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  • Review Article
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Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses

Nature Reviews Drug Discovery volume 6, pages 391–403 (2007)Cite this article

Key Points

  • Dual-specificity phosphatases (DUSPs) are a subclass of protein tyrosine phosphatases (PTPs) that specifically interact with and regulate mitogen-activated protein kinases (MAPKs) by dephosphorylating phosphothreonine and tyrosine residues, thereby inactivating them. DUSPs can also regulate the subcellular localization of MAPKs, another important control point of their activity.

  • The three main MAPKs, extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), have been intimately associated with immune responses, whereby the magnitude and duration of their activity determines the type of immune cell response, according to the type of stimuli they receive.

  • Approximately 16 DUSPs in the human genome have demonstrated activity towards MAPKs in vitro.

  • Individual DUSPs have different patterns of tissue expression, transcriptional regulation and subcellular localization, and have differing preferences for the MAPK subclasses that tightly modulate their activity.

  • Multiple inhibitors of the MAPK subclasses are in clinical trials for the treatment of inflammatory disorders. Important crosstalk and feedback loops within these pathways, as well as broad tissue expression profiles of MAPKs, may limit their success in the clinic.

  • Recent mouse knockout experiments have indicated for the first time individual, non-redundant functions for DUSPs in the regulation of cellular responses, particularly in inflammatory responses.

  • DUSPs have demonstrated both positive and negative control of immune responses such as sepsis, inflammatory arthritis and experimental autoimmune encephalomyelitis, which indicates that targeting DUSPs may be a viable approach for anti-inflammatory therapy.

Abstract

Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.

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Figure 1: The MAPK pathway and the role of DUSPs.
Figure 2: Regulation of DUSPs by MAPKs.
Figure 3: Phosphatases that regulate MAPKs.

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Acknowledgements

The authors would like to thank T. Brummer and R. Hooft van Huijsduijnen for critical evaluation of the manuscript, and S. Tange and K. Good for B-cell microarray data.

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Authors and Affiliations

  1. Immunology and Inflammation Research Program, The Garvan Institute, Darlinghurst, NSW 2010, Sydney, Australia

    Kate L. Jeffrey & Charles R. Mackay

  2. Merck Serono Research Centre, Merck Serono S.A., 9 Chemin des Mines, Geneva, 1202, Switzerland

    Montserrat Camps & Christian Rommel

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Supplementary information S1 (table)

Development status of MAPK inhibitors for inflammation and cancer (PDF 198 kb)

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FURTHER INFORMATION

Garvan Institute

Gene Expression Omnibus database

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Protein Tyrosine Phosphatases web site

Glossary

Rheumatoid arthritis

A chronic, inflammatory autoimmune disorder in which leukocyte invasion of the synovial lining and hyperplasia of resident synoviocytes occurs. The ensuing overproduction of cytokines and other soluble mediators results in neovascularization, cartilage destruction, bone erosion and anarchic remodelling of joint structures.

T-cell anergy

A state of T-cell unresponsiveness to stimulation with antigen. T-cell anergy can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

Thymocyte negative selection

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

Second-order reaction

A second-order reaction depends on the concentration of one second-order reactant or two first-order reactants. A kinase acting on a MAPK is a second-order reaction as it requires the MAPK and ATP (that is, two first-order reactants).

Experimental autoimmune encephalomyelitis

An animal model of brain inflammation. It is mostly used with rodents and is a model for the human disease multiple sclerosis. It is induced with myelin oligodendrocyte glycoprotein.

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Jeffrey, K., Camps, M., Rommel, C. et al. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov 6, 391–403 (2007). https://doi.org/10.1038/nrd2289

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