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Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. however, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. this study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/ reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. in addition, DUsP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. in summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. these findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

This study aimed to explore the role of dual specificity phosphatase 12 (DUSP12) in regulating myocardial ischemia–reperfusion (I/R) injury and the underlying mechanism. The expression of DUSP12 in myocardial tissues and heat‐shock protein beta‐8 (HSPB8) and mitophagy‐related proteins in myocardial tissues and H9c2 cells were detected by western blot analysis. The serum creatine kinase isoenzymes (CK‐MB) and lactate dehydrogenase (LDH), levels of reactive oxygen species and malondialdehyde, superoxide dismutase activity in myocardial tissues and H9c2 cells, and caspase‐3 activity in H9c2 cells were analyzed by corresponding assay kits. The infarct area in the rat's heart was observed by triphenyl tetrazolium chloride staining. The apoptosis of myocardial cells in myocardial tissues and H9c2 cells was detected by terminal‐deoxynucleotidyl transferase dUTP‐biotin nick‐end labeling assay. The interaction between DUSP12 and HSPB8 was clarified by the coimmunoprecipitation assay. The transfection efficacy of si‐HSPB8#1 and si‐HSPB8#2 in H9c2 cells was confirmed by real‐time quantitative‐polymerase chain reaction and western blot analysis. As a result, DUSP12 expression was downregulated in I/R rats, which was promoted by lentivirus‐expressing DUSP12. DUSP12 overexpression reduced the serum creatine kinase isoenzymes (CK‐MB) and LDH, decreased the infarct area in the rat's heart, and suppressed the apoptosis and oxidative stress in myocardial tissues. DUSP12 overexpression also upregulated the expression of HSPB8 to promote mitophagy. The coimmunoprecipitation assay indicated that DUSP12 could be combined with HSPB8. In addition, DUSP12 overexpression could inhibit hypoxia/reoxygenation‐elicited apoptosis as well as oxidative stress in H9c2 cells by upregulating HSPB8 expression to promote mitophagy, which was countervailed by HSPB8 deficiency. In conclusion, DUSP12 overexpression decreased the apoptosis and oxidative stress in myocardial I/R injury through HSPB8‐induced mitophagy. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is ventricular dysfunction that occurs in patients with diabetes mellitus (DM), independent of recognized risk factors, such as coronary artery disease, hypertension, and valvular heart disease. Dual-specificity phosphatase 12 (DUSP12) is a dual-specificity phosphatase expressed in all tissues. Genome-wide linkage studies have found an association between DUSP12 and type 2 diabetes (T2D). However, the role of DUSP12 in DCM remains largely unknown. Ubiquitously expressed DUSP12 is involved in nonalcoholic fatty liver disease, bacterial infection, and myocardial hypertrophy and plays a critical role in tumorigenesis. Herein, we observed an increased expression of DUSP12 in a hyperglycemia cell model and a high-fat diet (HFD) mouse model. Heart-specific DUSP12-deficient mice showed severe cardiac dysfunction and remodeling induced by an HFD. DUSP12 deficiency exacerbated oxidative stress injury and apoptosis, whereas DUSP12 overexpression had the opposite effect. At the molecular level, DUSP12 physically bound to apoptotic signal-regulated kinase 1 (ASK1), promoted its dephosphorylation, and inhibited its action on c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Rescue experiments have shown that oxidative stress injury and apoptosis, exacerbated by DUSP12 deficiency, are alleviated by ASK1 inhibition. Therefore, we consider DUSP12 an important signaling pathway in DCM. [Display omitted] • DUSP12 plays a protective role in the development of diabetic cardiomyopathy (DCM). • DUSP12 participates in the regulation of DCM by alleviating oxidative stress injury and apoptosis. • DUSP12 inhibits the ASK1-JNK/p38 signaling pathway in DCM. • The regulatory role of DUSP12 in DCM depends on ASK1. [ABSTRACT FROM AUTHOR]

Background. Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods. We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results. DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion. These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC. [ABSTRACT FROM AUTHOR]

Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. However, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. This study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. In addition, DUSP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. In summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. These findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury.

Abstract Dual Specificity Phosphatase 12 is a member of the Atypical DUSP Protein Tyrosine Phosphatase family, meaning that it does not contain typical MAP kinase targeting motifs, while being able to dephosphorylate tyrosine and serine/threonine residues. DUSP12 contains, apart from its catalytic domain, a zinc finger domain, making it one of the largest DUSPs, which displays strong nuclear expression in several tissues. In this work we identified nuclear targets of DUSP12 in two different cancer cell lines (A549 and MCF-7), challenging them with genotoxic stimuli to observe the effect on the networks and to link existing information about DUSP12 functions to the data obtained though mass spectrometry. We found network connections to the cytoskeleton (e.g. IQGAP1), to the chromatin (e.g. HP1BP3), to the splicing machinery and to the previously known pathway of ribosome maturation (e.g. TCOF1), which draw insight into many of the functions of this phosphatase, much likely connecting it to distinct, previously unknown genomic stability mechanisms. Graphical abstract Unlabelled Image Highlights • DUSP12 partners in the nucleus are affected by genotoxic stimuli. • Network analyses point to interactions with ribosomal maturation and stress granules. • Newfound connections to cytoskeleton, chromatin and RNA processing machinery. • Co-precipitation indicates interaction with TCOF1-containing particles and NAT10. • Confocal fluorescence shows colocalization with HP1BP3-enriched chromatin regions. [ABSTRACT FROM AUTHOR]

There is a correlation between obesity and the amount ofbrown adipose tissue; however, the molecular mechanism ofbrown adipogenic differentiation has not been as extensivelystudied. In this study, we performed a protein tyrosinephosphatase (PTP) profiling analysis during the brownadipogenic differentiation of mouse primary brown preadipocytes.Several PTPs, including PTPRF, PTPRZ, and DUSP12showing differential expression patterns were identified. In thecase of DUSP12, the expression level is dramatically downregulatedduring brown adipogenesis. The ectopic expression ofDUSP12 using a retroviral expression system induces thesuppression of adipogenic differentiation, whereas a catalyticinactive DUSP12 mutant showed no effect on differentiation.These results suggest that DUSP12 is involved in brownadipogenic differentiation and may be used as a target proteinfor the treatment or prevention of obesity by the regulation ofbrown adipogenic differentiation. [BMB Reports 2013; 46(11):539-543]

This commentary highlights the research presented by Li et al. [15]. In this issue of Clinical Science, which demonstrates that dual specific phosphatase 12 (DUSP12), through JNK1/2 inhibition, alleviates cardiac hypertrophy in response to pressure overload, making it a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Yeast VH1-related phosphatase (YVH1) (also known as DUSP12) is a member of the atypical dual-specificity phosphatase subfamily. Although no direct substrate has been firmly established, human YVH1 (hYVH1) has been shown to protect cells from cellular stressors, regulate the cell cycle, disassemble stress granules, and act as a 60S ribosome biogenesis factor. Despite knowledge of hYVH1 function, further research is needed to uncover mechanisms of its regulation. In this study, we investigate cellular effects of a Src-mediated phosphorylation site at Tyr 179 on hYVH1. We observed that this phosphorylation event attenuates localization of hYVH1 to stress granules, enhances shuttling of hYVH1 to the nucleus, and promotes hYVH1 partitioning to the 60S ribosomal subunit. Quantitative proteomics reveal that Src coexpression with hYVH1 reduces formation of ribosomal species that represent stalled intermediates through the alteration of associating factors that mediate translational repression. Collectively, these results implicate hYVH1 as a novel Src substrate and provide the first demonstrated role of tyrosine phosphorylation regulating the activity of a YVH1 ortholog. Moreover, the ribosome proteome alterations point to a collaborative function of hYVH1 and Src in maintaining translational fitness., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the content of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: A central feature of the protein tyrosine phosphatase (PTP) catalytic mechanism is an attack of the substrate’s phosphate moiety by a thiolate ion in the signature CX5R motif. In addition to being an effective nucleophile in this form, the thiolate ion is also susceptible to reversible redox regulation. This attribute permits temporal inhibition of PTP activities, which affects numerous cellular processes utilizing kinase-mediated signal propagation. Accumulating evidence has revealed diverse mechanisms adopted by PTPs to avoid irreversible thiol oxidation of the active site Cys residue, often involving structurally proximal thiols within the active site region. Therefore, there has been a significant effort made to develop thiol labeling strategies coupled to mass spectrometry to identify and characterize redox sensitive thiols within PTPs as a necessary step in understanding how a particular PTP is regulated by redox signaling. A common drawback to many current methods is the use of neutral pH labeling techniques, requiring special attention with regards to non-specific thiol oxidation during sample preparation. This study describes the use of rapid, low pH thiol labeling methods to overcome this issue. Mercury immobilized metal affinity chromatography (Hg-IMAC) demonstrated high selectivity and specificity while enriching for thiol-containing peptides from the atypical dual specificity phosphatase hYVH1 (also known as DUSP12). This approach revealed several reversibly oxidized thiols within the catalytic domain of hYVH1. Subsequently, use of another low pH labeling reagent, 4,4-dithiopyridine (4-DTP) helped identify novel disulfide linkages providing evidence that hYVH1 utilizes a disulfide exchange mechanism to prevent irreversible oxidation of the catalytic Cys residue in the active site. [Copyright &y& Elsevier]

Background: Dual specificity protein phosphatase ( DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood., Methods: We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression., Results: DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival)., Conclusion: These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC., Competing Interests: The authors declare there are no competing interests., (©2021 Ju et al.)

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., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Human YVH1 (hYVH1), also known as dual specificity phosphatase 12 (DUSP12), is a poorly characterized atypical dual specificity phosphatase widely conserved throughout evolution. Recent findings have demonstrated that hYVH1 expression affects cellular DNA content and is a novel cell survival phosphatase preventing both thermal and oxidative stress-induced cell death, whereas studies in yeast have established YVH1 as a novel 60S ribosome biogenesis factor. In this study, we have isolated novel hYVH1-associating proteins from human U2OS osteosarcoma cells using affinity chromatography coupled to mass spectrometry employing ion mobility separation. Numerous ribosomal proteins were identified, confirming the work done in yeast. Furthermore, proteins known to be present on additional RNP particles were identified, including Y box-binding protein 1 (YB-1) and fragile X mental retardation protein, proteins that function in translational repression and stress granule regulation. Follow-up studies demonstrated that hYVH1 co-localizes with YB-1 and fragile X mental retardation protein on stress granules in response to arsenic treatment. Interestingly, hYVH1-positive stress granules were significantly smaller, whereas knocking down hYVH1 expression attenuated stress granule breakdown during recovery from arsenite stress, indicating a possible role for hYVH1 in stress granule disassembly. These results propagate a role for dual specificity phosphatases at RNP particles and suggest that hYVH1 may affect a variety of fundamental cellular processes by regulating messenger ribonucleoprotein (mRNP) dynamics., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)