University of Utah
A unified approach to the development of protein tyrosine phosphatase targeted chemical probes
Tyrosine phosphorylation and dephosphorylation control all aspects of cell signaling from differentiation to the immune response. Misregulation of tyrosine phosphorylation has been implicated in numerous disease states including cancer, diabetes and autoimmunity. The enzymes that control tyrosine phosphorylation in vivo, the protein tyrosine kinases (PTKs), have been well-studied; their roles in several key cellular signaling pathways are known and PTK inhibitors have been successful in the clinic. While much less is known about the enzymes that control tyrosine dephosphorylation, there is ample evidence that these protein tyrosine phosphatases (PTPs) also play critical roles in cellular signaling. In addition, the PTPs are promising but recalcitrant therapeutic targets. However, the dearth of chemical tools available for studying PTP activity in cells and in vivo has impeded progress in the field.
My laboratory aims to restore balance to our understanding of PTP and PTK mediated cell signaling by providing a toolkit of PTP-targeted substrates and inhibitors. To date, the PTP-selective, fluorogenic substrates developed in our lab have illuminated the cellular activity of PTPs and facilitated single cell inhibitor screening, while the potent, selective PTP inhibitors identified by our lab have helped to validate the lymphoid tyrosine phosphatase (LYP) as a promising therapeutic target for the treatment of anaphylaxis. Thanks to the generous support provided by Teva Pharmaceuticals, we will now be able to take this project to the next level: developing a unified approach to PTP-selective substrate and inhibitor design and providing the toolkit necessary to elucidate the biological roles of the PTPs in health and disease.