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Review
. 2019 Jan;1866(1):124-143.
doi: 10.1016/j.bbamcr.2018.09.002. Epub 2018 Sep 8.

Dual-specificity MAP kinase phosphatases in health and disease

Ole-Morten Seternes  1 , Andrew M Kidger  2 , Stephen M Keyse  3
Affiliations
Review

Dual-specificity MAP kinase phosphatases in health and disease

Ole-Morten Seternes et al. Biochim Biophys Acta Mol Cell Res. 2019 Jan.

Abstract

It is well established that a family of dual-specificity MAP kinase phosphatases (MKPs) play key roles in the regulated dephosphorylation and inactivation of MAP kinase isoforms in mammalian cells and tissues. MKPs provide a mechanism of spatiotemporal feedback control of these key signalling pathways, but can also mediate crosstalk between distinct MAP kinase cascades and facilitate interactions between MAP kinase pathways and other key signalling modules. As our knowledge of the regulation, substrate specificity and catalytic mechanisms of MKPs has matured, more recent work using genetic models has revealed key physiological functions for MKPs and also uncovered potentially important roles in regulating the pathophysiological outcome of signalling with relevance to human diseases. These include cancer, diabetes, inflammatory and neurodegenerative disorders. It is hoped that this understanding will reveal novel therapeutic targets and biomarkers for disease, thus contributing to more effective diagnosis and treatment for these debilitating and often fatal conditions.

Keywords: Diabetes; MAP kinase; MAP kinase phosphatase; Neuropathology; Obesity; Oncogenic signalling.

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Figures

Fig. 1
Fig. 1
Schematic showing the domain structures of the three groups of dual-specificity MAP kinase phosphatases. A. The nuclear inducible MKPs. B. The cytoplasmic ERK-specific MKPs and C. the JNK/p38-specific MKPs. In addition to the amino-terminal non-catalytic domain and the PTPase active site, other key features and sequence motifs are indicated.
Fig. 2
Fig. 2
DUSP1/MKP-1 in innate immunity. Schematic showing the regulation of MAP kinase activities in cells of the innate immune system by DUSP1/MKP-1 and the consequences of genetic deletion of this MKP on the physiological responses of these cell populations. For details see text.
Fig. 3
Fig. 3
DUSP1/MKP-1 in metabolic homeostasis. Schematic showing the effects of either unconditional, or tissue-specific, deletion of DUSP1/MKP-1 on metabolic homeostasis. For details see text.
Fig. 4
Fig. 4
The effects of DUSP5 deletion on oncogenic signalling through the Ras-ERK pathway may depend on the nature of the driving oncogene. Deletion of DUSP5 in cells harbouring mutant HrasQ61L causes elevated nuclear ERK activity. This is associated with changes in gene expression and an increased susceptibility to Hras-driven skin carcinogenesis identifying DUSP5 as a tumour suppressor. In contrast, in MEFs expressing mutant BrafV600E deletion of DUSP5 causes a much stronger ERK activation that is associated with senescence, growth arrest and suppression of cell transformation indicating that in cancers driven by activated Braf DUSP5 may be essential for cancer cell survival.
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