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.
Highlights
Mammalian dual-specificity MAP kinase (MAPK) phosphatases (MKPs) comprise a subfamily of 10 catalytically active enzymes with a conserved domain structure
As is the case for other classes of protein phosphatases, it is abundantly clear that MAP kinase phosphatases (MKPs) are not merely passive “erasers” of protein phosphorylation, but instead form a complex network of activities in cells and tissues that act to regulate the spatiotemporal activity of the different MAP kinase pathways and play essential roles in regulating key physiological outcomes
One of which is the importance of compartmentalised regulation of MAPK signalling by activities in the nucleus and cytoplasm as exemplified by the regulation of nuclear Jun amino terminal kinases (JNKs) activity by DUSP1/MKP-1 in metabolic control [50] and nuclear extracellular-signal regulated kinase (ERK) activity by DUSP5 in cancer [128]
Summary
Mammalian dual-specificity MAP kinase (MAPK) phosphatases (MKPs) comprise a subfamily of 10 catalytically active enzymes with a conserved domain structure This consists of an amino-terminal non-catalytic domain and a carboxyl-terminal catalytic domain. The 10 enzymes can be divided into three subgroups based on amino acid sequence homology, subcellular localisation and substrate specificity These are the inducible nuclear MKPs, comprising DUSP1/MKP-1, DUSP2, DUSP4/MKP-2 and DUSP5, the cytoplasmic, extracellular-signal regulated kinase (ERK) -specific MKPs DUSP6/MKP-3, DUSP7/MKP-X and DUSP9/MKP-4 and a group of three MKPs DUSP8, DUSP10/MKP-5 and DUSP16/MKP-7 that are found in both the cytoplasm and cell nucleus and are relatively selective in their ability to dephosphorylate the p38 and c-Jun amino terminal kinases (JNKs), having little or no activity towards the classical extracellular signalregulated kinase (ERK) MAPKs (Fig. 1). In this review we will detail the current level of understanding for each of the MKPs in turn, highlighting recent advances and future perspectives in the field
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