Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

MAPK phosphatases — regulating the immune response

Nature Reviews Immunology volume 7, pages 202–212 (2007)Cite this article

Key Points

  • Mitogen-activated protein kinases (MAPKs) are essential regulators of both the innate and the adaptive immune responses. MAPK activity is regulated by reversible phosphorylation at threonine and tyrosine residues.

  • MAPK phosphatases (MKPs) are dual-specificity protein phosphatases that deactivate MAPKs by simultaneously removing the phosphate groups from both the threonine and tyrosine residues on active MAPKs. MKPs serve as a feedback control mechanism of MAPK pathways. There are at least ten MKPs in mammalian cells. These phosphatases have substantial differences in their subcellular localization, expression and biochemical properties, including substrate specificity and catalytic activation.

  • MKPs have been shown to have an important role in innate immune responses by regulating the production of inflammatory and anti-inflammatory cytokines, innate immune cell viability, and the function of antigen-presenting cells (APCs).

  • MKPs can also regulate the adaptive immune responses through regulation of cytokine biosynthesis and cell proliferation.

  • Different members of the MKP family have distinct roles in the immune responses. They can either positively or negatively regulate immune responses.

  • A number of immunomodulatory agents, including glucocorticoids and anti-inflammatory and pro-inflammatory cytokines can modulate the expression of MKP1.

Abstract

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are protein phosphatases that dephosphorylate both the phosphothreonine and phosphotyrosine residues on activated MAPKs. Removal of the phosphates renders MAPKs inactive, effectively halting their cellular function. In recent years, evidence has emerged that, similar to MAPKs, MKPs are pivotal in the regulation of immune responses. By deactivating MAPKs, MKPs can modulate both innate and adaptive immunity. A number of immunomodulatory agents have been found to influence the expression of MKP1 in particular, highlighting the central role of this phosphatase in immune regulation. This Review discusses the properties, function and regulation of MKPs during immune responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic diagram of the three mammalian mitogen-activated protein kinase (MAPK) signalling pathways.
Figure 2: Structural features of the MKP family.
Figure 3: The function and regulation of MKP1 during the innate immune response to microbial infection.
Figure 4: Regulation of MKP1 expression by immunomodulatory agents.

Similar content being viewed by others

References

  1. Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Dong, C., Davis, R. J. & Flavell, R. A. MAP kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Hanks, S. K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Cobb, M. H. & Goldsmith, E. J. Dimerization in MAP-kinase signaling. Trends Biochem. Sci. 25, 7–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Davis, R. J. The mitogen-activated protein kinase signal transduction pathway. J. Biol. Chem. 268, 14553–14556 (1993).

    CAS  PubMed  Google Scholar 

  7. Hazzalin, C. A. & Mahadevan, L. C. MAPK-regulated transcription: a continuously variable gene switch? Nature Rev. Mol. Cell Biol. 3, 30–40 (2002).

    Article  CAS  Google Scholar 

  8. Ricci, R. et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 306, 1558–1561 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Han, Z. et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108, 73–81 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dumitru, C. D. et al. TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071–1083 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Kotlyarov, A. et al. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nature Cell Biol. 1, 94–97 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Jordan, J. D., Landau, E. M. & Iyengar, R. Signaling networks: the origins of cellular multitasking. Cell 103, 193–200 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bhalla, U. S., Ram, P. T. & Iyengar, R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023 (2002). This paper shows that the concentration of MKPs determines the bistable or monostable state of MAPKs.

    Article  CAS  PubMed  Google Scholar 

  15. Sun, H., Charles, C. H., Lau, L. F. & Tonks, N. K. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75, 487–493 (1993). This paper was the first to show that MKP1 serves as a phosphatase of MAPKs in vivo . This study is important, because it defined a new class of protein phosphatases. The authors proposed the concept that MKPs function as a feedback control mechanism for MAPK regulation.

    Article  CAS  PubMed  Google Scholar 

  16. Keyse, S. M. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol. 12, 186–192 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, Y., Gorospe, M., Yang, C. & Holbrook, N. J. 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. J. Biol. Chem. 270, 8377–8380 (1995). This paper proposed for the first time that MKP1 functions as a phosphatase of JNK in the feedback control of gene expression in response to cellular stress.

    Article  CAS  PubMed  Google Scholar 

  18. Matsuguchi, T., Musikacharoen, T., Johnson, T. R., Kraft, A. S. & Yoshikai, Y. A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines. Mol. Cell. Biol. 21, 6999–7009 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mandl, M., Slack, D. N. & Keyse, S. M. Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5. Mol. Cell. Biol. 25, 1830–1845 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu, J. J., Zhang, L. & Bennett, A. M. The noncatalytic amino terminus of mitogen-activated protein kinase phosphatase 1 directs nuclear targeting and serum response element transcriptional regulation. Mol. Cell. Biol. 25, 4792–4803 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Karlsson, M., Mathers, J., Dickinson, R. J., Mandl, M. & Keyse, S. M. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J. Biol. Chem. 279, 41882–41891 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Wu, J. J. et al. Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab. 4, 61–73 (2006). This is the first paper to show that MKP1 has an important role in the regulation of metabolism.

    Article  CAS  PubMed  Google Scholar 

  23. Jeffrey, K. L. et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nature Immunol. 7, 274–283 (2006). This paper described Dusp2−/− mice and the alterations in immune-cell function and inflammatory responses found in these mice.

    Article  CAS  Google Scholar 

  24. Brondello, J. M., Pouyssegur, J. & McKenzie, F. R. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286, 2514–2517 (1999). This paper was the first report to show that MKP protein stability can be regulated by MAPK-mediated phosphorylation.

    Article  CAS  PubMed  Google Scholar 

  25. Sohaskey, M. L. & Ferrell, J. E. Jr. Activation of p42 mitogen-activated protein kinase (MAPK), but not c-Jun NH2-terminal kinase, induces phosphorylation and stabilization of MAPK phosphatase XCL100 in Xenopus oocytes. Mol. Biol. Cell 13, 454–468 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Katagiri, C. et al. Phosphorylation of Ser-446 determines stability of MKP-7. J. Biol. Chem. 280, 14716–14722 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Marchetti, S. et al. Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Mol. Cell. Biol. 25, 854–864 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Camps, M. et al. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science 280, 1262–1265 (1998). This paper was the first report to show that the catalytic activity of some MKPs can be influenced by interaction with their substrate MAPKs.

    Article  CAS  PubMed  Google Scholar 

  29. Stewart, A. E., Dowd, S., Keyse, S. M. & McDonald, N. Q. Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nature Struct. Biol. 6, 174–181 (1999). This article described the crystal structure of the catalytic domain of MKP3. The authors proposed that catalytic activation of MKPs are mediated by the movement of the conserved aspartic acid residue closer to the catalytic site, and such conformational change allows the aspartic acid to function as a general acid.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, Y. et al. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430, 793–797 (2004). This paper was the first to show the physiological function of MKP5 in immune responses by using knockout mice.

    Article  CAS  PubMed  Google Scholar 

  31. Zhao, Q. et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med. 203, 131–140 (2006). Reference 31–34 were the first reports to show that MKP1 is a crucial negative regulator of p38 and JNK, and has a pivotal role in the regulation of the inflammatory responses to bacterial components. These papers also show that Mkp1−/− mice are profoundly sensitive to endotoxin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hammer, M. et al. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J. Exp. Med. 203, 15–20 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Salojin, K. V. et al. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J. Immunol. 176, 1899–1907 (2006). In addition to the findings of references 31–34, this paper provided specific evidence that MKP1 has a role in adaptive immune responses. It shows that Mkp1−/− mice are more sensitive to type II collagen-induced arthritis.

    Article  CAS  PubMed  Google Scholar 

  34. Chi, H. et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl Acad. Sci. USA 103, 2274–2279 (2006). In addition to the findings of references 31–34, this paper specifically shows that MKP1 is induced by TLR stimulation through pathways mediated by both MyD88 and TRIF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, P. et al. Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J. Immunol. 169, 6408–6416 (2002). This paper was the earliest report to show that MKP1 is a negative regulator of p38 and JNK in macrophages. It established the concept that MKP1 functions as a feedback control mechanism to restrain the production of pro-inflammatory cytokines, and that anti-inflammatory agents suppress the production of inflammatory cytokines through enhancing MKP1 expression.

    Article  CAS  PubMed  Google Scholar 

  36. Dorfman, K. et al. Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene 13, 925–931 (1996). This paper shows that Mkp1−/− mice have no obvious phenotype.

    CAS  PubMed  Google Scholar 

  37. Zhao, Q. et al. The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J. Biol. Chem. 280, 8101–8108 (2005). This paper was the first report to show that MKP1 has a physiological role in the regulation of cytokine production using cells deficient in MKP1. It also showed that the relative anti-inflammatory potencies of synthetic corticosteroids are correlated with their abilities to induce MKP1 expression.

    Article  CAS  PubMed  Google Scholar 

  38. Howard, M., Muchamuel, T., Andrade, S. & Menon, S. Interleukin 10 protects mice from lethal endotoxemia. J. Exp. Med. 177, 1205–1208 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Gerard, C. et al. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J. Exp. Med. 177, 547–550 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Hammer, M. et al. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol. 35, 2991–3001 (2005). This paper showed that the expression of MKP1 is enhanced by the anti-inflammatory cytokine IL-10.

    Article  CAS  PubMed  Google Scholar 

  41. Shepherd, E. G. et al. The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages. J. Biol. Chem. 279, 54023–54031 (2004). This was the first report to show that MKP1 has an important role in the host inflammatory response to TLR ligands other than LPS.

    Article  CAS  PubMed  Google Scholar 

  42. Philpott, D. J. & Girardin, S. E. The role of Toll-like receptors and Nod proteins in bacterial infection. Mol. Immunol. 41, 1099–1108 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Yoshimura, A. et al. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 163, 1–5 (1999).

    CAS  PubMed  Google Scholar 

  45. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Tanoue, T., Adachi, M., Moriguchi, T. & Nishida, E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nature Cell Biol. 2, 110–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Hutter, D., Chen, P., Barnes, J. & Liu, Y. Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase: critical role of the p38 C-terminal domain in its negative regulation. Biochem. J. 352 Pt 1, 155–163 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Nimah, M. et al. Contribution of MKP-1 regulation of p38 to endotoxin tolerance. Shock 23, 80–87 (2005). This paper was the first report to propose that MKP1 might have an important role in endotoxin tolerance.

    Article  CAS  PubMed  Google Scholar 

  49. Hu, J. H. et al. Feedback control of MKP-1 expression by p38. Cell Signal. 19, 393–400 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Theodosiou, A., Smith, A., Gillieron, C., Arkinstall, S. & Ashworth, A. MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases. Oncogene 18, 6981–6988 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Tanoue, T., Moriguchi, T. & Nishida, E. Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5. J. Biol. Chem. 274, 19949–19956 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Rohan, P.J. et al. PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science 259, 1763–1766 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Chu, Y., Solski, P. A., Khosravi-Far, R., Der, C. J. & Kelly, K. The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J. Biol. Chem. 271, 6497–6501 (1996). References 53 and 100 were the first reports to show that MKPs have distinct substrate specificities towards different members of the MAPK family. Reference 53 shows that DUSP2 prefers ERK and p38 as substrates.

    Article  CAS  PubMed  Google Scholar 

  54. Ward, Y. et al. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature 367, 651–654 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Tanoue, T., Yamamoto, T., Maeda, R. & Nishida, E. A novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38α and β MAPKs. J. Biol. Chem. 276, 26629–26639 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Shen, Y. H. et al. Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. J. Biol. Chem. 278, 26715–26721 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Pages, G. et al. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286, 1374–1377 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Agrawal, A., Dillon, S., Denning, T. L. & Pulendran, B. ERK1−/− mice exhibit TH1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis. J. Immunol. 176, 5788–5796 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Nekrasova, T. et al. ERK1-deficient mice show normal T cell effector function and are highly susceptible to experimental autoimmune encephalomyelitis. J. Immunol. 175, 2374–2380 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Park, J. H. & Levitt, L. Overexpression of mitogen-activated protein kinase (ERK1) enhances T-cell cytokine gene expression: role of AP1, NF-AT, and NF-kB. Blood 82, 2470–2477 (1993).

    CAS  PubMed  Google Scholar 

  61. Whitehurst, C. E. & Geppert, T. D. MEK1 and the extracellular signal-regulated kinases are required for the stimulation of IL-2 gene transcription in T cells. J. Immunol. 156, 1020–1029 (1996).

    CAS  PubMed  Google Scholar 

  62. Koike, T. et al. A novel ERK-dependent signaling process that regulates interleukin-2 expression in a late phase of T cell activation. J. Biol. Chem. 278, 15685–15692 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Rincon, M., Derijard, B., Chow, C. W., Davis, R. J. & Flavell, R. A. Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector TH1 and TH2 cells. Genes Funct. 1, 51–68 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Kurt, R. A., Urba, W. J., Smith, J. W. & Schoof, D. D. Peripheral T lymphocytes from women with breast cancer exhibit abnormal protein expression of several signaling molecules. Int. J. Cancer 78, 16–20 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Rincon, M. et al. Interferon-γ expression by TH1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J. 17, 2817–2829 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Han, J., Thompson, P. & Beutler, B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J. Exp. Med. 172, 391–394 (1990).

    Article  CAS  PubMed  Google Scholar 

  67. Swantek, J. L., Cobb, M. H. & Geppert, T. D. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor α (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK. Mol. Cell. Biol. 17, 6274–6282 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 10, 387–398 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Kassel, O. et al. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J. 20, 7108–7116 (2001). This is the earliest report to show that glucocorticoids might exert their anti-inflammatory effects through the induction of MKP1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lasa, M., Abraham, S. M., Boucheron, C., Saklatvala, J. & Clark, A. R. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol. Cell. Biol. 22, 7802–7811 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Abraham, S. M. et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203, 1883–1889 (2006). The paper showed that MKP1 is crucial for the anti-inflammatory activity of dexamethasone.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Eljaschewitsch, E. et al. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49, 67–79 (2006). This paper showed an important role of MKP1 in neuronal protection by the endocannabinoid anandamide.

    Article  CAS  PubMed  Google Scholar 

  73. Burkart, V., Kim, Y., Kauer, M. & Kolb, H. Induction of tolerance in macrophages by cholera toxin B chain. Pathobiology 67, 314–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Burkart, V. et al. Cholera toxin B pretreatment of macrophages and monocytes diminishes their proinflammatory responsiveness to lipopolysaccharide. J. Immunol. 168, 1730–1737 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Sun, J. B., Rask, C., Olsson, T., Holmgren, J. & Czerkinsky, C. Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit. Proc. Natl Acad. Sci. USA 93, 7196–7201 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bergerot, I. et al. A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc. Natl Acad. Sci. USA 94, 4610–4614 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tarkowski, A., Sun, J. B., Holmdahl, R., Holmgren, J. & Czerkinsky, C. Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen–cholera toxoid conjugate vaccine. Arthritis Rheum. 42, 1628–1634 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Collart, M. A., Belin, D., Vassalli, J. D., de Kossodo, S. & Vassalli, P. γ interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J. Exp. Med. 164, 2113–2118 (1986).

    Article  CAS  PubMed  Google Scholar 

  79. Dileepan, K. N., Page, J. C., Li, Y. & Stechschulte, D. J. Direct activation of murine peritoneal macrophages for nitric oxide production and tumor cell killing by interferon-γ. J. Interferon Cytokine Res. 15, 387–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Meyer, K. C., Powers, C., Cornwell, R. & Borden, E. C. Priming of human alveolar macrophages and blood monocytes for superoxide anion release by interferons and lipopolysaccharide. J. Interferon Res. 11, 283–290 (1991).

    Article  CAS  PubMed  Google Scholar 

  81. Hayes, M. P., Enterline, J. C., Gerrard, T. L. & Zoon, K. C. Regulation of interferon production by human monocytes: requirements for priming for lipopolysaccharide-induced production. J. Leukoc. Biol. 50, 176–181 (1991).

    Article  CAS  PubMed  Google Scholar 

  82. Calandra, T. & Roger, T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nature Rev. Immunol. 3, 791–800 (2003).

    Article  CAS  Google Scholar 

  83. Calandra, T. et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377, 68–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Roger, T., Chanson, A. L., Knaup-Reymond, M. & Calandra, T. Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1. Eur. J. Immunol. 35, 3405–3413 (2005). References 84 and 85 showed that MIF acts in an autocrine fashion to suppress glucocorticoid-induced MKP1 expression, thereby overriding the inhibition of cytokine production by glucocorticoids.

    Article  CAS  PubMed  Google Scholar 

  85. Aeberli, D. et al. Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase. FEBS Lett. 580, 974–981 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Lau, L. F. & Nathans, D. Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J. 4, 3145–3151 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dong, C. et al. JNK is required for effector T-cell function but not for T-cell activation. Nature 405, 91–94 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Wang, Z., Xu, J., Zhou, J. Y., Liu, Y. & Wu, G. S. Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance. Cancer Res. 66, 8870–8877 (2006). This paper provided evidence that MKP1 is involved in cellular resistance to chemotherapeutic drugs.

    Article  CAS  PubMed  Google Scholar 

  89. Vicent, S. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, H. Y., Cheng, Z. & Malbon, C. C. Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett. 191, 229–237 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Denkert, C. et al. Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int. J. Cancer 102, 507–513 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Liao, Q. et al. Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology 124, 1830–1845 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Charles, C. H., Abler, A. S. & Lau, L. F. cDNA sequence of a growth factor-inducible immediate early gene and characterization of its encoded protein. Oncogene 7, 187–190 (1992).

    CAS  PubMed  Google Scholar 

  94. Keyse, S. M. & Emslie, E. A. Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359, 644–647 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Kwak, S. P., Hakes, D. J., Martell, K. J. & Dixon, J. E. Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. J. Biol. Chem. 269, 3596–3604 (1994).

    CAS  PubMed  Google Scholar 

  96. Noguchi, T. et al. Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth. Mol. Cell. Biol. 13, 5195–5205 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Franklin, C. C. & Kraft, A. S. Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. J. Biol. Chem. 272, 16917–16923 (1997). This was the first paper to show that MKP1 prefers p38 and JNK as substrates.

    Article  CAS  PubMed  Google Scholar 

  98. Guan, K. L. & Butch, E. Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J. Biol. Chem. 270, 7197–7203 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. King, A. G., Ozanne, B. W., Smythe, C. & Ashworth, A. Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. Oncogene 11, 2553–2563 (1995).

    CAS  PubMed  Google Scholar 

  100. Muda, M. et al. 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 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Groom, L. A., Sneddon, A. A., Alessi, D. R., Dowd, S. & Keyse, S. M. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 15, 3621–3632 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mourey, R. J. et al. A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J. Biol. Chem. 271, 3795–3802 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Muda, M. et al. Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J. Biol. Chem. 272, 5141–5151 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Dickinson, R. J. et al. Characterization of a murine gene encoding a developmentally regulated cytoplasmic dual-specificity mitogen-activated protein kinase phosphatase. Biochem. J. 364, 145–155 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dowd, S., Sneddon, A. A. & Keyse, S. M. Isolation of the human genes encoding the Pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. J. Cell Sci. 111, 3389–3399 (1998).

    CAS  PubMed  Google Scholar 

  106. Shin, D. Y. et al. A novel human ERK phosphatase regulates H-ras and v-raf signal transduction. Oncogene 14, 2633–2639 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Ishibashi, T., Bottaro, D. P., Michieli, P., Kelley, C. A. & Aaronson, S. A. A novel dual specificity phosphatase induced by serum stimulation and heat shock. J. Biol. Chem. 269, 29897–29902 (1994).

    CAS  PubMed  Google Scholar 

  108. Martell, K. J., Seasholtz, A. F., Kwak, S. P., Clemens, K. K. & Dixon, J. E. HVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. J. Neurochem. 65, 1823–1833 (1995).

    Article  CAS  PubMed  Google Scholar 

  109. Theodosiou, A. M. et al. A member of the MAP kinase phosphatase gene family in mouse containing a complex trinucleotide repeat in the coding region. Hum. Mol. Genet. 5, 675–684 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Muda, M. et al. The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J. Biol. Chem. 271, 27205–27208 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Spriggs, D. R., Deutsch, S. & Kufe, D. W. Genomic structure, induction, and production of TNF-α. Immunol. Ser. 56, 3–34 (1992).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Owing to space limitations, many important studies could not be included in this Review, and we apologize for any such oversight. The work in our laboratory was supported in part by grants from the US National Institutes of Health. We are grateful to M. Gorospe and K. Liu for editing the original manuscript. We also want to thank the members of our laboratory and colleagues in the field for their helpful suggestions.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Center for Perinatal Research, Columbus Children's Research Institute, Columbus Children's Hospital, The Ohio State University College of Medicine, Columbus, 43205, Ohio, USA

    Yusen Liu, Edward G. Shepherd & Leif D. Nelin

Authors
  1. Yusen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward G. Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leif D. Nelin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusen Liu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Yusen Liu's homepage

Glossary

Microarray analysis

A technique for measuring the transcription of genes. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

Endotoxic-shock syndrome

A serious systemic disorder characterized by severely low blood pressure and low blood flow that often leads to multiple organ failure and death. It is caused by lipopolysaccharide (also known as endotoxin) present in the blood stream owing to systemic Gram-negative bacterial infection.

Endotoxin tolerance

Defined as a transient state of hyporesponsiveness of the host or of cultured macrophages and/or monocytes to lipopolysaccharide challenge following a first exposure to this stimulus.

Activator protein 1 family

(AP1). A group of transcription factors forming homodimers or heterodimers through leucine zipper interfaces. Although the prototype AP1 is formed by FOS and JUN, members of the ATF and JDP transcription factor families can also form heterodimers predominantly with JUN proteins and bind to AP1 sites in many gene promoters.

K/BxN transgenic mouse

A mouse strain formed by crossing non-obese diabetic (NOD)/Lt mice with KRN T-cell-receptor-transgenic mice on the C57BL/6 background. As the KRN receptor on the T cells recognizes a peptide from the autoantigen glucose-6-phosphate isomerase, these mice develop an arthritis that is mediated, and transferable, by circulating antibody against glucose-6-phosphate isomerase.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Glucocorticoids

A group of compounds that belongs to the corticosteroid family. These compounds can either be naturally produced (hormones) or synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Many synthetic glucocorticoids (for example, dexamethasone) are used in clinical medicine as anti-inflammatory drugs.

Endocannabinoids

A group of endogenous agonists for cannabinoid receptors that are present in animals. They are metabolites of eicosanoid fatty acids.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Y., Shepherd, E. & Nelin, L. MAPK phosphatases — regulating the immune response. Nat Rev Immunol 7, 202–212 (2007). https://doi.org/10.1038/nri2035

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2035

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing