This award from the Chemistry of Life Processes Program in the Chemistry Division to Dr. Amy Barrios at the University of Utah provides support for a project aimed at developing a platform-based approach for the discovery of potent and selective mechanism-based probes for the protein tyrosine phosphatase family of enzymes. Tyrosine phosphorylation is a key regulatory event in multiple cellular signaling pathways. The phosphorylation and dephosphorylation of tyrosine are catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), respectively, and are tightly regulated processes. Despite the approximately equal number of PTKs and of PTPs in the human genome and the fact that they have similar substrate selectivity and parallel biological regulation, comparatively little is known about PTP activity in contrast to the significant body of literature dealing with the roles of PTKs in cellular signaling. In particular, mechanism-based chemical probes that form a covalent bond with the catalytic cysteine residue of the PTPs are of great interest because they would provide the means to create "chemical knock-outs" of PTP activity and would facilitate the study of an individual PTP in complex signaling pathways. The long-term objective of this project is to develop chemical approaches for the study of PTP activity that can be used to answer key questions about PTP biology. In this context, the Barrios lab will create a library of electrophilic compounds capable of covalently labeling the catalytic cysteine residue in the PTP active site and will incorporate them in peptides with specificity for an enzyme of interest to create probes that are enzyme selective. This approach could be applied to any enzyme in the PTP family and could be useful in the development of generic PTP-targeted, mechanism-based probes as well.
The cellular signaling networks that govern all life processes are extremely complex, but at the molecular level are controlled by contributions from individual biomolecules. For example, it is known that protein tyrosine phosphatases (PTPs) form a family of enzymes that play critical roles in biological cellular signaling. Despite their importance, little is known about these key enzymes because there are few chemical tools to study them. This project at the interface between chemistry and biology aims to develop tools for studying PTP enzymes at the molecular level and make possible the identification of specific PTPs activated in a cell at a particular point in time. The trainees working on this project will acquire interdisciplinary research skills useful for the members of the 21st century workforce. In addition, Dr. Barrios participates in several outreach programs to introduce non-science college students, high school students and elementary school students to science.
