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TOR Controls Transcriptional and Translational Programs via Sap-Sit4 Protein Phosphatase Signaling Effectors

John R. Rohde,^1, Susan Campbell,² Sara A. Zurita-Martinez,¹ N. Shane Cutler,^1, Mark Ashe,² and Maria E. Cardenas^1*

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina,¹ Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester, United Kingdom²

Received 27 February 2004/ Returned for modification 2 June 2004/ Accepted 30 June 2004

The Tor kinases are the targets of the immunosuppressive drug rapamycin and couple nutrient availability to cell growth. In the budding yeast Saccharomyces cerevisiae, the PP2A-related phosphatase Sit4 together with its regulatory subunit Tap42 mediates several Tor signaling events. Sit4 interacts with other potential regulatory proteins known as the Saps. Deletion of the SAP or SIT4 genes confers increased sensitivity to rapamycin and defects in expression of subsets of Tor-regulated genes. Sap155, Sap185, or Sap190 can restore these responses. Strains lacking Sap185 and Sap190 are hypersensitive to rapamycin, and this sensitivity is Gcn2 dependent and correlated with a defect in translation, constitutive eukaryotic initiation factor 2 hyperphosphorylation, induction of GCN4 translation, and hypersensitivity to amino acid starvation. We conclude that Tor signals via Sap-Sit4 complexes to control both transcriptional and translational programs that couple cell growth to amino acid availability.

Present address: Unite de Pathogenie Microbienne Moleculaire, INSERM U389, Institut Pasteur, 75015 Paris, France.

Present address: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.

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