TOR pp 19-38 | Cite as

The Role of Phosphatases in TOR Signaling in Yeast

  • K. Düvel
  • J. R. Broach
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 279)


The TOR pathway controls cellular functions necessary for cell growth and proliferation of yeast and larger eukaryotes. The search for members of the TOR signaling cascade in yeast led to the discovery of type 2A protein phosphatases (PP2A) as important players within the pathway. We describe the roles in yeast of PP2A and the closely related phosphatase, Sit4, and then focus on complexes formed between the catalytic subunit of these phosphatases and Tap42, a direct target of the Tor protein kinases in yeast. Recent results suggest that Tap42 mediates many of the Tor functions in yeast, especially those involved in transcriptional modulation. However, whether Tap42 executes its function by inhibiting phosphatase activity or by activating phosphatases is still uncertain. In addition, Tor affects some transcriptional and physiological processes through Tap42 independent pathways. Thus, Tor proteins use multiple mechanisms to regulate transcriptional and physiological processes in yeast.


Rapamycin Treatment Spindle Checkpoint PP2A Activity Anaphase Promote Complex Amino Acid Permease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beck, T, and Hall, M.N. (1999) The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692PubMedCrossRefGoogle Scholar
  2. Beck, T., Schmidt, A., and Hall, M.N. (1999) Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast. J. Cell Biol. 146, 1227–1238PubMedCrossRefGoogle Scholar
  3. Booher, R.N., Deshaies, R.J., and Kirschner M.W. (1993) Properties of Saccharomyces cerevisiae weel and its differential regulation of p34CDC28 in response to G1 and G2 cyclins. EMBO J. 12, 3417–3426PubMedGoogle Scholar
  4. Cardenas, M.E., Cutler, N.S., Lorenz, M.C., Di Como, C.J., and Heitman, J. (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13, 3271–3279PubMedCrossRefGoogle Scholar
  5. Chen, J., Peterson, R.T., and Schreiber, S.L. (1998) α4 associates with protein phosphatases 2A, 4 and 6. Biochem. Biophys. Res. Commun. 247, 827–832PubMedCrossRefGoogle Scholar
  6. Chung, H., Nairn, A.C., Murata, K., and Brautigan, D.L. (1999) Mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the α4 subunit which promotes dephosphorylation of elongation factor-2. Biochemistry 38, 10371–10376PubMedCrossRefGoogle Scholar
  7. Cutler, N.S., Pan, X., Heitman, J., and Cardenas, M.E. (2001) The TOR signal transduction cascade controls cellular differentiation in response to nutrients. Mol. Biol. Cell 12, 4103–4113PubMedGoogle Scholar
  8. Di Como, C.J., and Arndt, K.T. (1996) Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 10, 1904–1916PubMedCrossRefGoogle Scholar
  9. Diivel, K., Santhanam, A., Garrett, S., Schneper, L., and Broach, J.R. (2003) Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast. Mol. Cell II, 1467–1478Google Scholar
  10. Evangelista, C.C. Jr., Rodriguez Torres, A.M., Limbach, M.P., and Zitomer, R.S. (1996) Rox3 and Rts1 function in the global stress response pathway in baker’s yeast. Genetics 142, 1083–1093PubMedGoogle Scholar
  11. Evans, D.R., and Stark, M.J. (1997) Mutations in the Saccharomyces cerevisiae type 2A protein phosphatase catalytic subunit reveal roles in cell wall integrity, actin cytoskeleton organization and mitosis. Genetics 145, 227–241PubMedGoogle Scholar
  12. Fernandez-Sarabia, M.J., Sutton, A., Zhong, T, and Arndt, K.T. (1992) SIT4 protein phosphatase is required for the normal accumulation of SWI4, CLN1, CLN2, and HCS26 RNAs during late G1. Genes Dev. 6, 2417–2428PubMedCrossRefGoogle Scholar
  13. Gancedo, J.M. (2001) Control of pseudohyphae formation in Saccharomyces cerevisiae. FEMS Microbiol. Rev. 25, 107–123PubMedCrossRefGoogle Scholar
  14. Grenson, M. (1983) Study of the positive control of the general amino-acid permease and other ammonia-sensitive uptake systems by the product of the NPR1 gene in the yeast Saccharomyces cerevisaie. Eur. J. Biochem. 133, 141–144PubMedCrossRefGoogle Scholar
  15. Grooves, M.R., Hanlon, N., Turowski, P., Hemmings, B.A., and Bradford D. (1999) The structure of the protein phosphatase 2A PC65/A subunit reveals the confirmation of its 15 tandemly repeats HEAT motifs. Dell 96, 99–110Google Scholar
  16. Hardwick, J.S., Kuruvilla, EG., Tong, J.K., Shamji, A.F., and Schreiber, S.L. (1999) Ra-pamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc. Natl. Acad. Sci. USA 96, 14866–14870.PubMedCrossRefGoogle Scholar
  17. Healy, A.M., Zolnierowicz, S., Stapleton, A.E., Goebl, M., DePaoli-Roach, A.A., and Pringle, J.R. (1991) CDC55, a Saccharomyces cerevisiae gene involved in cellular morphogenesis: identification, characterization, and homology to the B subunit of mammalian type 2 A protein phosphatase. Mol. Cell. Biol. 11, 5767–5780PubMedGoogle Scholar
  18. Jacinto, E., Guo, B., Arndt, K.T, Schmelzle, T, and Hall, M.N. (2001) TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol. Cell 8, 1017–1026PubMedCrossRefGoogle Scholar
  19. Jiang, Y., and Broach, J.R. (1999) Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J. 18, 2782–2792PubMedCrossRefGoogle Scholar
  20. Kamada, Y., Funakoshi, T, Shintani, T, Nagano, K., Ohsumi, M., and Ohsumi, Y. (2000) Tor-mediated induction of autophagy via an Apgl protein kinase complex. J. Cell. Biol. 150, 1507–1513PubMedCrossRefGoogle Scholar
  21. Kornitzer, D., Sharf, R., and Kleinberger, T. (2001) Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome. J. Cell. Biol. 154, 331–344PubMedCrossRefGoogle Scholar
  22. Kuwahara, K., Matsuo, T, Nomura, J., Igarashi, H., Kimoto, M., Inui, S., and Sakaguchi, N. (1994) Identification of a 52-kDa molecule (p52) coprecipitated with the Ig receptor-related MB-1 protein that is inducibly phosphorylated by the stimulation with phorbol myristate acetate. J. Immunol. 152, 2742–2752PubMedGoogle Scholar
  23. Lin, F.C., and Arndt, K.T. (1995) The role of Saccharomyces cerevisiae type 2A phosphatase in the actin cytoskeleton and in entry into mitosis. EMBO J. 14, 2745–2759PubMedGoogle Scholar
  24. Lorenz, M.C., and Heitman, J. (1998) The MEP2 ammonium permease regulates pseudohyphal differentiation in Saccharomyces cerevisiae. EMBO J. 17, 1236–1247PubMedCrossRefGoogle Scholar
  25. Luke, M.M., Delia Seta, R, Di Como, C.J., Sugimoto, H., Kobayashi, R., and Arndt, K.T. (1996) The SAPs, a new family of proteins, associate and function positively with the SIT4 phosphatase. Mol. Cell. Biol. 16, 2744–2755PubMedGoogle Scholar
  26. Masuda, C.A., Ramírez, J., Peña, A., and Montero-Lomelí, M. (2000) Regulation of monovalent ion homeostasis and pH by the Ser-Thr protein phosphatase SIT4 in Saccharomyces cerevisiae. J. Biol. Chem. 40, 30957–30961CrossRefGoogle Scholar
  27. Minshull, J., Straight, A., Rudner, A.D., Dernburg A.F., Belmont, A., and Murray A.W. (1996) Protein phosphatase 2A regulates MPF activity and sister chromatid cohesion in budding yeast. Curr. Biol. 6, 1609–1620PubMedCrossRefGoogle Scholar
  28. Murata, K., Wu, J., and Brautigan, D.L. (1997) B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc. Natl. Acad. Sci. USA 94, 10624–10629PubMedCrossRefGoogle Scholar
  29. Nanahoshi, M., Nishiuma, T, Tsujishita, Y., Hara, K., Inui, S., Sakaguchi, N., and Yonezawa, K. (1998) Regulation of protein phosphatase 2A catalytic activity by al-pha4 protein and its yeast homolog Tap42. Biochem. Biophys. Res. Commun. 251, 520–526PubMedCrossRefGoogle Scholar
  30. Noda, T, and Ohsumi, Y. (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966PubMedCrossRefGoogle Scholar
  31. Pan, X., Harashima, T, and Heitman, J. (2000) Signal transduction cascades regulating pseudohyphal differentiation of Saccharomyces cerevisiae. Curr. Opin. Microbiol. 3, 567–572PubMedCrossRefGoogle Scholar
  32. Peterson, R.T, Desai, B.N., Hardwick, J.S., and Schreiber, S.L. (1999) Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin-assocoated protein. Proc. Natl. Acad. Sci. USA 96, 4438–4442PubMedCrossRefGoogle Scholar
  33. Ronne, H., Carlberg, M., Hu, G.Z., and Nehlin, J.O. (1991) Protein phosphatase 2A in Saccharomyces cerevisiae: effects on cell growth and bud morphogenesis. Mol. Cell. Biol. 11,4876-4884PubMedGoogle Scholar
  34. Schmidt, A., Beck, T, Koller, A., Kunz, J., and Hall, M.N. (1998) The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J. 17, 6924–6931PubMedCrossRefGoogle Scholar
  35. Shamji, A.F., Kuruvilla, EG., and Schreiber, S.L. (2000) Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins. Curr. Biol. 10, 1574–1581PubMedCrossRefGoogle Scholar
  36. Shu, Y., and Hallberg, R.L. (1995) SCS1, a multicopy suppressor of hsp60-ts mutant alleles, does not encode a mitochondrially targeted protein. Mol. Cell. Biol. 15, 5618–5626PubMedGoogle Scholar
  37. Shu, Y., Yang, H., Hallberg, E., and Hallberg, R. (1997) Molecular genetic analysis of Rts1p, a B’ regulatory subunit of Saccharomyces cerevisiae protein phosphatase 2A. Mol. Cell. Biol. 17, 3242–3253PubMedGoogle Scholar
  38. Springael, J.Y., and André, B. (1998) Nitrogen-regulated ubiquitination of the Gapl permease of Saccharomyces cerevisiae. Mol. Biol. Cell 9, 1253–1263PubMedGoogle Scholar
  39. Stanbrough, M., and Magasanik, B. (1995) Transcriptional and posttranslational regulation of the general amino acid permease of Saccharomyces cerevisiae. J. Bacteriol. 177, 94–102PubMedGoogle Scholar
  40. Sutton, A., Immanuel, D., and Arndt, K.T. (1991) The SIT4 protein phosphatase functions in late G1 for progression into S phase. Mol. Cell. Biol. 11, 2133–2148PubMedGoogle Scholar
  41. Uesono, Y., Toh-e, A., and Kikuchi, Y. (1997) Ssd1p of Saccharomyces cerevisiae associates with RNA. J. Biol. Chem. 272, 16103–16109PubMedCrossRefGoogle Scholar
  42. van Zyl, W., Huang, W., Sneddon, A.A., Stark, M., Carnier, S., Werner, M., Marck, C, Sentenac, A., and Broach, J.R. (1992) Inactivation of the protein phosphatase 2A regulatory subunit A results in morphological and transcriptional defects in Saccharomyces cerevisiae. Mol. Cell. Biol. 12, 4946–4959PubMedGoogle Scholar
  43. Wang, Y., and Burke, D.J. (1997) Cdc55p, the B-type regulatory subunit of protein phosphatase 2A, has multiple functions in mitosis and is required for the kineto-chore/spindle checkpoint in Saccharomyces cerevisiae. Mol. Cell. Biol. 17, 620–626PubMedGoogle Scholar
  44. Yang, H., Jiang, W., Gentry, M., and Hallberg, R.L. (2000) Loss of a protein phosphatase 2A regulatory subunit (Cdc55p) elicits improper regulation of Swelp degradation. Mol. Cell. Biol. 20, 8143–8156PubMedCrossRefGoogle Scholar
  45. Zhao, Y., Boguslawski, G., Zitomer, R.S., and DePaoli-Roach, A.A. (1997) Saccharomyces cerevisiae homologs of mammalian B and B’ subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions. J. Biol. Chem. 272, 8256–8262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • K. Düvel
    • 1
  • J. R. Broach
    • 1
  1. 1.Department of Molecular BiologyPrinceton UniversityPrincetonUSA

Personalised recommendations