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PMID: 20399103 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

The extended PP1 toolkit: designed to create specificity.

Trends in biochemical sciences ·Vol. 35 ·No. 8 ·2010-08-00 ·Pages 450-8

Bollen M, Peti W, Ragusa MJ, Beullens M

Abstract

Protein Ser/Thr phosphatase-1 (PP1) catalyzes the majority of eukaryotic protein dephosphorylation reactions in a highly regulated and selective manner. Recent studies have identified an unusually diversified PP1 interactome with the properties of a regulatory toolkit. PP1-interacting proteins (PIPs) function as targeting subunits, substrates and/or inhibitors. As targeting subunits, PIPs contribute to substrate selection by bringing PP1 into the vicinity of specific substrates and by modulating substrate specificity via additional substrate docking sites or blocking substrate-binding channels. Many of the nearly 200 established mammalian PIPs are predicted to be intrinsically disordered, a property that facilitates their binding to a large surface area of PP1 via multiple docking motifs. These novel insights offer perspectives for the therapeutic targeting of PP1 by interfering with the binding of PIPs or substrates.

MeSH Terms
Amino Acid Motifs Animals Catalytic Domain Models, Molecular Protein Binding Protein Phosphatase 1/antagonists & inhibitors,chemistry,genetics,metabolism Substrate Specificity
Chemicals
Protein Phosphatase 1
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bollen Mathieu
Laboratory of Biosignaling & Therapeutics, Department of Molecular Cell Biology, University of Leuven, B-3000 Leuven, Belgium. [email protected]
Peti Wolfgang
Ragusa Michael J
Beullens Monique
References (85)
85 references, click to expand
  1. Protein phosphatase 1 regulates the phosphorylation state of the polarity scaffold Par-3.
    Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10402-7 PMID: 18641122
  2. Mitotic phosphatases: from entry guards to exit guides.
    Trends Cell Biol. 2009 Oct;19(10):531-41 PMID: 19734049
  3. Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1.
    Nat Immunol. 2008 May;9(5):533-41 PMID: 18362886
  4. Langerhans cell protein 1 (LCP1) binds to PNUTS in the nucleus: implications for this complex in transcriptional regulation.
    Exp Mol Med. 2009 Mar 31;41(3):189-200 PMID: 19293638
  5. Intrinsically disordered protein.
    J Mol Graph Model. 2001;19(1):26-59 PMID: 11381529
  6. PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation.
    Nat Cell Biol. 2009 May;11(5):644-51 PMID: 19396163
  7. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.
    Science. 2005 Feb 11;307(5711):935-9 PMID: 15705855
  8. Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor.
    Structure. 2007 Dec;15(12):1591-602 PMID: 18073109
  9. Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration.
    Biochem J. 2005 Oct 15;391(Pt 2):359-70 PMID: 15975092
  10. Protein phosphatase 1 regulates the histone code for long-term memory.
    J Neurosci. 2009 Oct 14;29(41):13079-89 PMID: 19828821
  11. Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation.
    Cancer Res. 2007 Dec 1;67(23):11186-94 PMID: 18056443
  12. Regulation of cellular protein phosphatase-1 (PP1) by phosphorylation of the CPI-17 family, C-kinase-activated PP1 inhibitors.
    J Biol Chem. 2009 Dec 18;284(51):35273-7 PMID: 19846560
  13. Dynamic targeting of protein phosphatase 1 within the nuclei of living mammalian cells.
    J Cell Sci. 2001 Dec;114(Pt 23):4219-28 PMID: 11739654
  14. PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit. Characterization of its PP1- and RNA-binding domains and regulation by phosphorylation.
    J Biol Chem. 2003 Apr 18;278(16):13819-28 PMID: 12574161
  15. Protein phosphatase 1--targeted in many directions.
    J Cell Sci. 2002 Jan 15;115(Pt 2):241-56 PMID: 11839776
  16. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.
    Sci Signal. 2010 Jan 12;3(104):ra3 PMID: 20068231
  17. Spinophilin: from partners to functions.
    Biochimie. 2006 Sep;88(9):1099-113 PMID: 16737766
  18. Structural basis for spinophilin-neurabin receptor interaction.
    Biochemistry. 2007 Mar 6;46(9):2333-44 PMID: 17279777
  19. A complex of catalytically inactive protein phosphatase-1 sandwiched between Sds22 and inhibitor-3.
    Biochemistry. 2007 Aug 7;46(31):8909-19 PMID: 17630778
  20. Nuclear inhibitor of protein phosphatase-1 (NIPP1) directs protein phosphatase-1 (PP1) to dephosphorylate the U2 small nuclear ribonucleoprotein particle (snRNP) component, spliceosome-associated protein 155 (Sap155).
    J Biol Chem. 2008 Dec 19;283(51):35805-14 PMID: 18842582
  21. Emerging roles of nuclear protein phosphatases.
    Nat Rev Mol Cell Biol. 2007 Mar;8(3):234-44 PMID: 17318227
  22. PNUTS forms a trimeric protein complex with GABA(C) receptors and protein phosphatase 1.
    Mol Cell Neurosci. 2008 Apr;37(4):808-19 PMID: 18325784
  23. Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo.
    Cell Signal. 2009 Jul;21(7):1123-34 PMID: 19275933
  24. Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors.
    J Mol Biol. 2009 Jan 9;385(1):11-21 PMID: 18992256
  25. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1.
    Dev Cell. 2008 May;14(5):787-97 PMID: 18477460
  26. Phosphorylation of TIMAP by glycogen synthase kinase-3beta activates its associated protein phosphatase 1.
    J Biol Chem. 2007 Aug 31;282(35):25960-9 PMID: 17609201
  27. Basis for the isoform-specific interaction of myosin phosphatase subunits protein phosphatase 1c beta and myosin phosphatase targeting subunit 1.
    J Biol Chem. 2010 Feb 26;285(9):6419-24 PMID: 20042605
  28. Scaffolds: interaction platforms for cellular signalling circuits.
    Trends Cell Biol. 2009 Aug;19(8):364-74 PMID: 19651513
  29. Docking motif-guided mapping of the interactome of protein phosphatase-1.
    Chem Biol. 2009 Apr 24;16(4):365-71 PMID: 19389623
  30. Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2.
    Dev Cell. 2009 Jun;16(6):856-66 PMID: 19531356
  31. Intrinsically unstructured proteins and their functions.
    Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208 PMID: 15738986
  32. Protein phosphatase-1 inhibitor-3 is an in vivo target of caspase-3 and participates in the apoptotic response.
    J Biol Chem. 2008 Jun 27;283(26):18135-46 PMID: 18450750
  33. Myosin phosphatase interacts with and dephosphorylates the retinoblastoma protein in THP-1 leukemic cells: its inhibition is involved in the attenuation of daunorubicin-induced cell death by calyculin-A.
    Cell Signal. 2008 Nov;20(11):2059-70 PMID: 18755268
  34. The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing.
    Oncogene. 2008 Feb 28;27(10):1449-60 PMID: 17724462
  35. Structural analysis of the protein phosphatase 1 docking motif: molecular description of binding specificities identifies interacting proteins.
    Chem Biol. 2006 Jan;13(1):49-59 PMID: 16426971
  36. Regulation of MYPT1 stability by the E3 ubiquitin ligase SIAH2.
    Exp Cell Res. 2010 Jan 1;316(1):68-77 PMID: 19744480
  37. Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1.
    Mol Cell Biol. 2001 Oct;21(20):6841-50 PMID: 11564868
  38. Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1.
    J Biol Chem. 2009 May 15;284(20):13869-13880 PMID: 19282287
  39. Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate.
    J Mol Biol. 1995 Dec 15;254(5):942-59 PMID: 7500362
  40. Spinophilin facilitates dephosphorylation of doublecortin by PP1 to mediate microtubule bundling at the axonal wrist.
    Cell. 2007 May 4;129(3):579-91 PMID: 17482550
  41. Displacement affinity chromatography of protein phosphatase one (PP1) complexes.
    BMC Biochem. 2008 Nov 10;9:28 PMID: 19000314
  42. Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1.
    Nature. 1995 Aug 31;376(6543):745-53 PMID: 7651533
  43. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail).
    Trends Biochem Sci. 2008 Mar;33(3):113-21 PMID: 18291659
  44. Selective targeting of the gamma1 isoform of protein phosphatase 1 to F-actin in intact cells requires multiple domains in spinophilin and neurabin.
    FASEB J. 2008 Jun;22(6):1660-71 PMID: 18216290
  45. Functional diversity of protein phosphatase-1, a cellular economizer and reset button.
    Physiol Rev. 2004 Jan;84(1):1-39 PMID: 14715909
  46. A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.
    J Proteome Res. 2007 Mar;6(3):1165-75 PMID: 17274640
  47. Phosphorylation-dependent autoinhibition of myosin light chain phosphatase accounts for Ca2+ sensitization force of smooth muscle contraction.
    J Biol Chem. 2009 Aug 7;284(32):21569-79 PMID: 19531490
  48. Regulation of protein phosphatase-1G from rabbit skeletal muscle. 2. Catalytic subunit translocation is a mechanism for reversible inhibition of activity toward glycogen-bound substrates.
    Eur J Biochem. 1989 Dec 22;186(3):711-6 PMID: 2558014
  49. Targeting protein serine/threonine phosphatases for drug development.
    Mol Pharmacol. 2009 Jun;75(6):1249-61 PMID: 19299564
  50. Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb.
    Cancer Cell Int. 2006 Feb 08;6:3 PMID: 16466572
  51. Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemia/reperfusion injury.
    Circ Res. 2009 Apr 24;104(8):1012-20 PMID: 19299645
  52. Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.
    EMBO J. 2007 Mar 21;26(6):1511-21 PMID: 17318175
  53. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.
    J Cell Biol. 2004 Jan 19;164(2):291-300 PMID: 14718519
  54. IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content.
    Bioinformatics. 2005 Aug 15;21(16):3433-4 PMID: 15955779
  55. GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress.
    Int J Mol Med. 2007 Mar;19(3):475-83 PMID: 17273797
  56. Protein phosphatase-1alpha regulates centrosome splitting through Nek2.
    Cancer Res. 2007 Feb 1;67(3):1082-9 PMID: 17283141
  57. Degeneracy and function of the ubiquitous RVXF motif that mediates binding to protein phosphatase-1.
    J Biol Chem. 2003 May 23;278(21):18817-23 PMID: 12657641
  58. Neurabins recruit protein phosphatase-1 and inhibitor-2 to the actin cytoskeleton.
    J Biol Chem. 2002 Nov 29;277(48):46535-43 PMID: 12270929
  59. Interactor-mediated nuclear translocation and retention of protein phosphatase-1.
    J Biol Chem. 2004 Dec 31;279(53):55978-84 PMID: 15501817
  60. Serine/threonine phosphatases: mechanism through structure.
    Cell. 2009 Oct 30;139(3):468-84 PMID: 19879837
  61. The rules of disorder or why disorder rules.
    Prog Biophys Mol Biol. 2009 Feb-Apr;99(2-3):94-103 PMID: 19344736
  62. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase.
    Nature. 2006 Aug 3;442(7102):576-9 PMID: 16885985
  63. From promiscuity to precision: protein phosphatases get a makeover.
    Mol Cell. 2009 Mar 13;33(5):537-45 PMID: 19285938
  64. A protein phosphatase-1gamma1 isoform selectivity determinant in dendritic spine-associated neurabin.
    J Biol Chem. 2004 May 21;279(21):21714-23 PMID: 15016827
  65. Structural basis of protein phosphatase 1 regulation.
    Nature. 2004 Jun 17;429(6993):780-4 PMID: 15164081
  66. Evidence for dynamically organized modularity in the yeast protein-protein interaction network.
    Nature. 2004 Jul 1;430(6995):88-93 PMID: 15190252
  67. Mechanisms of specificity in protein phosphorylation.
    Nat Rev Mol Cell Biol. 2007 Jul;8(7):530-41 PMID: 17585314
  68. Spinophilin/neurabin reciprocally regulate signaling intensity by G protein-coupled receptors.
    EMBO J. 2007 Jun 6;26(11):2768-76 PMID: 17464283
  69. A complex signaling pathway regulates SRp38 phosphorylation and pre-mRNA splicing in response to heat shock.
    Mol Cell. 2007 Oct 12;28(1):79-90 PMID: 17936706
  70. NIMA-related kinase 2 (Nek2), a cell-cycle-regulated protein kinase localized to centrosomes, is complexed to protein phosphatase 1.
    Biochem J. 2000 Jul 15;349(Pt 2):509-18 PMID: 10880350
  71. Protein phosphatase-1 is a novel regulator of the interaction between IRBIT and the inositol 1,4,5-trisphosphate receptor.
    Biochem J. 2007 Oct 15;407(2):303-11 PMID: 17635105
  72. The structure, role, and regulation of type 1 protein phosphatases.
    Crit Rev Biochem Mol Biol. 1992;27(3):227-81 PMID: 1350240
  73. Access denied: Snf1 activation loop phosphorylation is controlled by availability of the phosphorylated threonine 210 to the PP1 phosphatase.
    J Biol Chem. 2008 Jan 4;283(1):222-230 PMID: 17991748
  74. Spinophilin directs protein phosphatase 1 specificity by blocking substrate binding sites.
    Nat Struct Mol Biol. 2010 Apr;17(4):459-64 PMID: 20305656
  75. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1.
    EMBO J. 1997 Apr 15;16(8):1876-87 PMID: 9155014
  76. Combinatorial control of protein phosphatase-1.
    Trends Biochem Sci. 2001 Jul;26(7):426-31 PMID: 11440854
  77. Evolution of protein kinase signaling from yeast to man.
    Trends Biochem Sci. 2002 Oct;27(10):514-20 PMID: 12368087
  78. A role for PP1 in the Cdc2/Cyclin B-mediated positive feedback activation of Cdc25.
    Mol Biol Cell. 2006 Apr;17(4):1779-89 PMID: 16467385
  79. Structural basis for regulation of protein phosphatase 1 by inhibitor-2.
    J Biol Chem. 2007 Sep 28;282(39):28874-28883 PMID: 17636256
  80. Control of cellular GADD34 levels by the 26S proteasome.
    Mol Cell Biol. 2008 Dec;28(23):6989-7000 PMID: 18794359
  81. AMP-activated protein kinase phosphorylates R5/PTG, the glycogen targeting subunit of the R5/PTG-protein phosphatase 1 holoenzyme, and accelerates its down-regulation by the laforin-malin complex.
    J Biol Chem. 2009 Mar 27;284(13):8247-55 PMID: 19171932
  82. Detailed structural characterization of unbound protein phosphatase 1 inhibitors.
    Biochemistry. 2008 Nov 25;47(47):12346-56 PMID: 18954090
  83. TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs.
    Nat Struct Mol Biol. 2009 Apr;16(4):372-9 PMID: 19287395
  84. The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding.
    Biochem J. 2000 Dec 15;352 Pt 3:651-8 PMID: 11104670
  85. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development.
    Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1832-7 PMID: 19181853
Article Info
Journal
Trends in biochemical sciences
Abbr.
Trends Biochem Sci
ISSN
0968-0004
DOI
10.1016/j.tibs.2010.03.002
Email
[email protected]
Published
2010-08-00
Epub
2010-00-01
Pages
450-8
Language
English
Region
England
NLM ID
7610674
PMCID
PMC3131691
Subset
IM
Grants
NINDS NIH HHS · R01 NS056128 · United States
NINDS NIH HHS · R01 NS056128-04 · United States
NIGMS NIH HHS · T32 GM007601 · United States
NINDS NIH HHS · R01NS056128 · United States
External Links
PubMed source DOI: 10.1016/j.tibs.2010.03.002 PMC Full Text View journal details
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