulation of PTP1B activity, offering the possibility of developing small-molecule drugs that could inhibit the phosphatase and thereby modulate signaling by insulin and the oncoprotein tyrosine kinase HER2, potentially offering new ways to treat insulin resistance in type-2 diabetes and breast cancer.
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.
New understanding of a mechanism by which cells try to arrest oncogene action
August 28, 2014
Team reports validation of potentially powerful new way to treat HER2-positive breast cancer
May 21, 2014
Unexpected signaling role for foul-smelling hydrogen sulfide in cell response to protein misfolding
Powerful antibody-based strategy suggests a new therapeutic approach to diabetes and obesity
CSHL team identifies enzyme that is an important regulator of aggressive breast cancer development
Vallee Visiting Professor Award