title: The TOR signal transduction cascade controls cellular differentiation in response to nutrients.
abstract: Rapamycin binds and inhibits the Tor protein kinases, which function in a nutrient-sensing signal transduction pathway that has been conserved from the yeast Saccharomyces cerevisiae to humans. In yeast cells, the Tor pathway has been implicated in regulating cellular responses to nutrients, including proliferation, translation, transcription, autophagy, and ribosome biogenesis. We report here that rapamycin inhibits pseudohyphal filamentous differentiation of S. cerevisiae in response to nitrogen limitation. Overexpression of Tap42, a protein phosphatase regulatory subunit, restored pseudohyphal growth in cells exposed to rapamycin. The tap42-11 mutation compromised pseudohyphal differentiation and rendered it resistant to rapamycin. Cells lacking the Tap42-regulated protein phosphatase Sit4 exhibited a pseudohyphal growth defect and were markedly hypersensitive to rapamycin. Mutations in other Tap42-regulated phosphatases had no effect on pseudohyphal differentiation. Our findings support a model in which pseudohyphal differentiation is controlled by a nutrient-sensing pathway involving the Tor protein kinases and the Tap42-Sit4 protein phosphatase. Activation of the MAP kinase or cAMP pathways, or mutation of the Sok2 repressor, restored filamentation in rapamycin treated cells, supporting models in which the Tor pathway acts in parallel with these known pathways. Filamentous differentiation of diverse fungi was also blocked by rapamycin, demonstrating that the Tor signaling cascade plays a conserved role in regulating filamentous differentiation in response to nutrients.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Cutler
authors.forename: X
authors.initials: X
authors.lastname: Pan
authors.forename: J
authors.initials: J
authors.lastname: Heitman
authors.forename: M E
authors.initials: ME
authors.lastname: Cardenas
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D029721:Drosophila Proteins; D005656:Fungal Proteins / Q000378:metabolism; D025301:Hyphae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009584:Nitrogen / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054648:Protein Phosphatase 2; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D005656:Fungal Proteins; D012097:Repressor Proteins; C097076:SOK2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C100984:TAP42 protein, S cerevisiae; D020794:Receptor Protein-Tyrosine Kinases; C080148:tor protein, Drosophila; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C104343:SIT4 protein, S cerevisiae; D009584:Nitrogen; D020123:Sirolimus