IMMUNE NETWORK

  • 제16권2호
  • /
  • Pages.85-98
  • /
  • 2016
  • /
  • 1598-2629(pISSN)
  • /
  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
권호 표지
DOI QR코드

DOI QR Code

Regulatory Roles of MAPK Phosphatases in Cancer

  • Heng Boon Low (Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore) ;
  • Yongliang Zhang (Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore)
  • 투고 : 2016.01.03
  • 심사 : 2016.03.15
  • 발행 : 2016.04.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The mitogen-activated protein kinases (MAPKs) are key regulators of cell growth and survival in physiological and pathological processes. Aberrant MAPK signaling plays a critical role in the development and progression of human cancer, as well as in determining responses to cancer treatment. The MAPK phosphatases (MKPs), also known as dual-specificity phosphatases (DUSPs), are a family of proteins that function as major negative regulators of MAPK activities in mammalian cells. Studies using mice deficient in specific MKPs including MKP1/DUSP1, PAC-1/DUSP2, MKP2/DUSP4, MKP5/DUSP10 and MKP7/DUSP16 demonstrated that these molecules are important not only for both innate and adaptive immune responses, but also for metabolic homeostasis. In addition, the consequences of the gain or loss of function of the MKPs in normal and malignant tissues have highlighted the importance of these phosphatases in the pathogenesis of cancers. The involvement of the MKPs in resistance to cancer therapy has also gained prominence, making the MKPs a potential target for anti-cancer therapy. This review will summarize the current knowledge of the MKPs in cancer development, progression and treatment outcomes.

키워드

과제정보

This work was supported by grants from the National Medical Research Council (CBRG11nov101), the National Research Foundation (NRF-CRP-2010-03) and the National University Health System (T1-2014 Oct-12) of Singapore (to YZ).

참고문헌

  1. Dickinson, R. J., and S. M. Keyse. 2006. Diverse physiological functions for dual-specificity MAP kinase phosphatases. J. Cell Sci. 119: 4607-4615. https://doi.org/10.1242/jcs.03266
  2. Wagner, E. F., and A. R. Nebreda. 2009. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9: 537-549. https://doi.org/10.1038/nrc2694
  3. Zhang, Y. L., and C. Dong. 2005. MAP kinases in immune responses. Cell. Mol. Immunol. 2: 20-27.
  4. Chen, Z., T. B. Gibson, F. Robinson, L. Silvestro, G. Pearson, B. Xu, A. Wright, C. Vanderbilt, and M. H. Cobb. 2001. MAP kinases. Chem. Rev. 101: 2449-2476. https://doi.org/10.1021/cr000241p
  5. Cargnello, M., and P. P. Roux. 2011. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 75: 50-83. https://doi.org/10.1128/MMBR.00031-10
  6. Kuo, W. L., C. J. Duke, M. K. Abe, E. L. Kaplan, S. Gomes, and M. R. Rosner. 2004. ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome pathway. J. Biol. Chem. 279: 23073-23081. https://doi.org/10.1074/jbc.M313696200
  7. Kyriakis, J. M., P. Banerjee, E. Nikolakaki, T. Dai, E. A. Rubie, M. F. Ahmad, J. Avruch, and J. R. Woodgett. 1994. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156-160. https://doi.org/10.1038/369156a0
  8. Lechner, C., M. A. Zahalka, J. F. Giot, N. P. Moller, and A. Ullrich. 1996. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc. Natl. Acad. Sci. U. S. A. 93: 4355-4359. https://doi.org/10.1073/pnas.93.9.4355
  9. Dhillon, A. S., S. Hagan, O. Rath, and W. Kolch. 2007. MAP kinase signalling pathways in cancer. Oncogene 26: 3279-3290. https://doi.org/10.1038/sj.onc.1210421
  10. Wada, T., and J. M. Penninger. 2004. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23: 2838-2849. https://doi.org/10.1038/sj.onc.1207556
  11. Engelberg, D. 2004. Stress-activated protein kinases-tumor suppressors or tumor initiators? Semin. Cancer Biol. 14: 271-282. https://doi.org/10.1016/j.semcancer.2004.04.006
  12. Liu, Y., E. G. Shepherd, and L. D. Nelin. 2007. MAPK phosphatases--regulating the immune response. Nat. Rev. Immunol. 7: 202-212. https://doi.org/10.1038/nri2035
  13. Schubbert, S., K. Shannon, and G. Bollag. 2007. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7: 295-308. https://doi.org/10.1038/nrc2109
  14. Goffin, J. R., and K. Zbuk. 2013. Epidermal growth factor receptor: pathway, therapies, and pipeline. Clin. Ther. 35: 1282-1303. https://doi.org/10.1016/j.clinthera.2013.08.007
  15. Normanno, N., L. A. De, C. Bianco, L. Strizzi, M. Mancino, M. R. Maiello, A. Carotenuto, F. G. De, F. Caponigro, and D. S. Salomon. 2006. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366: 2-16. https://doi.org/10.1016/j.gene.2005.10.018
  16. Bancroft, C. C., Z. Chen, G. Dong, J. B. Sunwoo, N. Yeh, C. Park, and W. C. Van. 2001. Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappaB signal pathways. Clin. Cancer Res. 7: 435-442.
  17. Treinies, I., H. F. Paterson, S. Hooper, R. Wilson, and C. J. Marshall. 1999. Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal To stimulate DNA synthesis. Mol. Cell. Biol. 19: 321-329. https://doi.org/10.1128/MCB.19.1.321
  18. Lu, Z., and S. Xu. 2006. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 58: 621-631. https://doi.org/10.1080/15216540600957438
  19. Brancho, D., N. Tanaka, A. Jaeschke, J. J. Ventura, N. Kelkar, Y. Tanaka, M. Kyuuma, T. Takeshita, R. A. Flavell, and R. J. Davis. 2003. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 17: 1969-1978. https://doi.org/10.1101/gad.1107303
  20. Bulavin, D. V., C. Phillips, B. Nannenga, O. Timofeev, L. A. Donehower, C. W. Anderson, E. Appella, and A. J. Fornace, Jr. 2004. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat. Genet. 36: 343-350. https://doi.org/10.1038/ng1317
  21. Timofeev, O., T. Y. Lee, and D. V. Bulavin. 2005. A subtle change in p38 MAPK activity is sufficient to suppress in vivo tumorigenesis. Cell Cycle 4: 118-120. https://doi.org/10.4161/cc.4.1.1342
  22. Han, J., and P. Sun. 2007. The pathways to tumor suppression via route p38. Trends Biochem. Sci. 32: 364-371. https://doi.org/10.1016/j.tibs.2007.06.007
  23. Ventura, J. J., S. Tenbaum, E. Perdiguero, M. Huth, C. Guerra, M. Barbacid, M. Pasparakis, and A. R. Nebreda. 2007. p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat. Genet. 39: 750-758. https://doi.org/10.1038/ng2037
  24. Cellurale, C., G. Sabio, N. J. Kennedy, M. Das, M. Barlow, P. Sandy, T. Jacks, and R. J. Davis. 2011. Requirement of c-Jun NH(2)-terminal kinase for Ras-initiated tumor formation. Mol. Cell. Biol. 31: 1565-1576. https://doi.org/10.1128/MCB.01122-10
  25. Chang, Q., Y. Zhang, K. J. Beezhold, D. Bhatia, H. Zhao, J. Chen, V. Castranova, X. Shi, and F. Chen. 2009. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J. Hepatol. 50: 323-333. https://doi.org/10.1016/j.jhep.2008.07.037
  26. Hui, L., K. Zatloukal, H. Scheuch, E. Stepniak, and E. F. Wagner. 2008. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J. Clin. Invest. 118: 3943-3953. https://doi.org/10.1172/JCI37156
  27. Kennedy, N. J., and R. J. Davis. 2003. Role of JNK in tumor development. Cell Cycle 2: 199-201.
  28. Derijard, B., M. Hibi, I. H. Wu, T. Barrett, B. Su, T. Deng, M. Karin, and R. J. Davis. 1994. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76: 1025-1037. https://doi.org/10.1016/0092-8674(94)90380-8
  29. Johnson, R., B. Spiegelman, D. Hanahan, and R. Wisdom. 1996. Cellular transformation and malignancy induced by ras require c-jun. Mol. Cell. Biol. 16: 4504-4511. https://doi.org/10.1128/MCB.16.8.4504
  30. Sakurai, T., S. Maeda, L. Chang, and M. Karin. 2006. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl. Acad. Sci. U. S. A. 103: 10544-10551. https://doi.org/10.1073/pnas.0603499103
  31. Chen, N., M. Nomura, Q. B. She, W. Y. Ma, A. M. Bode, L. Wang, R. A. Flavell, and Z. Dong. 2001. Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res. 61: 3908-3912.
  32. She, Q. B., N. Chen, A. M. Bode, R. A. Flavell, and Z. Dong. 2002. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 62: 1343-1348.
  33. Tournier, C., P. Hess, D. D. Yang, J. Xu, T. K. Turner, A. Nimnual, D. Bar-Sagi, S. N. Jones, R. A. Flavell, and R. J. Davis. 2000. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870-874. https://doi.org/10.1126/science.288.5467.870
  34. Wang, Y., Q. Y. He, S. W. Tsao, Y. H. Cheung, A. Wong, and J. F. Chiu. 2008. Cytokeratin 8 silencing in human nasopharyngeal carcinoma cells leads to cisplatin sensitization. Cancer Lett. 265: 188-196. https://doi.org/10.1016/j.canlet.2008.02.015
  35. Picco, V., and G. Pages. 2013. Linking JNK Activity to the DNA Damage Response. Genes Cancer 4: 360-368. https://doi.org/10.1177/1947601913486347
  36. Sun, T., D. Li, L. Wang, L. Xia, J. Ma, Z. Guan, G. Feng, and X. Zhu. 2011. c-Jun NH2-terminal kinase activation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cells. J. Transl. Med. 9: 161.
  37. Xu, P., M. Das, J. Reilly, and R. J. Davis. 2011. JNK regulates FoxO-dependent autophagy in neurons. Genes Dev. 25: 310-322. https://doi.org/10.1101/gad.1984311
  38. Ventura, J. J., A. Hubner, C. Zhang, R. A. Flavell, K. M. Shokat, and R. J. Davis. 2006. Chemical genetic analysis of the time course of signal transduction by JNK. Mol. Cell 21: 701-710. https://doi.org/10.1016/j.molcel.2006.01.018
  39. Ebisuya, M., K. Kondoh, and E. Nishida. 2005. The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J. Cell Sci. 118: 2997-3002. https://doi.org/10.1242/jcs.02505
  40. Camps, M., A. Nichols, and S. Arkinstall. 2000. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 14: 6-16. https://doi.org/10.1096/fasebj.14.1.6
  41. Farooq, A., and M. M. Zhou. 2004. Structure and regulation of MAPK phosphatases. Cell. Signal. 16: 769-779. https://doi.org/10.1016/j.cellsig.2003.12.008
  42. Kondoh, K., and E. Nishida. 2007. Regulation of MAP kinases by MAP kinase phosphatases. Biochim. Biophys. Acta 1773: 1227-1237. https://doi.org/10.1016/j.bbamcr.2006.12.002
  43. Owens, D. M., and S. M. Keyse. 2007. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26: 3203-3213. https://doi.org/10.1038/sj.onc.1210412
  44. Keyse, S. M. 2008. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 27: 253-261. https://doi.org/10.1007/s10555-008-9123-1
  45. Vicent, S., M. Garayoa, J. M. Lopez-Picazo, M. D. Lozano, G. Toledo, F. B. Thunnissen, R. G. Manzano, and L. M. Montuenga. 2004. Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin. Cancer Res. 10: 3639-3649. https://doi.org/10.1158/1078-0432.CCR-03-0771
  46. Bang, Y. J., J. H. Kwon, S. H. Kang, J. W. Kim, and Y. C. Yang. 1998. Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. Biochem. Biophys. Res. Commun. 250: 43-47. https://doi.org/10.1006/bbrc.1998.9256
  47. Liao, Q., J. Guo, J. Kleeff, A. Zimmermann, M. W. Buchler, M. Korc, and H. Friess. 2003. Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology 124: 1830-1845. https://doi.org/10.1016/S0016-5085(03)00398-6
  48. Wang, H. Y., Z. Cheng, and C. C. Malbon. 2003. Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett. 191: 229-237. https://doi.org/10.1016/S0304-3835(02)00612-2
  49. Denkert, C., W. D. Schmitt, S. Berger, A. Reles, S. Pest, A. Siegert, W. Lichtenegger, M. Dietel, and S. Hauptmann. 2002. Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int. J. Cancer 102: 507-513. https://doi.org/10.1002/ijc.10746
  50. Tsujita, E., A. Taketomi, T. Gion, Y. Kuroda, K. Endo, A. Watanabe, H. Nakashima, S. Aishima, S. Kohnoe, and Y. Maehara. 2005. Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma. Oncology 69: 342-347. https://doi.org/10.1159/000089766
  51. Givant-Horwitz, V., B. Davidson, J. M. Goderstad, J. M. Nesland, C. G. Trope, and R. Reich. 2004. The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma. Gynecol. Oncol. 93: 517-523. https://doi.org/10.1016/j.ygyno.2004.03.009
  52. Kim, S. C., J. S. Hahn, Y. H. Min, N. C. Yoo, Y. W. Ko, and W. J. Lee. 1999. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1. Blood 93: 3893-3899. https://doi.org/10.1182/blood.V93.11.3893
  53. Yokoyama, A., H. Karasaki, N. Urushibara, K. Nomoto, Y. Imai, K. Nakamura, Y. Mizuno, K. Ogawa, and K. Kikuchi. 1997. The characteristic gene expressions of MAPK phosphatases 1 and 2 in hepatocarcinogenesis, rat ascites hepatoma cells, and regenerating rat liver. Biochem. Biophys. Res. Commun. 239: 746-751. https://doi.org/10.1006/bbrc.1997.7547
  54. Yip-Schneider, M. T., A. Lin, and M. S. Marshall. 2001. Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2. Biochem. Biophys. Res. Commun. 280: 992-997. https://doi.org/10.1006/bbrc.2001.4243
  55. Sieben, N. L., J. Oosting, A. M. Flanagan, J. Prat, G. M. Roemen, S. M. Kolkman-Uljee, E. R. van, C. J. Cornelisse, G. J. Fleuren, and E. M. van. 2005. Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors. J. Clin. Oncol. 23: 7257-7264. https://doi.org/10.1200/JCO.2005.02.2541
  56. Chitale, D., Y. Gong, B. S. Taylor, S. Broderick, C. Brennan, R. Somwar, B. Golas, L. Wang, N. Motoi, J. Szoke, J. M. Reinersman, J. Major, C. Sander, V. E. Seshan, M. F. Zakowski, V. Rusch, W. Pao, W. Gerald, and M. Ladanyi. 2009. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28: 2773-2783. https://doi.org/10.1038/onc.2009.135
  57. Armes, J. E., F. Hammet, S. M. de, J. Ciciulla, S. J. Ramus, W. K. Soo, A. Mahoney, N. Yarovaya, M. A. Henderson, K. Gish, A. M. Hutchins, G. R. Price, and D. J. Venter. 2004. Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers. Oncogene 23: 5697-5702. https://doi.org/10.1038/sj.onc.1207740
  58. Waha, A., J. Felsberg, W. Hartmann, K. A. von dem, T. Mikeska, S. Joos, M. Wolter, A. Koch, P. S. Yan, E. Endl, O. D. Wiestler, G. Reifenberger, T. Pietsch, and A. Waha. 2010. Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res. 70: 1689-1699. https://doi.org/10.1158/0008-5472.CAN-09-3218
  59. Staege, M. S., K. Muller, S. Kewitz, I. Volkmer, C. Mauz-Korholz, T. Bernig, and D. Korholz. 2014. Expression of dual-specificity phosphatase 5 pseudogene 1 (DUSP5P1) in tumor cells. PLoS One 9: e89577. https://doi.org/10.1371/journal.pone.0089577
  60. Furukawa, T., M. Sunamura, F. Motoi, S. Matsuno, and A. Horii. 2003. Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am. J. Pathol. 162: 1807-1815. https://doi.org/10.1016/S0002-9440(10)64315-5
  61. Furukawa, T., T. Yatsuoka, E. M. Youssef, T. Abe, T. Yokoyama, S. Fukushige, E. Soeda, M. Hoshi, Y. Hayashi, M. Sunamura, M. Kobari, and A. Horii. 1998. Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenet. Cell Genet. 82: 156-159. https://doi.org/10.1159/000015091
  62. Okudela, K., T. Yazawa, T. Woo, M. Sakaeda, J. Ishii, H. Mitsui, H. Shimoyamada, H. Sato, M. Tajiri, N. Ogawa, M. Masuda, T. Takahashi, H. Sugimura, and H. Kitamura. 2009. Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis. Am. J. Pathol. 175: 867-881. https://doi.org/10.2353/ajpath.2009.080489
  63. Warmka, J. K., L. J. Mauro, and E. V. Wattenberg. 2004. Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. J. Biol. Chem. 279: 33085-33092. https://doi.org/10.1074/jbc.M403120200
  64. Chan, D. W., V. W. Liu, G. S. Tsao, K. M. Yao, T. Furukawa, K. K. Chan, and H. Y. Ngan. 2008. Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis 29: 1742-1750. https://doi.org/10.1093/carcin/bgn167
  65. Lucci, M. A., R. Orlandi, T. Triulzi, E. Tagliabue, A. Balsari, and E. Villa-Moruzzi. 2010. Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell. Oncol. 32: 361-372. https://doi.org/10.1155/2010/386484
  66. Cui, Y., I. Parra, M. Zhang, S. G. Hilsenbeck, A. Tsimelzon, T. Furukawa, A. Horii, Z. Y. Zhang, R. I. Nicholson, and S. A. Fuqua. 2006. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Res. 66: 5950-5959. https://doi.org/10.1158/0008-5472.CAN-05-3243
  67. Wong, V. C., H. Chen, J. M. Ko, K. W. Chan, Y. P. Chan, S. Law, D. Chua, D. L. Kwong, H. L. Lung, G. Srivastava, J. C. Tang, S. W. Tsao, E. R. Zabarovsky, E. J. Stanbridge, and M. L. Lung. 2012. Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype. Int. J. Cancer 130: 83-95. https://doi.org/10.1002/ijc.25970
  68. Levy-Nissenbaum, O., O. Sagi-Assif, D. Kapon, S. Hantisteanu, T. Burg, P. Raanani, A. Avigdor, I. Ben-Bassat, and I. P. Witz. 2003. Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells. Oncogene 22: 7649-7660. https://doi.org/10.1038/sj.onc.1206971
  69. Liu, Y., J. Lagowski, A. Sundholm, A. Sundberg, and M. Kulesz-Martin. 2007. Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4. Cancer Res. 67: 10711-10719. https://doi.org/10.1158/0008-5472.CAN-07-1968
  70. Krishnan, A. V., J. Moreno, L. Nonn, S. Swami, D. M. Peehl, and D. Feldman. 2007. Calcitriol as a chemopreventive and therapeutic agent in prostate cancer: role of anti-inflammatory activity. J. Bone Miner. Res. 22 Suppl 2: V74-V80. https://doi.org/10.1359/jbmr.07s213
  71. Nonn, L., D. Duong, and D. M. Peehl. 2007. Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis 28: 1188-1196. https://doi.org/10.1093/carcin/bgl241
  72. Nonn, L., L. Peng, D. Feldman, and D. M. Peehl. 2006. Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. Cancer Res. 66: 4516-4524. https://doi.org/10.1158/0008-5472.CAN-05-3796
  73. Nomura, M., K. Shiiba, C. Katagiri, I. Kasugai, K. Masuda, I. Sato, M. Sato, Y. Kakugawa, E. Nomura, K. Hayashi, Y. Nakamura, T. Nagata, T. Otsuka, R. Katakura, Y. Yamashita, M. Sato, N. Tanuma, and H. Shima. 2012. Novel function of MKP-5/DUSP10, a phosphatase of stress-activated kinases, on ERK-dependent gene expression, and upregulation of its gene expression in colon carcinomas. Oncol. Rep. 28: 931-936.
  74. Hoornaert, I., P. Marynen, J. Goris, R. Sciot, and M. Baens. 2003. MAPK phosphatase DUSP16/MKP-7, a candidate tumor suppressor for chromosome region 12p12-13, reduces BCR-ABLinduced transformation. Oncogene 22: 7728-7736. https://doi.org/10.1038/sj.onc.1207089
  75. Grepmeier, U., W. Dietmaier, J. Merk, P. J. Wild, E. C. Obermann, M. Pfeifer, F. Hofstaedter, A. Hartmann, and M. Woenckhaus. 2005. Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers. Int. J. Oncol. 27: 481-488. https://doi.org/10.3892/ijo.27.2.481
  76. Kibel, A. S., J. Huagen, C. Guo, W. B. Isaacs, Y. Yan, K. J. Pienta, and P. J. Goodfellow. 2004. Expression mapping at 12p12-13 in advanced prostate carcinoma. Int. J. Cancer 109: 668-672. https://doi.org/10.1002/ijc.20060
  77. Zaidi, S. K., C. R. Dowdy, A. J. van Wijnen, J. B. Lian, A. Raza, J. L. Stein, C. M. Croce, and G. S. Stein. 2009. Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer Res. 69: 8249-8255. https://doi.org/10.1158/0008-5472.CAN-09-1567
  78. Lee, S., N. Syed, J. Taylor, P. Smith, B. Griffin, M. Baens, M. Bai, K. Bourantas, J. Stebbing, K. Naresh, M. Nelson, M. Tuthill, M. Bower, E. Hatzimichael, and T. Crook. 2010. DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma. Br. J. Cancer 103: 265-274. https://doi.org/10.1038/sj.bjc.6605711
  79. Zhou, J. Y., Y. Liu, and G. S. Wu. 2006. The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death. Cancer Res. 66: 4888-4894. https://doi.org/10.1158/0008-5472.CAN-05-4229
  80. Shi, H., E. Boadu, F. Mercan, A. M. Le, R. J. Flach, L. Zhang, K. J. Tyner, B. B. Olwin, and A. M. Bennett. 2010. MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy. FASEB J. 24: 2985-2997. https://doi.org/10.1096/fj.09-150045
  81. Chi, H., S. P. Barry, R. J. Roth, J. J. Wu, E. A. Jones, A. M. Bennett, and R. A. Flavell. 2006. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl. Acad. Sci. U. S. A. 103: 2274-2279. https://doi.org/10.1073/pnas.0510965103
  82. Zhang, Y., J. M. Reynolds, S. H. Chang, N. Martin-Orozco, Y. Chung, R. I. Nurieva, and C. Dong. 2009. MKP-1 is necessary for T cell activation and function. J. Biol. Chem. 284: 30815-30824. https://doi.org/10.1074/jbc.M109.052472
  83. Boutros, T., E. Chevet, and P. Metrakos. 2008. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol. Rev. 60: 261-310. https://doi.org/10.1124/pr.107.00106
  84. Magi-Galluzzi, C., R. Mishra, M. Fiorentino, R. Montironi, H. Yao, P. Capodieci, K. Wishnow, I. Kaplan, P. J. Stork, and M. Loda. 1997. Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab. Invest. 76: 37-51.
  85. Wang, H. Y., Z. Cheng, and C. C. Malbon. 2003. Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett. 191: 229-237. https://doi.org/10.1016/S0304-3835(02)00612-2
  86. Candas, D., C. L. Lu, M. Fan, F. Y. Chuang, C. Sweeney, A. D. Borowsky, and J. J. Li. 2014. Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Res. 74: 7498-7509. https://doi.org/10.1158/0008-5472.CAN-14-0844
  87. Rojo, F., I. Gonzalez-Navarrete, R. Bragado, A. Dalmases, S. Menendez, M. Cortes-Sempere, C. Suarez, C. Oliva, S. Servitja, V. Rodriguez-Fanjul, I. Sanchez-Perez, C. Campas, J. M. Corominas, I. Tusquets, B. Bellosillo, S. Serrano, R. Perona, A. Rovira, and J. Albanell. 2009. Mitogen-activated protein kinase phosphatase-1 in human breast cancer independently predicts prognosis and is repressed by doxorubicin. Clin. Cancer Res. 15: 3530-3539. https://doi.org/10.1158/1078-0432.CCR-08-2070
  88. Small, G. W., Y. Y. Shi, L. S. Higgins, and R. Z. Orlowski. 2007. Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res. 67: 4459-4466. https://doi.org/10.1158/0008-5472.CAN-06-2644
  89. Cimas, F. J., J. L. Callejas-Valera, R. Pascual-Serra, J. Garcia-Cano, E. Garcia-Gil, De la Cruz-Morcillo MA, M. Ortega-Muelas, L. Serrano-Oviedo, J. S. Gutkind, and R. Sanchez-Prieto. 2015. MKP1 mediates chemosensitizer effects of E1a in response to cisplatin in non-small cell lung carcinoma cells. Oncotarget 6: 44095-44107. https://doi.org/10.18632/oncotarget.6574
  90. Montagut, C., M. Iglesias, M. Arumi, B. Bellosillo, M. Gallen, A. Martinez-Fernandez, L. Martinez-Aviles, I. Canadas, A. Dalmases, E. Moragon, L. Lema, S. Serrano, A. Rovira, F. Rojo, J. Bellmunt, and J. Albanell. 2010. Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients. Br. J. Cancer 102: 1137-1144. https://doi.org/10.1038/sj.bjc.6605612
  91. Park, J., J. Lee, W. Kang, S. Chang, E. C. Shin, and C. Choi. 2013. TGF-beta1 and hypoxia-dependent expression of MKP-1 leads tumor resistance to death receptor-mediated cell death. Cell Death. Dis. 4: e521.
  92. Wang, J., J. Y. Zhou, and G. S. Wu. 2007. ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells. Cancer Res. 67: 11933-11941. https://doi.org/10.1158/0008-5472.CAN-07-5185
  93. Wang, J., J. Y. Zhou, L. Zhang, and G. S. Wu. 2009. Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells. Cell Cycle 8: 3191-3198. https://doi.org/10.4161/cc.8.19.9751
  94. Small, G. W., Y. Y. Shi, L. S. Higgins, and R. Z. Orlowski. 2007. Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res. 67: 4459-4466. https://doi.org/10.1158/0008-5472.CAN-06-2644
  95. Ma, G., Y. Pan, C. Zhou, R. Sun, J. Bai, P. Liu, Y. Ren, and J. He. 2015. Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells. Oncol. Rep. 34: 2423-2430. https://doi.org/10.3892/or.2015.4244
  96. Lee, M., K. S. Young, J. Kim, H. S. Kim, S. M. Kim, and E. J. Kim. 2013. Mitogen-activated protein kinase phosphatase-1 inhibition and sustained extracellular signal-regulated kinase 1/2 activation in camptothecin-induced human colon cancer cell death. Cancer Biol. Ther. 14: 1007-1015. https://doi.org/10.4161/cbt.26044
  97. Lawan, A., S. Al-Harthi, L. Cadalbert, A. G. McCluskey, M. Shweash, G. Grassia, A. Grant, M. Boyd, S. Currie, and R. Plevin. 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: 12933-12943. https://doi.org/10.1074/jbc.M110.181370
  98. Hasegawa, T., A. Enomoto, T. Kato, K. Kawai, R. Miyamoto, M. Jijiwa, M. Ichihara, M. Ishida, N. Asai, Y. Murakumo, K. Ohara, Y. Niwa, H. Goto, and M. Takahashi. 2008. Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. Oncogene 27: 5684-5695. https://doi.org/10.1038/onc.2008.182
  99. Groschl, B., M. Bettstetter, C. Giedl, M. Woenckhaus, T. Edmonston, F. Hofstadter, and W. Dietmaier. 2013. Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation. Int. J. Cancer 132: 1537-1546. https://doi.org/10.1002/ijc.27834
  100. Cagnol, S., and N. Rivard. 2013. Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition. Oncogene 32: 564-576. https://doi.org/10.1038/onc.2012.88
  101. Balko, J. M., R. S. Cook, D. B. Vaught, M. G. Kuba, T. W. Miller, N. E. Bhola, M. E. Sanders, N. M. Granja-Ingram, J. J. Smith, I. M. Meszoely, J. Salter, M. Dowsett, K. Stemke-Hale, A. M. Gonzalez-Angulo, G. B. Mills, J. A. Pinto, H. L. Gomez, and C. L. Arteaga. 2012. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat. Med. 18: 1052-1059. https://doi.org/10.1038/nm.2795
  102. Venter, D. J., S. J. Ramus, F. M. Hammet, S. M. de, A. M. Hutchins, V. Petrovic, G. Price, and J. E. Armes. 2005. Complex CGH alterations on chromosome arm 8p at candidate tumor suppressor gene loci in breast cancer cell lines. Cancer Genet. Cytogenet. 160: 134-140. https://doi.org/10.1016/j.cancergencyto.2004.12.007
  103. Haagenson, K. K., J. W. Zhang, Z. Xu, M. P. Shekhar, and G. S. Wu. 2014. Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity. Oncotarget 5: 1101-1110. https://doi.org/10.18632/oncotarget.1795
  104. Cadalbert, L., C. M. Sloss, P. Cameron, and R. Plevin. 2005. Conditional expression of MAP kinase phosphatase-2 protects against genotoxic stress-induced apoptosis by binding and selective dephosphorylation of nuclear activated c-jun N-terminal kinase. Cell. Signal. 17: 1254-1264. https://doi.org/10.1016/j.cellsig.2005.01.003
  105. Muda, M., U. Boschert, R. Dickinson, J. C. Martinou, I. Martinou, M. Camps, W. Schlegel, and S. Arkinstall. 1996. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J. Biol. Chem. 271: 4319-4326. https://doi.org/10.1074/jbc.271.8.4319
  106. Bloethner, S., B. Chen, K. Hemminki, J. Muller-Berghaus, S. Ugurel, D. Schadendorf, and R. Kumar. 2005. Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis 26: 1224-1232. https://doi.org/10.1093/carcin/bgi066
  107. Croonquist, P. A., M. A. Linden, F. Zhao, and B. G. Van Ness. 2003. Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations, and coculture with bone marrow stromal cells. Blood 102: 2581-2592. https://doi.org/10.1182/blood-2003-04-1227
  108. Warmka, J. K., L. J. Mauro, and E. V. Wattenberg. 2004. Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. J. Biol. Chem. 279: 33085-33092. https://doi.org/10.1074/jbc.M403120200
  109. Zhang, Z., S. Kobayashi, A. C. Borczuk, R. S. Leidner, T. Laframboise, A. D. Levine, and B. Halmos. 2010. Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 31: 577-586. https://doi.org/10.1093/carcin/bgq020
  110. Ma, J., X. Yu, L. Guo, and S. H. Lu. 2013. DUSP6, a tumor suppressor, is involved in differentiation and apoptosis in esophageal squamous cell carcinoma. Oncol. Lett. 6: 1624-1630. https://doi.org/10.3892/ol.2013.1605
  111. Bergholz, J., Y. Zhang, J. Wu, L. Meng, E. M. Walsh, A. Rai, M. Y. Sherman, and Z. X. Xiao. 2014. DeltaNp63alpha regulates Erk signaling via MKP3 to inhibit cancer metastasis. Oncogene 33: 212-224. https://doi.org/10.1038/onc.2012.564
  112. Luo, M. L., C. Gong, C. H. Chen, H. Hu, P. Huang, M. Zheng, Y. Yao, S. Wei, G. Wulf, J. Lieberman, X. Z. Zhou, E. Song, and K. P. Lu. 2015. The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. Cell Rep. 11: 111-124. https://doi.org/10.1016/j.celrep.2015.03.002
  113. Li, W., and D. W. Melton. 2012. Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene 31: 2412-2422. https://doi.org/10.1038/onc.2011.426
  114. Messina, S., L. Frati, C. Leonetti, C. Zuchegna, Z. E. Di, A. Calogero, and A. Porcellini. 2011. Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 30: 3813-3820. https://doi.org/10.1038/onc.2011.99
  115. Choi, B. K., C. H. Choi, H. L. Oh, and Y. K. Kim. 2004. Role of ERK activation in cisplatin-induced apoptosis in A172 human glioma cells. Neurotoxicology 25: 915-924. https://doi.org/10.1016/j.neuro.2004.06.002
  116. Tanoue, T., T. Moriguchi, and E. Nishida. 1999. Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5. J. Biol. Chem. 274: 19949-19956. https://doi.org/10.1074/jbc.274.28.19949
  117. Theodosiou, A., A. Smith, C. Gillieron, S. Arkinstall, and A. Ashworth. 1999. MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases. Oncogene 18: 6981-6988. https://doi.org/10.1038/sj.onc.1203185
  118. James, S. J., H. Jiao, H. Y. Teh, H. Takahashi, C. W. Png, M. C. Phoon, Y. Suzuki, T. Sawasaki, H. Xiao, V. T. Chow, N. Yamamoto, J. M. Reynolds, R. A. Flavell, C. Dong, and Y. Zhang. 2015. MAPK Phosphatase 5 Expression Induced by Influenza and Other RNA Virus Infection Negatively Regulates IRF3 Activation and Type I Interferon Response. Cell Rep. 10: 1722-1734. https://doi.org/10.1016/j.celrep.2015.02.030
  119. Zhang, Y., J. N. Blattman, N. J. Kennedy, J. Duong, T. Nguyen, Y. Wang, R. J. Davis, P. D. Greenberg, R. A. Flavell, and C. Dong. 2004. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430: 793-797. https://doi.org/10.1038/nature02764
  120. Qian, F., J. Deng, N. Cheng, E. J. Welch, Y. Zhang, A. B. Malik, R. A. Flavell, C. Dong, and R. D. Ye. 2009. A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury. EMBO J. 28: 2896-2907. https://doi.org/10.1038/emboj.2009.234
  121. Zhang, Y., T. Nguyen, P. Tang, N. J. Kennedy, H. Jiao, M. Zhang, J. M. Reynolds, A. Jaeschke, N. Martin-Orozco, Y. Chung, W. M. He, C. Wang, W. Jia, B. Ge, R. J. Davis, R. A. Flavell, and C. Dong. 2015. Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5. J. Biol. Chem. 290: 14875-14883. https://doi.org/10.1074/jbc.M115.660969
  122. Png, C. W., M. Weerasooriya, J. Guo, S. J. James, H. M. Poh, M. Osato, R. A. Flavell, C. Dong, H. Yang, and Y. Zhang. 2016. DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis. Oncogene 35: 206-217. https://doi.org/10.1038/onc.2015.74
  123. Song, M. K., Y. K. Park, and J. C. Ryu. 2013. Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK. Toxicol. Appl. Pharmacol. 273: 130-139. https://doi.org/10.1016/j.taap.2013.08.016
  124. He, G., L. Zhang, Q. Li, and L. Yang. 2014. miR-92a/DUSP10/JNK signalling axis promotes human pancreatic cancer cells proliferation. Biomed. Pharmacother. 68: 25-30. https://doi.org/10.1016/j.biopha.2013.11.004
  125. Tanoue, T., T. Yamamoto, R. Maeda, and E. Nishida. 2001. A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J. Biol. Chem. 276: 26629-26639. https://doi.org/10.1074/jbc.M101981200
  126. Masuda, K., H. Shima, M. Watanabe, and K. Kikuchi. 2001. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J. Biol. Chem. 276: 39002-39011. https://doi.org/10.1074/jbc.M104600200
  127. Zhang, Y., K. C. Nallaparaju, X. Liu, H. Jiao, J. M. Reynolds, Z. X. Wang, and C. Dong. 2015. MAPK phosphatase 7 regulates T cell differentiation via inhibiting ERK-mediated IL-2 expression. J. Immunol. 194: 3088-3095. https://doi.org/10.4049/jimmunol.1402638
  128. Wei, X., W. Guo, S. Wu, L. Wang, P. Huang, J. Liu, and B. Fang. 2010. Oxidative stress in NSC-741909-induced apoptosis of cancer cells. J. Transl. Med. 8: 37.
  129. Vogt, A., A. Tamewitz, J. Skoko, R. P. Sikorski, K. A. Giuliano, and J. S. Lazo. 2005. The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. J. Biol. Chem. 280: 19078-19086. https://doi.org/10.1074/jbc.M501467200
  130. Wang, Z., J. Y. Zhou, D. Kanakapalli, S. Buck, G. S. Wu, and Y. Ravindranath. 2008. High level of mitogen-activated protein kinase phosphatase-1 expression is associated with cisplatin resistance in osteosarcoma. Pediatr. Blood Cancer 51: 754-759. https://doi.org/10.1002/pbc.21727
  131. Arnold, D. M., C. Foster, D. M. Huryn, J. S. Lazo, P. A. Johnston, and P. Wipf. 2007. Synthesis and biological activity of a focused library of mitogen-activated protein kinase phosphatase inhibitors. Chem. Biol. Drug Des. 69: 23-30. https://doi.org/10.1111/j.1747-0285.2007.00474.x
  132. Lazo, J. S., J. J. Skoko, S. Werner, B. Mitasev, A. Bakan, F. Koizumi, A. Yellow-Duke, I. Bahar, and K. M. Brummond. 2007. Structurally unique inhibitors of human mitogen-activated protein kinase phosphatase-1 identified in a pyrrole carboxamide library. J. Pharmacol. Exp. Ther. 322: 940-947. https://doi.org/10.1124/jpet.107.122242
  133. Vogt, A., P. R. McDonald, A. Tamewitz, R. P. Sikorski, P. Wipf, J. J. Skoko, III, and J. S. Lazo. 2008. A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Mol. Cancer Ther. 7: 330-340. https://doi.org/10.1158/1535-7163.MCT-07-2165