Faculty and Research
Faculty by Name
Jeremy Thorner
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Jeremy Thorner
William V. Power Professor of Biochemistry and Molecular Biology*
*And Affiliate, Division of Cell and Developmental Biology
Research Interests
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Transmembrane and intracellular signal transduction mechanisms are the focus of our group, especially understanding how extracellular stimuli control gene expression, cell growth, cell morphology, and cell division at the biochemical level.
Current Projects
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Structural analysis of a peptide hormone receptor. To understand the molecular biology of peptide hormone action, we study response of budding yeast (Saccharomyces cerevisiae) to its peptide mating pheromones (a-factor and α-factor). The pheromone receptors have seven hydrophobic segments and are coupled to a heterotrimeric G protein. Receptors of this type are ubiquitous and transduce binding of a wide variety of extracellular ligands (peptide hormones, neurotransmitters and other bioactive compounds) into a physiological signal. Attempts to determine the three-dimensional structure of the purified α-factor receptor by NMR are underway in collaborative studies. We are also interested in proteins involved in adaptation and recovery after the pheromone-induced signal, especially the structure and function of Sst2, the prototype RGS (Regulator of G-protein Signaling) protein, and various classes of phosphotyrosine-directed, phosphoserine- / phosphothreonine-directed, and dual-specificity phosphoprotein phosphatases that can act to dephosphorylate activated MAPKs.
Molecular genetics and biochemistry of a protein kinase cascade. Activation of the receptor-coupled G protein initiates a cascade of three protein kinases, resulting in stimulation of two messenger-activated protein kinases (MAPKs) in the nucleus. A different developmental pathway (invasive or filamentous growth) triggered by nutrient limitation also stimulates these MAPKs. MAPK cascades are universally employed for signal transduction in eukaryotic cells, and every eukaryotic cell contains multiple MAPK pathways. We are investigating the mechanisms that impose specificity and fidelity at each tier in these signaling networks. We showed that one device used by the cell for discrimination between parallel MAPK pathways is a specific docking interaction between a MAPK and the N-terminus of its cognate upstream protein kinase (MEK). We also showed that a scaffold protein, Ste5, helps ensure signaling fidelity in pheromone response by binding the appropriate MAPK, MEK, and upstream activating kinase (MEKK) and by shuttling from the nucleus to the plasma membrane and delivering the MAPK module to its most proximal activator (a fourth membrane-associated protein kinase). A different scaffold protein, Ste50, is required for signal propagation in the invasive growth pathway and is also under study.
Control of gene expression. We used genetic and biochemical methods to demonstrate that two negative transcriptional regulators are substrates of the MAPKs. How the function of these targets is modified by phosphorylation is under study. We also discovered a general regulator of transcription, which has homologs in Drosophila and human cells, that catalyzes ATP-dependent dissociation of TATA box-binding protein (TBP)-DNA complexes. Structural analysis of the mechanism of action of this global transcriptional regulator is in progress.
Protein kinases involved in cell proliferation, differentiation, and cell cycle control. The function of the Wee1 class of protein-tyrosine kinase in cell cycle control is not well understood. We are investigating pathways that regulate the activity, localization, and stability of this enzyme, including its recruitment to septin filaments, which assemble at the presumptive site of cell division. We have shown that septin filaments are assembled from octameric complexes containing two each of four different septin subunits. A considerable effort is underway in the lab to understand the regulation of septin complex assembly, the formation, supramolecular architecture and disassembly of septin filaments, and the function of septin filaments in the events required for cell division and membrane septation during cytokinesis. A cascade of protein kinases involved in membrane stress responses that is conserved from yeast to humans is also under study.
Molecular biology of phosphoinositide-dependent signaling. In previous work, we have shown that phosphatidylinositol 4-phosphate generated by a specific phosphatidylinositol 4-kinase (Pik1) has a specific role in the Golgi-to-plasma membrane stage of the secretory pathway. This enzyme also has an essential role in supplying the PtdIns(4)P that is converted to PtdIns(4,5)P2 in the nucleus, where it is hydrolyzed by a specific phospholipase C to generate inositol polyphosphates that regulate transcription, chromatin remodeling and mRNA export. We found that the phosphatidylinositol 4-kinase is also regulated by a small calcium-binding protein, Frq1, whose ortholog in animal cells (frequenin or neuronal calcium sensor-1) is found mainly in neuronal and neuroendocrine cells.
Novel mechanisms for translocation across membranes. We discovered that export of a-factor pheromone requires an integral plasma membrane protein that is a dedicated ATP-dependent transporter, rather than the classical secretory pathway. The mechanism of transmembrane translocation of pheromone by the transporter (Ste6) is being examined. The functions of other members of the same transporter class, namely ABC transporters, are also under study.
Selected Publications
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Bertin A, McMurray MA, Grob P, Park S-S, Garcia G, Patanwala I, Ng H-L, Alber TC, Thorner J, Nogales E
(2008) Saccharomyces cerevisiae septins: supramolecular organization of hetero-oligomers and the
mechanism of filament assembly. Proc. Natl. Acad. Sci. USA, in press.
McMurray MA, Thorner J (2008) Biochemical properties and supramolecular architecture of septin hetero-
oligomers and septin filaments, In "The Septins" (Hall PA, Russell SEG, Pringle JR, Eds.), John Wiley &
Sons, Ltd., Chicester, West Sussex, UK, in press.
Blumer KJ, Thorner J (2007) An adrenaline (and gold?) rush for the GPCR community. ACS Chem. Biol.
2: 783-786.
Schüller C, Mamnun YM, Wolfger H, Rockwell N, Thorner J, Kuchler K (2007) Membrane-active compounds
activate the transcription factors Pdr1 and Pdr3 connecting pleiotropic drug resistance and membrane lipid
homeostasis in Saccharomyces cerevisiae. Mol. Biol. Cell 18: 4932-4944.
Strahl T, Huttner IG, Lusin JD, Osawa M, King D, Thorner J, Ames JB (2007) Structural insights into activa-
tion of phosphatidylinositol 4-kinase (Pik1) by yeast frequenin (Frq1). J. Biol. Chem. 282: 30949-30959.
Chen RE, Thorner J (2007) Function and regulation in MAPK signaling pathways: lessons learned from the
yeast, Saccharomyces cerevisiae. BBA-Molecular Cell Research 1773: 1311-1340.
Strahl T, Thorner J (2007) Synthesis and function of membrane phosphoinositides in budding yeast,
Saccharomyces cerevisiae. BBA-Molecular and Cell Biology of Lipids 1771: 353-404.
Ballon DR, Flanary P, Gladue D, Konopka JB, Dohlman HG, Thorner J (2006) DEP domain-mediated
regulation of GPCR signaling responses. Cell 126: 1079-1093.
Westfall PJ, Thorner J (2006) Analysis of MAPK signaling specificity in response to hyperosmotic stress: use of an analog-sensitive HOG1 allele. Eukaryot. Cell 5: 1215-1228.
Garrenton LS, Young SL, Thorner J (2006) Function of the MAPK scaffold protein, Ste5, requires a cryptic PH
domain. Genes Dev. 20: 1946-1958.
Truckses DM, Bloomekatz JE, Thorner J (2006) RA domain of Ste50 adaptor protein is required for delivery
of Ste11 MAPKKK to the plasma membrane in the filamentous growth signaling pathway of the yeast
Saccharomyces cerevisiae. Mol. Cell. Biol. 26: 912-928.
Thorner J (2006) "Signal Transduction", In Landmark Papers in Yeast Biology (Linder P, Shore D, Hall MN,
Eds.) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 193-210.
Last Updated 2008-05-14