Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Dual-Specificity Protein Phosphatases

  • Sheila Prabhakar
  • Swapna Asuthkar
  • Andrew J. Tsung
  • Kiran K. VelpulaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101694


Historical Background

In the 1980s, the regulatory role of protein phosphorylation in influencing cell growth, differentiation, and division was found to be mediated by the coordinated action of protein kinases and phosphatases. One particular family of protein ser/thr kinases, known as MAPKs, play key mitogen-activated protein kinases (MAPKs) play key regulatory roles by responding to various extracellular and intracellular stimuli and changes. By phosphorylating downstream targets including protein kinases and transcription factors, activated MAPKs regulate the transcription of MAPK-regulated genes, translation of proteins, and protein activity. The basic physiological processes of the cell growth and survival including cell division, differentiation, metabolism, motility,...

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  1. 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
  2. Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000;14:6–16.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Caunt CJ, Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 2013;280:489–504.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Cohen P. Protein kinases–the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1:309–15.PubMedPubMedCentralCrossRefGoogle Scholar
  5. De Vriendt V, De Roock W, Di Narzo AF, Tian S, Biesmans B, Jacobs B, Budinska E, Sagaert X, Rossi S, D’Ario G, Delorenzi M. DUSP 4 expression identifies a subset of colorectal cancer tumors that differ in MAPK activation, regardless of the genotype. Biomarkers. 2013;18(6):516–24.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ducruet AP, Vogt A, Wipf P, Lazo JS. Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer’s disease. Annu Rev Med. 2005;45:725–50.Google Scholar
  7. Golebski K, van Egmond D, de Groot EJ, Roschmann KI, Fokkens WJ, van Drunen CM. EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium. Mol Immunol. 2015;65(1):43–50.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Guan KL, Broyles SS, Dixon JE. A tyr/ser protein phosphatase encoded by vaccinia virus. Nature. 1991;350:359–62.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Hakes DJ, Martell KJ, Zhao WG, Massung RF, Esposito JJ, Dixon JE. A protein phosphatase related to the vaccinia virus VH1 is encoded in the genomes of several orthopoxviruses and a baculovirus. Proc Natl Acad Sci USA. 1993;90:4017–21.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Hamamura K, Nishimura A, Chen A, Takigawa S. Salubrinal acts as a Dusp2 inhibitor and suppresses inflamation in anti-collagen antibody-induced arthritis. Cell Signal. 2015;27(4):828–35.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Hannon GJ, Demetrick D, Beach D. Isolation of the rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev. 1993;7:2378–91.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Hendriks WJ, Pulido R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. BBA-Mol Basis Dis. 2013;1832(10):1673–96.CrossRefGoogle Scholar
  13. Hoekstra E, Peppelenbosch MP, Fuhler GM. Meeting report Europhosphatase 2015: phosphatases as drug targets in cancer. Cancer Res. 2016;76(2):193–6.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Huang CY, Tan TH. DUSPs, to MAP kinases and beyond. Cell Biosci. 2012;2:24.  https://doi.org/10.1186/2045-3701-2-24.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Jeffrey KL, Camps M, Rommel C, Mackay CR. Targeting dual-specificity phosphatases: Manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov. 2007;6:391–403.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Jeong DG, Wei CH, Ku B, Jeon TJ, Chien PN, Kim JK, et al. The family-wide structure and function of human dual-specificity protein phosphatases. Acta Crystallogr D Biol Crystallogr. 2014;70:421–35.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Korotchenko VN, Saydmohammed M, Vollmer LL, Bakan A. In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. Chembiochem. 2014;15(10):1436–45.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Kortenjann M, Shaw PE. Raf-1 kinase and ERK2 uncoupled from mitogenic signals in rat fibroblasts. Oncogene. 1995;11:2105–12.PubMedCentralPubMedGoogle Scholar
  19. Kwak SP, Hakes DJ, Martell KJ, Dixon JE. Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. J Biol Chem. 1994;269:3596–604.PubMedCentralPubMedGoogle Scholar
  20. Liu YC, Zhao J, Hu CE, Gan J, Zhang WH, Huang GJ. Comprehensive analysis of vascular endothelial growth factor-C related factors in stomach cancer. Asian Pacific journal of cancer prevention: APJCP. 2013;15(5):1925–29.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Lountos GT, Austin BP, Tropea JE, Waugh DS. Structure of human dual-specificity phosphatase 7, a potential cancer drug target. Acta Crystallogr F Struct Biol Commun. 2015;71:650–6.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Lyon MA, Ducruet AP, Wipf P, Lazo JS. Dual-specificity phosphatases as targets for antineoplastic agents. Nat Rev Drug Discov. 2002;1:961–76.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Moon SJ, Lim M, Park JS, Byun JK, Kim SM, Park MK, Kim EK, Moon YM, Min JK, Ahn SM, Park SH. Dual-specificity phosphatase 5 attenuates autoimmune arthritis in mice via reciprocal regulation of the Th17/Treg cell balance and inhibition of osteoclastogenesis. Arthritis Rheum. 2014;66(11):3083–95.CrossRefGoogle Scholar
  24. Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, et al. Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anti Cancer Agents Med Chem. 2011;11:109–32.CrossRefGoogle Scholar
  25. Patterson KI, Brummer T, O’Brien PM, Daly RJ. Dual-specificity phosphatases: Critical regulators with diverse cellular targets. Biochem J. 2009;418:475–89.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Pavic K, Duan G, Kohn M. VHR/DUSP3 phosphatase: structure, function and regulation. FEBS J. 2015;282:1871–90.CrossRefPubMedGoogle Scholar
  27. Prabhakar S, Asuthkar S, Lee W, Chigurupati S, Zakharian E, Tsung AJ, Velpula KK. Targeting DUSPs in glioblastomas – wielding a double-edged sword? Cell Biol Int. 2014;38(2):145–53.CrossRefPubMedGoogle Scholar
  28. Pramanik K, Chun CZ, Garnaas MK, Samant GV, Li K, Horswill MA, North PE, Ramchandran R. Dusp-5 and Snrk-1 coordinately function during vascular development and disease. Blood. 2009;113(5):1184–91.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Rios P, Nunes-Xavier CE, Tabernero L, Kohn M, Pulido R. Dual-specificity phosphatases as molecular targets for inhibition in human disease. Antioxid Redox Signal. 2014;20:2251–73.CrossRefPubMedGoogle Scholar
  30. Román-García P, Carrillo-López N, Naves-Díaz M, Rodríguez I, Ortiz A, Cannata-Andía JB. Dual-specificity phosphatases are implicated in severe hyperplasia and lack of response to FGF23 of uremic parathyroid glands from rats. Endocrinology. 2012;153(4):1627–37.CrossRefPubMedGoogle Scholar
  31. Sebastian B, Kakizuka A, Hunter T. Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15. Proc Natl Acad Sci USA. 1993;90:3521–4.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993;75:487–93.CrossRefPubMedGoogle Scholar
  33. Taylor DM, Moser R, Régulier E, Breuillaud L, Dixon M, Beesen AA, Elliston L, Santos MD, Kim J, Jones L, Goldstein DR. MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington’s disease via additive effects of JNK and p38 inhibition. J Neurosci. 2013;33(6):2313–25.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Vattakuzhi Y, Abraham SM, Freidin A, Clark AR, Horwood NJ. Dual-specificity phosphatase 1–null mice exhibit spontaneous osteolytic disease and enhanced inflammatory osteolysis in experimental arthritis. Arthritis Rheum. 2012;64(7):2201–10.CrossRefPubMedGoogle Scholar
  35. Wang D, Han S, Peng R, Jiao C, Wang X, Han Z, Li X. DUSP28 contributes to human hepatocellular carcinoma via regulation of the p38 MAPK signaling. Int J Oncol. 2014;45(6):2596–604.CrossRefPubMedGoogle Scholar
  36. Wei W, Jiao Y, Postlethwaite A, Stuart JM, Wang Y, Sun D, Gu W. Dual-specificity phosphatases 2: surprising positive effect at the molecular level and a potential biomarker of diseases. Genes Immun. 2013;14(1):1–6.CrossRefPubMedGoogle Scholar
  37. Zhang K, Civan J, Mukherjee S, Patel F, Yang H. Genetic variations in colorectal cancer risk and clinical outcome. World J Gastroenterol. 2014;20(15):4167–77.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Zhou G, Denu JM, Wu L, Dixon JE. The catalytic role of Cys124 in the dual specificity phosphatase VHR. J Biol Chem. 1994;269(45):28084–90.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sheila Prabhakar
    • 1
  • Swapna Asuthkar
    • 2
  • Andrew J. Tsung
    • 2
    • 3
  • Kiran K. Velpula
    • 2
    • 3
    Email author
  1. 1.College of Natural and Health SciencesSoutheastern UniversityLakelandUSA
  2. 2.Department of Cancer Biology and PharmacologyUniversity of Illinois College of Medicine at PeoriaPeoriaUSA
  3. 3.Department of NeurosurgeryUniversity of Illinois College of Medicine at PeoriaPeoriaUSA