Our interests in the MAPKs are the following:
Mechanisms of catalysis: fundamental knowledge of the enzymatic mechanisms that underlie how proteins evolve to be substrates for MAP kinases is obscure. We study the mechanisms of substrate phosphorylation by MAPKs in vitro and in cells. Knowledge of these mechanism aid in the design of MAPK inhibitors, as well as in the understanding of their cellular signaling mechanisms and specificity.
Ets-1 docks onto ERK2 using two remote non-canonical docking interactions. The docking generates an ensemble of conformations of the still dynamic phospho-acceptor near the ERK2 active site. This ensemble comprises of states in which the phospho-acceptor and surrounding regions (including the Pro in the P+1 position) are in appropriate conformation (along with the catalytic elements of ERK2) for chemistry (high-activity state), and those in which they are not (low-activity state). In principle, this could involve multiple states of varying inherent activity. Systems that substantially populate the states of high-activity are efficiently phosphorylated. We are interested in understanding MAPK specificity in the general context of this model.
Regulation and cellular functions of MAPK isoforms: We study how MAPK isoforms are regulated and investigate isoform-specific signaling pathways. Knowledge of these processes help us define isoform-specific functions in human cancers, which we hope will provide opportunities for new therapeutic modalities.
Inhibitors: through our biochemical studies we have identified novel inhibitors of ERK. Our hope is to develop potent inhibitors, which can overcome common mechanisms of resistance observed for current ERK pathway inhibitors that are in the clinic
Biomarkers: Currently, there is a lack of reliable technology to quantify MAPKs isolated from human tissue, which is essential for understanding their functions. We have created a MAPK array that we will optimize to quantitate the activity of human MAPK isoforms. Our goal is to establish a MAPK array as the basis for a new point-of-care assay guiding cancer treatment.