Abstract
Mitogen-activated protein kinases (MAPKs) are essential for proper cell functioning as they regulate many molecular effectors. Careful regulation of MAPKs is therefore required to avoid MAPK pathway dysfunctions and pathologies. The mammalian genome encodes about 200 phosphatases, many of which dephosphorylate the MAPKs and bring them back to an inactive state. In this review, we focus on the normal and pathological functions of dual-specificity phosphatase 9 (DUSP9)/MAP kinase phosphatases-4 (MKP-4). This cytoplasmic phosphatase, which belongs to the threonine/tyrosine dual-specific phosphatase family and was first described in 1997, is known to dephosphorylate ERK1/2, p38, JNK and ASK1, and thereby to control various MAPK pathway cascades. As a consequence, DUSP9 plays a major role in human pathologies and more specifically in cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer including drug response and cell stemness. Here, we recapitulate the mechanism of action of DUSP9 in the cell, its levels of regulation and its roles in the most frequent human diseases, and discuss its potential as a therapeutic target.
Highlights
INSERM, MIRCADE Team, UMR1035 Biothérapie des Maladies Génétiques, Désordres Inflammatoires et Cancer, BMGIC, Université de Bordeaux, 146 Rue Léo Saignat, F-33000 Bordeaux, France; Citation: Khoubai, F.Z.; Grosset, C.F
This catalytic activity of with of increasing concentrations of dual-specificity phosphatase 9 (DUSP9) in the dose-dependent blockade is effectively inhibited by sodium vanadate, which is an inhibitor of protein tyrosine phosof ERK2 target phosphorylation such as stathmin [18]
DUSP9 by bone morphogenetic protein 4 (Bmp4) is accompanied by inhibition of ERK pathway activity and downregulation of its targets Egr1 and Fos (Figure 2). This DUSP9-mediated dephosphorylation was not observed for p38 and JNK, showing its specificity for ERK1/2 signaling which is crucial for the renewal and differentiation of mouse embryonic stem cells (mESCs) [31]
Summary
The mitogen-activated protein kinase (MAPK) signaling pathways are crucial in cell function and homeostasis. MAPK signaling and ERK kinases play a key role in cancer by regulating proliferation, migration, angiogenesis and metastasis [8]. Typical DUSPs are the best characterized within the DUSP family [20] and this comprises the typical DUSP named DUSP9 or MKP4, which was first described in 1997 by Muda and collaborators [18] This 42-kDa protein dephosphorylates several substrates including JNK, p38, the MAPKKK apoptosis signal-regulating kinase 1 (ASK1) and ERK1/2 with a high specificity for ERK kinases [3,18].
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