A major paradox in cell biology is how a number of cell surface receptors generate signals that converge on the same downstream targets and yet they are still able to elicit specific effects. Furthermore, a number of receptor-mediated events require precise spatial and temporal control over these signaling molecules, which charges the cell with the difficult task, not just of activating the correct enzyme but ensuring that its activity is carried out in the proper place. Dr. DeFea’s laboratory is interested in the molecular mechanisms underlying G-protein-coupled-receptor (GPCR) signaling specificity and the role molecular scaffolds in this process. Of particular interest is signaling by a receptor called protease-activated-receptor-2 (PAR-2) and the role of family of proteins called beta-arrestins in this process. PAR-2 is implicated in the pathology of a number of inflammatory disorders as well as tumor cell metastasis. The physiological outcome of its activation appears to differ depending on where and how it is activated. b-arrestins were once thought to turn off GPCR signaling, but we now know they can bind to a wide variety proteins to promote either localized activation or inhibition of their activities. Current projects include a molecular characterization of the role of b-arrestins in localized actin assembly, the physiological consequences of b-arrestin-dependent PAR-2 sigaling, and the possibility that PAR2-induced chemotaxis plays a role in diseases such as cancer, asthma, inflammatory bowel disease and metabolic syndrome.