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  • Review Article
  • Published:

Emerging roles of nuclear protein phosphatases

Nature Reviews Molecular Cell Biology volume 8, pages 234–244 (2007)Cite this article

Key Points

  • Genomics has provided an inventory of the catalytic subunits of human protein phosphatases, which can be classified into three groups: Ser and Thr phosphatases (comprising the phosphoprotein phosphatase (PPP) and protein phosphatase, Mg2+ or Mn2+ dependent (PPM) families); the protein Tyr phosphatase (PTP) superfamily; and Asp-based protein phosphatases.

  • Various members from each phosphatase group are enriched or exclusive to the nucleus and often have associated regulatory subunits that have a targeting role.

  • In the DNA-damage response, PP2Cδ (also known as WIP1) has emerged as a key nuclear phosphatase that regulates the activities of the DNA-damage-response proteins ataxia telangiectasia mutated (ATM), CHK1, CHK2, p53, p38 MAPK and uracil DNA glycosylase.

  • Cell-cycle progression is highly regulated by protein phosphorylation events and involves the phosphatases CDC25, CDC14, PP1 and PP2A.

  • The roles of PP1, PP2A and PP2Cγ and PP2Cδ in pre-mRNA maturation are presented, along with recent progress in understanding how the phosphatases TFIIF-associating C-terminal domain (CTD) phosphatase-1 (FCP1), the small CTD phosphatases (SCPs), PP1 and Ssu72 control the phosphorylation state of RNA polymerase II CTD in the nucleus.

  • A functional genomics screen for phosphatases that regulate C-terminal dephosphorylation of SMAD2 and SMAD3 revealed that nuclearly localized PP2Cα has a key role in transforming growth factor-β (TGFβ) and bone-morphogenetic protein (BMP) signalling. Additional searches for the N-terminal and linker-region phosphatases uncovered the SCPs as the enzymes that target these regions of the SMADs.

Abstract

The phosphorylation state of any protein represents a balance of the actions of specific protein kinases and protein phosphatases. Many protein phosphatases are highly enriched in, or exclusive to, the nuclear compartment, where they dephosphorylate key substrates to regulate various nuclear processes. In this review we will discuss recent findings that define the role of nuclear protein phosphatases in controlling transforming growth factor-β (TGFβ) and bone-morphogenetic protein (BMP) signalling, the DNA-damage response, RNA processing, cell-cycle progression and gene transcription.

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Figure 1: The localization and activity of PP1 are regulated by a pool of targeting subunits.
Figure 2: PP2Cδ and the DNA-damage response.
Figure 3: Nuclear protein phosphatases in spliceosome assembly and catalysis.
Figure 4: The phosphorylation state of the C-terminal domain of RNA polymerase II controls transcript maturation.
Figure 5: PP2Cα attenuates TGFβ signalling in the nucleus.

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References

  1. Olsen, J. V. et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635–648 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Cohen, P. Protein kinases — the major drug targets of the twenty-first century? Nature Rev. Drug Discov. 1, 309–315 (2002).

    Article  CAS  Google Scholar 

  3. Tonks, N. K. Protein tyrosine phosphatases: from genes, to function, to disease. Nature Rev. Mol. Cell Biol. 7, 833–846 (2006). An up-to-date review with a regulatory, structural and genomics perspective on the PTPs.

    Article  CAS  Google Scholar 

  4. Cohen, P. The twentieth century struggle to decipher insulin signalling. Nature Rev. Mol. Cell Biol. 7, 867–873 (2006).

    Article  CAS  Google Scholar 

  5. Zhang, Y. et al. Determinants for dephosphorylation of the RNA polymerase II C-terminal domain by Scp1. Mol. Cell 24, 759–770 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. MacKintosh, C. & MacKintosh, R. W. Inhibitors of protein kinases and phosphatases. Trends Biochem. Sci. 19, 444–448 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Janssens, V. & Goris, J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353, 417–439 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. MacKeigan, J. P., Murphy, L. O. & Blenis, J. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nature Cell Biol. 7, 591–600 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Mukherji, M. et al. Genome-wide functional analysis of human cell-cycle regulators. Proc. Natl Acad. Sci. USA 103, 14819–14824 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Begley, M. J. & Dixon, J. E. The structure and regulation of myotubularin phosphatases. Curr. Opin. Struct. Biol. 15, 614–620 (2005). An examination of the myotubularin subfamily of the PTPs, which discusses the molecular basis of their unique substrate specificity as revealed by structural studies.

    Article  CAS  PubMed  Google Scholar 

  12. Mustelin, T. in Methods in Molecular Biology. (ed. Moorhead, G.) 9–22 (Humana Press, Totawa, 2007).

    Google Scholar 

  13. Li, X. et al. Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis. Nature 426, 247–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Tootle, T. L. et al. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426, 299–302 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Meinhart, A., Kamenski, T., Hoeppner, S., Baumli, S. & Cramer, P. A structural perspective of CTD function. Genes Dev. 19, 1401–1415 (2005). A comprehensive look at the regulation of RNA Pol II CTD by protein kinases and phosphatases with a structural emphasis.

    Article  CAS  PubMed  Google Scholar 

  16. Yeo, M. et al. Small CTD phosphatases function in silencing neuronal gene expression. Science 307, 596–600 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Yeo, M., Lin, P. S., Dahmus, M. E. & Gill, G. N. A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5. J. Biol. Chem. 278, 26078–26085 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Shenolikar, S. in Methods in Molecular Biology. (ed. Moorhead, G.) 1–8 (Humana Press, Totawa, 2007).

    Google Scholar 

  19. Jakes, S., Mellgren, R. L. & Schlender, K. K. Isolation and characterization of an inhibitor-sensitive and a polycation-stimulated protein phosphatase from rat liver nuclei. Biochim. Biophys. Acta 888, 135–142 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Kuret, J., Bell, H. & Cohen, P. Identification of high levels of protein phosphatase-1 in rat liver nuclei. FEBS Lett. 203, 197–202 (1986).

    Article  CAS  PubMed  Google Scholar 

  21. Andreassen, P. R., Lacroix, F. B., Villa-Moruzzi, E. & Margolis, R. L. Differential subcellular localization of protein phosphatase-1 α, γ1, and δ isoforms during both interphase and mitosis in mammalian cells. J. Cell Biol. 141, 1207–1215 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Trinkle-Mulcahy, L., Sleeman, J. E. & Lamond, A. I. Dynamic targeting of protein phosphatase 1 within the nuclei of living mammalian cells. J. Cell Sci. 114, 4219–4228 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Lesage, B., Beullens, M., Ceulemans, H., Himpens, B. & Bollen, M. Determinants of the nucleolar targeting of protein phosphatase-1. FEBS Lett. 579, 5626–5630 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Brush, M. H., Weiser, D. C. & Shenolikar, S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1α to the endoplasmic reticulum and promotes dephosphorylation of the α subunit of eukaryotic translation initiation factor 2. Mol. Cell. Biol. 23, 1292–1303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Egloff, M. P. et al. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 16, 1876–1887 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Terrak, M., Kerff, F., Langsetmo, K., Tao, T. & Dominguez, R. Structural basis of protein phosphatase 1 regulation. Nature 429, 780–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Johnson, D. F. et al. Identification of protein-phosphatase-1-binding domains on the glycogen and myofibrillar targetting subunits. Eur. J. Biochem. 239, 317–325 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Zhao, S. & Lee, E. Y. A protein phosphatase-1-binding motif identified by the panning of a random peptide display library. J. Biol. Chem. 272, 28368–28372 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Roadcap, D., Matthew, H. & Shenolikar, S. in Methods in Molecular Biology. (ed. Moorhead, G.) 181–196 (Humana Press, Totawa, 2007).

    Google Scholar 

  30. Wakula, P., Beullens, M., Ceulemans, H., Stalmans, W. & Bollen, M. Degeneracy and function of the ubiquitous RVXF motif that mediates binding to protein phosphatase-1. J. Biol. Chem. 278, 18817–18823 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Meiselbach, H., Sticht, H. & Enz, R. Structural analysis of the protein phosphatase 1 docking motif: molecular description of binding specificities identifies interacting proteins. Chem. Biol. 13, 49–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Jagiello, I., Beullens, M., Stalmans, W. & Bollen, M. Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. J. Biol. Chem. 270, 17257–17263 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Tran, H. T., Ulke, A., Morrice, N., Johannes, C. J. & Moorhead, G. B. Proteomic characterization of protein phosphatase complexes of the mammalian nucleus. Mol. Cell. Proteomics 3, 257–265 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Trinkle-Mulcahy, L. et al. Repo-Man recruits PP1γ to chromatin and is essential for cell viability. J. Cell Biol. 172, 679–692 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kwiek, N. C., Thacker, D. F., Datto, M. B., Megosh, H. B. & Haystead, T. A. PITK, a PP1 targeting subunit that modulates the phosphorylation of the transcriptional regulator hnRNP K. Cell Signal 18, 1769–1778 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Llorian, M., Beullens, M., Andres, I., Ortiz, J. M. & Bollen, M. SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1. Biochem. J. 378, 229–238 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sagara, J. et al. Scapinin, a putative protein phosphatase-1 regulatory subunit associated with the nuclear nonchromatin structure. J. Biol. Chem. 278, 45611–45619 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Mann, M. Functional and quantitative proteomics using SILAC. Nature Rev. Mol. Cell Biol. 7, 952–958 (2006).

    Article  CAS  Google Scholar 

  39. Vagnarelli, P. et al. Condensin and Repo-Man/PP1 co-operate in the regulation of chromosome architecture during mitosis. Nature Cell Biol. 8, 1133–1142 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Xing, Y. et al. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 127, 341–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Cho, U. S. & Xu, W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445, 53–57 (2006).

    Article  PubMed  CAS  Google Scholar 

  42. Xu, Y. et al. Structure of the protein phosphatase 2A holoenzyme. Cell 127, 1239–1251 (2006). References 41 and 42 are landmark studies reporting the characterization of the first structure of a trimeric PP2A. The interaction of each subunit with the others and how the B′ subunits probably define substrate specificity are revealed.

    Article  CAS  PubMed  Google Scholar 

  43. Jacinto, E., Guo, B., Arndt, K. T., Schmelzle, T. & Hall, M. N. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol. Cell 8, 1017–1026 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Gingras, A. C. et al. A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity. Mol. Cell. Proteomics 4, 1725–1740 (2005). Excellent study in which TAP-tagged stable cell lines were used to define the binding partners and complexes of human PP4.

    Article  CAS  PubMed  Google Scholar 

  45. Turowski, P., Favre, B., Campbell, K. S., Lamb, N. J. & Hemmings, B. A. Modulation of the enzymatic properties of protein phosphatase 2A catalytic subunit by the recombinant 65-kDa regulatory subunit PR65α. Eur. J. Biochem. 248, 200–208 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. McCright, B., Rivers, A. M., Audlin, S. & Virshup, D. M. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J. Biol. Chem. 271, 22081–22089 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Strack, S., Chang, D., Zaucha, J. A., Colbran, R. J. & Wadzinski, B. E. Cloning and characterization of Bδ, a novel regulatory subunit of protein phosphatase 2A. FEBS Lett. 460, 462–466 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Yan, Z., Fedorov, S. A., Mumby, M. C. & Williams, R. S. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Mol. Cell. Biol. 20, 1021–1029 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shtrichman, R., Sharf, R. & Kleinberger, T. Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Bα. Oncogene 19, 3757–3765 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Gentry, M. S. & Hallberg, R. L. Localization of Saccharomyces cerevisiae protein phosphatase 2A subunits throughout mitotic cell cycle. Mol. Biol. Cell 13, 3477–3492 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Prickett, T. D. & Brautigan, D. L. The α-4 regulatory subunit exerts opposing allosteric effects on protein phosphatases PP6 and PP2A. J. Biol. Chem. 281, 30503–30511 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Stefansson, B. & Brautigan, D. L. Protein phosphatase 6 subunit with conserved Sit4-associated protein domain targets IκBɛ. J. Biol. Chem. 281, 22624–22634 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Yang, J. et al. Molecular basis for TPR domain-mediated regulation of protein phosphatase 5. EMBO J. 24, 1–10 (2005).

    Article  PubMed  CAS  Google Scholar 

  54. Borthwick, E. B., Zeke, T., Prescott, A. R. & Cohen, P. T. Nuclear localization of protein phosphatase 5 is dependent on the carboxy-terminal region. FEBS Lett. 491, 279–284 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Jeong, J. Y., Johns, J., Sinclair, C., Park, J. M. & Rossie, S. Characterization of Saccharomyces cerevisiae protein Ser/Thr phosphatase T1 and comparison to its mammalian homolog PP5. BMC Cell Biol. 4, 3 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Huang, X. & Honkanen, R. E. Molecular cloning, expression, and characterization of a novel human serine/threonine protein phosphatase, PP7, that is homologous to Drosophila retinal degeneration C gene product (rdgC). J. Biol. Chem. 273, 1462–1468 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Moller, S. G., Kim, Y. S., Kunkel, T. & Chua, N. H. PP7 is a positive regulator of blue light signaling in Arabidopsis. Plant Cell 15, 1111–1119 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Das, A. K., Helps, N. R., Cohen, P. T. & Barford, D. Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 Å resolution. EMBO J. 15, 6798–6809 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schweighofer, A., Hirt, H. & Meskiene, I. Plant PP2C phosphatases: emerging functions in stress signaling. Trends Plant Sci. 9, 236–243 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Dai, J. et al. Characterization of a novel human protein phosphatase 2C family member, PP2Cκ. Int. J. Mol. Med. 17, 1117–1123 (2006).

    CAS  PubMed  Google Scholar 

  61. Wenk, J. & Mieskes, G. Cytosolic and nuclear localization of protein phosphatase 2C β 1 in COS and BHK cells. Eur. J. Cell. Biol. 68, 377–386 (1995).

    CAS  PubMed  Google Scholar 

  62. Komaki, K. et al. Molecular cloning of PP2Cɛ, a novel member of the protein phosphatase 2C family. Biochim. Biophys. Acta 1630, 130–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Murray, M. V., Kobayashi, R. & Krainer, A. R. The type 2C Ser/Thr phosphatase PP2Cγ is a pre-mRNA splicing factor. Genes Dev. 13, 87–97 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhou, Z., Licklider, L. J., Gygi, S. P. & Reed, R. Comprehensive proteomic analysis of the human spliceosome. Nature 419, 182–185 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Deshpande, T., Takagi, T., Hao, L., Buratowski, S. & Charbonneau, H. Human PIR1 of the protein-tyrosine phosphatase superfamily has RNA 5′-triphosphatase and diphosphatase activities. J. Biol. Chem. 274, 16590–16594 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Tillmann, U., Wagner, J., Boerboom, D., Westphal, H. & Tremblay, M. L. Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase. Mol. Cell. Biol. 14, 3030–3040 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Cuppen, E., van Ham, M., Pepers, B., Wieringa, B. & Hendriks, W. Identification and molecular characterization of BP75, a novel bromodomain-containing protein. FEBS Lett. 459, 291–298 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Kraut, J., Volohonsky, G., Toledano-Katchalski, H. & Elson, A. Nuclear localization of non-receptor protein tyrosine phosphatase ɛ is regulated by its unique N-terminal domain. Exp. Cell Res. 281, 182–199 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. He, D., Song, X., Liu, L., Burk, D. H. & Zhou, G. W. EGF-stimulation activates the nuclear localization signal of SHP-1. J. Cell Biochem. 94, 944–953 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Tiganis, T., Bennett, A. M., Ravichandran, K. S. & Tonks, N. K. Epidermal growth factor receptor and the adaptor protein p52Shc are specific substrates of T-cell protein tyrosine phosphatase. Mol. Cell. Biol. 18, 1622–1634 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kharbanda, S. et al. The stress response to ionizing radiation involoves c-Abl-dependent phosphorylation of SHPTP1. Proc. Natl Acad. Sci. USA 93, 6898–6901 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wadham, C., Gamble, J. R., Vadas, M. A. & Khew-Goodall, Y. Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation. J. Cell Sci. 113, 3117–3123 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Flores, E., Roy, G., Patel, D., Shaw, A. & Thomas, M. L. Nuclear localization of the PEP protein tyrosine phosphatase. Mol. Cell. Biol. 14, 4938–4946 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Archambault, J. et al. FCP1, the RAP74-interacting subunit of a human protein phosphatase that dephosphorylates the carboxyl-terminal domain of RNA polymerase IIO. J. Biol. Chem. 273, 27593–27601 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Gohla, A., Birkenfeld, J. & Bokoch, G. M. Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics. Nature Cell Biol. 7, 21–29 (2005). Reports the identification of chronophin, a HAD-type phosphatase as a cofilin protein phosphatase.

    Article  CAS  PubMed  Google Scholar 

  76. Shi, Y., Reddy, B. & Manley, J. L. PP1/PP2A phosphatases are required for the second step of pre-mRNA splicing and target specific snRNP proteins. Mol. Cell 23, 819–829 (2006). Re-addresses the role of PP1 and PP2A in spliceosome catalysis.

    Article  CAS  PubMed  Google Scholar 

  77. Bollen, M. & Beullens, M. Signaling by protein phosphatases in the nucleus. Trends Cell Biol. 12, 138–145 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Kitajima, T. S. et al. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441, 46–52 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Riedel, C. G. et al. Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature 441, 53–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Tang, Z. et al. PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev. Cell 10, 575–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Vagnarelli, P. et al. Condensin and Repo-Man-PP1 co-operate in the regulation of chromosome architecture during mitosis. Nature Cell Biol. 8, 1133–1142 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Trinkle-Mulcahy, L. & Lamond, A. I. Mitotic phosphatases: no longer silent partners. Curr. Opin. Cell Biol. 18, 623–631 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Fiscella, M. et al. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc. Natl Acad. Sci. USA 94, 6048–6053 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takekawa, M. et al. p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J. 19, 6517–6526 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Takekawa, M., Maeda, T. & Saito, H. Protein phosphatase 2Cα inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J. 17, 4744–4752 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lu, X. et al. The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Mol. Cell 15, 621–634 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Yamaguchi, H. et al. Substrate specificity of the human protein phosphatase 2Cδ, Wip1. Biochemistry 44, 5285–5294 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Lu, X., Nannenga, B. & Donehower, L. A. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 19, 1162–1174 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ohta, M., Guo, Y., Halfter, U. & Zhu, J. K. A novel domain in the protein kinase SOS2 mediates interaction with the protein phosphatase 2C ABI2. Proc. Natl Acad. Sci. USA 100, 11771–11776 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yoda, A. et al. Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. J. Biol. Chem. 281, 24847–24862 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Leroy, C. et al. PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. Mol. Cell 11, 827–835 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Shreeram, S. et al. Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol. Cell 23, 757–764 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Goodarzi, A. A. et al. Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A. EMBO J. 23, 4451–4461 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Keogh, M. C. et al. A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery. Nature 439, 497–501 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Chowdhury, D. et al. γ-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol. Cell 20, 801–809 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Douglas, P., Moorhead, G. B., Ye, R. & Lees-Miller, S. P. Protein phosphatases regulate DNA-dependent protein kinase activity. J. Biol. Chem. 276, 18992–18998 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Bennett, D. Transcriptional control by chromosome-associated protein phosphatase-1. Biochem. Soc. Trans. 33, 1444–1446 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Mermoud, J. E., Cohen, P. & Lamond, A. I. Ser/Thr-specific protein phosphatases are required for both catalytic steps of pre-mRNA splicing. Nucleic Acids Res. 20, 5263–5269 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Beullens, M. & Bollen, M. The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly. J. Biol. Chem. 277, 19855–19860 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Hirano, K., Erdodi, F., Patton, J. G. & Hartshorne, D. J. Interaction of protein phosphatase type 1 with a splicing factor. FEBS Lett. 389, 191–194 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Ajuh, P. et al. Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry. EMBO J. 19, 6569–6581 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cho, E. J., Kobor, M. S., Kim, M., Greenblatt, J. & Buratowski, S. Opposing effects of Ctk1 kinase and Fcp1 phosphatase at Ser 2 of the RNA polymerase II C-terminal domain. Genes Dev. 15, 3319–3329 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kong, S. E. et al. Interaction of Fcp1 phosphatase with elongating RNA polymerase II holoenzyme, enzymatic mechanism of action, and genetic interaction with elongator. J. Biol. Chem. 280, 4299–4306 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Lin, X. et al. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell 125, 915–928 (2006). Using a functional genomics approach, PP2Cα was identified as the SMAD2 and SMAD3 C-terminal phosphatase in the nucleus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wrighton, K. H. et al. Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-β signaling. J. Biol. Chem. 281, 38365–38375 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Bennett, D. & Alphey, L. PP1 binds Sara and negatively regulates Dpp signaling in Drosophila melanogaster. Nature Genet. 31, 419–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Sapkota, G. et al. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small CTD phosphatases (SCPs) has distinct outcomes for BMP and TGFβ pathways. J. Biol. Chem. 281, 40412–40419 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Wrighton, K. H. et al. Small carboxy-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance TGF-β signaling. J. Biol. Chem. 281, 38365–38375 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Chen, H. B., Shen, J., Ip, Y. T. & Xu, L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 20, 648–653 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Knockaert, M., Sapkota, G., Alarcon, C., Massague, J. & Brivanlou, A. H. Unique players in the BMP pathway: small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling. Proc. Natl Acad. Sci. USA 103, 11940–11945 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Duan, X., Liang, Y. Y., Feng, X. H. & Lin, X. Dephosphorylation of Smad1 in the BMP signaling pathway by PPM1A. J. Biol. Chem. 281, 36526–36532 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Ong, S. E. et al. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol. Cell. Proteomics 1, 376–386 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Cohen, P. T. Protein phosphatase 1 — targeted in many directions. J. Cell Sci. 115, 241–256 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Andersen, J. N. et al. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J. 18, 8–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Loh, C. et al. Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J. Biol. Chem. 271, 10884–10891 (1996).

    Article  CAS  PubMed  Google Scholar 

  118. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. Huang, T. Y., DerMardirossian, C. & Bokoch, G. M. Cofilin phosphatases and regulation of actin dynamics. Curr. Opin. Cell Biol. 18, 26–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Robinson, F. L. & Dixon, J. E. Myotubularin phosphatases: policing 3-phosphoinositides. Trends Cell Biol. 16, 403–412 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the group of G.B.G.M. is supported by the Natural Sciences and Engineering Research Council of Canada. L.T.M. is funded by the Wellcome Trust.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, T2N 1N4, Alberta, Canada

    Greg B. G. Moorhead & Annegret Ulke-Lemée

  2. MSI/WTB Complex, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland

    Laura Trinkle-Mulcahy

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  1. Greg B. G. Moorhead
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Correspondence to Greg B. G. Moorhead.

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FURTHER INFORMATION

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A Protein Phosphatase Information Resource

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Protein phosphatase-1 PP1 binding proteins

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Glossary

SILAC

A mass-spectrometry-based quantitative proteomics method that uses stable-isotope labelling with amino acids in cell culture.

HEAT repeat

A tandemly repeated module, 37–47 amino acids in length, that is present in a number of proteins, including the four proteins that gave the module its name: huntingtin, elongation factor-3 (EF3), the A subunit of PP2A and target of rapamycin kinase-1 (TOR1).

TOR signalling

Signal-transduction events that are mediated through the target of rapamycin (TOR) protein complexes.

LC–MS/MS

Liquid chromatography coupled with tandem mass spectrometry. This involves the separation of peptides by high-pressure liquid chromatography and their detection by an interfaced mass spectrometer. Peptides are then selected, fragmented and the products are detected by a second mass spectrometer.

TPR domain

(Tetratricopeptide repeat). A motif that consists of tandem repeats of a degenerate sequence of ∼34 amino acids and that functions as an interaction scaffold in proteins.

Calmodulin

(CaM). A Ca2+-binding protein that can bind to and regulate a large number of different protein targets and is considered a major transducer of Ca2+ signals in the cell.

EF-hand domain

An EF-hand has two nearly perpendicular α-helices that are connected by a loop, forming a single Ca2+-binding site. EF-hand units generally, but not always, bind Ca2+. EF-hand-containing proteins include CaM, recoverin and the B subunit of PP2B.

Spliceosome

A large nuclear complex of RNA and protein subunits that catalyses the removal of the non-coding introns from unprocessed mRNA.

BRCT domain

A phosphopeptide-binding module that recognizes specific phosphorylation motifs and occurs as a single module or as multiple repeats.

Base-excision repair

(BER). The main DNA-repair pathway that is responsible for the repair of apurinic and apyrimidinic (AP) sites in DNA. BER is catalysed in four consecutive steps: a DNA glycosylase removes the damaged base; an AP endonuclease processes the abasic site; a DNA polymerase inserts the new nucleotide(s); and DNA ligase rejoins the DNA strand.

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Moorhead, G., Trinkle-Mulcahy, L. & Ulke-Lemée, A. Emerging roles of nuclear protein phosphatases. Nat Rev Mol Cell Biol 8, 234–244 (2007). https://doi.org/10.1038/nrm2126

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