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

Abstract

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 2α 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.

We are in debt to Alan Hinnebusch and Vera Cherkasova for generous gifts of plasmids and antisera and for criticism. We thank Joseph Heitman, Daniel Lew, and Raphael Valdivia for critical and constructive reading of the manuscript.

This work was supported by K22 award CA94925-01 from the NCI (to M.E.C.) and by Wellcome Trust project grant 067328/Z/02/Z (to M.P.A).