MERIT Award Recipient: Benjamin F. Cravatt III, Ph.D.
Chemical Approaches for Activity-Based Proteomics
Cancer cells display many abnormal properties that support their pathogenic behavior, including: 1) indefinite growth (immortalization), 2) unregulated proliferation (transformation), and 3) invasion and colonization of surrounding (malignancy) and distant (metastasis) tissues. Enzymes such as proteases, through their ability to regulate cellular metabolism, intracellular signal transduction, and cell-host interaction pathways, have long been hypothesized to serve as critical mediators of the pathogenic properties of cancer cells. For example, excessive or unregulated protease activity is proposed to be one of the main factors that permits tumor cells to invade and eventually take over normal tissues. Nonetheless, the identity and precise biochemical functions of enzymes in cancer remain elusive, in large part due to a dearth of technologies that can monitor their functional states and substrate pathways in native biological systems. To address these problems, we have introduced chemical proteomic strategies to measure changes in enzyme activity directly in native cancer cells. We will apply our suite of functional proteomic technologies to both identify and functionally characterize novel enzyme activities that are dysregulated in malignant cancer cells and tumors. We are particularly interested in a set of dysregulated proteases that we hypothesize contribute to cancer pathogenicity by activating and/or inactivating key cellular signaling pathways. Finally, we will continue to develop advanced proteomic methods toward the goal of creating a general and quantitative technology to map small molecule-protein interactions directly in living cancer cells. We anticipate that these studies will define key enzymatic pathways that support cancer malignancy and contain new biomarkers and therapeutic targets, as well as produce methodological advances that greatly expand the scope and utility of the proteomic technologies for biological discovery.