Complexity of Protein Tyrosine Phosphatase Oxidation

Project Summary The long-term goal of my research program is to elucidate redox signaling mechanisms underlying disease initiation and progression and develop therapeutic strategies that target deregulated pathways. In a physiological context, the reversible oxidation of reactive cysteine residues within proteins elicits a spectrum of structural alterations that allow cellular oxidants production to be coupled with changes in protein activity and cell function. Protein tyrosine phosphatases (PTPs) are such proteins whose function is transiently inactivated in response to regulated and localized rises in hydrogen peroxide (H2O2) in cells. PTPs dephosphorylate and modulate the activity of protein kinases and other signaling proteins, underscoring the importance of physiological mechanisms that inhibit specific PTPs through reversible oxidation. While we know that the inactivation of specific PTPs is essential to regulate phosphorylation-dependent signaling, we have recently shown that the underlying mechanisms that regulate the oxidation and reduction of PTPs are far more complex than anticipated. Building on our seminal discoveries on PTP regulation, we have uncovered novel oxidation and reduction mechanisms that regulate PTP activity in vivo. Based on published and pilot studies, we propose to characterize and further explore the broad mechanistic and biological impacts of projects in which we show: 1) oxidation relay-mediated reversible oxidation of PTPs; 2) non-canonical allosteric PTP reduction by cholesterol; and 3) approaches to leverage our mechanistic insights to develop small molecules that activate specific PTPs and fine-tune exacerbated phosphorylation-dependent signaling. Based on our productive track record working on the redox regulation of PTPs, my research program proposes ways to elucidate the underlying mechanism by which PTPs are turned off in cells and novel means to specifically activate members of this large, understudied, family of enzymes. PTPs are an untapped resource, and understanding the complexity of their catalytic regulation by redox mechanisms will generate knowledge and resources with high potential for translation into therapeutic modalities.