Dual-specificity Phosphatase Family Research Articles

SSH3 promotes pancreatic cancer proliferation and migration by activating the notch signaling pathway.

Recent studies have indicated that the dual-specificity phosphatases (DUSP) family may play a role in the advancement of pancreatic cancer. Exploring the role of the DUSP family in pancreatic cancer development and discovering novel therapeutic targets are crucial for pancreatic cancer therapy. A critical subset of 20 genes exhibiting differential expression was identified, with particular emphasis on four key genes: DUSP10, PTP4A2, SSH3, and CDKN3 by multivariate Cox proportional hazards analysis. These genes were integral to developing a novel risk model for PC, which has been independently validated as a prognostic factor for patients. To provide help for clinical treatment, we performed tumor immune analysis and predicted potential chemical drugs. Notably, our research unveiled elevated expression levels of SSH3 in human PC cells and tissues. Intriguingly, SSH3 expression correlates with the patient grade, staging, and T stage in PC. Additional studies reveal SSH3's role in enhancing PC cell proliferation and migration, intricately linked to the activation of the Notch signaling pathway. These insights provide a deeper understanding of PC pathophysiology and pave the way for novel therapeutic interventions.

Dual-specificity phosphatase 1 inhibits Singapore grouper iridovirus replication via regulating apoptosis in Epinephelus coioides

The dual-specificity phosphatase (DUSP) family plays key roles in the maintenance of cellular homeostasis and apoptosis etc. In this study, the DUSP member DUSP1 of Epinephelus coioides was characterized: the length was 2371 bp including 281 bp 5′ UTR, 911 bp 3′ UTR, and a 1125 bp open reading frame encoding 374 amino acids. E. coioides DUSP1 has two conserved domains, a ROHD and DSPc along with a p38 MAPK phosphorylation site, localized at Ser308. E. coioides DUSP1 mRNA can be detected in all of the tissues examined, and the subcellular localization showed that DUSP1 was mainly distributed in the nucleus. Singapore grouper iridovirus (SGIV) infection could induce the differential expression of E. coioides DUSP1. Overexpression of DUSP1 could inhibit SGIV-induced cytopathic effect (CPE), the expressions of SGIV key genes, and the viral titers. Overexpression of DUSP1 could also regulate SGIV-induced apoptosis, and the expression of apoptosis-related factor caspase 3. The results would be helpful to further study the role of DUSP1 in viral infection.

Dual-Specificity Phosphatases in Regulation of Tumor-Associated Macrophage Activity.

The regulation of protein kinases by dephosphorylation is a key mechanism that defines the activity of immune cells. A balanced process of the phosphorylation/dephosphorylation of key protein kinases by dual-specificity phosphatases is required for the realization of the antitumor immune response. The family of dual-specificity phosphatases is represented by several isoforms found in both resting and activated macrophages. The main substrate of dual-specificity phosphatases are three components of mitogen-activated kinase signaling cascades: the extracellular signal-regulated kinase ERK1/2, p38, and Janus kinase family. The results of the study of model tumor-associated macrophages supported the assumption of the crucial role of dual-specificity phosphatases in the formation and determination of the outcome of the immune response against tumor cells through the selective suppression of mitogen-activated kinase signaling cascades. Since mitogen-activated kinases mostly activate the production of pro-inflammatory mediators and the antitumor function of macrophages, the excess activity of dual-specificity phosphatases suppresses the ability of tumor-associated macrophages to activate the antitumor immune response. Nowadays, the fundamental research in tumor immunology is focused on the search for novel molecular targets to activate the antitumor immune response. However, to date, dual-specificity phosphatases received limited discussion as key targets of the immune system to activate the antitumor immune response. This review discusses the importance of dual-specificity phosphatases as key regulators of the tumor-associated macrophage function.

The Role of Epinephelus coioides DUSP5 in Regulating Singapore Grouper Iridovirus Infection.

The dual-specificity phosphatase (DUSP) family plays an important role in response to adverse external factors. In this study, the DUSP5 from Epinephelus coioides, an important marine fish in Southeast Asia and China, was isolated and characterized. As expected, E. coioides DUSP5 contained four conserved domains: a rhodanese homology domain (RHOD); a dual-specificity phosphatase catalytic domain (DSPc); and two regions of low compositional complexity, indicating that E. coioides DUSP5 belongs to the DUSP family. E. coioides DUSP5 mRNA could be detected in all of the examined tissues, and was mainly distributed in the nucleus. Infection with Singapore grouper iridovirus (SGIV), one of the most important pathogens of marine fish, could inhibit the expression of E. coioides DUSP5. The overexpression of DUSP5 could significantly downregulate the expression of the key SGIV genes (MCP, ICP18, VP19, and LITAF), viral titers, the activity of NF-κB and AP-I, and the expression of pro-inflammatory factors (IL-6, IL-8, and TNF-α) of E. coioides, but could upregulate the expressions of caspase3 and p53, as well as SGIV-induced apoptosis. The results demonstrate that E. coioides DUSP5 could inhibit SGIV infection by regulating E. coioides immune-related factors, indicating that DUSP5 might be involved in viral infection.

The diverging role of CDC14B: from mitotic exit in yeast to cell fate control in humans.

CDC14, originally identified as crucial mediator of mitotic exit in budding yeast, belongs to the family of dual-specificity phosphatases (DUSPs) that are present in most eukaryotes. Contradicting data have sparked a contentious discussion whether a cell cycle role is conserved in the human paralogs CDC14A and CDC14B but possibly masked due to redundancy. Subsequent studies on CDC14A and CDC14B double knockouts in human and mouse demonstrated that CDC14 activity is dispensable for mitotic progression in higher eukaryotes and instead suggested functional specialization. In this review, we provide a comprehensive overview of our current understanding of how faithful cell division is linked to phosphorylation and dephosphorylation and compare functional similarities and divergences between the mitotic phosphatases CDC14, PP2A, and PP1 from yeast and higher eukaryotes. Furthermore, we review the latest discoveries on CDC14B, which identify this nuclear phosphatase as a key regulator of gene expression and reveal its role in neuronal development. Finally, we discuss CDC14B functions in meiosis and possible implications in other developmental processes.

Pseudophosphatase STYXL1 depletion enhances glucocerebrosidase trafficking to lysosomes via ER stress.

Pseudophosphatases are catalytically inactive but share sequence and structural similarities with classical phosphatases. STYXL1 is a pseudophosphatase that belongs to the family of dual-specificity phosphatases and is known to regulate stress granule formation, neurite formation and apoptosis in different cell types. However, the role of STYXL1 in regulating cellular trafficking or the lysosome function has not been elucidated. Here, we show that the knockdown of STYXL1 enhances the trafficking of β-glucocerebrosidase (β-GC) and its lysosomal activity in HeLa cells. Importantly, the STYXL1-depleted cells display enhanced distribution of endoplasmic reticulum (ER), late endosome and lysosome compartments. Further, knockdown of STYXL1 causes the nuclear translocation of unfolded protein response (UPR) and lysosomal biogenesis transcription factors. However, the upregulated β-GC activity in the lysosomes is independent of TFEB/TFE3 nuclear localization in STYXL1 knockdown cells. The treatment of STYXL1 knockdown cells with 4-PBA (ER stress attenuator) significantly reduces the β-GC activity equivalent to control cells but not additive with thapsigargin, an ER stress activator. Additionally, STYXL1-depleted cells show the enhanced contact of lysosomes with ER, possibly via increased UPR. The depletion of STYXL1 in human primary fibroblasts derived from Gaucher patients showed moderately enhanced lysosomal enzyme activity. Overall, these studies illustrated the unique role of pseudophosphatase STYXL1 in modulating the lysosome function both in normal and lysosome-storage disorder cell types. Thus, designing small molecules against STYXL1 possibly can restore the lysosome activity by enhancing ER stress in Gaucher disease.

DUSP10 alleviates ischemic stroke-induced neuronal damage by restricting p38/JNK pathway

Neuronal apoptosis is considered one of the hallmarks of ischemic stroke. Dual specificity phosphatase 10 (DUSP10), a member of the dual-specificity phosphatase family, which is involved in the regulation of apoptosis process. This study aimed to investigate the effect of on apoptosis in primary cortical neurons exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and mice suffered from transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results showed that DUSP10 overexpression improved survival and reduced apoptosis in neurons subjected to OGD/R, which was manifested by decreased apoptotic proteins (cleaved caspase 3 and bax) and TUNEL+ cells, as well as increased the anti-apoptotic protein (bcl-2). DUSP10 overexpression inhibited the p38/JNK signaling pathway after OGD/R treatment, whilst DUSP10 knockdown had opposite effects. In addition, the p38 inhibitor SB203580 or JNK inhibitor SP600125 attenuated the increased apoptosis of OGD/R-stimulated neurons treated with DUSP10 silencing. Consistently, DUSP10 knockdown exacerbated infarct volume in MCAO/R injury. The data of Nissl staining and TUNEL-NeuN double staining revealed that DUSP10 interference aggravated neuronal damage in the ischemic penumbra of mice. Furthermore, DUSP10 inhibition activated the p38/JNK axis accompanied by enhanced phosphorylation of p38 and JNK in vivo. In summary, DUSP10 is a neuroprotective agent against ischemic stroke-induced neuronal damage via suppressing the p38/JNK signaling pathway.

Abstract P4-08-22: Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer

Abstract Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer Wenxiao Ji1, Emily Ling Xin1,2, Lin Ye1, Eleri Davies3, Wen G. Jiang1, Tracey A. Martin1 1CCMRC, Cardiff University School of Medicine, Cardiff, Wales, UK 2Breast Centre, Peking University First Hospital, Xicheng District, Beijing, China 3Wales Breast Centre, University Llandough Hospital, Cardiff CF64 2XX, UK Introduction. DUSP7 is a member of the large Dual specific phosphatase family, able to regulate the phosphorylation of both tyrosine and serine/threonine protein kinases. The role of DUSP7 in cancer is not clear, however, it has been identified as a possible target for therapy in cancers including breast cancer. It has also been reported as having value in prognosis of certain cancers, such as haematological malignancies, breast cancer and certain types of gynaecological cancer. The signalling network for DUSP7 is not fully established but is known to connect to ERKs and MAP2Ks. DUSP7 also appears to be linked with salt inducible kinases (SIKs), a small family of kinases linked with progression and response to therapies in breast cancer. Thus, DUSP7 and salt inducible kinases may interact with each other and with the downstream kinases including MAP2Ks and STK11 to influence the clinical course of breast cancer. The present study explored if the pattern of DUSP7 together with salt inducible kinases and the downstream MKKs in breast cancer. Methods. The expression of DUSP7 was quantified in a cohort of breast cancer tissues (both normal mammary tissues and breast cancer tissues). The expression of the potential downstream kinases including MKK1, MKK2, MKK3, MKK4 and STK11 was also quantified. The expression profile of these molecule, together with the salt inducible kinases reported to be aberrant in our previous studies, were analysed against clinical and outcome information. Results. Breast cancer tissues expressed high levels of DUSP7 compared with normal mammary tissues, although not statistically significant. When we explored the relationship between DUSP7 and other potential related molecules in the database of the cohort, we found a highly significant correlation between DUSP7 and SIK1 (r=0.385, p< 0.001), SIK2 (r=0.590, p< 0.001), but not SIK3 (r=0.158, p>0.05). Together with SIK1 and SIK2 (known to link to drug sensitivity), DUSP7, MKK1 (MAP2K1) and MKK3 (MAP2K3) appear to form a gene signature that is of significant value in predicting the overall survival of the patients (ROC 0.723, p=0.001). This allowed us to significantly distinguish between those with good OS and poor OS (p< 0.001, Hazard Ration (HR) =1.443 (95%CI 1.154-1.804)). Multivariate analysis has shown that this signature is independent in predicting overall survival (p=0.013, HR=1.432). The signature is more significant in predicting OS in ER(-) tumours (p< 0.001) than ER(+) tumours (p=0.61). The same is seen when predicting OS with triple negative breast cancers (TNBC) (p< 0.001) than non-TNBC tumours (p=0.044). The gene signature also predicted disease free outcome (p=0.007, HR=1.266 (95% CI 1.065-1.504)). Conclusion. The dual specific phosphatase DUSP7 together with potentially correlated salt inducible kinases (SIK-1 and SIK-2) and downstream MKKs (MKK-1 and MKK3) have important clinical value in breast cancer. This provides support that DUSP7 may be a valuable therapeutic target in breast cancer. Citation Format: WENXIAO JI, Ling Xin, Eleri Davies, Wen G. Jiang, Lin Ye. Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-22.

Concanavalin A-Based Sedimentation Assay to Measure Substrate Binding of Glucan Phosphatases

Glucan phosphatases belong to the larger family of dual specificity phosphatases (DSP) that dephosphorylate glucan substrates, such as glycogen in animals and starch in plants. The crystal structures of glucan phosphatase with model glucan substrates reveal distinct glucan-binding interfaces made of DSP and carbohydrate-binding domains. However, quantitative measurements of glucan-glucan phosphatase interactions with physiologically relevant substrates are fundamental to the biological understanding of the glucan phosphatase family of enzymes and the regulation of energy metabolism. This manuscript reports a Concanavalin A (ConA)-based in vitro sedimentation assay designed to detect the substrate binding affinity of glucan phosphatases against different glucan substrates.As a proof of concept, the dissociation constant (KD) of glucan phosphatase Arabidopsis thaliana Starch Excess4 (SEX4) and amylopectin was determined. The characterization of SEX4 mutants and other members of the glucan phosphatase family of enzymes further demonstrates the utility of this assay to assess the differential binding of protein- carbohydrate interactions. These data demonstrate the suitability of this assay to characterize a wide range of starch and glycogen interacting proteins.

Role of dual specificity phosphatases (DUSPs) in melanoma cellular plasticity and drug resistance

Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often associated with drug resistance. The mechanisms that control melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that emergence of MAPK inhibitor (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated melanoma cells. Here, we show that knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decrease the survival of MAPKi-resistant cells and sensitizes them to BRAFi and MEKi. Pharmacological inhibition of DUSP1/6 upregulated nestin, a neural crest stem cell marker, in both MAPKi-sensitive cells and cells with acquired MAPKi-resistance. In contrast, treatment with BCI resulted in upregulation of MAP2, a neuronal differentiation marker, only in MAPKi-sensitive cells but caused downregulation of both MAP2 and GFAP, a glial marker, in all MAPKi-resistant cell lines. These data suggest that DUSP proteins are involved in the regulation of cellular plasticity cells and melanoma drug resistance and are potential targets for treatment of MAPKi-resistant melanoma.

P-293 Increased expression of dual-specificity phosphatase 7 in gastric cancer is associated with poor prognosis and chemoresistance

Dual specificity phosphatases (DUSPs) are pivotal regulators of protein activation through dephosphorylating key molecules such as mitogen activated protein kinases, thereby co-ordinating signal transduction and biological processes. DUSP7 specifically dephosphorylates extracellular signal regulated kinases (ERK) 1 and 2 (pertinent for cellular growth) whilst being associated to the induction of inflammatory and apoptotic pathways involving p38-α and JNKs. Unlike other members of the DUSP family, DUSP7’s physiological function remains largely elusive with further exploration required of its involvement in healthy and cancerous tissue.

Evolutionary genomic relationships and coupling in MK-STYX and STYX pseudophosphatases

The dual specificity phosphatase (DUSP) family has catalytically inactive members, called pseudophosphatases. They have mutations in their catalytic motifs that render them enzymatically inactive. This study analyzes the significance of two pseudophosphatases, MK-STYX [MAPK (mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding protein]) and STYX (serine/threonine/tyrosine-interacting protein), throughout their evolution and provides measurements and comparison of their evolutionary conservation. Phylogenetic trees were constructed to show any deviation from various species evolutionary paths. Data was collected on a large set of proteins that have either one of the two domains of MK-STYX, the DUSP domain or the cdc-25 homology (CH2) /rhodanese-like domain. The distance between species pairs for MK-STYX or STYX and Ka/Ks ratio were calculated. In addition, both pseudophosphatases were ranked among a large set of related proteins, including the active homologs of MK-STYX, MKP (MAPK phosphatase)-1 and MKP-3. MK-STYX had one of the highest species-species protein distances and was under weaker purifying selection pressure than most proteins with its domains. In contrast, the protein distances of STYX were lower than 82% of the DUSP-containing proteins and was under one of the strongest purifying selection pressures. However, there was similar selection pressure on the N-terminal sequences of MK-STYX, STYX, MKP-1, and MKP-3. We next perform statistical coupling analysis, a process that reveals interconnected regions within the proteins. We find that while MKP-1,-3, and STYX all have 2 functional units (sectors), MK-STYX only has one, and that MK-STYX is similar to MKP-3 in the evolutionary coupling of the active site and KIM domain. Within those two domains, the mean coupling is also most similar for MK-STYX and MKP-3. This study reveals striking distinctions between the evolutionary patterns of MK-STYX and STYX, suggesting a very specific role for each pseudophosphatase, further highlighting the relevance of these atypical members of DUSP as signaling regulators. Therefore, our study provides computational evidence and evolutionary reasons to further explore the properties of pseudophosphatases, in particular MK-STYX and STYX.

Dual-specificity phosphatases: therapeutic targets in cancer therapy resistance.

Therapy resistance is the principal obstacle to achieving cures in cancer patients and its successful tackling requires a deep understanding of the resistance mediators. Increasing evidence indicates that tumor phosphatases are novel and druggable targets in translational oncology and their modulation may hinder tumor growth and motility and potentiate therapeutic sensitivity in various neoplasms via regulation of various signal transduction pathways. Dual-specificity phosphatases (DUSPs) are key players of cell growth, survival and death and have essential roles in tumor initiation, malignant progression and therapy resistance through regulation of the MAPK signaling pathway. In this review, different aspects of DUSPs are discussed. A comprehensive literature review was performed using various websites including PubMed. We provide mechanistic insights into the roles of well-known DUSPs in resistance to a wide range of cancer therapeutic approaches including chemotherapy, radiation and molecular targeted therapy in human malignancies. Moreover, we discuss the development of DUSP modulators, with a focus on DUSP1 and 6 inhibitors. Ultimately, the preclinical investigations of small molecule inhibitors of DUSP1 and 6 are outlined. Emerging evidence indicates that the DUSP family is aberrantly expressed in human malignancies and plays critical roles in determining sensitivity to a wide range of cancer therapeutic strategies through regulation of the MAPK signaling pathways. Consequently, targeting DUSPs and their downstream molecules can pave the way for more effective cancer therapies.

The MAP Kinase Phosphatase MKP-1 Modulates Neurogenesis via Effects on BNIP3 and Autophagy.

Inherited and acquired defects in neurogenesis contribute to neurodevelopmental disorders, dysfunctional neural plasticity, and may underlie pathology in a range of neurodegenerative conditions. Mitogen-activated protein kinases (MAPKs) regulate the proliferation, survival, and differentiation of neural stem cells. While the balance between MAPKs and the family of MAPK dual-specificity phosphatases (DUSPs) regulates axon branching and synaptic plasticity, the specific role that DUSPs play in neurogenesis remains unexplored. In the current study, we asked whether the canonical DUSP, MAP Kinase Phosphatase-1 (MKP-1), influences neural stem cell differentiation and the extent to which DUSP-dependent autophagy is operational in this context. Under basal conditions, Mkp-1 knockout mice generated fewer doublecortin (DCX) positive neurons within the dentate gyrus (DG) characterized by the accumulation of LC3 puncta. Analyses of wild-type neural stem cell (NSC) differentiation in vitro revealed increased Mkp-1 mRNA expression during the initial 24-h period. Notably, Mkp-1 KO NSC differentiation produced fewer Tuj1-positive neurons and was associated with increased expression of the BCL2/adenovirus E1B 19-kD protein-interacting protein 3 (BNIP3) and levels of autophagy. Conversely, Bnip3 knockdown in differentiated Mkp-1 KO NSCs reduced levels of autophagy and increased neuronal yields. These results indicate that MKP-1 exerts a pro-neurogenic bias during a critical window in NSC differentiation by regulating BNIP3 and basal autophagy levels.

DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases.

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.

Transcriptional regulation of human DUSP4 gene by cancer-related transcription factors.

Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is responsible for the dephosphorylation and inactivation of ERK, JNK and p38, which are mitogen-activated protein kinases involved in cell proliferation, differentiation and apoptosis, but also in inflammation processes. Given its importance for cellular signalling, DUSP4 is subjected to a tight regulation and there is growing evidence that its expression is dysregulated in several tumours. However, the mechanisms underlying DUSP4 transcriptional regulation remain poorly understood. Here, we analysed the regulation of the human DUSP4 promoters 1 and 2, located upstream of exons 1 and 2, respectively, by the cancer-related transcription factors (TFs) STAT3, FOXA1, CTCF and YY1. The presence of binding sites for these TFs was predicted in both promoters through the in silico analysis of DUSP4, and their functionality was assessed through luciferase activity assays. Regulatory activity of the TFs tested was found to be promoter-specific. While CTCF stimulated the activity of promoter 2 that controls the transcription of variants 2 and X1, STAT3 stimulated the activity of promoter 1 that controls the transcription of variant 1. YY1 positively regulated both promoters, although to different extents. Through site-directed mutagenesis, the functionality of YY1 binding sites present in promoter 2 was confirmed. This study provides novel insights into the transcriptional regulation of DUSP4, contributing to a better comprehension of the mechanisms of its dysregulation observed in several types of cancer.

Dual‐Specificity Phosphatase 26 Protects Against Cardiac Hypertrophy Through TAK1

BackgroundHeart pathological hypertrophy has been recognized as a predisposing risk factor for heart failure and arrhythmia. DUSP (dual‐specificity phosphatase) 26 is a member of the DUSP family of proteins, which has a significant effect on nonalcoholic fatty liver disease, neuroblastoma, glioma, and so on. However, the involvement of DUSP26 in cardiac hypertrophy remains unclear.Methods and ResultsOur study showed that DUSP26 expression was significantly increased in mouse hearts in response to pressure overload as well as in angiotensin II–treated cardiomyocytes. Cardiac‐specific overexpression of DUSP26 mice showed attenuated cardiac hypertrophy and fibrosis, while deficiency of DUSP26 in mouse hearts resulted in increased cardiac hypertrophy and deteriorated cardiac function. Similar effects were also observed in cellular hypertrophy induced by angiotensin II. Importantly, we showed that DUSP26 bound to transforming growth factor‐β activated kinase 1 and inhibited transforming growth factor‐β activated kinase 1 phosphorylation, which led to suppression of the mitogen‐activated protein kinase signaling pathway. In addition, transforming growth factor‐β activated kinase 1–specific inhibitor inhibited cardiomyocyte hypertrophy induced by angiotensin II and attenuated the exaggerated hypertrophic response in DUSP26 conditional knockout mice.ConclusionsTaken together, DUSP26 was induced in cardiac hypertrophy and protected against pressure overload induced cardiac hypertrophy by modulating transforming growth factor‐β activated kinase 1–p38/ c‐Jun N‐terminal kinase–signaling axis. Therefore, DUSP26 may provide a therapeutic target for treatment of cardiac hypertrophy and heart failure.

LIN28A inhibits DUSP family phosphatases and activates MAPK signaling pathway to maintain pluripotency in porcine induced pluripotent stem cells.

LIN28A, an RNA-binding protein, plays an important role in porcine induced pluripotent stem cells (piPSCs). However, the molecular mechanism underlying the function of LIN28A in the maintenance of pluripotency in piPSCs remains unclear. Here, we explored the function of LIN28A in piPSCs based on its overexpression and knockdown. We performed total RNA sequencing (RNA-seq) of piPSCs and detected the expression levels of relevant genes by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and immunofluorescence staining. Results indicated that piPSC proliferation ability decreased following LIN28A knockdown. Furthermore, when LIN28A expression in the shLIN28A2 group was lower (by 20%) than that in the negative control knockdown group (shNC), the pluripotency of piPSCs disappeared and they differentiated into neuroectoderm cells. Results also showed that LIN28A overexpression inhibited the expression of DUSP (dual-specificity phosphatases) family phosphatases and activated the mitogen-activated protein kinase (MAPK) signaling pathway. Thus, LIN28A appears to activate the MAPK signaling pathway to maintain the pluripotency and proliferation ability of piPSCs. Our study provides a new resource for exploring the functions of LIN28A in piPSCs.

Dual-specificity phosphatases in mental and neurological disorders

The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and phospho-serine/phospho-threonine residues within a single substrate. These protein phosphatases have many substrates and modulate diverse neural functions, such as neurogenesis, differentiation, and apoptosis. DUSP genes have furthermore been associated with mental disorders such as depression and neurological disorders such as Alzheimer's disease. Herein, we review the current literature on the DUSP family of genes concerning mental and neurological disorders. This review i) outlines the structure and general functions of DUSP genes, and ii) overviews the literature on DUSP genes concerning mental and neurological disorders, including model systems, while furthermore providing perspectives for future research.

DUSP12 protects against hepatic ischemia–reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo

Hepatic ischemia-reperfusion (I/R) injury is an important risk factor resulting in liver failure during liver surgery. However, there is still lack of effective therapeutic methods to treat hepatic I/R injury. DUSP12 is a member of the dual specific phosphatase (DUSP) family. Some DUSPs have been identified as being involved in the regulation of hepatic I/R injury. However, the role of DUSP12 during hepatic I/R injury is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in a hepatic I/R injury mouse model in vivo and in hypoxia/reoxygenation (H/R) model in vitro. Using hepatocyte-specific DUSP12 knockout mice and DUSP12 transgenic mice, we demonstrated that DUSP12 apparently relieved I/R-induced liver injury. Moreover, DUSP12 inhibited hepatic inflammatory responses and alleviated apoptosis both in vitro and in vivo. Furthermore, we demonstrated that JNK and p38 activity, but not ERK1/2, was increased in the DUSP12-deficient mice and decreased in the DUSP12 transgenic mice under I/R condition. ASK1 was required for DUSP12 function in hepatic I/R injury and inhibition of ASK1 prevented inflammation and apoptosis in DUSP12-deficient hepatocytes and mice. In conclusion, DUSP12 protects against hepatic I/R injury and related inflammation and apoptosis. This regulatory role of DUSP12 is primarily through ASK1-JNK/p38 signaling pathway. Taken together, DUSP12 could be a potential therapeutic target for hepatic I/R injury.