Loss of ypk1 function causes rapamycin sensitivity, inhibition of translation initiation and synthetic lethality in 14-3-3-deficient yeast.
14-3-3 proteins bind to phosphorylated proteins and regulate a variety of cellular activities as effectors of serine/threonine phosphorylation. To define processes requiring 14-3-3 function in yeast, mutants with increased sensitivity to reduced 14-3-3 protein levels were identified by synthetic lethal screening. One mutation was found to be allelic to YPK1, which encodes a Ser/Thr protein kinase. Loss of Ypk function causes hypersensitivity to rapamycin, similar to 14-3-3 mutations and other mutations affecting the TOR signaling pathway in yeast. Similar to treatment with rapamycin, loss of Ypk function disrupted translation, at least in part by causing depletion of eIF4G, a central adaptor protein required for cap-dependent mRNA translation initiation. In addition, Ypk1 as well as eIF4G protein levels were rapidly depleted upon nitrogen starvation, but not during glucose starvation, even though both conditions inhibit translation initiation. These results suggest that Ypk regulates translation initiation in response to nutrient signals, either through the TOR pathway or in a functionally related pathway parallel to TOR.
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Daniel
D
Gelperin
Lynn
L
Horton
Anne
A
DeChant
Jack
J
Hensold
Sandra K
SK
Lemmon
D048948:14-3-3 Proteins; D000935:Antifungal Agents / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000235:genetics; D038362:Glycogen Synthase Kinase 3; D009687:Nuclear Proteins / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics
D048948:14-3-3 Proteins; D000935:Antifungal Agents; C436684:Bms1 protein, S cerevisiae; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D014446:Tyrosine 3-Monooxygenase; D011505:Protein-Tyrosine Kinases; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae; D019204:GTP-Binding Proteins; D020123:Sirolimus