DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases

  • Lucas Falcão Monteiro
  • Pault Yeison Minaya Ferruzo
  • Lilian Cristina Russo
  • Jessica Oliveira Farias
  • Fábio Luís FortiEmail author
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 176)


Protein tyrosine kinases (PTK), discovered in the 1970s, have been considered master regulators of biological processes with high clinical significance as targets for human diseases. Their actions are countered by protein tyrosine phosphatases (PTP), enzymes yet underrepresented as drug targets because of the high homology of their catalytic domains and high charge of their catalytic pocket. This scenario is still worse for some PTP subclasses, for example, for the atypical dual-specificity phosphatases (ADUSPs), whose biological functions are not even completely known. In this sense, the present work focuses on the dual-specificity phosphatase 3 (DUSP3), also known as VH1-related phosphatase (VHR), an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 expression and activities are suggestive of a tumor suppressor or tumor-promoting enzyme in different types of human cancers. Furthermore, DUSP3 has other biological functions involving immune response mediation, thrombosis, hemostasis, angiogenesis, and genomic stability that occur through either MAPK-dependent or MAPK-independent mechanisms. This broad spectrum of actions is likely due to the large substrate diversity and molecular mechanisms that are still under scrutiny. The growing advances in characterizing new DUSP3 substrates will allow the development of pharmacological inhibitors relevant for possible future clinical trials. This review covers all aspects of DUSP3, since its gene cloning and crystallographic structure resolution, in addition to its classical and novel substrates and the biological processes involved, followed by an update of what is currently known about the DUSP3/VHR-inhibiting compounds that might be considered potential drugs to treat human diseases.


Dual-specificity phosphatase 3 (DUSP3) Mitogen-activated protein kinases (MAPK) Pharmacological DUSP3 inhibitors Phosphatases on human diseases Protein tyrosine phosphatases (PTP) Vaccinia H1-related phosphatase (VHR) 



This project was supported by FAPESP (Grants # 2008/58264-5 and # 2015/03983-0) and CNPq (Grant # 402230/2016-7) to FLF, head of the Laboratory of Signaling in Biomolecular Systems (LSBS). LCR is a senior postdoctoral fellow from the CAPES-PNPD program at the Institute of Chemistry, University of Sao Paulo. JOF is a PhD student fellow of Fapesp (# 2017/16491-4), and PYFM is a master’s fellow of CNPq, both enrolled at the postgraduation program in Biochemistry and Molecular Biology, Institute of Chemistry, University of Sao Paulo. LFM is a master’s fellow of CAPES at the Biotechnology program, also in University of Sao Paulo. All authors thank BO and JRD for technical assistance in the LSBS laboratory.

Financial Support

Fapesp, Capes, and CNPq.


  1. Ahnstrom M, Nordenskjold B, Rutqvist LE, Skoog L, Stal O (2005) Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance. Breast Cancer Res Treat 91:145–151PubMedGoogle Scholar
  2. Alonso A, Saxena M, Williams S, Mustelin T (2001) Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem 276:4766–4771PubMedGoogle Scholar
  3. Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, Mustelin T (2003) Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat Immunol 4:44–48PubMedGoogle Scholar
  4. Alonso A, Narisawa S, Bogetz J, Tautz L, Hadzic R, Huynh H, Williams S, Gjorloff-Wingren A, Bremer MC, Holsinger LJ, Millan JL, Mustelin T (2004a) VHY, a novel myristoylated testis-restricted dual specificity protein phosphatase related to VHX. J Biol Chem 279:32586–32591PubMedGoogle Scholar
  5. Alonso A, Rojas A, Godzik A, Mustelin T (2004b) The dual-specific protein tyrosine phosphatase family. In: Arino J, Alexander DR (eds) Protein phosphatases, vol 5. Springer, Berlin, pp 333–358Google Scholar
  6. Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004c) Protein tyrosine phosphatases in the human genome. Cell 117:699–711PubMedGoogle Scholar
  7. Amand M, Erpicum C, Bajou K, Cerignoli F, Blacher S, Martin M, Dequiedt F, Drion P, Singh P, Zurashvili T, Vandereyken M, Musumeci L, Mustelin T, Moutschen M, Gilles C, Noel A, Rahmouni S (2014) DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase. Mol Cancer 13:108PubMedPubMedCentralGoogle Scholar
  8. Arabaci G, Yi T, Fu H, Porter ME, Beebe KD, Pei D (2002) Alpha-bromoacetophenone derivatives as neutral protein tyrosine phosphatase inhibitors: structure-activity relationship. Bioorg Med Chem Lett 12:3047–3050PubMedGoogle Scholar
  9. Arimura Y, Yagi J (2010) Comprehensive expression profiles of genes for protein tyrosine phosphatases in immune cells. Sci Signal 3:rs1PubMedGoogle Scholar
  10. Arnoldussen YJ, Saatcioglu F (2009) Dual specificity phosphatases in prostate cancer. Mol Cell Endocrinol 309:1–7PubMedGoogle Scholar
  11. Arnoldussen YJ, Lorenzo PI, Pretorius ME, Waehre H, Risberg B, Maelandsmo GM, Danielsen HE, Saatcioglu F (2008) The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. Cancer Res 68:9255–9264PubMedGoogle Scholar
  12. Bae EY, Oh H, Oh WK, Kim MS, Kim BS, Kim BY, Sohn CB, Osada H, Ahn JS (2004) A new VHR dual-specificity protein tyrosine phosphatase inhibitor from Dendrobium moniliforme. Planta Med 70:869–870PubMedGoogle Scholar
  13. Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ (2003) Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981–1989PubMedGoogle Scholar
  14. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821PubMedGoogle Scholar
  15. Barford D, Flint AJ, Tonks NK (1994) Crystal structure of human protein tyrosine phosphatase 1B. Science 263:1397–1404PubMedGoogle Scholar
  16. Bayón Y, Alonso A (2010) Atypical DUSPs: 19 phosphatases in search of a role, vol 661. Transworld Research Network, Kerala, pp 185–208Google Scholar
  17. Bennardo N, Cheng A, Huang N, Stark JM (2008) Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4:e1000110PubMedPubMedCentralGoogle Scholar
  18. Bermudez O, Pages G, Gimond C (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol 299:C189–C202PubMedGoogle Scholar
  19. Carneiro VM, Trivella DB, Scorsato V, Beraldo VL, Dias MP, Sobreira TJ, Aparicio R, Pilli RA (2015) Is RK-682 a promiscuous enzyme inhibitor? Synthesis and in vitro evaluation of protein tyrosine phosphatase inhibition of racemic RK-682 and analogues. Eur J Med Chem 97:42–54PubMedGoogle Scholar
  20. Cerignoli F, Rahmouni S, Ronai Z, Mustelin T (2006) Regulation of MAP kinases by the VHR dual-specific phosphatase: implications for cell growth and differentiation. Cell Cycle 5:2210–2215PubMedGoogle Scholar
  21. Cha H, Hancock C, Dangi S, Maiguel D, Carrier F, Shapiro P (2004) Phosphorylation regulates nucleophosmin targeting to the centrosome during mitosis as detected by cross-reactive phosphorylation-specific MKK1/MKK2 antibodies. Biochem J 378:857–865PubMedPubMedCentralGoogle Scholar
  22. Chau AS, Shibuya EK (1999) Inactivation of p42 mitogen-activated protein kinase is required for exit from M-phase after cyclin destruction. J Biol Chem 274:32085–32090PubMedGoogle Scholar
  23. Chen YR, Chou HC, Yang CH, Chen HY, Liu YW, Lin TY, Yeh CL, Chao WT, Tsou HH, Chuang HC, Tan TH (2017) Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration. Oncogene 36:6509–6517PubMedGoogle Scholar
  24. Cho SSL, Han J, James SJ, Png CW, Weerasooriya M, Alonso S, Zhang Y (2017) Dual-specificity phosphatase 12 targets p38 MAP kinase to regulate macrophage response to intracellular bacterial infection. Front Immunol 8:1259–1269PubMedPubMedCentralGoogle Scholar
  25. Christian KJ, Lang MA, Raffalli-Mathieu F (2008) Interaction of heterogeneous nuclear ribonucleoprotein C1/C2 with a novel cis-regulatory element within p53 mRNA as a response to cytostatic drug treatment. Mol Pharmacol 73:1558–1567PubMedGoogle Scholar
  26. Chung HS, Wang SB, Venkatraman V, Murray CI, Van Eyk JE (2013) Cysteine oxidative posttranslational modifications: emerging regulation in the cardiovascular system. Circ Res 112:382–392PubMedPubMedCentralGoogle Scholar
  27. Daniely Y, Dimitrova DD, Borowiec JA (2002) Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation. Mol Cell Biol 22:6014–6022PubMedPubMedCentralGoogle Scholar
  28. Denu JM, Dixon JE (1995) A catalytic mechanism for the dual-specific phosphatases. Proc Natl Acad Sci U S A 92:5910–5914PubMedPubMedCentralGoogle Scholar
  29. Denu JM, Dixon JE (1998) Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Curr Opin Chem Biol 2:633–641PubMedGoogle Scholar
  30. ElShamy WM, Livingston DM (2004) Identification of BRCA1-IRIS, a BRCA1 locus product. Nat Cell Biol 6:954–967PubMedGoogle Scholar
  31. Engedal N, Korkmaz CG, Saatcioglu F (2002) C-Jun N-terminal kinase is required for phorbol ester- and thapsigargin-induced apoptosis in the androgen responsive prostate cancer cell line LNCaP. Oncogene 21:1017–1027PubMedGoogle Scholar
  32. Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR (2006) Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 23:561–574PubMedPubMedCentralGoogle Scholar
  33. Farooq A, Zhou MM (2004) Structure and regulation of MAPK phosphatases. Cell Signal 16:769–779PubMedGoogle Scholar
  34. Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1:34–45PubMedGoogle Scholar
  35. Foley EA, Kapoor TM (2013) Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev Mol Cell Biol 14:25–37PubMedPubMedCentralGoogle Scholar
  36. Forti FL (2015) Combined experimental and bioinformatics analysis for the prediction and identification of VHR/DUSP3 nuclear targets related to DNA damage and repair. Integr Biol (Camb) 7:73–89Google Scholar
  37. Goldstein M, Derheimer FA, Tait-Mulder J, Kastan MB (2013) Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair. Proc Natl Acad Sci U S A 110:16874–16879PubMedPubMedCentralGoogle Scholar
  38. Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6:493–505PubMedGoogle Scholar
  39. Hamaguchi T, Sudo T, Osada H (1995) RK-682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at G1phase. FEBS Lett 372:54–58PubMedGoogle Scholar
  40. Hamaguchi T, Masuda A, Morino T, Osada H (1997) Stevastelins, a novel group of immunosuppressants, inhibit dual-specificity protein phosphatases. Chem Biol 4:279–286PubMedGoogle Scholar
  41. Hao L, ElShamy WM (2007) BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR. Int J Cancer 121:39–46PubMedGoogle Scholar
  42. He R, Zeng LF, He Y, Zhang S, Zhang ZY (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J 280:731–750PubMedGoogle Scholar
  43. Hendriks WJ, Elson A, Harroch S, Pulido R, Stoker A, den Hertog J (2013) Protein tyrosine phosphatases in health and disease. FEBS J 280:708–730PubMedGoogle Scholar
  44. Henkens R, Delvenne P, Arafa M, Moutschen M, Zeddou M, Tautz L, Boniver J, Mustelin T, Rahmouni S (2008) Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. BMC Cancer 8:147PubMedPubMedCentralGoogle Scholar
  45. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359:1367–1380PubMedGoogle Scholar
  46. Hirai G, Tsuchiya A, Koyama Y, Otani Y, Oonuma K, Dodo K, Simizu S, Osada H, Sodeoka M (2011) Development of a Vaccinia H1-related (VHR) phosphatase inhibitor with a nonacidic phosphate-mimicking core structure. ChemMedChem 6:617–622PubMedGoogle Scholar
  47. Hoyt R, Zhu W, Cerignoli F, Alonso A, Mustelin T, David M (2007) Cutting edge: selective tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase. J Immunol 179:3402–3406PubMedPubMedCentralGoogle Scholar
  48. Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21:177–184PubMedGoogle Scholar
  49. Hynes NE, Stern DF (1994) The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198:165–184PubMedGoogle Scholar
  50. Ishibashi T, Bottaro DP, Chan A, Miki T, Aaronson SA (1992) Expression cloning of a human dual-specificity phosphatase. Proc Natl Acad Sci U S A 89:12170–12174PubMedPubMedCentralGoogle Scholar
  51. Jeffrey KL, Camps M, Rommel C, Mackay CR (2007) Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov 6:391–403PubMedGoogle Scholar
  52. Jeong DG, Cho YH, Yoon TS, Kim JH, Son JH, Ryu SE, Kim SJ (2006) Structure of human DSP18, a member of the dual-specificity protein tyrosine phosphatase family. Acta Crystallogr D Biol Crystallogr 62:582–588PubMedGoogle Scholar
  53. Kang TH, Kim KT (2006) Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase. Nat Cell Biol 8:863–869PubMedGoogle Scholar
  54. Kim JH, Cho H, Ryu SE, Choi MU (2000) Effects of metal ions on the activity of protein tyrosine phosphatase VHR: highly potent and reversible oxidative inactivation by Cu2+ ion. Arch Biochem Biophys 382:72–80PubMedGoogle Scholar
  55. Koike A, Nishikawa H, Wu W, Okada Y, Venkitaraman AR, Ohta T (2010) Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. Cancer Res 70:6746–6756PubMedGoogle Scholar
  56. Kondoh K, Nishida E (2007) Regulation of MAP kinases by MAP kinase phosphatases. Biochim Biophys Acta 1773:1227–1237PubMedGoogle Scholar
  57. Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M (2004) Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5:465–475PubMedGoogle Scholar
  58. Lang R, Hammer M, Mages J (2006) DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response. J Immunol 177:7497–7504PubMedGoogle Scholar
  59. Lawan A, Al-Harthi S, Cadalbert L, McCluskey AG, Shweash M, Grassia G, Grant A, Boyd M, Currie S, Plevin R (2011) Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival. J Biol Chem 286:12933–12943PubMedPubMedCentralGoogle Scholar
  60. Lazo JS, Nunes R, Skoko JJ, Queiroz de Oliveira PE, Vogt A, Wipf P (2006) Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1. Bioorg Med Chem 14:5643–5650PubMedGoogle Scholar
  61. Lee C, Smith BA, Bandyopadhyay K, Gjerset RA (2005a) DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. Cancer Res 65:9834–9842PubMedGoogle Scholar
  62. Lee SY, Park JH, Kim S, Park EJ, Yun Y, Kwon J (2005b) A proteomics approach for the identification of nucleophosmin and heterogeneous nuclear ribonucleoprotein C1/C2 as chromatin-binding proteins in response to DNA double-strand breaks. Biochem J 388:7–15PubMedPubMedCentralGoogle Scholar
  63. Levenson RM, Blackshear PJ (1989) Insulin-stimulated protein tyrosine phosphorylation in intact cells evaluated by giant two-dimensional gel electrophoresis. J Biol Chem 264:19984–19993PubMedGoogle Scholar
  64. Liljebris C, Baranczewski P, Bjorkstrand E, Bystrom S, Lundgren B, Tjernberg A, Warolen M, James SR (2004) Oxidation of protein tyrosine phosphatases as a pharmaceutical mechanism of action: a study using 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione. J Pharmacol Exp Ther 309:711–719PubMedGoogle Scholar
  65. Lim KH, Park JJ, Gu BH, Kim JO, Park SG, Baek KH (2015) HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response. Sci Rep 5:12793PubMedPubMedCentralGoogle Scholar
  66. Lin CY, Tan BC, Liu H, Shih CJ, Chien KY, Lin CL, Yung BY (2010) Dephosphorylation of nucleophosmin by PP1beta facilitates pRB binding and consequent E2F1-dependent DNA repair. Mol Biol Cell 21:4409–4417PubMedPubMedCentralGoogle Scholar
  67. Lorenzo PI, Saatcioglu F (2008) Inhibition of apoptosis in prostate cancer cells by androgens is mediated through downregulation of c-Jun N-terminal kinase activation. Neoplasia 10:418–428PubMedPubMedCentralGoogle Scholar
  68. Mandl M, Slack DN, Keyse SM (2005) Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5. Mol Cell Biol 25:1830–1845PubMedPubMedCentralGoogle Scholar
  69. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934PubMedGoogle Scholar
  70. Matta H, Surabhi RM, Zhao J, Punj V, Sun Q, Schamus S, Mazzacurati L, Chaudhary PM (2007) Induction of spindle cell morphology in human vascular endothelial cells by human herpesvirus 8-encoded viral FLICE inhibitory protein K13. Oncogene 26:1656–1660PubMedGoogle Scholar
  71. Mercader M, Sengupta S, Bodner BK, Manecke RG, Cosar EF, Moser MT, Ballman KV, Wojcik EM, Kwon ED (2007) Early effects of pharmacological androgen deprivation in human prostate cancer. BJU Int 99:60–67PubMedGoogle Scholar
  72. Miranda GA, Chokler I, Aguilera RJ (1995) The murine nucleolin protein is an inducible DNA and ATP binding protein which is readily detected in nuclear extracts of lipopolysaccharide-treated splenocytes. Exp Cell Res 217:294–308PubMedGoogle Scholar
  73. Mitsui H, Kiecker F, Shemer A, Cannizzaro MV, Wang CQF, Gulati N, Ohmatsu H, Shah KR, Gilleaudeau P, Sullivan-Whalen M, Cueto I, McNutt NS, Suarez-Farinas M, Krueger JG (2016) Discrimination of dysplastic nevi from common melanocytic nevi by cellular and molecular criteria. J Invest Dermatol 136:2030–2040PubMedGoogle Scholar
  74. Mustelin T (2007) A brief introduction to the protein phosphatase families. In: Moorhead G (ed) Protein phosphatase protocols, vol 365. Springer, Totowa, pp 9–122Google Scholar
  75. Musumeci L, Kuijpers MJ, Gilio K, Hego A, Theatre E, Maurissen L, Vandereyken M, Diogo CV, Lecut C, Guilmain W, Bobkova EV, Eble JA, Dahl R, Drion P, Rascon J, Mostofi Y, Yuan H, Sergienko E, Chung TD, Thiry M, Senis Y, Moutschen M, Mustelin T, Lancellotti P, Heemskerk JW, Tautz L, Oury C, Rahmouni S (2014) Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis. Circulation 131:656–668PubMedPubMedCentralGoogle Scholar
  76. Nakuci E, Mahner S, Direnzo J, ElShamy WM (2006) BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells. Exp Cell Res 312:3120–3131PubMedGoogle Scholar
  77. Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37(Suppl 4):S9–S15PubMedGoogle Scholar
  78. Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, Pulido R (2011) Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anti Cancer Agents Med Chem 11:109–132Google Scholar
  79. Olson MO, Dundr M, Szebeni A (2000) The nucleolus: an old factory with unexpected capabilities. Trends Cell Biol 10:189–196PubMedGoogle Scholar
  80. Panico K, Forti FL (2013) Proteomic, cellular, and network analyses reveal new DUSP3 interactions with nucleolar proteins in HeLa cells. J Proteome Res 12:5851–5866PubMedGoogle Scholar
  81. Park J, Fu H, Pei D (2004) Peptidyl aldehydes as slow-binding inhibitors of dual-specificity phosphatases. Bioorg Med Chem Lett 14:685–687PubMedGoogle Scholar
  82. Park H, Jung SK, Jeong DG, Ryu SE, Kim SJ (2008) Discovery of VHR phosphatase inhibitors with micromolar activity based on structure-based virtual screening. ChemMedChem 3:877–880PubMedGoogle Scholar
  83. Park S-J, Song M-A, Cho S-Y (2009) Regulation of vaccinia H1-related (VHR) phosphatase activity by NSC-87877. Bull Kor Chem Soc 30:3098–3100Google Scholar
  84. Patterson KI, Brummer T, O’Brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418:475–489PubMedGoogle Scholar
  85. Pfender S, Kuznetsov V, Pasternak M, Tischer T, Santhanam B, Schuh M (2015) Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes. Nature 524:239–242PubMedPubMedCentralGoogle Scholar
  86. Pinol-Roma S (1999) Association of nonribosomal nucleolar proteins in ribonucleoprotein complexes during interphase and mitosis. Mol Biol Cell 10:77–90PubMedPubMedCentralGoogle Scholar
  87. Pulido R, Hooft van Huijsduijnen R (2008) Protein tyrosine phosphatases: dual-specificity phosphatases in health and disease. FEBS J 275:848–866PubMedGoogle Scholar
  88. Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T (2006) Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol 8:524–531PubMedGoogle Scholar
  89. Roberts EC, Shapiro PS, Nahreini TS, Pages G, Pouyssegur J, Ahn NG (2002) Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis. Mol Cell Biol 22:7226–7241PubMedPubMedCentralGoogle Scholar
  90. Salojin K, Oravecz T (2007) Regulation of innate immunity by MAPK dual-specificity phosphatases: knockout models reveal new tricks of old genes. J Leukoc Biol 81:860–869PubMedGoogle Scholar
  91. Schwertassek U, Buckley DA, Xu CF, Lindsay AJ, McCaffrey MW, Neubert TA, Tonks NK (2010) Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis. FEBS J 277:2463–2473PubMedPubMedCentralGoogle Scholar
  92. Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8:829–833PubMedGoogle Scholar
  93. Shi Z, Tabassum S, Jiang W, Zhang J, Mathur S, Wu J, Shi Y (2007) Identification of a potent inhibitor of human dual-specific phosphatase, VHR, from computer-aided and NMR-based screening to cellular effects. Chembiochem 8:2092–2099PubMedGoogle Scholar
  94. Shinohara M, Mikhailov AV, Aguirre-Ghiso JA, Rieder CL (2006) Extracellular signal-regulated kinase 1/2 activity is not required in mammalian cells during late G2 for timely entry into or exit from mitosis. Mol Biol Cell 17:5227–5240PubMedPubMedCentralGoogle Scholar
  95. Sicinski P, Weinberg RA (1997) A specific role for cyclin D1 in mammary gland development. J Mammary Gland Biol Neoplasia 2:335–342PubMedGoogle Scholar
  96. Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630PubMedGoogle Scholar
  97. Singh P, Dejager L, Amand M, Theatre E, Vandereyken M, Zurashvili T, Singh M, Mack M, Timmermans S, Musumeci L, Dejardin E, Mustelin T, Van Ginderachter JA, Moutschen M, Oury C, Libert C, Rahmouni S (2015) DUSP3 genetic deletion confers M2-like macrophage-dependent tolerance to septic shock. J Immunol 194:4951–4962PubMedPubMedCentralGoogle Scholar
  98. Srivastava M, Pollard HB (1999) Molecular dissection of nucleolin’s role in growth and cell proliferation: new insights. FASEB J 13:1911–1922PubMedGoogle Scholar
  99. Stanford SM, Bottini N (2017) Targeting tyrosine phosphatases: time to end the stigma. Trends Pharmacol Sci 38:524–540PubMedPubMedCentralGoogle Scholar
  100. Stein GH, Drullinger LF, Robetorye RS, Pereira-Smith OM, Smith JR (1991) Senescent cells fail to express cdc2, cycA, and cycB in response to mitogen stimulation. Proc Natl Acad Sci U S A 88:11012–11016PubMedPubMedCentralGoogle Scholar
  101. Takagi M, Absalon MJ, McLure KG, Kastan MB (2005) Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123:49–63PubMedGoogle Scholar
  102. Tambe MB, Narvi E, Kallio M (2016) Reduced levels of Dusp3/Vhr phosphatase impair normal spindle bipolarity in an Erk1/2 activity-dependent manner. FEBS Lett 590:2757–2767PubMedGoogle Scholar
  103. Tamura S, Brown TA, Whipple JH, Fujita-Yamaguchi Y, Dubler RE, Cheng K, Larner J (1984) A novel mechanism for the insulin-like effect of vanadate on glycogen synthase in rat adipocytes. J Biol Chem 259:6650–6658PubMedGoogle Scholar
  104. Tanzola MB, Kersh GJ (2006) The dual specificity phosphatase transcriptome of the murine thymus. Mol Immunol 43:754–762PubMedGoogle Scholar
  105. Tautz L, Senis YA, Oury C, Rahmouni S (2015) Perspective: tyrosine phosphatases as novel targets for antiplatelet therapy. Bioorg Med Chem 23:2786–2797PubMedPubMedCentralGoogle Scholar
  106. Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426PubMedGoogle Scholar
  107. Todd JL, Tanner KG, Denu JM (1999) Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. J Biol Chem 274:13271–13280PubMedGoogle Scholar
  108. Tonks NK (2013) Protein tyrosine phosphatases – from housekeeping enzymes to master regulators of signal transduction. FEBS J 280:346–378PubMedPubMedCentralGoogle Scholar
  109. Torres TE, Russo LC, Santos A, Marques GR, Magalhaes YT, Tabassum S, Forti FL (2017) Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways. Biochim Biophys Acta 1861:1879–1894Google Scholar
  110. Ueda K, Usui T, Nakayama H, Ueki M, Takio K, Ubukata M, Osada H (2002) 4-isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase. FEBS Lett 525:48–52PubMedGoogle Scholar
  111. Vandereyken M, Jacques S, Van Overmeire E, Amand M, Rocks N, Delierneux C, Singh P, Singh M, Ghuysen C, Wathieu C, Zurashvili T, Sounni NE, Moutschen M, Gilles C, Oury C, Cataldo D, Van Ginderachter JA, Rahmouni S (2017a) Dusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner. PLoS One 12:e0185786PubMedPubMedCentralGoogle Scholar
  112. Vandereyken MM, Singh P, Wathieu CP, Jacques S, Zurashvilli T, Dejager L, Amand M, Musumeci L, Singh M, Moutschen MP, Libert CRF, Rahmouni S (2017b) Dual-specificity phosphatase 3 deletion protects female, but not male, mice from endotoxemia-induced and polymicrobial-induced septic shock. J Immunol 199:2515–2527PubMedGoogle Scholar
  113. Vang T, Miletic AV, Arimura Y, Tautz L, Rickert RC, Mustelin T (2008) Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol 26:29–55PubMedGoogle Scholar
  114. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849PubMedGoogle Scholar
  115. Wagner KW, Alam H, Dhar SS, Giri U, Li N, Wei Y, Giri D, Cascone T, Kim JH, Ye Y, Multani AS, Chan CH, Erez B, Saigal B, Chung J, Lin HK, Wu X, Hung MC, Heymach JV, Lee MG (2013) KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest 123:5231–5246PubMedPubMedCentralGoogle Scholar
  116. Wang JY, Yeh CL, Chou HC, Yang CH, Fu YN, Chen YT, Cheng HW, Huang CY, Liu HP, Huang SF, Chen YR (2011) Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down-regulated in non-small cell lung cancer. J Biol Chem 286:10177–10184PubMedPubMedCentralGoogle Scholar
  117. Weinstein IB, Joe A (2008) Oncogene addiction. Cancer Res 68:3077–3080 discussion 3080PubMedGoogle Scholar
  118. Willard FS, Crouch MF (2001) MEK, ERK, and p90RSK are present on mitotic tubulin in Swiss 3T3 cells: a role for the MAP kinase pathway in regulating mitotic exit. Cell Signal 13:653–664PubMedGoogle Scholar
  119. Wu MH, Chang JH, Chou CC, Yung BY (2002a) Involvement of nucleophosmin/B23 in the response of HeLa cells to UV irradiation. Int J Cancer 97:297–305PubMedGoogle Scholar
  120. Wu MH, Chang JH, Yung BY (2002b) Resistance to UV-induced cell-killing in nucleophosmin/B23 over-expressed NIH 3T3 fibroblasts: enhancement of DNA repair and up-regulation of PCNA in association with nucleophosmin/B23 over-expression. Carcinogenesis 23:93–100PubMedGoogle Scholar
  121. Wu S, Vossius S, Rahmouni S, Miletic AV, Vang T, Vazquez-Rodriguez J, Cerignoli F, Arimura Y, Williams S, Hayes T, Moutschen M, Vasile S, Pellecchia M, Mustelin T, Tautz L (2009) Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. J Med Chem 52:6716–6723PubMedPubMedCentralGoogle Scholar
  122. Yan Q, Sharma-Kuinkel BK, Deshmukh H, Tsalik EL, Cyr DD, Lucas J, Woods CW, Scott WK, Sempowski GD, Thaden JT, Rude TH, Ahn SH, Fowler VG Jr (2014) Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis. PLoS Pathog 10:e1004149PubMedPubMedCentralGoogle Scholar
  123. Yang C, Maiguel DA, Carrier F (2002) Identification of nucleolin and nucleophosmin as genotoxic stress-responsive RNA-binding proteins. Nucleic Acids Res 30:2251–2260PubMedPubMedCentralGoogle Scholar
  124. Yano K, Morotomi-Yano K, Wang SY, Uematsu N, Lee KJ, Asaithamby A, Weterings E, Chen DJ (2008) Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9:91–96PubMedGoogle Scholar
  125. Yuvaniyama J, Denu JM, Dixon JE, Saper MA (1996) Crystal structure of the dual specificity protein phosphatase VHR. Science 272:1328–1331PubMedGoogle Scholar
  126. Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY (2002) The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem 277:31818–31825PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Lucas Falcão Monteiro
    • 1
  • Pault Yeison Minaya Ferruzo
    • 1
  • Lilian Cristina Russo
    • 1
  • Jessica Oliveira Farias
    • 1
  • Fábio Luís Forti
    • 1
    Email author
  1. 1.Department of Biochemistry, Institute of ChemistryUniversity of São PauloSão PauloBrazil

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