Cancer and Metastasis Reviews

, Volume 26, Issue 3–4, pp 579–585 | Cite as

Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer

Article

Abstract

The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are a family of dual-specificity protein phosphatases that dephosphorylate both phospho-threonine and phospho-tyrosine residues in MAP kinases, including the c-Jun N-terminal protein kinase (JNK)/stress-activated protein kinase (SAPK), the p38 MAPK, and the extracellular signal-related kinase (ERK). Since phosphorylation is required for the activation of MAP kinases, dephosphorylation by MKPs inhibits MAPK activity, thereby negatively regulating MAPK signaling. It is known that deregulation of MAPK signaling is the most common alteration in human cancers. Recent studies have suggested that MKPs play an important role not only in the development of cancers, but also in the response of cancer cells to chemotherapy. Thus, understanding the roles of MKPs in the development of cancer and their impact on chemotherapy can be exploited for therapeutic benefits for the treatment of human cancer.

Keywords

Cancer MKP MAPKs 

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References

  1. 1.
    Davis, R. J. (2000). Signal transduction by the JNK group of MAP kinases. Cell, 103, 239–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Johnson, G. L., & Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 298, 1911–912.CrossRefPubMedGoogle Scholar
  3. 3.
    Pearson, G., Robinson, F., Beers Gibson, T., Xu, B., Karandikar, M., Berman, K., et al. (2001). Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocrine Reviews, 22, 153–83.CrossRefPubMedGoogle Scholar
  4. 4.
    Chang, L., & Karin, M. (2001). Mammalian MAP kinase signalling cascades. Nature, 410, 37–0.CrossRefPubMedGoogle Scholar
  5. 5.
    Kennedy, N. J., & Davis, R. J. (2003). Role of JNK in tumor development. Cell Cycle, 2, 199–01.PubMedGoogle Scholar
  6. 6.
    Camps, M., Nichols, A., & Arkinstall, S. (2000). Dual specificity phosphatases: A gene family for control of MAP kinase function. FASEB Journal, 14, 6–6.PubMedGoogle Scholar
  7. 7.
    Dickinson, R. J., & Keyse, S. M. (2006). Diverse physiological functions for dual-specificity MAP kinase phosphatases. Journal of Cell Science, 119(Pt 22), 4607–615.CrossRefPubMedGoogle Scholar
  8. 8.
    Kondoh, K., & Nishida, E. (2006). Regulation of MAP kinases by MAP kinase phosphatases. Biochim Biophys Acta, 1773(8), 1227–237.PubMedGoogle Scholar
  9. 9.
    Zhan, X. L., Wishart, M. J., & Guan, K. L. (2001). Nonreceptor tyrosine phosphatases in cellular signaling: Regulation of mitogen-activated protein kinases. Chemical Reviews, 101(8), 2477–496.CrossRefPubMedGoogle Scholar
  10. 10.
    Theodosiou, A., & Ashworth, A. (2002). MAP kinase phosphatases. Genome Biology, 3(7), REVIEWS3009.Google Scholar
  11. 11.
    Rohan, P. J., Davis, P., Moskaluk, C. A., Kearns, M., Krutzsch, H., Siebenlist, U., et al. (1993). PAC-1: A mitogen-induced nuclear protein tyrosine phosphatase. Science, 259(5102), 1763–766.CrossRefPubMedGoogle Scholar
  12. 12.
    Muda, M., Boschert, U., Smith, A., Antonsson, B., Gillieron, C., Chabert, C., et al. (1997). Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. Journal of Biological Chemistry, 272(8), 5141–151.CrossRefPubMedGoogle Scholar
  13. 13.
    Lau, L. F., & Nathans, D. (1985). Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO Journal, 4(12), 3145–151.PubMedGoogle Scholar
  14. 14.
    Charles, C. H., Abler, A. S., & Lau, L. F. (1992). cDNA sequence of a growth factor-inducible immediate early gene and characterization of its encoded protein. Oncogene, 7, 187–90.PubMedGoogle Scholar
  15. 15.
    Keyse, S. M., & Emslie, E. A. (1992). Oxidative stress and heat shock induce a human gene encoding a protein’tyrosine phosphatase. Nature, 359, 644–47.CrossRefPubMedGoogle Scholar
  16. 16.
    Li, J., Gorospe, M., Hutter, D., Barnes, J., Keyse, S. M., & Liu, Y. (2001). Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation’acetylation. Molecular and Cellular Biology, 21, 8213–224.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu, Y., Gorospe, M., Yang, C., & Holbrook, N. J. (1995). Role of mitogen-activated protein kinase phosphatase during the cellular response to genotoxic stress. Inhibition of c-Jun N-terminal kinase activity and AP-1-dependent gene activation. Journal of Biological Chemistry, 270(15), 8377–380.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou, J. Y., Liu, Y., & Wu, G. S. (2006). The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death. Cancer Research, 66(9), 4888–894.CrossRefPubMedGoogle Scholar
  19. 19.
    Wang, Z., Xu, J., Zhou, J. Y., Liu, Y., & Wu, G. S. (2006). Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance. Cancer Research, 66(17), 8870–877.CrossRefPubMedGoogle Scholar
  20. 20.
    Sun, H., Charles, C. H., Lau, L. F., & Tonks, N. K. (1993). MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell, 75, 487–93.CrossRefPubMedGoogle Scholar
  21. 21.
    Noguchi, T., Metz, R., Chen, L., Mattei, M. G., Carrasco, D., & Bravo, R. (1993). Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth. Molecular and Cellular Biology, 13, 5195–205.PubMedGoogle Scholar
  22. 22.
    Franklin, C. C., & Kraft, A. S. (1997). Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. Journal of Biological Chemistry, 272, 16917–6923.CrossRefPubMedGoogle Scholar
  23. 23.
    Brondello, J. M., McKenzie, F. R., Sun, H., Tonks, N. K., Pouyssegur, J. (1995). Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts. Oncogene, 10, 1895–904.PubMedGoogle Scholar
  24. 24.
    Li, M., Zhou, J. Y., Ge, Y., Matherly, L. H., & Wu, G. S. (2003). The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. Journal of Biological Chemistry, 278, 41059–1068.CrossRefPubMedGoogle Scholar
  25. 25.
    Yang, H., & Wu, G. S. (2004). p53 Transactivates the phosphatase MKP1 through both intronic and exonic p53 responsive elements. Cancer Biology and Therapy, 3(12), 1277–282.PubMedCrossRefGoogle Scholar
  26. 26.
    Wu, G. S. (2004). The Functional Interactions Between the p53 and MAPK Signaling Pathways. Cancer Biology and Therapy, 3, 156–61.PubMedGoogle Scholar
  27. 27.
    Franklin, C. C., Srikanth, S., & Kraft, A. S. (1998). Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Proceedings of the National Academy of Sciences, U.S.A., 95, 3014–019.CrossRefGoogle Scholar
  28. 28.
    Sanchez-Perez, I., Martinez-Gomariz, M., Williams, D., Keyse, S. M., & Perona, R. (2000). CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin. Oncogene, 19, 5142–152.CrossRefPubMedGoogle Scholar
  29. 29.
    Wu, J. J., & Bennett, A. M. (2005). Essential role for MAP kinase phosphatase-1 in stress-responsive MAP kinase and cell survival signaling. Journal of Biological Chemistry, 280, 16461–6466.CrossRefPubMedGoogle Scholar
  30. 30.
    Chattopadhyay, S., Machado-Pinilla, R., Manguan-Garcia, C., Belda-Iniesta, C., Moratilla, C., Cejas, P., et al. (2006). MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer. Oncogene, 25(23), 3335–345.CrossRefPubMedGoogle Scholar
  31. 31.
    Dorfman, K., Carrasco, D., Gruda, M., Ryan, C., Lira, S. A., & Bravo, R. (1996). Disruption of the erp/mkp-1 gene does not affect mouse development: Normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene, 13, 925–31.PubMedGoogle Scholar
  32. 32.
    Wang, H. Y., Cheng, Z., & Malbon, C. C. (2003). Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Letters, 191(2), 229–37.CrossRefPubMedGoogle Scholar
  33. 33.
    Loda, M., Capodieci, P., Mishra, R., Yao, H., Corless, C., Grigioni, W., et al. (1996). Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. American Journal of Pathology, 149(5), 1553–564.PubMedGoogle Scholar
  34. 34.
    Vicent, S., Garayoa, M., Lopez-Picazo, J. M., Lozano, M. D., Toledo, G., Thunnissen, F. B., et al. (2004). Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clinical Cancer Research, 10(11), 3639–649.CrossRefPubMedGoogle Scholar
  35. 35.
    Denkert, C., Schmitt, W. D., Berger, S., Reles, A., Pest, S., Siegert, A., et al. (2002). Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. International Journal of Cancer, 102(5), 507–13.CrossRefGoogle Scholar
  36. 36.
    Manzano, R. G., Montuenga, L. M., Dayton, M., Dent, P., Kinoshita, I., Vicent, S., et al. (2002). CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential. Oncogene, 21(28), 4435–447.CrossRefPubMedGoogle Scholar
  37. 37.
    Rauhala, H. E., Porkka, K. P., Tolonen, T. T., Martikainen, P. M., Tammela, T. L., & Visakorpi, T. (2005). Dual-specificity phosphatase 1 and serum/glucocorticoid-regulated kinase are downregulated in prostate cancer. International Journal of Cancer, 117(5), 738–45.CrossRefGoogle Scholar
  38. 38.
    Liao Q., Guo J., Kleeff J., Zimmermann, A., Büchler, M. W., Korc, M., et al. (2003). Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology, 124(7), 1830–845.CrossRefPubMedGoogle Scholar
  39. 39.
    Tsujita, E., Taketomi, A., Gion, T., Kuroda, Y., Endo, K., Watanabe, A., et al. (2005). Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma. Oncology, 69(4), 342–47.CrossRefPubMedGoogle Scholar
  40. 40.
    Yokoyama, A., Karasaki, H., Urushibara, N., Nomoto, K., Imai, Y., Nakamura, K., et al. (1997). The characteristic gene expressions of MAPK phosphatases 1 and 2 in hepatocarcinogenesis, rat ascites hepatoma cells, and regenerating rat liver. Biochemical and Biophysical Research Communications, 239(3), 746–51.CrossRefPubMedGoogle Scholar
  41. 41.
    Bang, Y. J., Kwon, J. H., Kang, S. H., Kim, J. W., & Yang, Y. C. (1998). Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. BBRC, 250(1), 43–7.PubMedGoogle Scholar
  42. 42.
    Groom, L. A., Sneddon, A. A., Alessi, D. R., Dowd, S., & Keyse, S. M. (1996). Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO Journal, 15(14), 3621–632.PubMedGoogle Scholar
  43. 43.
    Muda, M., Boschert, U., Dickinson, R., Martinou, J.-C., Martinou, I., Camps, M., et al. (1996). MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. Journal of Biological Chemistry, 271(8), 4319–326.CrossRefPubMedGoogle Scholar
  44. 44.
    Kawakami, Y., Rodriguez-Leon, J., Koth, C. M., Büscher, D., Itoh, T., Raya, A., et al. (2003). MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb. Nature Cell Biology, 5(6), 513–19.CrossRefPubMedGoogle Scholar
  45. 45.
    Furukawa, T., Sunamura, M., Motoi, F., Matsuno, S., & Horii, A. (2003). Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. American Journal of Pathology, 162(6), 1807–815.PubMedGoogle Scholar
  46. 46.
    Furukawa, T., Fujisaki, R., Yoshida, Y., Kanai, N., Sunamura, M., Abe, T., et al. (2005). Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary’mucinous neoplasms of the pancreas. Modern Pathology, 18(8), 1034–042.CrossRefPubMedGoogle Scholar
  47. 47.
    Xu, S., Furukawa, T., Kanai, N., Sunamura, M., & Horii, A. (2005). Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of Human Genetics, 50(4), 159–67.CrossRefPubMedGoogle Scholar
  48. 48.
    Marchetti, S., Gimond, C., Roux, D., Gothie, E., Pouyssegur, J., & Pages, G. (2004). Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice. Journal of Cellular Physiology, 199(3), 441–50.CrossRefPubMedGoogle Scholar
  49. 49.
    Chen, H. Y., Yu, S. L., Chen, C. H., Chang, G.-C., Chen, C.-Y., Yuan, A., et al. (2007). A five-gene signature and clinical outcome in non-small-cell lung cancer. New England Journal of Medicine, 356(1), 11–0.CrossRefPubMedGoogle Scholar
  50. 50.
    Givant-Horwitz, V., Davidson, B., Goderstad, J. M., Nesland, J. M., Trope, C. G., & Reich, R. (2004). The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma. Gynecologic Oncology, 93(2), 517–23.CrossRefPubMedGoogle Scholar
  51. 51.
    Sieben, N. L., Oosting, J., Flanagan, A. M., Prat, J., Roemen,G. M. J. M., Kolkman-Uljee, S. M., et al. (2005). Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors. Journal of Clinical Oncology, 23(29), 7257–264.CrossRefPubMedGoogle Scholar
  52. 52.
    Levy-Nissenbaum, O., Sagi-Assif, O., Kapon, D., Hantisteanu, S., Burg, T., Raanani, P., et al. (2003). Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells. Oncogene, 22(48), 7649–660.CrossRefPubMedGoogle Scholar
  53. 53.
    Levy-Nissenbaum, O., Sagi-Assif, O., Raanani, P., Avigdor, A., Ben-Bassat, I., & Witz, I. P. (2003). Overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia. Cancer Letters, 199(2), 185–92.CrossRefPubMedGoogle Scholar
  54. 54.
    Srikanth, S., Franklin, C. C., Duke, R. C., & Kraft, A. S. (1999). Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis. Molecular and Cellular Biochemistry, 199, 169–78.CrossRefPubMedGoogle Scholar
  55. 55.
    Orlowski, R. Z., Small, G. W., & Shi, Y. Y. (2002). Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. Journal of Biological Chemistry, 277(31), 27864–7871.CrossRefPubMedGoogle Scholar
  56. 56.
    Small, G. W., Shi, Y. Y., Edmund, N. A., Somasundaram, S., Moore, D. T., & Orlowski, R. Z. (2004). Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Molecular Pharmacology, 66(6), 1478–490.CrossRefPubMedGoogle Scholar
  57. 57.
    Wu, W., Chaudhuri, S., Brickley, D. R., Pang, D., Karrison, T., & Conzen, S. D. (2004). Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Research, 64(5), 1757–764.CrossRefPubMedGoogle Scholar
  58. 58.
    Wu, W., Pew, T., Zou, M., Pang, D., & Conzen, S. D. (2005). Glucocorticoid receptor-induced MAPK phosphatase-1 (MKP-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. Journal of Biological Chemistry, 280(6), 4117–124.CrossRefPubMedGoogle Scholar
  59. 59.
    Cui, Y., Parra, I., Zhang, M., Hilsenbeck, S. G., Tsimelzon, A., Furukawa, T., et al. (2006). Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: A mechanism of tamoxifen resistance. Cancer Research, 66(11), 5950–959.CrossRefPubMedGoogle Scholar
  60. 60.
    Vogt, A., Cooley, K. A., Brisson, M., Tarpley, M. G., Wipf, P., & Lazo, J. S. (2003). Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology, 10(8), 733–42.CrossRefPubMedGoogle Scholar
  61. 61.
    Lazo, J. S., Nunes, R., Skoko, J. J., Queiroz de Oliveira, P. E., Vogt, A., & Wipf, P. (2006). Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1. Bioorganic & Medicinal Chemistry, 14(16), 5643–650.CrossRefGoogle Scholar
  62. 62.
    Vogt, A., Tamewitz, A., Skoko, J., Sikorski, R. P., Giuliano, K. A., & Lazo, J. S. (2005). The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. Journal of Biological Chemistry, 280(19), 19078–9086.CrossRefPubMedGoogle Scholar
  63. 63.
    Arnold, D. M., Foster, C., Huryn, D. M., Lazo, J. S., Johnston,P. A., & Wipf, P. (2007). Synthesis and biological activity of a focused library of mitogen-activated protein kinase phosphatase inhibitors. Chemical Biology and Drug Design, 69(1), 23–0.CrossRefPubMedGoogle Scholar
  64. 64.
    Chen, P., Li, J., Barnes, J., Kokkonen, G. C., Lee, J. C., & Liu, Y. (2002). Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. Journal of Immunology, 169, 6408–416.Google Scholar
  65. 65.
    Wang, X., Matta, R., Shen, G., Nelin, L. D., Pei, D., & Liu, Y. (2006). Mechanism of triptolide-induced apoptosis: Effect on caspase activation and Bid cleavage and essentiality of the hydroxyl group of triptolide. Journal of Molecular Medicine, 84(5), 405–15.CrossRefPubMedGoogle Scholar
  66. 66.
    Gonzalez-Santiago, L., Suarez, Y., Zarich, N., Muñoz-Alonso,M. J., Cuadrado, A., Martínez, T., et al. (2006). Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation. Cell Death and Differentiation, 13(11), 1968–981.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Program in Molecular Biology and Genetics, Department of Pathology, Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA

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