Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Protein Phosphatase 1 (PP1)

  • Filipa Martins
  • Joana B. Serrano
  • Ana M. Marafona
  • Odete A. B. da Cruz e Silva
  • Sandra RebeloEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101767


Historical Background

Protein phosphatase 1 (PP1), also known as phosphorylase phosphatase, was first studied in 1943 by Cori and Green in the context of glycogen metabolism, as the enzyme responsible for the conversion of phosphorylase a to phosphorylase b (Cori and Green 1943). A decade later, the discovery that this enzyme is in fact a phosphatase, together with the discovery of phosphorylase kinase by Fischer and Krebs in 1955, marked the beginning of the study of protein phosphorylation/dephosphorylation as a ubiquitous regulatory mechanism (Fischer and Krebs 1955). Research on PP1 further focused on the understanding of its enzymology and its role in glycogen metabolism. In fact, in the 1970s, PP1 catalytic subunits (PP1c) were isolated from both the liver and muscle (Brandt et al. 1975; Gratecos et al. 1977). Subsequent studies led to the discovery of PP1...

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  1. Allen PB, Ouimet CC, Greengard P. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci U S A. 1997;94:9956–61.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Andreassen PR, Lacroix FB, Villa-Moruzzi E, Margolis RL. Differential subcellular localization of protein phosphatase-1 alpha, gamma1, and delta isoforms during both interphase and mitosis in mammalian cells. J Cell Biol. 1998;141:1207–15.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aoyama H, Ikeda Y, Miyazaki Y, Yoshimura K, Nishino S, Yamamoto T, Yano M, Inui M, Aoki H, Matsuzaki M. Isoform-specific roles of protein phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated Ca(2+) cycling. Cardiovasc Res. 2011;89:79–88.CrossRefPubMedGoogle Scholar
  4. Ayllón V, Martínez-A C, García A, Cayla X, Rebollo A. Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J. 2000;19:2237–46.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Barford D, Das AK, Egloff MP. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu Rev Biophys Biomol Struct. 1998;27:133–64.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Blitzer RD, Connor JH, Brown GP, Wong T, Shenolikar S, Iyengar R, Landau EM. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science. 1998;280:1940–2.CrossRefPubMedGoogle Scholar
  7. Boens S, Szekér K, Van EA, Bollen M. Interactor-guided dephosphorylation by protein phosphatase-1. Methods Mol Biol. 2013;1053:271–81.CrossRefPubMedGoogle Scholar
  8. Bollen M, Gerlich DW, Lesage B. Mitotic phosphatases: from entry guards to exit guides. Trends Cell Biol. 2009;19:531–41.CrossRefPubMedGoogle Scholar
  9. Bollen M, Peti W, Ragusa MJ, Beullens M. The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci. 2010;35:450–8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brandt H, Capulong ZL, Lee EY. Purification and properties of rabbit liver phosphorylase phosphatase. J Biol Chem. 1975;250:8038–44.PubMedCentralPubMedGoogle Scholar
  11. Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.CrossRefPubMedGoogle Scholar
  12. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem. 1989;58:453–508.CrossRefPubMedGoogle Scholar
  13. Cohen PTW. Protein phosphatase 1 – targeted in many directions. J Cell Sci. 2002;115:241–56.PubMedGoogle Scholar
  14. Cori G, Green A. Crystalline muscle phosphorylase II. prosthetic group. J Biol Chem. 1943;151:31–8.Google Scholar
  15. da Cruz e Silva EF, Fox CA, Ouimet CC, Gustafson E, Watson SJ, Greengard P. Differential expression of protein phosphatase 1 isoforms in mammalian brain. J Neurosci. 1995;15:3375–89.PubMedCrossRefGoogle Scholar
  16. da Cruz e Silva OAB, Fardilha M, Henriques AG, Rebelo S, Vieira S, da Cruz e Silva EF. Signal transduction therapeutics: relevance for Alzheimer’s disease. J Mol Neurosci. 2004;23:123–42.CrossRefPubMedGoogle Scholar
  17. Egloff MP, Johnson DF, Moorhead G, Cohen PT, Cohen P, Barford D. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 1997;16:1876–87.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fardilha M, Esteves SLC, Korrodi-Gregório L, da Cruz e Silva OAB, da Cruz e Silva FF. The physiological relevance of protein phosphatase 1 and its interacting proteins to health and disease. Curr Med Chem. 2010;17:3996–4017.CrossRefPubMedGoogle Scholar
  19. Fardilha M, Esteves SLC, Korrodi-Gregório L, Pelech S, Cruz E, Silva OAB d, Cruz E, Silva E d. Protein phosphatase 1 complexes modulate sperm motility and present novel targets for male infertility. Mol Hum Reprod. 2011;17:466–77.CrossRefPubMedGoogle Scholar
  20. Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P. Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci U S A. 2000;97:9287–92.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Fischer E, Krebs E. Conversion of phosphorylase b to phosphorylase a in muscle extracts. J Biol Chem. 1955;216:121–32.PubMedGoogle Scholar
  22. Godet AN, Guergnon J, Maire V, Croset A, Garcia A. The combinatorial PP1-binding consensus Motif (R/K)x( (0,1))V/IxFxx(R/K)x(R/K) is a new apoptotic signature. PLoS ONE. 2010;5:e9981.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Gong C-X, Grundke-Iqbal I, Damuni Z, Iqbal K. Dephosphorylation of microtubule-associated protein tau by protein phosphatase-1 and -2C and its implication in Alzheimer disease. No longer published by Elsevier; 1994;341:94–8.PubMedCrossRefGoogle Scholar
  24. Grassie ME, Moffat LD, Walsh MP, MacDonald JA. The myosin phosphatase targeting protein (MYPT) family: a regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1δ. Arch Biochem Biophys. 2011;510:147–59.CrossRefPubMedGoogle Scholar
  25. Gratecos D, Detwiler TC, Hurd S, Fischer EH. Rabbit muscle phosphorylase phosphatase. 1. purification and chemical properties. Biochemistry. 1977;16:4812–7.CrossRefPubMedGoogle Scholar
  26. Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron. 1999;23:435–47.CrossRefPubMedGoogle Scholar
  27. Han Y, Haines CJ, Feng HL. Role(s) of the serine/threonine protein phosphatase 1 on mammalian sperm motility. Arch Androl. 2007;53:169–77.CrossRefPubMedGoogle Scholar
  28. Hendrickx A, Beullens M, Ceulemans H, Den AT, Van EA, Nicolaescu E, Lesage B, Bollen M. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009;16(4):365–71.CrossRefPubMedGoogle Scholar
  29. Heroes E, Lesage B, Görnemann J, Beullens M, Van Meervelt L, Bollen M. The PP1 binding code: a molecular-lego strategy that governs specificity. FEBS J. 2013;280:584–95.CrossRefPubMedGoogle Scholar
  30. Honkanen RE, Golden T. Regulators of serine/threonine protein phosphatases at the dawn of a clinical era? Curr Med Chem. 2002;9:2055–75.CrossRefPubMedGoogle Scholar
  31. Hsieh-Wilson LC, Benfenati F, Snyder GL, Allen PB, Nairn AC, Greengard P. Phosphorylation of spinophilin modulates its interaction with actin filaments. J Biol Chem. 2003;278:1186–94.CrossRefPubMedGoogle Scholar
  32. Hu XD, Huang Q, Roadcap DW, Shenolikar SS, Xia H. Actin-associated neurabin-protein phosphatase-1 complex regulates hippocampal plasticity. J Neurochem. 2006;98:1841–51.CrossRefPubMedGoogle Scholar
  33. Killilea SD, Mellgren RL, Aylward JH, Metieh ME, Lee EY. Liver protein phosphatases: studies of the presumptive native forms of phosphorylase phosphatase activity in liver extracts and their dissociation to a catalytic subunit of Mr 35,000. Arch Biochem Biophys. 1979;193:130–9.CrossRefPubMedGoogle Scholar
  34. Korrodi-Gregório L, Esteves SLC, Fardilha M. Protein phosphatase 1 catalytic isoforms: specificity toward interacting proteins. Transl Res. 2014;164:366–91.CrossRefPubMedGoogle Scholar
  35. Liao H, Li Y, Brautigan DL, Gundersen GG. Protein phosphatase 1 is targeted to microtubules by the microtubule-associated protein Tau. J Biol Chem. 1998;273:21901–8.CrossRefPubMedGoogle Scholar
  36. Lin Q, Buckler ES, Muse SV, Walker JC. Molecular evolution of type 1 serine/threonine protein phosphatases. Mol Phylogenet Evol. 1999;12:57–66.CrossRefPubMedGoogle Scholar
  37. Llanos S, Royer C, Lu M, Bergamaschi D, Lee WH, Lu X. Inhibitory member of the apoptosis-stimulating proteins of the p53 family (iASPP) interacts with protein phosphatase 1 via a noncanonical binding motif. J Biol Chem. 2011;286:43039–44.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Lüss H, Klein-Wiele O, Bokník P, Herzig S, Knapp J, Linck B, Müller FU, et al. Regional expression of protein phosphatase type 1 and 2A catalytic subunit isoforms in the human heart. J Mol Cell Cardiol. 2000;32:2349–59.CrossRefPubMedGoogle Scholar
  39. Malchiodi-Albedi F, Petrucci TC, Picconi B, Iosi F, Falchi M. Protein phosphatase inhibitors induce modification of synapse structure and tau hyperphosphorylation in cultured rat hippocampal neurons. J Neurosci Res. 1997;48:425–38.CrossRefPubMedGoogle Scholar
  40. Martins F, Rebelo S, Santos M, Cotrim CZ, Cruz E, Silva EF d, Cruz E, Silva OAB d. BRI2 and BRI3 are functionally distinct phosphoproteins. Cell Signal. 2016a;28:130–44.CrossRefPubMedGoogle Scholar
  41. Martins F, Serrano J, Muller T, da Cruz e Silva O, Rebelo S. BRI2 processing and neuritogenic role is modulated by complexing with protein phosphatase 1. Cell Signal. 2016b. (submitted).Google Scholar
  42. McAvoy T, Allen PB, Obaishi H, Nakanishi H, Takai Y, Greengard P, Nairn AC, Hemmings HC. Regulation of neurabin I interaction with protein phosphatase 1 by phosphorylation. Biochemistry. 1999;38:12943–9.CrossRefPubMedGoogle Scholar
  43. Mellgren RL, Aylward JH, Killilea SD, Lee EY. The activation and dissociation of a native high molecular weight form of rabbit skeletal muscle phosphorylase phosphatase by endogenous CA2+-dependent proteases. J Biol Chem. 1979;254:648–52.PubMedGoogle Scholar
  44. Monroe JD, Heathcote RD. Protein phosphatases regulate the growth of developing neurites. Int J Dev Neurosci. 2013;31:250–7.CrossRefPubMedGoogle Scholar
  45. Mulkey RM, Endo S, Shenolikar S, Malenka RC. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994;369:486–8.CrossRefPubMedGoogle Scholar
  46. Oliver CJ, Terry-Lorenzo RT, Elliott E, Bloomer WAC, Li S, Brautigan DL, Colbran RJ, Shenolikar S. Targeting protein phosphatase 1 (PP1) to the actin cytoskeleton: the neurabin I/PP1 complex regulates cell morphology. Mol Cell Biol. 2002;22:4690–701.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ouimet CC, da Cruz e Silva EF, Greengard P. The alpha and gamma 1 isoforms of protein phosphatase 1 are highly and specifically concentrated in dendritic spines. Proc Natl Acad Sci U S A. 1995;92:3396–400.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Paul A, Jozef B. Human cardiac tissues, control and diseased. 2004. http://cardiogenomics.med.harvard.edu/home (2004).
  49. Ragusa MJ, Allaire M, Nairn AC, Page R, Peti W. Flexibility in the PP1:spinophilin holoenzyme. FEBS Lett. 2011;585:36–40.CrossRefPubMedGoogle Scholar
  50. Rebelo S, Domingues SC, Santos M, Fardilha M, Esteves SLC, Vieira SI, Vintém APB, Wu W, da Cruz e Silva EF, da Cruz e Silva OAB. Identification of a novel complex AβPP:Fe65:PP1 that regulates AβPP Thr668 phosphorylation levels. J Alzheimers Dis. 2013;35:761–75.PubMedCrossRefGoogle Scholar
  51. Rebelo S, Santos M, Martins F, da Cruz e Silva EF, da Cruz e Silva OAB. Protein phosphatase 1 is a key player in nuclear events. Cell Signal. 2015;27:2589–98.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Santos M, Rebelo S, da Cruz e Silva OAB, da Cruz e Silva EF. Immunolocalization of PPP1C isoforms in SH-SY5Y cells during the cell cycle. MicroScopy. 2012;18(S5):41–2.Google Scholar
  53. Santos M, Rebelo S, Van Kleeff PJM, Kim CE, Dauer WT, Fardilha M, da Cruz e Silva OA, da Cruz e Silva EF. The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. PLoS One. 2013;8:e76788.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Santos M, Costa P, Martins F, Cruz E, da Silva EF, Cruz E, da Silva OAB, Rebelo S. LAP1 is a crucial protein for the maintenance of the nuclear envelope structure and cell cycle progression. Mol Cell Biochem. 2014a;399:143–53.CrossRefPubMedGoogle Scholar
  55. Santos M, Domingues SC, Costa P, Muller T, Galozzi S, Marcus K, Cruz E, Silva EF d, Cruz E, Silva OA d, Rebelo S. Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation. PLoS ONE. 2014b;9:e113732.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Serrano J, Martins F, Sousa J, VanPelt A, Rebelo S, da Cruz e Silva O. The distribution of LAP1 and associated proteins throughout spermatogenesis. Reprod Fertil Dev. 2016. (submitted).Google Scholar
  57. Shi Y. Serine/threonine phosphatases: mechanism through structure. Cell. 2009;139:468–84.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Silva JV, Freitas MJ, Fardilha M. Phosphoprotein phosphatase 1 complexes in spermatogenesis. Curr Mol Pharmacol. 2014;7:136–46.CrossRefPubMedGoogle Scholar
  59. Soderling TR, Derkach VA. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 2000;23:75–80.CrossRefPubMedGoogle Scholar
  60. Strack S, Kini S, Ebner FF, Wadzinski BE, Colbran RJ. Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain. J Comp Neurol. 1999;413:373–84.CrossRefPubMedGoogle Scholar
  61. Terrak M, Kerff F, Langsetmo K, Tao T, Dominguez R. Structural basis of protein phosphatase 1 regulation. Nature. 2004;429:780–4.CrossRefPubMedGoogle Scholar
  62. Terry-Lorenzo RT, Inoue M, Connor JH, Haystead TA, Armbruster BN, Gupta RP, Oliver CJ, Shenolikar S. Neurofilament-L is a protein phosphatase-1-binding protein associated with neuronal plasma membrane and post-synaptic density. J Biol Chem. 2000;275:2439–46.CrossRefPubMedGoogle Scholar
  63. Trinkle-Mulcahy L, Andrews PD, Wickramasinghe S, Sleeman J, Prescott A, Lam YW, Lyon C, Swedlow JR, Lamond AI. Time-lapse imaging reveals dynamic relocalization of PP1gamma throughout the mammalian cell cycle. Mol Biol Cell. 2003;14:107–17.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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. 2003;278:18817–23.CrossRefPubMedGoogle Scholar
  65. Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID, Langeberg LK, Sheng M, Scott JD. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science. 1999;285:93–6.CrossRefPubMedGoogle Scholar
  66. Xia D, Stull JT, Kamm KE. Myosin phosphatase targeting subunit, affects cell migration by regulating myosin phosphorylation and action assembly. Exp Cell Res. 2005;304:506–17.PubMedCrossRefGoogle Scholar
  67. Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P. Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. Nat Neurosci. 1999;2:13–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Filipa Martins
    • 1
  • Joana B. Serrano
    • 1
  • Ana M. Marafona
    • 1
  • Odete A. B. da Cruz e Silva
    • 1
  • Sandra Rebelo
    • 1
    Email author
  1. 1.Neuroscience and Signaling Laboratory, Department of Medical SciencesInstitute of Biomedicine-iBiMED, University of AveiroAveiroPortugal