My group has a long-standing interest in signaling pathways regulating cell proliferation/differentiation and their derangement in human diseases. A major focus of my work is the role of ser/thr phosphatases (PPPs) and protein tyrosine phosphatases (PTPs) in these pathways, with a long-term goal of elucidating how these enzymes dephosphorylate thousands of different protein substrates while allowing the level of phosphorylation to be individually and exquisitely regulated. To achieve this, my group integrates a diversity biophysical, biochemical and cell biological methods.

We have made fundamental contributions to this field, revealing the PP1 regulatory code used by PP1-specific regulators to bind and direct the activity of PP1; the discovery of the LxVP SLiM binding site on CN which showed that immunosuppressants bind CN at the LxVP site and thus inhibit CN activity by blocking its ability to bind substrates; and the discovery that the B-subunits of PP2A engage regulators and substrates using a phosphorylation-specific SLiM. Further, we have discovered how small molecular toxins/inhibitor selectively inactivate PP1, CN, SHP2 and PTP1B. These data are transforming our understanding of the highly specific and exquisitely regulated function of phosphatases in signaling and disease.

Toxin-antitoxin (TA) systems are regulatory switches that allow bacteria to adapt to rapidly changing environments. Under conditions of growth, these systems are repressed. However, under conditions of stress, these systems are activated, leading to growth arrest and dormancy. Remarkably, very little is understood about how these systems are regulated at a molecular level. Many TA toxins are ribonucleases (RNases). In order to control bacterial growth and especially biofilm formation, we need to understand how RNase toxins arrest bacterial growth, how their cognate antitoxins block this function and how these proteins are regulated in cells.

We also study the target of β-lactam antibiotics: penicillin binding proteins (PBPs). Multi-resistant Enterococcus faecium and E. faecalis represent one of the most dangerous challenges in infectious diseases therapeutics. While several novel antimicrobials with in vitro activity against E. faecium are available, their clinical use is plagued by limited efficacy and emerging resistance. β-lactam resistance in E. faecium and in E. faecalis is attributed to expression of low-affinity penicillin-binding protein PBP5 and PBP4, respectively. These PBPs bind most β–lactams poorly, yet remain fully capable of performing transpeptidation. However, the mechanism(s) by which low-affinity PBPs can bind endogenous substrates and carry-out transpeptidation, while at the same time be resistant to inhibition by β–lactam substrate mimics, is poorly understood. We are using an integrated, multidisciplinary approach to determine how these PBPs achieve β–lactam resistance at a molecular level.