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Gene Review

SIT4  -  type 2A-related serine/threonine-protein...

Saccharomyces cerevisiae S288c

Synonyms: D2693, PPH1, Serine/threonine-protein phosphatase PP1-1, YDL047W
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Disease relevance of SIT4


High impact information on SIT4

  • Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4 [2].
  • We have also determined that yeast cells contain a ceramide-activated protein phosphatase composed of regulatory subunits encoded by TPD3 and CDC55 and a catalytic subunit encoded by SIT4 [3].
  • In addition, Tap42/Sit4 and Tap42/PP2A complex formation is regulated by nutrient growth signals and the rapamycin-sensitive Tor signaling pathway [4].
  • Rescue results from dephosphorylation of the Sso t-SNAREs by a ceramide-activated type 2A protein phosphatase (Sit4) involved in cell cycle control [5].
  • Cells lacking both BEM2 and SIT4 exhibit a synthetic lethal phenotype even in the presence of the SSD1-v1 suppressor [6].

Biological context of SIT4

  • This Sit4 activity masked nitrogen source-dependent changes in Gln3-Myc(13) phosphorylation which were clearly visible when SIT4 was deleted [7].
  • Here we report that correct down-regulation of both basal and induced activity of the PKC1-MAPK pathway requires the SIT4 function [8].
  • Inactivation of HAL3 in the absence of SIT4 function leads to cell cycle arrest at the G(1)-S transition [9].
  • We conclude that Tor signals via Sap-Sit4 complexes to control both transcriptional and translational programs that couple cell growth to amino acid availability [10].
  • The Saccharomyces cerevisiae SIS2 gene was identified by its ability, when present on a high copy number plasmid, to increase dramatically the growth rate of sit4 mutants [11].

Anatomical context of SIT4

  • Both genes represent glucanases, indicating that SIT4 may play a role in controlling cell wall biogenesis [12].
  • Rapamycin also induces depolarization of the actin cytoskeleton through the TOR proteins, Sit4 and Tap42, in an osmotically suppressible manner [13].
  • Cellular localization studies using GFP-tagged proteins reveals that yPtpa1 is localized to the cytoplasm and the nucleus, while the Sit4 protein shows an intense staining spot in the cytoplasm and diffused staining in this organelle [1].

Associations of SIT4 with chemical compounds


Physical interactions of SIT4

  • Here, we describe TIP41, a conserved TAP42-interacting protein involved in the regulation of SIT4 [17].

Enzymatic interactions of SIT4

  • In the presence of a good nitrogen source, TOR (target of rapamycin) maintains GLN3 and NPR1 phosphorylated and inactive by inhibiting the type 2A-related phosphatase SIT4 [18].
  • When TOR is inactivated by rapamycin treatment or nitrogen starvation, downstream effectors of TOR such as the serine/threonine protein kinase NPR1 and the TAP42 interacting protein TIP41 are dephosphorylated in a SIT4-dependent manner [19].

Regulatory relationships of SIT4

  • In Saccharomyces cerevisiae, the rapamycin-sensitive TOR kinases negatively regulate the type 2A-related phosphatase SIT4 by promoting the association of this phosphatase with the inhibitor TAP42 [17].
  • In addition, we have identified a polymorphic gene, SSD1, that in some versions can suppress the lethality due to a deletion of SIT4 and can also partially suppress the phenotypic defects due to a null mutation in BCY1 [20].
  • However, analysis of rapamycin-treated cells suggests that Sit4 represses INO1 transcription through multiple mechanisms, only one of which may involve inhibition of TOR signaling [21].

Other interactions of SIT4

  • First, CLA4 and SIT4 were synthetically lethal [22].
  • In addition, three PP2A-related phosphatases, encoded by PPH3, SIT4 and PPG1, have been identified [14].
  • Zymocin sensitivity therefore requires a Sap185p/Sap190p-dependent function of Sit4p protein phosphatase [23].
  • Both SAP155 and SAP185 require the presence of SIT4 for function, which encodes a PP2A-like phosphatase important for the G1-S transition through the cell cycle [24].
  • In the budding yeast Saccharomyces cerevisiae, the PP2A-related phosphatase Sit4 together with its regulatory subunit Tap42 mediates several Tor signaling events [10].

Analytical, diagnostic and therapeutic context of SIT4


  1. The yeast phosphotyrosyl phosphatase activator protein, yPtpa1/Rrd1, interacts with Sit4 phosphatase to mediate resistance to 4-nitroquinoline-1-oxide and UVA. Douville, J., David, J., Fortier, P.K., Ramotar, D. Curr. Genet. (2004) [Pubmed]
  2. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Beck, T., Hall, M.N. Nature (1999) [Pubmed]
  3. A ceramide-activated protein phosphatase mediates ceramide-induced G1 arrest of Saccharomyces cerevisiae. Nickels, J.T., Broach, J.R. Genes Dev. (1996) [Pubmed]
  4. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Di Como, C.J., Arndt, K.T. Genes Dev. (1996) [Pubmed]
  5. t-SNARE dephosphorylation promotes SNARE assembly and exocytosis in yeast. Marash, M., Gerst, J.E. EMBO J. (2001) [Pubmed]
  6. Control of cellular morphogenesis by the Ip12/Bem2 GTPase-activating protein: possible role of protein phosphorylation. Kim, Y.J., Francisco, L., Chen, G.C., Marcotte, E., Chan, C.S. J. Cell Biol. (1994) [Pubmed]
  7. Saccharomyces cerevisiae Sit4 Phosphatase Is Active Irrespective of the Nitrogen Source Provided, and Gln3 Phosphorylation Levels Become Nitrogen Source-responsive in a sit4-deleted Strain. Tate, J.J., Feller, A., Dubois, E., Cooper, T.G. J. Biol. Chem. (2006) [Pubmed]
  8. Sit4 is required for proper modulation of the biological functions mediated by Pkc1 and the cell integrity pathway in Saccharomyces cerevisiae. Angeles de la Torre-Ruiz, M., Torres, J., Arino, J., Herrero, E. J. Biol. Chem. (2002) [Pubmed]
  9. Identification of multicopy suppressors of cell cycle arrest at the G1-S transition in Saccharomyces cerevisiae. Muñoz, I., Simón, E., Casals, N., Clotet, J., Ariño, J. Yeast (2003) [Pubmed]
  10. TOR controls transcriptional and translational programs via Sap-Sit4 protein phosphatase signaling effectors. Rohde, J.R., Campbell, S., Zurita-Martinez, S.A., Cutler, N.S., Ashe, M., Cardenas, M.E. Mol. Cell. Biol. (2004) [Pubmed]
  11. Overexpression of SIS2, which contains an extremely acidic region, increases the expression of SWI4, CLN1 and CLN2 in sit4 mutants. Di Como, C.J., Bose, R., Arndt, K.T. Genetics (1995) [Pubmed]
  12. The serine/threonine protein phosphatase SIT4 modulates yeast-to-hypha morphogenesis and virulence in Candida albicans. Lee, C.M., Nantel, A., Jiang, L., Whiteway, M., Shen, S.H. Mol. Microbiol. (2004) [Pubmed]
  13. Regulation of the cell integrity pathway by rapamycin-sensitive TOR function in budding yeast. Torres, J., Di Como, C.J., Herrero, E., De La Torre-Ruiz, M.A. J. Biol. Chem. (2002) [Pubmed]
  14. Protein phosphatase 2A on track for nutrient-induced signalling in yeast. Zabrocki, P., Van Hoof, C., Goris, J., Thevelein, J.M., Winderickx, J., Wera, S. Mol. Microbiol. (2002) [Pubmed]
  15. Characterization of SIS1, a Saccharomyces cerevisiae homologue of bacterial dnaJ proteins. Luke, M.M., Sutton, A., Arndt, K.T. J. Cell Biol. (1991) [Pubmed]
  16. The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine. Crespo, J.L., Powers, T., Fowler, B., Hall, M.N. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  17. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Jacinto, E., Guo, B., Arndt, K.T., Schmelzle, T., Hall, M.N. Mol. Cell (2001) [Pubmed]
  18. NPR1 kinase and RSP5-BUL1/2 ubiquitin ligase control GLN3-dependent transcription in Saccharomyces cerevisiae. Crespo, J.L., Helliwell, S.B., Wiederkehr, C., Demougin, P., Fowler, B., Primig, M., Hall, M.N. J. Biol. Chem. (2004) [Pubmed]
  19. Phosphatase Targets in TOR Signaling. Jacinto, E. Methods Mol. Biol. (2006) [Pubmed]
  20. The SIT4 protein phosphatase functions in late G1 for progression into S phase. Sutton, A., Immanuel, D., Arndt, K.T. Mol. Cell. Biol. (1991) [Pubmed]
  21. The Snf1 protein kinase and Sit4 protein phosphatase have opposing functions in regulating TATA-binding protein association with the Saccharomyces cerevisiae INO1 promoter. Shirra, M.K., Rogers, S.E., Alexander, D.E., Arndt, K.M. Genetics (2005) [Pubmed]
  22. The phosphotyrosyl phosphatase activator, Ncs1p (Rrd1p), functions with Cla4p to regulate the G(2)/M transition in Saccharomyces cerevisiae. Mitchell, D.A., Sprague, G.F. Mol. Cell. Biol. (2001) [Pubmed]
  23. Sit4p protein phosphatase is required for sensitivity of Saccharomyces cerevisiae to Kluyveromyces lactis zymocin. Jablonowski, D., Butler, A.R., Fichtner, L., Gardiner, D., Schaffrath, R., Stark, M.J. Genetics (2001) [Pubmed]
  24. Ability of Sit4p to promote K+ efflux via Nha1p is modulated by Sap155p and Sap185p. Manlandro, C.M., Haydon, D.H., Rosenwald, A.G. Eukaryotic Cell (2005) [Pubmed]
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