Protein Tyrosine Phosphatases:  Structure and Function, Chemical Biology,
Activity-Based Proteomics, Signaling Mechanisms and Roles in Diseases

The initial and crucial event for many signaling pathways inside the cell is protein tyrosine phosphorylation/dephosphorylation, which is regulated by two opposing activities catalyzed by protein tyrosine kinases(PTKs) and protein tyrosine phosphatases (PTPs). PTKs have been studied extensively for the past two decades. However, the importance of PTPs has not been fully appreciated until recently.  PTPsform a large family of enzymes that play important roles in regulating cellular growth, differentiation, metabolism, cell cycle progression, cell-cell communication, cell migration, gene transcription, ion channel activity, the immune response and survival. Defective or inappropriate regulation of PTP activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers, diabetes, inflammation and neurodegenerative diseases. Thus, further understanding of the fundamental role of protein tyrosine phosphorylation in complex and critical signal transduction pathways requires detailed studies of both PTKs and PTPs.

Our research effort is focused on developing novel biochemical, chemical, proteomic and cellular approaches to study the physiological functions of PTPs. Specifically, using physiological substrates  (i.e., phosphoproteins), we are investigating the molecular basis for PTP catalysis and substrate  recognition. Understanding the molecular basis for tyrosine dephosphorylation by PTPs will open doors to new experimental approaches (such as the creation of PTPs with altered catalytic and regulatory properties and the design and development of specific PTP inhibitors) that will elucidate mechanisms by which these enzymes control cell functions. We are empoying high affinity PTP substrate-trapping mutants in combination with mass spectrometry for rapid isolation, identification, and characterization of physiological PTP substrates. Identification and characterization of cellular PTP substrates will help elucidate the function of individual PTPs as well as assignment of PTPs  to specific signaling pathwasy. We are developing activity-based probes to analyze globally PTP activity both in normal physiology and in pathological conditions. The ability to profile the entire PTP family on the basis of changes in their activity should greatly accelerate  both the assignment of PTP function and the identification of potential therapeutic targets. We are also developing potent and selective PTP inhibitors using combinatory chemistry and high-throughput screening of small molecule libraries. Highly potent and selective PTP inhibitors not only serve as powerful tools to delineate the physiological roles of these enzymes in vivo, but also as leads for therapeutic development. Finally, we are elucidating the functional roles of PTPs implicated in a number of disease processes including diabetes and cancer.