Key Points
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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.
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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.
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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).
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MKPs can also regulate the adaptive immune responses through regulation of cytokine biosynthesis and cell proliferation.
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Different members of the MKP family have distinct roles in the immune responses. They can either positively or negatively regulate immune responses.
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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.
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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.
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Glossary
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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.
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(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.
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(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.
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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
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A group of endogenous agonists for cannabinoid receptors that are present in animals. They are metabolites of eicosanoid fatty acids.
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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
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DOI: https://doi.org/10.1038/nri2035
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