A Web-Accessible Resource of Information on Protein Tyrosine Phosphatases

email tonks@cshl.edu, phone (516) 367-8846, fax (516) 367-6812

Cells respond to environmental stimuli by initiating integrated networks of signaling transduction pathways that are governed by reversible protein phosphorylation. We study this from the perspective of the Protein Tyrosine Phosphatase (PTP) superfamily of enzymes. We use a variety of experimental strategies to characterize the structure, regulation and function of members of the PTP superfamily, ultimately with the goal of defining their physiological function and establishing links to human disease.

We have completed a bioinformatics analysis to define the composition and diversity of the PTP superfamily in several genomes (see our PTP web site http://ptp.cshl.edu) and are using this analysis to develop approaches to explore PTP function from the perspective of the family as a whole. We are using RNA interference and the generation of knockout mice to define the function of individual PTPs. We have developed substrate trapping mutant forms of the PTPs that are catalytically-impaired, but maintain the ability to bind and form stable complexes with substrates, allowing us to examine physiological substrate specificity.

A major emphasis of the lab involves characterization of the regulation of PTP function by reversible oxidation. Reactive Oxygen Species, such as hydrogen peroxide, which are produced in response to a wide variety of physiological stimuli, may fine-tune tyrosine phosphorylation-dependent signaling by transient oxidation and inactivation of those PTPs that normally downregulate the signaling response. We have developed strategies to identify those PTPs that become oxidized in response to a physiological stimulus allowing us to establish functional links between individual PTPs and the regulation of specific signaling responses.

Selected Publications

Tonks, N.K. 2006. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 7: 833–846.

Tonks, N.K. 2005. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121: 667–670.

Fukada, T., and N.K. Tonks. 2003. Identification of YB-1 as a regulator of PTP1B expression: implications for regulation of insulin and cytokine signaling. EMBO J. 22: 479-493.

Meng, T.-C., T. Fukada, and N.K. Tonks. 2002. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9: 387–399.

Myers, M.P., J.N. Anderson, A. Cheng, M.L. Tremblay, C.M. Horvath, J.-P. Parisien, A. Salmeen, D. Barford, and N.K. Tonks. 2001. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276: 47771-47774.