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Review
. 2017 Aug 10;18(1):154.
doi: 10.1186/s12931-017-0637-3.

Role and regulation of MKP-1 in airway inflammation

Seyed M Moosavi  1   2 , Pavan Prabhala  3   4   5 , Alaina J Ammit  6   7
Affiliations
Review

Role and regulation of MKP-1 in airway inflammation

Seyed M Moosavi et al. Respir Res. .

Abstract

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a protein with anti-inflammatory properties and the archetypal member of the dual-specificity phosphatases (DUSPs) family that have emerged over the past decade as playing an instrumental role in the regulation of airway inflammation. Not only does MKP-1 serve a critical role as a negative feedback effector, controlling the extent and duration of pro-inflammatory MAPK signalling in airway cells, upregulation of this endogenous phosphatase has also emerged as being one of the key cellular mechanism responsible for the beneficial actions of clinically-used respiratory medicines, including β2-agonists, phosphodiesterase inhibitors and corticosteroids. Herein, we review the role and regulation of MKP-1 in the context of airway inflammation. We initially outline the structure and biochemistry of MKP-1 and summarise the multi-layered molecular mechanisms responsible for MKP-1 production more generally. We then focus in on some of the key in vitro studies in cell types relevant to airway disease that explain how MKP-1 can be regulated in airway inflammation at the transcriptional, post-translation and post-translational level. And finally, we address some of the potential challenges with MKP-1 upregulation that need to be explored further to fully exploit the potential of MKP-1 to repress airway inflammation in chronic respiratory disease.

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Figures

Fig. 1
Fig. 1
The structure of MKP-1. KIM is located in the NH2 terminus, between two cdc25 homology domains. The catalytic domain is located at the carboxyl terminus. The oxidation of the catalytic Cys258 of MKP-1 protein inactivates its phosphatase activity. In the C-terminus is the DEF docking site for MAPKs, the phosphorylation of Ser359 and Ser364 enhances protein stability, whereas Ser296/Ser323 phosphorylation is involved in the proteasomal degradation of MKP-1
Fig. 2
Fig. 2
Multi-level regulation of MKP-1 expression. MKP-1 expression is regulated at three levels: transcriptional; post-transcriptional; and the post-translational. Upon extracellular stimulation transcription factors bind to consensus sequences within the MKP-1 5′-promoter region to induce transcription of the MKP-1 gene. Once the gene has been transcribed into mRNA, RNA binding proteins and various micro RNAs (miR) are able to bind to the 3′-untranslated region to modulate the stability of MKP-1 mRNA transcripts. MKP-1 can also be modified at the post-translational level, serines can be phosphorylated, lysines can be acetylated and cysteines can be oxidised, causing MKP-1 protein activity, stability and degradation status to change. See text for abbreviations
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