University of Pittsburgh Department of Cell Biology
  • Research

    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.

  • Publications

    1. O'Donnell AF, Alvaro CG, Prosser DC, Wendland B, and Thorner J. α-arrestins regulate endocytosis of the yeast mating pathway GPCRs, Ste2 and Ste3. In preparation.
    2. Prosser DC, Wendland B, Thorner J, and O'Donnell AF. α-arrestins are required for Rho1-mediated clathrin-independent endocytosis in yeast. In preparation.
    3. O'Donnell AF, Cyert MS and Thorner J. Calcineurin regulation of α-arrestins Aly1 is required for Aly1-mediated endocytosis of the Dip5 nutrient permease. In preparation.
    4. Minear S, O'Donnell AF, Ballew A, Giaever G, Nislow C, Stearns T, Cyert MS. (2011) Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation. Eukaryotic Cell 10(11):1574-81.
    5. Piña FJ, O'Donnell AF, Pagant S, Piao HL, Miller JP, Fields S, Miller EA, and Cyert MS. (2011) Hph1 and Hph2 are novel components of the Sec63/Sec62 posttranslational translocation complex that aid in vacuolar proton ATPase biogenesis. Eukaryotic Cell 10 (1): 63-71.
    6. Stevens JR, O'Donnell AF, Perry TE, Benjamin JR, Barnes CA, Johnston GC, and Singer RA. (2011) FACT, the Bur kinase pathway, and the histone co-repressor HirC have overlapping nucleosome-related roles in yeast transcription elongation. PLoS One 6(10): e25644.
    7. O'Donnell AF, Apffel A, Gardner RG, and Cyert MS. (2010) α-arrestins Aly1 and Aly2 regulate intracellular trafficking in response to nutrient signaling. Molecular Biology of the Cell 21 (20): 3552-3566.
    8. O'Donnell AF, Stevens JR, Kepkay R, Barnes CA, Johnston GC, and Singer RA. (2009) New mutant versions of yeast FACT subunit Spt16 affect cell integrity. Molecular Genetics and Genomics 282 (5): 487-502.
    9. O'Donnell AF, Brewster NK, Kurniawan J, Minard LV, Johnston GC, and Singer RA. (2004) Domain organization of the yeast histone chaperone FACT: the conserved N-terminal domain of FACT subunit Spt16 mediates recovery from replication stress. Nucleic Acids Research 32 (19): 5894-5906.
    10. O'Donnell AF, Tiong S, Nash D, Clark DV. (2000) The Drosophila melanogaster ade5 gene encodes a bifunctional enzyme for two steps in the de novo purine synthesis pathway Genetics 154(3): 1239-53.

     

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