Nearly half of all prescription drugs alter G-protein coupled receptor (GPCR) signaling, including treatments for asthma, hypertension, neurodegenerative disorders and depression. β-arrestins are critical regulators of GPCRs: they act as trafficking adaptors to control GPCR endocytosis and impede G-protein signaling. β-arrestins are themselves therapeutic targets, highlighting the clinical importance of understanding arrestin function. However, β-arrestins are only a small branch of the larger arrestin family that includes the widely-conserved but functionally uncharacterized α-arrestins, the primary focus of my research. My work has shown that α-arrestins, like β-arrestins, regulate GPCR signaling1, but also operate in unexpected trafficking pathways, including endosomal recycling7 and clathrin-independent endocytosis2. Using Saccharomyces cerevisiae as a model, I've identified α-arrestin interactions with signaling regulators3,7, cargos1,2,7 and vesicle coat proteins7, and have begun to define the molecular mechanisms underlying α-arrestin-mediated trafficking2,7. All of the α-arrestin-interacting partners identified in yeast are conserved. My research will apply insights gained in yeast to initiate studies on the relatively unstudied mammalian α-arrestins.
The study of α-arrestins is in its infancy. There are still many unanswered questions about arrestin biology: What are the initial signaling cues that regulate α-arrestin trafficking? How are specific cargo proteins recognized? How does the arrestin-cargo interaction direct a protein cargo to its final destination? My research employs molecular, biochemical, genetic and advanced microscopy methods to address these fundamental questions about arrestin function in yeast to expand our understanding of GPCR signaling and protein trafficking.