DUSP8 phosphatase: structure, functions, expression regulation and the role in human diseases

Abstract

Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases (PTPs), many of which dephosphorylate the residues of phosphor-serine/threonine and phosphor-tyrosine on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). Homologue of Vaccinia virus H1 phosphatase gene clone 5 (HVH-5), also known as DUSP8, is a unique member of the DUSPs family of phosphatases. Accumulating evidence has shown that DUSP8 plays an important role in phosphorylation-mediated signal transduction of MAPK signaling ranging from cell oxidative stress response, cell apoptosis and various human diseases. It is generally believed that DUSP8 exhibits significant dephosphorylation activity against JNK, however, with the deepening of research, plenty of new literature reports that DUSP8 also has effective dephosphorylation activity on p38 MAPK and ERKs, successfully affects the transduction of MAPKs pathway, indicating that DUSP8 presents a unknown diversity of DUSPs family on distinct corresponding dephosphorylated substrates in different biological events. Therefore, the in-depth study of DUSP8 not only throws a new light on the multi-biological function of DUSPs, but also is much valuable for the reveal of complex pathobiology of clinical diseases. In this review, we provide a detail overview of DUSP8 phosphatase structure, biological function and expression regulation, as well as its role in related clinical human diseases, which might be help for the understanding of biological function of DUSP8 and the development of prevention, diagnosis and therapeutics in related human diseases.

Comparative Transcriptome Analysis Suggests Key Roles for 5-Hydroxytryptamlne Receptors in Control of Goose Egg Production

“…In these pathways, BAMBI, WNT9A, SFRP1, PRKCB, SGK1, DUSP8, and DUSP6 were upregulated in the SWG group. BAMBI [58,59] and DUSP8 [60] can promote granulosa cell differentiation. These findings suggest that the differentiation ability of granulosa cells in the SWG ovarian stroma is better than that of the LG ovarian stroma at 730 days.…”

25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes

“…The top 20 pathways (from the most significant, P < 10 −9 ) were shown in Fig. 2 C. Among these pathways, MAPK-ERK and calcium-cAMP signaling are believed as the master pathways regulating cell survival, antioxidants, antiapoptosis ( 36 , 37 ), energy metabolism, and lipid homeostasis ( 38 , 39 ). Previous report has showed that HG incubation, an in vitro model for study of NAFLD, induces lipid accumulation via increasing DNA promoter methylation signaling ( 28 ).…”

“…To explore the relationship of promoter 5m CpG demethylation and gene expression from the results of KEGG pathway analysis, the expression of key genes ( DUSP7 , DUSP8 , and MAPK1 ) and their target genes cAMP response element-binding protein 5 ( CREB5 ), peroxiredoxin 6, and BCL2-associated agonist of cell death in the MAPK pathway, as well as the key genes CACNA1D (calcium voltage-gated channel subunit alpha1 D,), CACNA1A (calcium voltage-gated channel subunit alpha1 A), and CACNA1H (calcium voltage-gated channel subunit alpha1 H) (encoding for calcium voltage-gated channel subunits) and their targeting genes [ PGC1A , 3-hydroxy-3-methylglutaryl-coenzyme A reductase ( HMGR ), and FAS ] in the calcium-AMP-activated protein kinase ( AMPK ) pathway were determined by RT-PCR analysis. The DUSP-MAPK signaling pathway is the major pathway involved in cell survival/death and antioxidization ( 37 , 40 ), and the calcium signaling pathway controls lipid and energy metabolism ( 38 , 39 ). As expected, 25HC3S increased expression of DUSP8 by 5-fold and its targeting gene, CREB5 , by up to 20-fold, which is the key element involved in cell survival and death ( Fig.…”

“…The DUSP family is a subset of protein tyrosine phosphatases, many of which dephosphorylate MAPKs and hence are referred to as MAPK phosphatases ( 45 ). DUSP8 , a unique member of DUSP family, plays an important role in signal transduction of the phosphorylation-mediated MAPK pathway, which regulates responses to oxidative stress and cell death signals in various human diseases ( 37 ). The results from this study showed that 25HC3S greatly demethylated 5m CpG in promoter regions of DUSP genes, including DUSP8 , DUSP1 , and DUSP7 , and their downstream genes, CREB5 , peroxiredoxin 6, BCL2-associated agonist of cell death, and ERK, and increased their expression.…”

Naringenin and Vanillin Mitigate Cadmium-Induced Pancreatic Injury in Rats via Inhibition of JNK and p38 MAPK Pathways

“…Upon activation via phosphorylation, MAPKs phosphorylate other protein kinases and transcription factors, including many inflammatory and apoptotic biomarkers. 28 Oxidative stress with increased ROS generation is a well-known inducer of MAPKs. It was reported that cadmium-mediated oxidative stress induced phosphorylation and activation of JNK and p38 MAPKs and subsequently enhanced the downstream inflammatory and apoptotic cascades.…”