{"gene":"DUSP4","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1995,"finding":"HVH2 (DUSP4) is a dual-specificity phosphatase that selectively dephosphorylates both phosphothreonine and phosphotyrosine residues of activated ERK1 and ERK2 in vitro, and localizes to the cell nucleus. Transfection into NIH3T3 cells inhibited v-src and MEK-induced transcriptional activation of SRE-containing promoters.","method":"In vitro phosphatase assay with recombinant protein, immunofluorescence of epitope-tagged protein, transfection/reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with recombinant protein, direct localization by immunofluorescence, and functional reporter assay; foundational characterization paper with multiple orthogonal methods","pmids":["7535768"],"is_preprint":false},{"year":1995,"finding":"TYP1 (DUSP4) encodes a nuclear dual-specificity phosphatase that inactivates both ERK2 and p54 JNK. Purified TYP1 protein efficiently dephosphorylates both phosphothreonine and phosphotyrosine of recombinant ERK2 in vitro. In COS cells, TYP1 protein is stabilized by EGF treatment.","method":"In vitro phosphatase assay with purified protein, transfection in COS-1 cells, northern analysis for expression kinetics","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein plus ERK2/JNK substrate specificity established; corroborated by independent lab (PMID:7535768)","pmids":["8545112"],"is_preprint":false},{"year":1996,"finding":"MKP-2 (DUSP4) has a unique in vivo substrate specificity toward ERK and JNK (but not p38), distinguishing it from PAC1 (ERK/p38) and MKP-1 (ERK/p38/JNK). A hyperactive ERK2 allele (D319N, sevenmaker) showed significantly reduced sensitivity to MKP-2 dephosphorylation in vivo.","method":"In vivo substrate specificity assay in T cells using phorbol ester stimulation, co-expression of phosphatases with MAP kinase substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo substrate specificity established with multiple kinase substrates and gain-of-function ERK2 mutant, replicated across three phosphatases in the same study","pmids":["8626452"],"is_preprint":false},{"year":1997,"finding":"DUSP4 (MKP-2) gene maps to chromosomal location 8p11-p12 by fluorescence in situ hybridization and radiation hybrid mapping.","method":"Fluorescence in situ hybridization (FISH), radiation hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by two independent mapping methods in a single study","pmids":["9205128"],"is_preprint":false},{"year":2002,"finding":"The C-terminal domain of MKP-2 (DUSP4) exerts an inhibitory effect on its phosphatase activity. C-terminal truncation of MKP-2 substantially increased phosphatase activity toward MAPK substrates both in vivo and in vitro without changing substrate affinity or substrate-mediated catalytic activation.","method":"C-terminal deletion mutagenesis, in vivo and in vitro phosphatase activity assays","journal":"Molecular and cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay combined with mutagenesis; both in vivo and in vitro measurements in single study","pmids":["12083364"],"is_preprint":false},{"year":2003,"finding":"I1-imidazoline receptor stimulation with moxonidine induces MKP-2 (DUSP4) protein levels approximately 3-fold in PC12 cells and reverses NGF-induced ERK activation, effects blocked by the I1-antagonist efaroxan or by D609 (phosphatidylcholine-selective PLC inhibitor), placing DUSP4 induction downstream of I1-receptor/phospholipase C signaling.","method":"Western blot for MKP-2 protein, pharmacological inhibitors, ERK activation assay in PC12 cells","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, pharmacological pathway dissection with multiple inhibitors","pmids":["12865160"],"is_preprint":false},{"year":2006,"finding":"AMPK activation (by AICAR) induces DUSP4 expression in hepatocytes via transcriptional induction of EGR1, which directly binds the DUSP4 promoter. DUSP4 in turn inhibits promoter activity and expression of gluconeogenic genes PEPCK and Glucose-6-phosphatase. Constitutively active p38 rescued DUSP4-mediated repression of PEPCK. siRNA depletion of EGR1 or DUSP4 partially abrogated AICAR-mediated inhibition of PEPCK and glucose production.","method":"Reporter gene assays, real-time PCR, siRNA knockdown, ChIP (EGR1 binding to DUSP4 promoter), constitutively active p38 rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, siRNA, constitutively active rescue) in one study establishing AMPK→EGR1→DUSP4→p38→PEPCK axis","pmids":["16849326"],"is_preprint":false},{"year":2008,"finding":"dusp4 is essential for early zebrafish endoderm specification; morpholino-mediated knockdown caused necrosis of head tissues and a specific loss of sox17 expression (but not other endoderm markers), indicating a required role in foregut and pancreatic endoderm formation.","method":"Antisense morpholino oligonucleotide knockdown in zebrafish, marker analysis (in situ hybridization for sox17), transplantation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific marker readout in zebrafish ortholog; single study","pmids":["18719100"],"is_preprint":false},{"year":2010,"finding":"Oncogenic KRAS(G12V) and BRAF(V600E) induce rapid nuclear accumulation of DUSP4 (in an MEK-dependent manner), which dephosphorylates and restricts ERK phosphorylation specifically to the cytoplasm in intestinal epithelial cells. MEK-dependent phosphorylation of DUSP4 at T361, T363, S390, and S395 residues stabilizes the protein. In human colorectal cancer cells, ERK activity was similarly confined to the cytoplasm and treatment with pervanadate reactivated nuclear ERK.","method":"Expression of oncogenic KRAS/BRAF in IECs, immunofluorescence for ERK phosphorylation, MEK inhibitor treatment, phospho-site mapping, pervanadate treatment in CRC cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — spatial ERK activity mapping combined with pharmacological and genetic perturbation and phospho-site identification; multiple orthogonal methods","pmids":["22430215"],"is_preprint":false},{"year":2010,"finding":"MKP-2 (DUSP4) is phosphorylated by ERK at Ser386 and Ser391 in its C-terminus, and this phosphorylation stabilizes MKP-2 protein by protecting it from proteasomal degradation. Blockade of ERK activation enhanced proteasomal degradation of MKP-2, and phosphorylation had no effect on MKP-2 phosphatase activity.","method":"Site-directed mutagenesis of phospho-sites (S386, S391), ERK inhibitor treatment, proteasome inhibitor assay, Western blot for protein stability","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — phospho-site mutagenesis combined with proteasome inhibitor and ERK inhibitor experiments; identifies ERK as writer of stabilizing phosphorylation","pmids":["21084841"],"is_preprint":false},{"year":2010,"finding":"DUSP4/MKP-2 promoter CpG island hypermethylation in gliomas reduces MKP-2 mRNA and protein expression. Treatment with 5-aza-2'-deoxycytidine (demethylating agent) increased MKP-2 mRNA, and exogenous MKP-2 overexpression inhibited glioblastoma cell growth.","method":"Differential methylation hybridization, 5-aza-2'-deoxycytidine demethylation, overexpression growth assay in glioblastoma cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism (promoter methylation) linked to expression and functional outcome; single lab but methylation and functional overexpression assays performed","pmids":["20124482"],"is_preprint":false},{"year":2011,"finding":"DUSP4/MKP-2 knockout MEFs show enhanced PDGF-induced sustained ERK phosphorylation and moderately increased JNK phosphorylation, reduced cellular proliferation (with block at G2/M associated with cyclin B accumulation and enhanced cdc2 phosphorylation), and enhanced anisomycin-induced apoptosis (increased caspase-3 cleavage and γH2AX). Adenoviral re-expression of MKP-2 reversed both proliferation defects and JNK-associated apoptosis.","method":"MKP-2 knockout MEFs from deletion mouse model, adenoviral MKP-2 rescue, cell cycle analysis, Western blot for cyclin B/cdc2/caspase-3/γH2AX","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO model with multiple phenotypic readouts and adenoviral rescue; establishes non-redundant roles in cell cycle and apoptosis","pmids":["21317287"],"is_preprint":false},{"year":2011,"finding":"DUSP4 deficiency in mice results in hyperproliferation of activated CD4+ T cells (but not CD8+ T cells) due to enhanced CD25 expression and increased IL-2 signaling through elevated STAT5 phosphorylation, revealing a role for DUSP4 in suppressing CD4+ T-cell proliferation via STAT5/IL-2 pathway regulation.","method":"DUSP4 knockout mouse, T-cell proliferation assays, STAT5 phosphorylation by Western blot, immunization recall response","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with specific cellular phenotype, STAT5 phosphorylation mechanistic readout; multiple immune readouts","pmids":["22101742"],"is_preprint":false},{"year":2012,"finding":"DUSP4 is an ERK phosphatase whose loss in basal-like breast cancer (BLBC) correlates with DUSP4 promoter methylation and activates the Ras-ERK pathway. DUSP4 overexpression increased chemotherapy-induced apoptosis in BLBC cells, while DUSP4 depletion dampened the chemotherapy response. MEK inhibition synergized with docetaxel in BLBC xenografts.","method":"DUSP4 overexpression and siRNA knockdown in breast cancer cell lines, xenograft model, MEK inhibitor combination, digital transcript counting of post-NAC tumors","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cancer cell line gain/loss-of-function experiments plus in vivo xenograft validation; mechanistic link to ERK pathway confirmed","pmids":["22683778"],"is_preprint":false},{"year":2012,"finding":"MKP-2 (DUSP4) knockdown in macrophages attenuated the proinflammatory cytokine production and neutrophil infiltration in a murine LPS-induced acute lung injury model. MKP-2 knockdown was associated with increased ERK phosphorylation and induction of MKP-1, suggesting a regulatory interplay between these DUSPs.","method":"MKP-2 null mice (MKP-2−/−), MKP-2 knockdown in macrophage cell line, intratracheal LPS model, cytokine measurement, neutrophil counting","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse and cell-based knockdown with defined inflammatory phenotype; single lab","pmids":["22683570"],"is_preprint":false},{"year":2013,"finding":"DUSP4 loss in basal-like breast cancer activates both MEK/ERK and JNK pathways, increasing mammosphere formation, CD44+/CD24- cancer stem cell-like populations, and IL-6/IL-8 expression through downstream ETS-1 and c-JUN transcription factors. Enforced DUSP4 expression reduced cancer stem cell populations in a MEK-dependent manner.","method":"DUSP4 knockdown/overexpression in BLBC cell lines, mammosphere assay, flow cytometry for CD44+/CD24−, cytokine measurement, MEK inhibitor rescue, xenograft tumor formation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple BLBC cell lines, multiple orthogonal readouts (mammosphere, flow cytometry, cytokines), MEK-dependent rescue, in vivo xenograft","pmids":["23966295"],"is_preprint":false},{"year":2013,"finding":"DUSP4 is induced by hCG/LH in MA-10 Leydig cells via cAMP/PKA signaling, and MKP-2 downregulation by shRNA elevated phosphorylated ERK1/2 after 8Br-cAMP stimulation and increased CYP11A1 (P450scc) promoter activity and mRNA levels, demonstrating that MKP-2 modulates the late phase of cAMP-induced ERK1/2 activity and consequently CYP11A1 expression.","method":"shRNA knockdown, promoter-reporter assay, hCG/8Br-cAMP stimulation, phospho-ERK1/2 Western blot, mRNA quantification","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA-mediated knockdown with multiple readouts (ERK phosphorylation, promoter activity, mRNA); single lab","pmids":["23471219"],"is_preprint":false},{"year":2014,"finding":"Inhibition of the histone methyltransferase G9a induces DUSP4-dependent ERK inactivation and autophagic cell death in head and neck squamous cell carcinoma cells, identifying DUSP4 as a downstream mediator linking G9a inhibition to autophagy.","method":"G9a genetic/pharmacological inhibition, Affymetrix microarray for target identification, immunoblot, flow cytometry, fluorescent/electron microscopy, xenograft model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — G9a inhibition→DUSP4→ERK→autophagy pathway established with multiple methods; single lab","pmids":["25027955"],"is_preprint":false},{"year":2014,"finding":"DUSP4 regulates neuronal differentiation and calcium homeostasis by modulating ERK1/2 phosphorylation. DUSP4 knockdown reduced neurite outgrowth and neuronal marker expression (rescued by DUSP4 reintroduction), enhanced ERK activation during differentiation, and altered calcium signaling by regulating CaMKI phosphorylation and Cav1.2 expression and plasma membrane localization.","method":"DUSP4 knockdown/reintroduction in embryonic stem cell-derived neurons, neurite outgrowth assay, Western blot for ERK/CaMKI, Cav1.2 localization by imaging","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with rescue, multiple downstream readouts linking DUSP4-ERK to calcium pathway; single lab","pmids":["25397900"],"is_preprint":false},{"year":2014,"finding":"MKP-2 (DUSP4) stability in macrophages is regulated by ERK-mediated phosphorylation of two C-terminal serine residues. Mutation of these serines to alanine decreased MKP-2 half-life, while aspartate substitution dramatically increased it. C-terminal truncation also increased stability. Enhanced stability was not associated with decreased ubiquitination; degradation required proteasome activity.","method":"Site-directed mutagenesis of C-terminal serines, half-life measurement by cycloheximide chase, proteasome inhibitor, ubiquitination assays, ERK pathway inhibitor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — phospho-site mutagenesis combined with half-life measurement, proteasome inhibition, and ubiquitination assay; replicated finding from PMID:21084841 with additional mechanistic detail","pmids":["25204653"],"is_preprint":false},{"year":2015,"finding":"Ectopic expression of wild-type DUSP4, but not a phosphatase-deficient mutant, dephosphorylates JNK and induces apoptosis in diffuse large B cell lymphoma (DLBCL) cells. DUSP4 loss is caused by CpG island promoter hypermethylation and genomic deletion, and DLBCL cells depend on JNK signaling for survival.","method":"Ectopic expression of WT vs. phosphatase-dead DUSP4 mutant, JNK phosphorylation assay, apoptosis assay, genome-wide DNA methylation analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphatase-dead mutant used to confirm catalytic requirement; JNK dephosphorylation directly demonstrated; replicated in multiple DLBCL models","pmids":["25847947"],"is_preprint":false},{"year":2015,"finding":"DUSP4 modulates p38 phosphorylation in endothelial cells and heart. DUSP4 is degraded by hypoxia/reoxygenation (H/R) and its loss correlates with p38 hyperphosphorylation and apoptosis. DUSP4-/- hearts showed larger infarcts with overactivated p38 after ischemia/reperfusion. p38 inhibition rescued both WT and DUSP4-/- cardiac function.","method":"DUSP4 knockdown (siRNA), DUSP4-/- mouse Langendorff-perfused heart model, TUNEL assay, Western blot for p38/caspase-3, p38 inhibitor (SB203580)","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus siRNA knockdown in endothelial cells, p38 inhibitor pharmacological rescue, in vivo infarct measurement","pmids":["26184564"],"is_preprint":false},{"year":2015,"finding":"Increased DUSP4 expression in CD4+ T cells from idiopathic CD4 lymphopenia (ICL) patients suppresses TCR-induced ERK activation and downregulates CD27 and CD40L. siRNA normalization of DUSP4 expression in ICL cells restored ERK activation and costimulatory molecule expression. Repeated TCR stimulation in control T cells induced DUSP4 overexpression and TCR signal dampening, both curtailed by DUSP4 silencing.","method":"siRNA knockdown in primary human T cells from ICL patients, TCR stimulation, ERK phosphorylation assay, flow cytometry for surface markers","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA in primary human cells with multiple functional readouts; single lab study","pmids":["25733583"],"is_preprint":false},{"year":2016,"finding":"Restoration of DUSP4 expression in pancreatic cancer cells suppressed invasiveness and anoikis resistance via ERK inactivation, and MEK inhibition was effective in an orthotopic xenograft model. DUSP4 genomic loss at 8p is associated with progression from noninvasive intraepithelial neoplasm to invasive carcinoma.","method":"DUSP4 re-expression in pancreatic cancer cell lines, invasion/anoikis assays, MEK inhibitor in orthotopic xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with invasion/survival readouts and in vivo confirmation; ERK mechanism inferred from MEK inhibitor data","pmids":["26941286"],"is_preprint":false},{"year":2016,"finding":"Induced DUSP4 expression in triple-negative breast cancer cells blocks cell cycle at G1/S checkpoint and inhibits ERK1/2, p38, JNK1, RB, and NFκB p65 phosphorylation, as well as in vitro and in vivo growth and invasiveness. Protein microarray of 172 phosphoproteins was used to map DUSP4-regulated signaling.","method":"DUSP4 overexpression, protein/phosphoprotein microarray (172 proteins), cell cycle analysis, in vivo xenograft, invasion assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic array provides broad pathway mapping; multiple functional readouts; single lab","pmids":["27393618"],"is_preprint":false},{"year":2017,"finding":"DUSP4 associates with GR (glucocorticoid receptor) and JNK1 in a complex, dephosphorylates JNK1, and prevents phosphorylation of GR at Ser226 (which impairs GR nuclear translocation). DUSP4 knockdown enhanced JNK1 and GR-Ser226 phosphorylation, reduced GR nuclear translocation, and decreased corticosteroid sensitivity. Formoterol enhanced DUSP4 phosphatase activity and restored corticosteroid sensitivity reduced by DUSP4 siRNA.","method":"Co-immunoprecipitation of DUSP4-GR-JNK1, siRNA knockdown, fluorescence-based IP-DUSP4 phosphatase activity assay, imaging flow cytometry for GR nuclear translocation, Western blot for phospho-JNK1 and phospho-GR-Ser226","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-immunoprecipitation identifying ternary complex, direct phosphatase activity assay, siRNA and formoterol perturbations, multiple orthogonal methods","pmids":["28283554"],"is_preprint":false},{"year":2018,"finding":"Compound heterozygous deletion of Dok2 and Dusp4 in mice results in lung tumorigenesis with short latency and high incidence, synergistically activating MAPK signaling and promoting cell proliferation. Restoration of both DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation.","method":"Mouse ortholog compound heterozygous knockout, lung tumor incidence monitoring, MAPK signaling assays in primary cells and cell lines, DOK2/DUSP4 restoration experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic model plus cell line restoration experiments; establishes synthetic functional interaction","pmids":["30475228"],"is_preprint":false},{"year":2019,"finding":"VIP signaling in the suprachiasmatic nucleus (SCN) requires ERK1/2 activity and is tuned by DUSP4 as a negative regulator to drive circadian re-programming. ERK1/2 and DUSP4 are critical elements of VIP-directed synchronization of SCN circadian oscillations.","method":"SCN organotypic slice culture with VIP treatment, ERK inhibition, transcriptional profiling, circadian clock assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic perturbation in ex vivo SCN slices; mechanistic role of DUSP4 in VIP/ERK/circadian circuit established; single study","pmids":["30710088"],"is_preprint":false},{"year":2019,"finding":"DUSP4 expression is induced by PDGF-BB in an ERK1/2-, STAT3-, and p53-dependent manner. ERK1/2 inhibition reduced DUSP4 mRNA levels; STAT3 was necessary for maintaining p53 expression; and p53, which has binding sites in the DUSP4 promoter, was found to promote DUSP4 transcription.","method":"PDGF-BB stimulation, ERK/STAT3/p53 inhibitors and knockdown, DUSP4 mRNA quantification, promoter binding analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic dissection of transcriptional induction with multiple regulators; single lab","pmids":["31526568"],"is_preprint":false},{"year":2019,"finding":"Diabetes-induced reduction of DUSP4 in podocytes enhances p38 and JNK activity and podocyte dysfunction. DUSP4 overexpression prevented activation of p38, JNK, caspase 3/7, and NADPH oxidase 4 (Nox4) expression induced by high glucose. DUSP4-/- diabetic mice showed exacerbated albuminuria, mesangial expansion, glomerular fibrosis, podocyte foot process effacement, and sustained p38/JNK activation. PKC-δ inhibition prevented DUSP4 expression decline.","method":"DUSP4 overexpression in cultured podocytes, DUSP4-/- diabetic mouse model, PKC-δ inhibitor, Western blot for p38/JNK/caspase-3/Nox4, glomerular histology","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell culture gain-of-function plus KO mouse model; multiple mechanistic readouts identifying p38/JNK/Nox4 as downstream effectors; PKC-δ as upstream regulator","pmids":["30862678"],"is_preprint":false},{"year":2020,"finding":"ΔNp63α induces DUSP4 expression in endometrial epithelial cells, activating a DUSP4/GSK-3β/SNAI1 pathway that drives epithelial-mesenchymal transition (EMT). bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis by blocking this pathway.","method":"ΔNp63α forced expression in endometrial epithelial cells, transcriptomic analysis, Western blot for GSK-3β/SNAI1, bFGF rescue in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway established by transcriptomics plus functional perturbation with bFGF rescue; single lab","pmids":["32528070"],"is_preprint":false},{"year":2021,"finding":"DUSP4 transcriptionally modulates DUSP4 expression through STAT3 and YY1 binding sites in DUSP4 promoters. CTCF stimulated promoter 2 activity while STAT3 stimulated promoter 1 activity; YY1 positively regulated both promoters. Functionality of YY1 binding sites confirmed by site-directed mutagenesis.","method":"Luciferase reporter assays, site-directed mutagenesis of TF binding sites, in silico prediction of binding sites","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assays with mutagenesis to confirm YY1 binding sites; multiple TFs tested","pmids":["34254709"],"is_preprint":false},{"year":2022,"finding":"ARID1A loss in endometrial epithelial cells downregulates DUSP4 via decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 regulatory regions, leading to MAPK pathway activation. Ectopic DUSP4 expression decreased cell proliferation, and pharmacological MAPK pathway inhibition mitigated tumor formation in vivo.","method":"RNA-seq of ARID1A-deficient cells, ChIP-seq for H3K27Ac/H3K9Ac on DUSP4 locus, DUSP4 ectopic expression, MEK inhibitor in vivo, genetically engineered mouse models","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq defines epigenetic mechanism, RNA-seq for transcriptome, ectopic DUSP4 rescue, and in vivo validation; multiple orthogonal methods","pmids":["38071325"],"is_preprint":false},{"year":2022,"finding":"DUSP4 depletion in BRAF/NRAS-mutant melanoma leads to toxic levels of MAPK hyperactivation (oncogene overdose) and downregulation of lineage-defining genes including MITF. This phenotype occurs in both drug-naive and drug-resistant melanoma cells.","method":"DUSP4 depletion in melanoma cell lines, ERK/MAPK activation assays, MITF and lineage gene expression analysis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with multiple melanoma lines and downstream readouts; single lab","pmids":["35580987"],"is_preprint":false},{"year":2022,"finding":"DUSP4 inactivation in melanoma unexpectedly leads to reduced ERK1/2 phosphorylation rather than ERK activation, through upregulation of DUSP6 at a post-transcriptional level. DUSP6 knockout eliminated the DUSP4-depletion effect on ERK activity and cell growth, placing DUSP4 upstream of DUSP6 in ERK regulation in melanoma.","method":"DUSP4 depletion and DUSP6 knockout in melanoma lines, kinase translocation reporter for ERK activity, immunoblotting for DUSP4/DUSP6/pERK","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-KO epistasis and kinase reporter; single lab; finding challenges the direct ERK-phosphatase model","pmids":["35189148"],"is_preprint":false},{"year":2022,"finding":"MKP-2 (DUSP4) is upregulated in obesity and fatty liver disease. MKP-2 deficient mice are protected against diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Loss of MKP-2 enhanced p38, JNK, and ERK activities in insulin-responsive tissues and was associated with enhanced Akt activity linked to downregulated PTEN in liver.","method":"MKP-2 KO mice on high-fat diet, glucose/insulin tolerance tests, PTEN/Akt/MAPK Western blots, respiratory exchange ratio measurement","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse metabolic phenotyping with mechanistic pathway readouts; single lab","pmids":["35745205"],"is_preprint":false},{"year":2023,"finding":"DUSP4 directly binds HSP90β and dephosphorylates it at T214 and Y216, promoting HSP90β ATPase activity. These dephosphorylation events stabilize JAK1/2-STAT3 signaling and promote p-STAT3(Y705) nuclear translocation in esophageal squamous cell carcinoma. HSP90β inhibitor NVP-BEP800 inhibited PDX tumor growth and inactivated JAK1/2-STAT3 signaling.","method":"Co-IP/pulldown of DUSP4-HSP90β, phospho-site mapping (T214/Y216), ATPase activity assay, HSP90β inhibitor treatment, in vivo PDX model, Dusp4 KO mouse in carcinogen model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding (Co-IP), substrate dephosphorylation with phospho-site identification, functional ATPase assay, in vivo KO and PDX validation; multiple orthogonal methods","pmids":["37141098"],"is_preprint":false},{"year":2024,"finding":"DUSP4 forms a signaling complex with TBK1, ERK1/2, and IRF3 and regulates TBK1 and ERK1/2 activation to modulate production of type I interferons downstream of RIG-I and STING nucleic acid sensors. DUSP4-deficient mice were more resistant to RNA and DNA virus infections but more susceptible to malaria parasites.","method":"Co-IP identifying DUSP4-TBK1-ERK1/2-IRF3 complex, DUSP4-/- mouse infection models (RNA virus, DNA virus, malaria parasite), type I IFN measurement","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of multi-protein complex, KO mouse with multiple infection phenotypes; establishes DUSP4 as regulator of innate immune TBK1/ERK/IRF3 axis","pmids":["38383887"],"is_preprint":false},{"year":2024,"finding":"DUSP4 interacts with ALDOB (aldolase B) and dephosphorylates it, thereby inhibiting G6PD (glucose-6-phosphate dehydrogenase) activity and the ROS/pentose phosphate pathway in HER2-positive breast cancer cells.","method":"Co-IP and mass spectrometry (IP-MS) identifying DUSP4-ALDOB interaction, DUSP4 KO cells, G6PD activity assay, ROS measurement, RNA-seq of KO cells","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS interaction plus functional enzyme assay; mechanistic link to G6PD/ROS pathway; single lab","pmids":["38843658"],"is_preprint":false},{"year":2025,"finding":"DUSP4 dephosphorylates p-ERK and disrupts ERK-PGK1 interaction, reducing PGK1 S203 phosphorylation and its mitochondrial localization, thereby decreasing lactate production and increasing ROS levels in ovarian cancer cells. Phosphoproteomic profiling identified MAPK pathway and cellular metabolism as key downstream targets of DUSP4.","method":"LC-MS/MS phosphoproteomic profiling of DUSP4 overexpressing cells, PGK1 co-immunoprecipitation with ERK, mitochondrial fractionation, lactate/ROS assays, in vivo mouse tumor model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus Co-IP and functional metabolic assays; single lab; novel substrate (PGK1) identified","pmids":["40082940"],"is_preprint":false},{"year":2025,"finding":"DUSP4 suppresses ferroptosis in MSI colorectal cancer cells by reducing lipid peroxidation and inhibiting intracellular Fe2+ accumulation through downregulation of transferrin receptor (TFRC), which is transcriptionally regulated by c-MYC. DUSP4 also dephosphorylates CDK7, promoting CXCL16 expression and CD8+ T cell infiltration.","method":"Ferroptosis assays (lipid peroxidation, MDA, 4-HNE, Fe2+), phosphoproteomic analysis, TFRC/c-MYC expression studies, cytokine array, CDK7 dephosphorylation assay, flow cytometry for CD8+ T cells","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic analysis plus functional ferroptosis/immune assays identifying novel DUSP4 substrates CDK7 and TFRC regulation; single lab preprint-level evidence pending broader replication","pmids":["40847010"],"is_preprint":false}],"current_model":"DUSP4 (MKP-2/HVH2/TYP) is a nuclear dual-specificity phosphatase that dephosphorylates and inactivates multiple MAPK substrates—primarily ERK1/2 and JNK, and to a lesser extent p38—and functions as a negative feedback regulator of MAPK signaling; it is induced downstream of oncogenic RAS/RAF/MEK signaling and other stimuli (PDGF, AMPK, LH/hCG, VIP) and its own stability is regulated by ERK-mediated phosphorylation of C-terminal serine residues; beyond canonical MAPK substrates, DUSP4 has been shown to dephosphorylate JNK1 within a GR-JNK1-DUSP4 complex to regulate glucocorticoid receptor nuclear translocation, to dephosphorylate HSP90β at T214/Y216 to activate its ATPase and stabilize JAK-STAT3 signaling, to dephosphorylate ALDOB to inhibit G6PD/ROS metabolism, to dephosphorylate CDK7 to regulate immune chemokine expression, and to participate in a TBK1-ERK1/2-IRF3 signaling complex governing type I interferon production; loss of DUSP4 through promoter hypermethylation, genomic deletion, or upstream regulation drives cancer progression, chemoresistance, and metabolic disease by hyperactivating MAPK and related pathways."},"narrative":{"mechanistic_narrative":"DUSP4 (MKP-2/HVH2/TYP) is a nuclear dual-specificity phosphatase that serves as a negative-feedback brake on MAPK signaling, dephosphorylating both the phosphothreonine and phosphotyrosine of activated ERK1/2 and JNK—but not p38—to terminate kinase activity and restrain transcriptional output [PMID:7535768, PMID:8545112, PMID:8626452]. Its catalytic output is governed by an autoinhibitory C-terminus, removal of which markedly increases phosphatase activity toward MAPK substrates [PMID:12083364], and its abundance is set by an ERK-driven feedback loop in which ERK phosphorylates C-terminal serine residues (S386/S391 and additional MEK-dependent sites) to protect the protein from proteasomal degradation [PMID:21084841, PMID:25204653, PMID:22430215]. DUSP4 is transcriptionally induced downstream of diverse stimuli—oncogenic KRAS/BRAF via MEK [PMID:22430215], AMPK via EGR1 [PMID:16849326], PDGF via ERK/STAT3/p53 [PMID:31526568], and through STAT3/YY1/CTCF promoter elements [PMID:34254709]—and acts as a tumor suppressor whose silencing by promoter hypermethylation, genomic 8p loss, or chromatin remodeling (ARID1A loss, G9a) hyperactivates ERK and JNK to drive proliferation, cancer stem-cell expansion, invasion, and chemoresistance across breast, lymphoma, pancreatic, and other cancers [PMID:20124482, PMID:22683778, PMID:23966295, PMID:25847947, PMID:30475228, PMID:38071325]. Beyond canonical MAPK kinases, DUSP4 has substrate and complex roles extending its reach: it forms a GR–JNK1 complex to dephosphorylate JNK1 and control glucocorticoid receptor nuclear translocation [PMID:28283554], binds and dephosphorylates HSP90β at T214/Y216 to activate its ATPase and stabilize JAK-STAT3 signaling [PMID:37141098], dephosphorylates ALDOB to restrict G6PD/ROS metabolism [PMID:38843658], and participates in a TBK1–ERK1/2–IRF3 complex governing type I interferon production [PMID:38383887]. Genetic loss-of-function in mice and zebrafish establishes non-redundant roles in cell-cycle progression and apoptosis [PMID:21317287], CD4+ T-cell proliferation via STAT5/IL-2 [PMID:22101742], endoderm specification [PMID:18719100], cardiac and podocyte protection through p38/JNK control [PMID:26184564, PMID:30862678], and metabolic regulation of obesity and hepatic steatosis [PMID:35745205].","teleology":[{"year":1995,"claim":"Established DUSP4 as a catalytically active dual-specificity phosphatase that directly inactivates ERK MAPKs and acts in the nucleus, answering what biochemical activity the gene encodes.","evidence":"In vitro phosphatase assays with recombinant/purified protein on ERK1/2 and ERK2/JNK, immunofluorescence localization, and SRE reporter assays in NIH3T3 and COS cells","pmids":["7535768","8545112"],"confidence":"High","gaps":["In vivo substrate hierarchy not yet resolved","Regulation of phosphatase activity unaddressed"]},{"year":1996,"claim":"Defined the in vivo substrate specificity of DUSP4 as ERK and JNK but not p38, distinguishing it from related MKPs and clarifying which pathways it feeds back upon.","evidence":"In vivo co-expression substrate specificity assays in T cells with a hyperactive ERK2 (sevenmaker) allele","pmids":["8626452"],"confidence":"High","gaps":["Does not explain p38 effects seen later in disease models","Cellular context-dependence of specificity unresolved"]},{"year":2002,"claim":"Showed that the C-terminal domain autoinhibits catalytic activity, revealing an intrinsic regulatory mechanism controlling phosphatase output.","evidence":"C-terminal deletion mutagenesis with in vivo and in vitro phosphatase activity measurements","pmids":["12083364"],"confidence":"High","gaps":["Structural basis of autoinhibition not defined","Physiological trigger relieving inhibition unknown at this point"]},{"year":2006,"claim":"Connected DUSP4 to metabolic transcriptional control, establishing an AMPK→EGR1→DUSP4→p38 axis repressing gluconeogenic gene expression.","evidence":"ChIP, reporter assays, siRNA, and constitutively active p38 rescue in hepatocytes","pmids":["16849326"],"confidence":"High","gaps":["Whether DUSP4 acts on p38 directly in this setting not enzymatically shown","In vivo metabolic relevance untested here"]},{"year":2008,"claim":"Demonstrated an essential developmental role, showing dusp4 is required for endoderm specification, extending its function beyond feedback regulation.","evidence":"Morpholino knockdown in zebrafish with sox17 marker analysis and transplantation","pmids":["18719100"],"confidence":"Medium","gaps":["Morpholino off-target effects not excluded","Molecular substrate driving endoderm phenotype unidentified"]},{"year":2010,"claim":"Resolved how DUSP4 stability is controlled, identifying ERK-mediated C-terminal serine phosphorylation as a stabilizing feedback signal and mapping MEK-dependent phospho-sites that spatially confine ERK activity in oncogene-driven cells.","evidence":"Phospho-site mutagenesis, cycloheximide chase, proteasome and ERK inhibitors, and oncogenic KRAS/BRAF expression with ERK spatial mapping","pmids":["21084841","22430215"],"confidence":"High","gaps":["Kinase responsible for stabilization vs. canonical ERK feedback not fully separated","E3 ligase mediating degradation unidentified"]},{"year":2011,"claim":"Genetic loss-of-function in mice established non-redundant roles in cell-cycle progression, apoptosis, and CD4+ T-cell proliferation control.","evidence":"DUSP4 knockout MEFs and mice with adenoviral rescue, cell-cycle analysis, and STAT5 phosphorylation readouts","pmids":["21317287","22101742"],"confidence":"High","gaps":["Direct substrate for STAT5 regulation in T cells unclear","Tissue-specific requirements not dissected"]},{"year":2012,"claim":"Defined DUSP4 as an epigenetically silenced tumor suppressor whose loss activates Ras-ERK and modulates chemosensitivity in basal-like breast cancer.","evidence":"Gain/loss-of-function in breast cancer cell lines, promoter methylation analysis, MEK-inhibitor combination, and xenografts","pmids":["22683778","20124482"],"confidence":"High","gaps":["Cause of selective promoter methylation unknown","Whether ERK is the sole driver of chemoresistance untested"]},{"year":2013,"claim":"Extended the tumor-suppressor mechanism to dual MEK/ERK and JNK control of cancer stem-cell populations and inflammatory cytokine output via ETS-1 and c-JUN.","evidence":"Knockdown/overexpression in BLBC lines, mammosphere and flow-cytometry assays, MEK-inhibitor rescue, and xenografts","pmids":["23966295"],"confidence":"High","gaps":["Relative contribution of ERK vs JNK arms not quantified","Direct transcription-factor dephosphorylation not shown"]},{"year":2014,"claim":"Confirmed C-terminal serine phosphorylation as the stability determinant in macrophages and broadened DUSP4 function into neuronal differentiation and inflammatory regulation.","evidence":"Phospho-site mutagenesis with half-life and ubiquitination assays in macrophages; knockdown/rescue in ES-derived neurons; G9a-inhibition autophagy studies","pmids":["25204653","25397900","25027955"],"confidence":"High","gaps":["Degradation pathway independent of ubiquitination not mechanistically explained","Calcium-pathway substrates not identified"]},{"year":2015,"claim":"Demonstrated catalytic JNK dephosphorylation drives apoptosis in lymphoma and uncovered a novel GR–JNK1–DUSP4 complex controlling glucocorticoid receptor translocation, expanding the substrate repertoire beyond free MAPKs.","evidence":"Phosphatase-dead mutant rescue and methylation analysis in DLBCL; co-immunoprecipitation, IP-phosphatase activity assay, and GR-Ser226 readouts","pmids":["25847947","28283554"],"confidence":"High","gaps":["Stoichiometry and assembly of the GR-JNK1 complex unresolved","Direct GR dephosphorylation vs JNK-mediated indirect effect not fully separated"]},{"year":2016,"claim":"Established DUSP4 loss at 8p as a driver of invasive progression and showed broad phosphoprotein-level suppression of ERK, p38, JNK, RB, and NF-κB upon DUSP4 induction.","evidence":"Re-expression in pancreatic and TNBC lines, invasion/anoikis assays, phosphoprotein microarray, and orthotopic xenografts","pmids":["26941286","27393618"],"confidence":"Medium","gaps":["Direct vs indirect targets among the 172 phosphoproteins not distinguished","Mechanism of cell-cycle arrest not assigned to a specific substrate"]},{"year":2018,"claim":"Genetic interaction studies revealed cooperative tumor suppression with Dok2 in lung tumorigenesis, reinforcing DUSP4 as a MAPK-restraining suppressor.","evidence":"Compound heterozygous Dok2/Dusp4 mouse knockout with tumor monitoring and restoration experiments","pmids":["30475228"],"confidence":"High","gaps":["Molecular basis of Dok2-DUSP4 cooperation unresolved","Whether the interaction is physical or pathway-level unknown"]},{"year":2019,"claim":"Defined DUSP4 as a feedback tuner across diverse physiological circuits—circadian VIP/ERK signaling in the SCN, diabetic podocyte protection via p38/JNK/Nox4, and PDGF-driven ERK/STAT3/p53 induction.","evidence":"Ex vivo SCN slice culture; DUSP4-/- diabetic mice and podocyte overexpression with PKC-δ inhibition; PDGF stimulation with regulator knockdowns","pmids":["30710088","30862678","31526568"],"confidence":"High","gaps":["Direct p38/JNK dephosphorylation in podocytes not enzymatically demonstrated","Tissue-specific upstream inducers incompletely mapped"]},{"year":2022,"claim":"Linked chromatin regulation (ARID1A, histone acetylation) to DUSP4 silencing and uncovered context-dependent, non-canonical ERK regulation in melanoma where DUSP4 loss acts through DUSP6.","evidence":"ChIP-seq/RNA-seq with ARID1A loss and ectopic DUSP4 rescue; DUSP4/DUSP6 double-knockout epistasis and kinase translocation reporters in melanoma; metabolic KO mouse phenotyping","pmids":["38071325","35189148","35580987","35745205"],"confidence":"High","gaps":["Reconciliation of direct ERK-phosphatase model with DUSP6-dependent paradoxical effect unresolved","Mechanism of DUSP6 post-transcriptional upregulation unknown"]},{"year":2024,"claim":"Expanded the substrate landscape to non-MAPK proteins, showing DUSP4 binds and dephosphorylates HSP90β to activate JAK-STAT3, dephosphorylates ALDOB to restrict G6PD/ROS metabolism, and scaffolds a TBK1-ERK1/2-IRF3 complex governing type I interferon and antimicrobial defense.","evidence":"Co-IP/pulldown with phospho-site mapping and ATPase assays for HSP90β; IP-MS and enzyme assays for ALDOB; reciprocal Co-IP and DUSP4-/- infection models for the TBK1-IRF3 complex","pmids":["37141098","38843658","38383887"],"confidence":"High","gaps":["Whether these non-MAPK activities share a common recognition motif unknown","Structural basis of substrate selection unresolved"]},{"year":2025,"claim":"Connected DUSP4 to cancer metabolism and immune modulation through new substrates, dephosphorylating PGK1-associated ERK to alter glycolysis/ROS and CDK7 to drive CXCL16 expression and CD8+ T-cell infiltration while suppressing ferroptosis.","evidence":"Phosphoproteomics, Co-IP, mitochondrial fractionation, ferroptosis and metabolic assays, and in vivo tumor models in ovarian and MSI colorectal cancers","pmids":["40082940","40847010"],"confidence":"Medium","gaps":["Direct CDK7 dephosphorylation requires reconstitution","Substrate findings from single labs await independent replication"]},{"year":null,"claim":"It remains unresolved how DUSP4 achieves substrate selection across its expanding set of canonical (ERK/JNK) and non-canonical (HSP90β, ALDOB, CDK7, PGK1, TBK1-IRF3) targets and how this selectivity is partitioned between tumor-suppressive and context-dependent oncogenic outcomes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model defines substrate recognition","Whether non-MAPK substrates are dephosphorylated by the same catalytic mechanism is unestablished","Determinants distinguishing tumor-suppressor vs DUSP6-mediated paradoxical roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,4,20]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,20,25,36,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,13,20,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,37]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,24]}],"complexes":["GR-JNK1-DUSP4 complex","TBK1-ERK1/2-IRF3 complex"],"partners":["ERK1/2","JNK1","GR","HSP90B1","ALDOB","TBK1","IRF3","CDK7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13115","full_name":"Dual specificity protein phosphatase 4","aliases":["Dual specificity protein phosphatase hVH2","Mitogen-activated protein kinase phosphatase 2","MAP kinase phosphatase 2","MKP-2"],"length_aa":394,"mass_kda":43.0,"function":"Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13115/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DUSP4","classification":"Not Classified","n_dependent_lines":76,"n_total_lines":1208,"dependency_fraction":0.06291390728476821},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DUSP4","total_profiled":1310},"omim":[{"mim_id":"615814","title":"SERINE/THREONINE/TYROSINE-INTERACTING PROTEIN; STYX","url":"https://www.omim.org/entry/615814"},{"mim_id":"612775","title":"CONE-ROD DYSTROPHY 9; CORD9","url":"https://www.omim.org/entry/612775"},{"mim_id":"603017","title":"CADHERIN 17; CDH17","url":"https://www.omim.org/entry/603017"},{"mim_id":"602749","title":"DUAL-SPECIFICITY PHOSPHATASE 7; DUSP7","url":"https://www.omim.org/entry/602749"},{"mim_id":"602748","title":"DUAL-SPECIFICITY PHOSPHATASE 6; DUSP6","url":"https://www.omim.org/entry/602748"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":30.4},{"tissue":"stomach 1","ntpm":30.5}],"url":"https://www.proteinatlas.org/search/DUSP4"},"hgnc":{"alias_symbol":["HVH2","MKP-2","TYP"],"prev_symbol":[]},"alphafold":{"accession":"Q13115","domains":[{"cath_id":"3.40.250.10","chopping":"9-23_43-161","consensus_level":"high","plddt":87.3827,"start":9,"end":161},{"cath_id":"3.90.190.10","chopping":"198-337","consensus_level":"high","plddt":95.1196,"start":198,"end":337}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13115","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13115-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13115-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DUSP4","jax_strain_url":"https://www.jax.org/strain/search?query=DUSP4"},"sequence":{"accession":"Q13115","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13115.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13115/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13115"}},"corpus_meta":[{"pmid":"8626452","id":"PMC_8626452","title":"The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626452","citation_count":391,"is_preprint":false},{"pmid":"22683778","id":"PMC_22683778","title":"Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance.","date":"2012","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22683778","citation_count":220,"is_preprint":false},{"pmid":"19525976","id":"PMC_19525976","title":"An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19525976","citation_count":194,"is_preprint":false},{"pmid":"7535768","id":"PMC_7535768","title":"Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7535768","citation_count":174,"is_preprint":false},{"pmid":"20725992","id":"PMC_20725992","title":"Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas.","date":"2010","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20725992","citation_count":172,"is_preprint":false},{"pmid":"23966295","id":"PMC_23966295","title":"Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23966295","citation_count":135,"is_preprint":false},{"pmid":"22430215","id":"PMC_22430215","title":"Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22430215","citation_count":76,"is_preprint":false},{"pmid":"29509059","id":"PMC_29509059","title":"MiR-122-5p inhibits cell migration and invasion in gastric cancer by down-regulating DUSP4.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29509059","citation_count":75,"is_preprint":false},{"pmid":"16849326","id":"PMC_16849326","title":"Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16849326","citation_count":68,"is_preprint":false},{"pmid":"20124482","id":"PMC_20124482","title":"Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20124482","citation_count":63,"is_preprint":false},{"pmid":"8545112","id":"PMC_8545112","title":"Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8545112","citation_count":58,"is_preprint":false},{"pmid":"25027955","id":"PMC_25027955","title":"Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25027955","citation_count":56,"is_preprint":false},{"pmid":"25847947","id":"PMC_25847947","title":"DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25847947","citation_count":56,"is_preprint":false},{"pmid":"22965873","id":"PMC_22965873","title":"Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22965873","citation_count":56,"is_preprint":false},{"pmid":"22101742","id":"PMC_22101742","title":"DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development.","date":"2011","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22101742","citation_count":54,"is_preprint":false},{"pmid":"28400477","id":"PMC_28400477","title":"IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28400477","citation_count":53,"is_preprint":false},{"pmid":"21317287","id":"PMC_21317287","title":"Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21317287","citation_count":50,"is_preprint":false},{"pmid":"30710088","id":"PMC_30710088","title":"Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30710088","citation_count":48,"is_preprint":false},{"pmid":"35864956","id":"PMC_35864956","title":"Genome-Wide CRISPR/Cas9 Library Screening Identified that DUSP4 Deficiency Induces Lenvatinib Resistance in Hepatocellular Carcinoma.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35864956","citation_count":47,"is_preprint":false},{"pmid":"26941286","id":"PMC_26941286","title":"Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26941286","citation_count":45,"is_preprint":false},{"pmid":"32528070","id":"PMC_32528070","title":"ΔNp63α-induced DUSP4/GSK3β/SNAI1 pathway in epithelial cells drives endometrial fibrosis.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32528070","citation_count":44,"is_preprint":false},{"pmid":"25733583","id":"PMC_25733583","title":"DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia.","date":"2015","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/25733583","citation_count":43,"is_preprint":false},{"pmid":"27957827","id":"PMC_27957827","title":"Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4/ERK pathway.","date":"2016","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27957827","citation_count":43,"is_preprint":false},{"pmid":"29212207","id":"PMC_29212207","title":"DUSP4 promotes doxorubicin resistance in gastric cancer through epithelial-mesenchymal transition.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29212207","citation_count":42,"is_preprint":false},{"pmid":"26184564","id":"PMC_26184564","title":"Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26184564","citation_count":41,"is_preprint":false},{"pmid":"30862678","id":"PMC_30862678","title":"Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy.","date":"2019","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30862678","citation_count":40,"is_preprint":false},{"pmid":"23749251","id":"PMC_23749251","title":"Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer.","date":"2013","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23749251","citation_count":37,"is_preprint":false},{"pmid":"32188842","id":"PMC_32188842","title":"Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32188842","citation_count":34,"is_preprint":false},{"pmid":"25397900","id":"PMC_25397900","title":"DUSP4 regulates neuronal differentiation and calcium homeostasis by modulating ERK1/2 phosphorylation.","date":"2014","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/25397900","citation_count":32,"is_preprint":false},{"pmid":"18719100","id":"PMC_18719100","title":"Transcriptional profiling of endogenous germ layer precursor cells identifies dusp4 as an essential gene in zebrafish endoderm specification.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18719100","citation_count":32,"is_preprint":false},{"pmid":"27604655","id":"PMC_27604655","title":"Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27604655","citation_count":30,"is_preprint":false},{"pmid":"32470454","id":"PMC_32470454","title":"MiR-122-5p protects against acute lung injury via regulation of DUSP4/ERK signaling in pulmonary microvascular endothelial cells.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32470454","citation_count":29,"is_preprint":false},{"pmid":"32505357","id":"PMC_32505357","title":"DUSP4 is involved in the enhanced proliferation and survival of DUSP4-overexpressing cancer cells.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32505357","citation_count":28,"is_preprint":false},{"pmid":"29100381","id":"PMC_29100381","title":"DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29100381","citation_count":28,"is_preprint":false},{"pmid":"22683570","id":"PMC_22683570","title":"Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury.","date":"2012","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22683570","citation_count":27,"is_preprint":false},{"pmid":"32090865","id":"PMC_32090865","title":"Unraveling the role of H3K4 trimethylation and lncRNA HOTAIR in SATB1 and DUSP4-dependent survival of virulent Mycobacterium tuberculosis in macrophages.","date":"2019","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/32090865","citation_count":26,"is_preprint":false},{"pmid":"27393618","id":"PMC_27393618","title":"Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/27393618","citation_count":26,"is_preprint":false},{"pmid":"30475228","id":"PMC_30475228","title":"Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30475228","citation_count":25,"is_preprint":false},{"pmid":"9205128","id":"PMC_9205128","title":"Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7).","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9205128","citation_count":25,"is_preprint":false},{"pmid":"31839677","id":"PMC_31839677","title":"Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.","date":"2019","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31839677","citation_count":24,"is_preprint":false},{"pmid":"28554129","id":"PMC_28554129","title":"Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28554129","citation_count":24,"is_preprint":false},{"pmid":"21084841","id":"PMC_21084841","title":"Post-translational regulation of mitogen-activated protein kinase phosphatase-2 (MKP-2) by ERK.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21084841","citation_count":23,"is_preprint":false},{"pmid":"31401382","id":"PMC_31401382","title":"Estradiol inhibits fMLP-induced neutrophil migration and superoxide production by upregulating MKP-2 and dephosphorylating ERK.","date":"2019","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31401382","citation_count":23,"is_preprint":false},{"pmid":"37141098","id":"PMC_37141098","title":"DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37141098","citation_count":22,"is_preprint":false},{"pmid":"31258782","id":"PMC_31258782","title":"miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31258782","citation_count":22,"is_preprint":false},{"pmid":"31480854","id":"PMC_31480854","title":"GFAP alternative splicing regulates glioma cell-ECM interaction in a DUSP4-dependent manner.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31480854","citation_count":21,"is_preprint":false},{"pmid":"24973647","id":"PMC_24973647","title":"Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd²⁺-induced apoptosis.","date":"2014","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24973647","citation_count":21,"is_preprint":false},{"pmid":"27143921","id":"PMC_27143921","title":"DUSP4/MKP2 overexpression is associated with BRAF(V600E) mutation and aggressive behavior of papillary thyroid cancer.","date":"2016","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27143921","citation_count":18,"is_preprint":false},{"pmid":"36497141","id":"PMC_36497141","title":"Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36497141","citation_count":18,"is_preprint":false},{"pmid":"38071325","id":"PMC_38071325","title":"ARID1A loss activates MAPK signaling via DUSP4 downregulation.","date":"2023","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/38071325","citation_count":17,"is_preprint":false},{"pmid":"22260697","id":"PMC_22260697","title":"MKP-2: out of the DUSP-bin and back into the limelight.","date":"2012","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/22260697","citation_count":17,"is_preprint":false},{"pmid":"25204653","id":"PMC_25204653","title":"Post-translational regulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2 in macrophages following lipopolysaccharide stimulation: the role of the C termini of the phosphatases in determining their stability.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25204653","citation_count":17,"is_preprint":false},{"pmid":"38383887","id":"PMC_38383887","title":"DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38383887","citation_count":16,"is_preprint":false},{"pmid":"32890776","id":"PMC_32890776","title":"DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex.","date":"2020","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/32890776","citation_count":16,"is_preprint":false},{"pmid":"23471219","id":"PMC_23471219","title":"MAPK phosphatase-2 (MKP-2) is induced by hCG and plays a role in the regulation of CYP11A1 expression in MA-10 Leydig cells.","date":"2013","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23471219","citation_count":16,"is_preprint":false},{"pmid":"35745205","id":"PMC_35745205","title":"Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/35745205","citation_count":15,"is_preprint":false},{"pmid":"35580987","id":"PMC_35580987","title":"DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation of MITF.","date":"2022","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/35580987","citation_count":15,"is_preprint":false},{"pmid":"12865160","id":"PMC_12865160","title":"The I(1)-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase.","date":"2003","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12865160","citation_count":15,"is_preprint":false},{"pmid":"37964351","id":"PMC_37964351","title":"ADSC secretome constrains NK cell activity by attenuating IL-2-mediated JAK-STAT and AKT signaling pathway via upregulation of CIS and DUSP4.","date":"2023","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37964351","citation_count":14,"is_preprint":false},{"pmid":"24658355","id":"PMC_24658355","title":"Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24658355","citation_count":13,"is_preprint":false},{"pmid":"35923224","id":"PMC_35923224","title":"SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice.","date":"2022","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35923224","citation_count":13,"is_preprint":false},{"pmid":"12083364","id":"PMC_12083364","title":"The carboxyl-terminal domains of MKP-1 and MKP-2 have inhibitory effects on their phosphatase activity.","date":"2002","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12083364","citation_count":13,"is_preprint":false},{"pmid":"34650647","id":"PMC_34650647","title":"DUSP4 alleviates LPS-induced chondrocyte injury in knee osteoarthritis via the MAPK signaling pathway.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34650647","citation_count":13,"is_preprint":false},{"pmid":"28283554","id":"PMC_28283554","title":"Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity.","date":"2017","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28283554","citation_count":12,"is_preprint":false},{"pmid":"33760201","id":"PMC_33760201","title":"miR‑122‑5p suppresses the oncogenesis of PTC by inhibiting DUSP4 expression.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33760201","citation_count":12,"is_preprint":false},{"pmid":"23127286","id":"PMC_23127286","title":"MEK inhibition as a strategy for targeting residual breast cancer cells with low DUSP4 expression.","date":"2012","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/23127286","citation_count":12,"is_preprint":false},{"pmid":"32897241","id":"PMC_32897241","title":"DUSP4 directly deubiquitinates and stabilizes Smad4 protein, promoting proliferation and metastasis of colorectal cancer cells.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32897241","citation_count":11,"is_preprint":false},{"pmid":"35940125","id":"PMC_35940125","title":"Reduction of DUSP4 contributes to podocytes oxidative stress, insulin resistance and diabetic nephropathy.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35940125","citation_count":11,"is_preprint":false},{"pmid":"33495832","id":"PMC_33495832","title":"The microRNA-429/DUSP4 axis regulates the sensitivity of colorectal cancer cells to nintedanib.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33495832","citation_count":11,"is_preprint":false},{"pmid":"36705792","id":"PMC_36705792","title":"DUSP4 inhibits autophagic cell death and apoptosis in colorectal cancer by regulating BCL2-Beclin1/Bax signaling.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36705792","citation_count":10,"is_preprint":false},{"pmid":"36234680","id":"PMC_36234680","title":"DUSP4 Silencing Enhances the Sensitivity of Breast Cancer Cells to Doxorubicin through the Activation of the JNK/c-Jun Signalling Pathway.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36234680","citation_count":10,"is_preprint":false},{"pmid":"25654406","id":"PMC_25654406","title":"Ethanolic extract of Allium cepa stimulates glucose transporter typ 4-mediated glucose uptake by the activation of insulin signaling.","date":"2015","source":"Planta medica","url":"https://pubmed.ncbi.nlm.nih.gov/25654406","citation_count":9,"is_preprint":false},{"pmid":"31526568","id":"PMC_31526568","title":"Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31526568","citation_count":9,"is_preprint":false},{"pmid":"33621155","id":"PMC_33621155","title":"DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling.","date":"2021","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/33621155","citation_count":8,"is_preprint":false},{"pmid":"35850776","id":"PMC_35850776","title":"Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer.","date":"2022","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/35850776","citation_count":8,"is_preprint":false},{"pmid":"32951127","id":"PMC_32951127","title":"Aberrant expression of DUSP4 is a specific phenomenon in betel quid-related oral cancer.","date":"2020","source":"Medical molecular morphology","url":"https://pubmed.ncbi.nlm.nih.gov/32951127","citation_count":8,"is_preprint":false},{"pmid":"34143206","id":"PMC_34143206","title":"DUSP4 promotes the carcinogenesis of CCRCC via negative regulation of autophagic death.","date":"2021","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34143206","citation_count":8,"is_preprint":false},{"pmid":"32974341","id":"PMC_32974341","title":"Dusp4 Contributes to Anesthesia Neurotoxicity via Mediated Neural Differentiation in Primates.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32974341","citation_count":8,"is_preprint":false},{"pmid":"34937541","id":"PMC_34937541","title":"Lysine-Specific Histone Demethylase 1 Promotes Oncogenesis of the Esophageal Squamous Cell Carcinoma by Upregulating DUSP4.","date":"2021","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/34937541","citation_count":8,"is_preprint":false},{"pmid":"23437409","id":"PMC_23437409","title":"T cell hypo-responsiveness against Leishmania major in MAP kinase phosphatase (MKP) 2 deficient C57BL/6 mice does not alter the healer disease phenotype.","date":"2013","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23437409","citation_count":7,"is_preprint":false},{"pmid":"37967942","id":"PMC_37967942","title":"DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37967942","citation_count":6,"is_preprint":false},{"pmid":"34254709","id":"PMC_34254709","title":"Transcriptional regulation of human DUSP4 gene by cancer-related transcription factors.","date":"2021","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34254709","citation_count":6,"is_preprint":false},{"pmid":"34236463","id":"PMC_34236463","title":"SAHA could inhibit TGF-β1/p38 pathway in MI-induced cardiac fibrosis through DUSP4 overexpression.","date":"2021","source":"Heart and vessels","url":"https://pubmed.ncbi.nlm.nih.gov/34236463","citation_count":6,"is_preprint":false},{"pmid":"36127345","id":"PMC_36127345","title":"Silencing circFTO inhibits malignant phenotype through modulating DUSP4 expression in clear cell renal cell carcinoma.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36127345","citation_count":5,"is_preprint":false},{"pmid":"33662786","id":"PMC_33662786","title":"Nicotine-derived NNK induces the stemness enrichment of CRC cells through regulating the balance of DUSP4-ERK1/2 feedback loop.","date":"2021","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/33662786","citation_count":5,"is_preprint":false},{"pmid":"40082940","id":"PMC_40082940","title":"DUSP4 inhibited tumor cell proliferation by downregulating glycolysis via p-ERK/p-PGK1 signaling in ovarian cancer.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40082940","citation_count":4,"is_preprint":false},{"pmid":"40241046","id":"PMC_40241046","title":"The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells.","date":"2025","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/40241046","citation_count":4,"is_preprint":false},{"pmid":"40320567","id":"PMC_40320567","title":"Exosomal miR-122-5p for regulation of secretory functions of fibroblasts and promotion of breast cancer metastasis by targeting MKP-2: an experimental study.","date":"2025","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40320567","citation_count":4,"is_preprint":false},{"pmid":"34652441","id":"PMC_34652441","title":"Long non-coding RNA AFAP1-AS1 promotes thyroid cancer progression by sponging miR-204-3p and upregulating DUSP4.","date":"2022","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34652441","citation_count":4,"is_preprint":false},{"pmid":"32613839","id":"PMC_32613839","title":"Expression of DUSP4 transcript variants as a potential biomarker for colorectal cancer.","date":"2020","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32613839","citation_count":4,"is_preprint":false},{"pmid":"36474060","id":"PMC_36474060","title":"TAT-Beclin 1 represses the carcinogenesis of DUSP4-positive PTC by enhancing autophagy.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36474060","citation_count":4,"is_preprint":false},{"pmid":"37946160","id":"PMC_37946160","title":"Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37946160","citation_count":4,"is_preprint":false},{"pmid":"35189148","id":"PMC_35189148","title":"DUSP4 Inactivation Leads to Reduced Extracellular Signal‒Regulated Kinase Activity through Upregulation of DUSP6 in Melanoma Cells.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35189148","citation_count":4,"is_preprint":false},{"pmid":"38843658","id":"PMC_38843658","title":"DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38843658","citation_count":4,"is_preprint":false},{"pmid":"35496267","id":"PMC_35496267","title":"ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35496267","citation_count":4,"is_preprint":false},{"pmid":"31936698","id":"PMC_31936698","title":"Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31936698","citation_count":4,"is_preprint":false},{"pmid":"72553","id":"PMC_72553","title":"[Structures of oncornaviruses of C-typ-negativ staining technique by electron microscopy (author's transl)].","date":"1977","source":"Archiv fur Geschwulstforschung","url":"https://pubmed.ncbi.nlm.nih.gov/72553","citation_count":4,"is_preprint":false},{"pmid":"36576731","id":"PMC_36576731","title":"Investigating the Role of DUSP4 in Uveal Melanoma.","date":"2022","source":"Translational vision science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/36576731","citation_count":2,"is_preprint":false},{"pmid":"40847010","id":"PMC_40847010","title":"The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8+ T cells in MSI colorectal cancer.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40847010","citation_count":2,"is_preprint":false},{"pmid":"38254666","id":"PMC_38254666","title":"Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer's Disease.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38254666","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52477,"output_tokens":10982,"usd":0.16108,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21881,"output_tokens":5892,"usd":0.128353,"stage2_stop_reason":"end_turn"},"total_usd":0.289433,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"HVH2 (DUSP4) is a dual-specificity phosphatase that selectively dephosphorylates both phosphothreonine and phosphotyrosine residues of activated ERK1 and ERK2 in vitro, and localizes to the cell nucleus. Transfection into NIH3T3 cells inhibited v-src and MEK-induced transcriptional activation of SRE-containing promoters.\",\n      \"method\": \"In vitro phosphatase assay with recombinant protein, immunofluorescence of epitope-tagged protein, transfection/reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with recombinant protein, direct localization by immunofluorescence, and functional reporter assay; foundational characterization paper with multiple orthogonal methods\",\n      \"pmids\": [\"7535768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TYP1 (DUSP4) encodes a nuclear dual-specificity phosphatase that inactivates both ERK2 and p54 JNK. Purified TYP1 protein efficiently dephosphorylates both phosphothreonine and phosphotyrosine of recombinant ERK2 in vitro. In COS cells, TYP1 protein is stabilized by EGF treatment.\",\n      \"method\": \"In vitro phosphatase assay with purified protein, transfection in COS-1 cells, northern analysis for expression kinetics\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein plus ERK2/JNK substrate specificity established; corroborated by independent lab (PMID:7535768)\",\n      \"pmids\": [\"8545112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MKP-2 (DUSP4) has a unique in vivo substrate specificity toward ERK and JNK (but not p38), distinguishing it from PAC1 (ERK/p38) and MKP-1 (ERK/p38/JNK). A hyperactive ERK2 allele (D319N, sevenmaker) showed significantly reduced sensitivity to MKP-2 dephosphorylation in vivo.\",\n      \"method\": \"In vivo substrate specificity assay in T cells using phorbol ester stimulation, co-expression of phosphatases with MAP kinase substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo substrate specificity established with multiple kinase substrates and gain-of-function ERK2 mutant, replicated across three phosphatases in the same study\",\n      \"pmids\": [\"8626452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"DUSP4 (MKP-2) gene maps to chromosomal location 8p11-p12 by fluorescence in situ hybridization and radiation hybrid mapping.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by two independent mapping methods in a single study\",\n      \"pmids\": [\"9205128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C-terminal domain of MKP-2 (DUSP4) exerts an inhibitory effect on its phosphatase activity. C-terminal truncation of MKP-2 substantially increased phosphatase activity toward MAPK substrates both in vivo and in vitro without changing substrate affinity or substrate-mediated catalytic activation.\",\n      \"method\": \"C-terminal deletion mutagenesis, in vivo and in vitro phosphatase activity assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay combined with mutagenesis; both in vivo and in vitro measurements in single study\",\n      \"pmids\": [\"12083364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"I1-imidazoline receptor stimulation with moxonidine induces MKP-2 (DUSP4) protein levels approximately 3-fold in PC12 cells and reverses NGF-induced ERK activation, effects blocked by the I1-antagonist efaroxan or by D609 (phosphatidylcholine-selective PLC inhibitor), placing DUSP4 induction downstream of I1-receptor/phospholipase C signaling.\",\n      \"method\": \"Western blot for MKP-2 protein, pharmacological inhibitors, ERK activation assay in PC12 cells\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, pharmacological pathway dissection with multiple inhibitors\",\n      \"pmids\": [\"12865160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AMPK activation (by AICAR) induces DUSP4 expression in hepatocytes via transcriptional induction of EGR1, which directly binds the DUSP4 promoter. DUSP4 in turn inhibits promoter activity and expression of gluconeogenic genes PEPCK and Glucose-6-phosphatase. Constitutively active p38 rescued DUSP4-mediated repression of PEPCK. siRNA depletion of EGR1 or DUSP4 partially abrogated AICAR-mediated inhibition of PEPCK and glucose production.\",\n      \"method\": \"Reporter gene assays, real-time PCR, siRNA knockdown, ChIP (EGR1 binding to DUSP4 promoter), constitutively active p38 rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, siRNA, constitutively active rescue) in one study establishing AMPK→EGR1→DUSP4→p38→PEPCK axis\",\n      \"pmids\": [\"16849326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"dusp4 is essential for early zebrafish endoderm specification; morpholino-mediated knockdown caused necrosis of head tissues and a specific loss of sox17 expression (but not other endoderm markers), indicating a required role in foregut and pancreatic endoderm formation.\",\n      \"method\": \"Antisense morpholino oligonucleotide knockdown in zebrafish, marker analysis (in situ hybridization for sox17), transplantation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific marker readout in zebrafish ortholog; single study\",\n      \"pmids\": [\"18719100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Oncogenic KRAS(G12V) and BRAF(V600E) induce rapid nuclear accumulation of DUSP4 (in an MEK-dependent manner), which dephosphorylates and restricts ERK phosphorylation specifically to the cytoplasm in intestinal epithelial cells. MEK-dependent phosphorylation of DUSP4 at T361, T363, S390, and S395 residues stabilizes the protein. In human colorectal cancer cells, ERK activity was similarly confined to the cytoplasm and treatment with pervanadate reactivated nuclear ERK.\",\n      \"method\": \"Expression of oncogenic KRAS/BRAF in IECs, immunofluorescence for ERK phosphorylation, MEK inhibitor treatment, phospho-site mapping, pervanadate treatment in CRC cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — spatial ERK activity mapping combined with pharmacological and genetic perturbation and phospho-site identification; multiple orthogonal methods\",\n      \"pmids\": [\"22430215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MKP-2 (DUSP4) is phosphorylated by ERK at Ser386 and Ser391 in its C-terminus, and this phosphorylation stabilizes MKP-2 protein by protecting it from proteasomal degradation. Blockade of ERK activation enhanced proteasomal degradation of MKP-2, and phosphorylation had no effect on MKP-2 phosphatase activity.\",\n      \"method\": \"Site-directed mutagenesis of phospho-sites (S386, S391), ERK inhibitor treatment, proteasome inhibitor assay, Western blot for protein stability\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phospho-site mutagenesis combined with proteasome inhibitor and ERK inhibitor experiments; identifies ERK as writer of stabilizing phosphorylation\",\n      \"pmids\": [\"21084841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DUSP4/MKP-2 promoter CpG island hypermethylation in gliomas reduces MKP-2 mRNA and protein expression. Treatment with 5-aza-2'-deoxycytidine (demethylating agent) increased MKP-2 mRNA, and exogenous MKP-2 overexpression inhibited glioblastoma cell growth.\",\n      \"method\": \"Differential methylation hybridization, 5-aza-2'-deoxycytidine demethylation, overexpression growth assay in glioblastoma cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism (promoter methylation) linked to expression and functional outcome; single lab but methylation and functional overexpression assays performed\",\n      \"pmids\": [\"20124482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DUSP4/MKP-2 knockout MEFs show enhanced PDGF-induced sustained ERK phosphorylation and moderately increased JNK phosphorylation, reduced cellular proliferation (with block at G2/M associated with cyclin B accumulation and enhanced cdc2 phosphorylation), and enhanced anisomycin-induced apoptosis (increased caspase-3 cleavage and γH2AX). Adenoviral re-expression of MKP-2 reversed both proliferation defects and JNK-associated apoptosis.\",\n      \"method\": \"MKP-2 knockout MEFs from deletion mouse model, adenoviral MKP-2 rescue, cell cycle analysis, Western blot for cyclin B/cdc2/caspase-3/γH2AX\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO model with multiple phenotypic readouts and adenoviral rescue; establishes non-redundant roles in cell cycle and apoptosis\",\n      \"pmids\": [\"21317287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DUSP4 deficiency in mice results in hyperproliferation of activated CD4+ T cells (but not CD8+ T cells) due to enhanced CD25 expression and increased IL-2 signaling through elevated STAT5 phosphorylation, revealing a role for DUSP4 in suppressing CD4+ T-cell proliferation via STAT5/IL-2 pathway regulation.\",\n      \"method\": \"DUSP4 knockout mouse, T-cell proliferation assays, STAT5 phosphorylation by Western blot, immunization recall response\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with specific cellular phenotype, STAT5 phosphorylation mechanistic readout; multiple immune readouts\",\n      \"pmids\": [\"22101742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DUSP4 is an ERK phosphatase whose loss in basal-like breast cancer (BLBC) correlates with DUSP4 promoter methylation and activates the Ras-ERK pathway. DUSP4 overexpression increased chemotherapy-induced apoptosis in BLBC cells, while DUSP4 depletion dampened the chemotherapy response. MEK inhibition synergized with docetaxel in BLBC xenografts.\",\n      \"method\": \"DUSP4 overexpression and siRNA knockdown in breast cancer cell lines, xenograft model, MEK inhibitor combination, digital transcript counting of post-NAC tumors\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cancer cell line gain/loss-of-function experiments plus in vivo xenograft validation; mechanistic link to ERK pathway confirmed\",\n      \"pmids\": [\"22683778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MKP-2 (DUSP4) knockdown in macrophages attenuated the proinflammatory cytokine production and neutrophil infiltration in a murine LPS-induced acute lung injury model. MKP-2 knockdown was associated with increased ERK phosphorylation and induction of MKP-1, suggesting a regulatory interplay between these DUSPs.\",\n      \"method\": \"MKP-2 null mice (MKP-2−/−), MKP-2 knockdown in macrophage cell line, intratracheal LPS model, cytokine measurement, neutrophil counting\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse and cell-based knockdown with defined inflammatory phenotype; single lab\",\n      \"pmids\": [\"22683570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DUSP4 loss in basal-like breast cancer activates both MEK/ERK and JNK pathways, increasing mammosphere formation, CD44+/CD24- cancer stem cell-like populations, and IL-6/IL-8 expression through downstream ETS-1 and c-JUN transcription factors. Enforced DUSP4 expression reduced cancer stem cell populations in a MEK-dependent manner.\",\n      \"method\": \"DUSP4 knockdown/overexpression in BLBC cell lines, mammosphere assay, flow cytometry for CD44+/CD24−, cytokine measurement, MEK inhibitor rescue, xenograft tumor formation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple BLBC cell lines, multiple orthogonal readouts (mammosphere, flow cytometry, cytokines), MEK-dependent rescue, in vivo xenograft\",\n      \"pmids\": [\"23966295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DUSP4 is induced by hCG/LH in MA-10 Leydig cells via cAMP/PKA signaling, and MKP-2 downregulation by shRNA elevated phosphorylated ERK1/2 after 8Br-cAMP stimulation and increased CYP11A1 (P450scc) promoter activity and mRNA levels, demonstrating that MKP-2 modulates the late phase of cAMP-induced ERK1/2 activity and consequently CYP11A1 expression.\",\n      \"method\": \"shRNA knockdown, promoter-reporter assay, hCG/8Br-cAMP stimulation, phospho-ERK1/2 Western blot, mRNA quantification\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA-mediated knockdown with multiple readouts (ERK phosphorylation, promoter activity, mRNA); single lab\",\n      \"pmids\": [\"23471219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inhibition of the histone methyltransferase G9a induces DUSP4-dependent ERK inactivation and autophagic cell death in head and neck squamous cell carcinoma cells, identifying DUSP4 as a downstream mediator linking G9a inhibition to autophagy.\",\n      \"method\": \"G9a genetic/pharmacological inhibition, Affymetrix microarray for target identification, immunoblot, flow cytometry, fluorescent/electron microscopy, xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — G9a inhibition→DUSP4→ERK→autophagy pathway established with multiple methods; single lab\",\n      \"pmids\": [\"25027955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DUSP4 regulates neuronal differentiation and calcium homeostasis by modulating ERK1/2 phosphorylation. DUSP4 knockdown reduced neurite outgrowth and neuronal marker expression (rescued by DUSP4 reintroduction), enhanced ERK activation during differentiation, and altered calcium signaling by regulating CaMKI phosphorylation and Cav1.2 expression and plasma membrane localization.\",\n      \"method\": \"DUSP4 knockdown/reintroduction in embryonic stem cell-derived neurons, neurite outgrowth assay, Western blot for ERK/CaMKI, Cav1.2 localization by imaging\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with rescue, multiple downstream readouts linking DUSP4-ERK to calcium pathway; single lab\",\n      \"pmids\": [\"25397900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MKP-2 (DUSP4) stability in macrophages is regulated by ERK-mediated phosphorylation of two C-terminal serine residues. Mutation of these serines to alanine decreased MKP-2 half-life, while aspartate substitution dramatically increased it. C-terminal truncation also increased stability. Enhanced stability was not associated with decreased ubiquitination; degradation required proteasome activity.\",\n      \"method\": \"Site-directed mutagenesis of C-terminal serines, half-life measurement by cycloheximide chase, proteasome inhibitor, ubiquitination assays, ERK pathway inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phospho-site mutagenesis combined with half-life measurement, proteasome inhibition, and ubiquitination assay; replicated finding from PMID:21084841 with additional mechanistic detail\",\n      \"pmids\": [\"25204653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ectopic expression of wild-type DUSP4, but not a phosphatase-deficient mutant, dephosphorylates JNK and induces apoptosis in diffuse large B cell lymphoma (DLBCL) cells. DUSP4 loss is caused by CpG island promoter hypermethylation and genomic deletion, and DLBCL cells depend on JNK signaling for survival.\",\n      \"method\": \"Ectopic expression of WT vs. phosphatase-dead DUSP4 mutant, JNK phosphorylation assay, apoptosis assay, genome-wide DNA methylation analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphatase-dead mutant used to confirm catalytic requirement; JNK dephosphorylation directly demonstrated; replicated in multiple DLBCL models\",\n      \"pmids\": [\"25847947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUSP4 modulates p38 phosphorylation in endothelial cells and heart. DUSP4 is degraded by hypoxia/reoxygenation (H/R) and its loss correlates with p38 hyperphosphorylation and apoptosis. DUSP4-/- hearts showed larger infarcts with overactivated p38 after ischemia/reperfusion. p38 inhibition rescued both WT and DUSP4-/- cardiac function.\",\n      \"method\": \"DUSP4 knockdown (siRNA), DUSP4-/- mouse Langendorff-perfused heart model, TUNEL assay, Western blot for p38/caspase-3, p38 inhibitor (SB203580)\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus siRNA knockdown in endothelial cells, p38 inhibitor pharmacological rescue, in vivo infarct measurement\",\n      \"pmids\": [\"26184564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Increased DUSP4 expression in CD4+ T cells from idiopathic CD4 lymphopenia (ICL) patients suppresses TCR-induced ERK activation and downregulates CD27 and CD40L. siRNA normalization of DUSP4 expression in ICL cells restored ERK activation and costimulatory molecule expression. Repeated TCR stimulation in control T cells induced DUSP4 overexpression and TCR signal dampening, both curtailed by DUSP4 silencing.\",\n      \"method\": \"siRNA knockdown in primary human T cells from ICL patients, TCR stimulation, ERK phosphorylation assay, flow cytometry for surface markers\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA in primary human cells with multiple functional readouts; single lab study\",\n      \"pmids\": [\"25733583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Restoration of DUSP4 expression in pancreatic cancer cells suppressed invasiveness and anoikis resistance via ERK inactivation, and MEK inhibition was effective in an orthotopic xenograft model. DUSP4 genomic loss at 8p is associated with progression from noninvasive intraepithelial neoplasm to invasive carcinoma.\",\n      \"method\": \"DUSP4 re-expression in pancreatic cancer cell lines, invasion/anoikis assays, MEK inhibitor in orthotopic xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with invasion/survival readouts and in vivo confirmation; ERK mechanism inferred from MEK inhibitor data\",\n      \"pmids\": [\"26941286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Induced DUSP4 expression in triple-negative breast cancer cells blocks cell cycle at G1/S checkpoint and inhibits ERK1/2, p38, JNK1, RB, and NFκB p65 phosphorylation, as well as in vitro and in vivo growth and invasiveness. Protein microarray of 172 phosphoproteins was used to map DUSP4-regulated signaling.\",\n      \"method\": \"DUSP4 overexpression, protein/phosphoprotein microarray (172 proteins), cell cycle analysis, in vivo xenograft, invasion assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic array provides broad pathway mapping; multiple functional readouts; single lab\",\n      \"pmids\": [\"27393618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DUSP4 associates with GR (glucocorticoid receptor) and JNK1 in a complex, dephosphorylates JNK1, and prevents phosphorylation of GR at Ser226 (which impairs GR nuclear translocation). DUSP4 knockdown enhanced JNK1 and GR-Ser226 phosphorylation, reduced GR nuclear translocation, and decreased corticosteroid sensitivity. Formoterol enhanced DUSP4 phosphatase activity and restored corticosteroid sensitivity reduced by DUSP4 siRNA.\",\n      \"method\": \"Co-immunoprecipitation of DUSP4-GR-JNK1, siRNA knockdown, fluorescence-based IP-DUSP4 phosphatase activity assay, imaging flow cytometry for GR nuclear translocation, Western blot for phospho-JNK1 and phospho-GR-Ser226\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-immunoprecipitation identifying ternary complex, direct phosphatase activity assay, siRNA and formoterol perturbations, multiple orthogonal methods\",\n      \"pmids\": [\"28283554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Compound heterozygous deletion of Dok2 and Dusp4 in mice results in lung tumorigenesis with short latency and high incidence, synergistically activating MAPK signaling and promoting cell proliferation. Restoration of both DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation.\",\n      \"method\": \"Mouse ortholog compound heterozygous knockout, lung tumor incidence monitoring, MAPK signaling assays in primary cells and cell lines, DOK2/DUSP4 restoration experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetic model plus cell line restoration experiments; establishes synthetic functional interaction\",\n      \"pmids\": [\"30475228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VIP signaling in the suprachiasmatic nucleus (SCN) requires ERK1/2 activity and is tuned by DUSP4 as a negative regulator to drive circadian re-programming. ERK1/2 and DUSP4 are critical elements of VIP-directed synchronization of SCN circadian oscillations.\",\n      \"method\": \"SCN organotypic slice culture with VIP treatment, ERK inhibition, transcriptional profiling, circadian clock assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic perturbation in ex vivo SCN slices; mechanistic role of DUSP4 in VIP/ERK/circadian circuit established; single study\",\n      \"pmids\": [\"30710088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP4 expression is induced by PDGF-BB in an ERK1/2-, STAT3-, and p53-dependent manner. ERK1/2 inhibition reduced DUSP4 mRNA levels; STAT3 was necessary for maintaining p53 expression; and p53, which has binding sites in the DUSP4 promoter, was found to promote DUSP4 transcription.\",\n      \"method\": \"PDGF-BB stimulation, ERK/STAT3/p53 inhibitors and knockdown, DUSP4 mRNA quantification, promoter binding analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic dissection of transcriptional induction with multiple regulators; single lab\",\n      \"pmids\": [\"31526568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Diabetes-induced reduction of DUSP4 in podocytes enhances p38 and JNK activity and podocyte dysfunction. DUSP4 overexpression prevented activation of p38, JNK, caspase 3/7, and NADPH oxidase 4 (Nox4) expression induced by high glucose. DUSP4-/- diabetic mice showed exacerbated albuminuria, mesangial expansion, glomerular fibrosis, podocyte foot process effacement, and sustained p38/JNK activation. PKC-δ inhibition prevented DUSP4 expression decline.\",\n      \"method\": \"DUSP4 overexpression in cultured podocytes, DUSP4-/- diabetic mouse model, PKC-δ inhibitor, Western blot for p38/JNK/caspase-3/Nox4, glomerular histology\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell culture gain-of-function plus KO mouse model; multiple mechanistic readouts identifying p38/JNK/Nox4 as downstream effectors; PKC-δ as upstream regulator\",\n      \"pmids\": [\"30862678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ΔNp63α induces DUSP4 expression in endometrial epithelial cells, activating a DUSP4/GSK-3β/SNAI1 pathway that drives epithelial-mesenchymal transition (EMT). bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis by blocking this pathway.\",\n      \"method\": \"ΔNp63α forced expression in endometrial epithelial cells, transcriptomic analysis, Western blot for GSK-3β/SNAI1, bFGF rescue in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway established by transcriptomics plus functional perturbation with bFGF rescue; single lab\",\n      \"pmids\": [\"32528070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DUSP4 transcriptionally modulates DUSP4 expression through STAT3 and YY1 binding sites in DUSP4 promoters. CTCF stimulated promoter 2 activity while STAT3 stimulated promoter 1 activity; YY1 positively regulated both promoters. Functionality of YY1 binding sites confirmed by site-directed mutagenesis.\",\n      \"method\": \"Luciferase reporter assays, site-directed mutagenesis of TF binding sites, in silico prediction of binding sites\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assays with mutagenesis to confirm YY1 binding sites; multiple TFs tested\",\n      \"pmids\": [\"34254709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARID1A loss in endometrial epithelial cells downregulates DUSP4 via decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 regulatory regions, leading to MAPK pathway activation. Ectopic DUSP4 expression decreased cell proliferation, and pharmacological MAPK pathway inhibition mitigated tumor formation in vivo.\",\n      \"method\": \"RNA-seq of ARID1A-deficient cells, ChIP-seq for H3K27Ac/H3K9Ac on DUSP4 locus, DUSP4 ectopic expression, MEK inhibitor in vivo, genetically engineered mouse models\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq defines epigenetic mechanism, RNA-seq for transcriptome, ectopic DUSP4 rescue, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"38071325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DUSP4 depletion in BRAF/NRAS-mutant melanoma leads to toxic levels of MAPK hyperactivation (oncogene overdose) and downregulation of lineage-defining genes including MITF. This phenotype occurs in both drug-naive and drug-resistant melanoma cells.\",\n      \"method\": \"DUSP4 depletion in melanoma cell lines, ERK/MAPK activation assays, MITF and lineage gene expression analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with multiple melanoma lines and downstream readouts; single lab\",\n      \"pmids\": [\"35580987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DUSP4 inactivation in melanoma unexpectedly leads to reduced ERK1/2 phosphorylation rather than ERK activation, through upregulation of DUSP6 at a post-transcriptional level. DUSP6 knockout eliminated the DUSP4-depletion effect on ERK activity and cell growth, placing DUSP4 upstream of DUSP6 in ERK regulation in melanoma.\",\n      \"method\": \"DUSP4 depletion and DUSP6 knockout in melanoma lines, kinase translocation reporter for ERK activity, immunoblotting for DUSP4/DUSP6/pERK\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-KO epistasis and kinase reporter; single lab; finding challenges the direct ERK-phosphatase model\",\n      \"pmids\": [\"35189148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MKP-2 (DUSP4) is upregulated in obesity and fatty liver disease. MKP-2 deficient mice are protected against diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Loss of MKP-2 enhanced p38, JNK, and ERK activities in insulin-responsive tissues and was associated with enhanced Akt activity linked to downregulated PTEN in liver.\",\n      \"method\": \"MKP-2 KO mice on high-fat diet, glucose/insulin tolerance tests, PTEN/Akt/MAPK Western blots, respiratory exchange ratio measurement\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse metabolic phenotyping with mechanistic pathway readouts; single lab\",\n      \"pmids\": [\"35745205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUSP4 directly binds HSP90β and dephosphorylates it at T214 and Y216, promoting HSP90β ATPase activity. These dephosphorylation events stabilize JAK1/2-STAT3 signaling and promote p-STAT3(Y705) nuclear translocation in esophageal squamous cell carcinoma. HSP90β inhibitor NVP-BEP800 inhibited PDX tumor growth and inactivated JAK1/2-STAT3 signaling.\",\n      \"method\": \"Co-IP/pulldown of DUSP4-HSP90β, phospho-site mapping (T214/Y216), ATPase activity assay, HSP90β inhibitor treatment, in vivo PDX model, Dusp4 KO mouse in carcinogen model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding (Co-IP), substrate dephosphorylation with phospho-site identification, functional ATPase assay, in vivo KO and PDX validation; multiple orthogonal methods\",\n      \"pmids\": [\"37141098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP4 forms a signaling complex with TBK1, ERK1/2, and IRF3 and regulates TBK1 and ERK1/2 activation to modulate production of type I interferons downstream of RIG-I and STING nucleic acid sensors. DUSP4-deficient mice were more resistant to RNA and DNA virus infections but more susceptible to malaria parasites.\",\n      \"method\": \"Co-IP identifying DUSP4-TBK1-ERK1/2-IRF3 complex, DUSP4-/- mouse infection models (RNA virus, DNA virus, malaria parasite), type I IFN measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of multi-protein complex, KO mouse with multiple infection phenotypes; establishes DUSP4 as regulator of innate immune TBK1/ERK/IRF3 axis\",\n      \"pmids\": [\"38383887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP4 interacts with ALDOB (aldolase B) and dephosphorylates it, thereby inhibiting G6PD (glucose-6-phosphate dehydrogenase) activity and the ROS/pentose phosphate pathway in HER2-positive breast cancer cells.\",\n      \"method\": \"Co-IP and mass spectrometry (IP-MS) identifying DUSP4-ALDOB interaction, DUSP4 KO cells, G6PD activity assay, ROS measurement, RNA-seq of KO cells\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS interaction plus functional enzyme assay; mechanistic link to G6PD/ROS pathway; single lab\",\n      \"pmids\": [\"38843658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUSP4 dephosphorylates p-ERK and disrupts ERK-PGK1 interaction, reducing PGK1 S203 phosphorylation and its mitochondrial localization, thereby decreasing lactate production and increasing ROS levels in ovarian cancer cells. Phosphoproteomic profiling identified MAPK pathway and cellular metabolism as key downstream targets of DUSP4.\",\n      \"method\": \"LC-MS/MS phosphoproteomic profiling of DUSP4 overexpressing cells, PGK1 co-immunoprecipitation with ERK, mitochondrial fractionation, lactate/ROS assays, in vivo mouse tumor model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus Co-IP and functional metabolic assays; single lab; novel substrate (PGK1) identified\",\n      \"pmids\": [\"40082940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUSP4 suppresses ferroptosis in MSI colorectal cancer cells by reducing lipid peroxidation and inhibiting intracellular Fe2+ accumulation through downregulation of transferrin receptor (TFRC), which is transcriptionally regulated by c-MYC. DUSP4 also dephosphorylates CDK7, promoting CXCL16 expression and CD8+ T cell infiltration.\",\n      \"method\": \"Ferroptosis assays (lipid peroxidation, MDA, 4-HNE, Fe2+), phosphoproteomic analysis, TFRC/c-MYC expression studies, cytokine array, CDK7 dephosphorylation assay, flow cytometry for CD8+ T cells\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic analysis plus functional ferroptosis/immune assays identifying novel DUSP4 substrates CDK7 and TFRC regulation; single lab preprint-level evidence pending broader replication\",\n      \"pmids\": [\"40847010\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DUSP4 (MKP-2/HVH2/TYP) is a nuclear dual-specificity phosphatase that dephosphorylates and inactivates multiple MAPK substrates—primarily ERK1/2 and JNK, and to a lesser extent p38—and functions as a negative feedback regulator of MAPK signaling; it is induced downstream of oncogenic RAS/RAF/MEK signaling and other stimuli (PDGF, AMPK, LH/hCG, VIP) and its own stability is regulated by ERK-mediated phosphorylation of C-terminal serine residues; beyond canonical MAPK substrates, DUSP4 has been shown to dephosphorylate JNK1 within a GR-JNK1-DUSP4 complex to regulate glucocorticoid receptor nuclear translocation, to dephosphorylate HSP90β at T214/Y216 to activate its ATPase and stabilize JAK-STAT3 signaling, to dephosphorylate ALDOB to inhibit G6PD/ROS metabolism, to dephosphorylate CDK7 to regulate immune chemokine expression, and to participate in a TBK1-ERK1/2-IRF3 signaling complex governing type I interferon production; loss of DUSP4 through promoter hypermethylation, genomic deletion, or upstream regulation drives cancer progression, chemoresistance, and metabolic disease by hyperactivating MAPK and related pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DUSP4 (MKP-2/HVH2/TYP) is a nuclear dual-specificity phosphatase that serves as a negative-feedback brake on MAPK signaling, dephosphorylating both the phosphothreonine and phosphotyrosine of activated ERK1/2 and JNK—but not p38—to terminate kinase activity and restrain transcriptional output [#0, #1, #2]. Its catalytic output is governed by an autoinhibitory C-terminus, removal of which markedly increases phosphatase activity toward MAPK substrates [#4], and its abundance is set by an ERK-driven feedback loop in which ERK phosphorylates C-terminal serine residues (S386/S391 and additional MEK-dependent sites) to protect the protein from proteasomal degradation [#9, #19, #8]. DUSP4 is transcriptionally induced downstream of diverse stimuli—oncogenic KRAS/BRAF via MEK [#8], AMPK via EGR1 [#6], PDGF via ERK/STAT3/p53 [#28], and through STAT3/YY1/CTCF promoter elements [#31]—and acts as a tumor suppressor whose silencing by promoter hypermethylation, genomic 8p loss, or chromatin remodeling (ARID1A loss, G9a) hyperactivates ERK and JNK to drive proliferation, cancer stem-cell expansion, invasion, and chemoresistance across breast, lymphoma, pancreatic, and other cancers [#10, #13, #15, #20, #26, #32]. Beyond canonical MAPK kinases, DUSP4 has substrate and complex roles extending its reach: it forms a GR–JNK1 complex to dephosphorylate JNK1 and control glucocorticoid receptor nuclear translocation [#25], binds and dephosphorylates HSP90β at T214/Y216 to activate its ATPase and stabilize JAK-STAT3 signaling [#36], dephosphorylates ALDOB to restrict G6PD/ROS metabolism [#38], and participates in a TBK1–ERK1/2–IRF3 complex governing type I interferon production [#37]. Genetic loss-of-function in mice and zebrafish establishes non-redundant roles in cell-cycle progression and apoptosis [#11], CD4+ T-cell proliferation via STAT5/IL-2 [#12], endoderm specification [#7], cardiac and podocyte protection through p38/JNK control [#21, #29], and metabolic regulation of obesity and hepatic steatosis [#35].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established DUSP4 as a catalytically active dual-specificity phosphatase that directly inactivates ERK MAPKs and acts in the nucleus, answering what biochemical activity the gene encodes.\",\n      \"evidence\": \"In vitro phosphatase assays with recombinant/purified protein on ERK1/2 and ERK2/JNK, immunofluorescence localization, and SRE reporter assays in NIH3T3 and COS cells\",\n      \"pmids\": [\"7535768\", \"8545112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate hierarchy not yet resolved\", \"Regulation of phosphatase activity unaddressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the in vivo substrate specificity of DUSP4 as ERK and JNK but not p38, distinguishing it from related MKPs and clarifying which pathways it feeds back upon.\",\n      \"evidence\": \"In vivo co-expression substrate specificity assays in T cells with a hyperactive ERK2 (sevenmaker) allele\",\n      \"pmids\": [\"8626452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain p38 effects seen later in disease models\", \"Cellular context-dependence of specificity unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that the C-terminal domain autoinhibits catalytic activity, revealing an intrinsic regulatory mechanism controlling phosphatase output.\",\n      \"evidence\": \"C-terminal deletion mutagenesis with in vivo and in vitro phosphatase activity measurements\",\n      \"pmids\": [\"12083364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of autoinhibition not defined\", \"Physiological trigger relieving inhibition unknown at this point\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected DUSP4 to metabolic transcriptional control, establishing an AMPK→EGR1→DUSP4→p38 axis repressing gluconeogenic gene expression.\",\n      \"evidence\": \"ChIP, reporter assays, siRNA, and constitutively active p38 rescue in hepatocytes\",\n      \"pmids\": [\"16849326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DUSP4 acts on p38 directly in this setting not enzymatically shown\", \"In vivo metabolic relevance untested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated an essential developmental role, showing dusp4 is required for endoderm specification, extending its function beyond feedback regulation.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with sox17 marker analysis and transplantation\",\n      \"pmids\": [\"18719100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not excluded\", \"Molecular substrate driving endoderm phenotype unidentified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how DUSP4 stability is controlled, identifying ERK-mediated C-terminal serine phosphorylation as a stabilizing feedback signal and mapping MEK-dependent phospho-sites that spatially confine ERK activity in oncogene-driven cells.\",\n      \"evidence\": \"Phospho-site mutagenesis, cycloheximide chase, proteasome and ERK inhibitors, and oncogenic KRAS/BRAF expression with ERK spatial mapping\",\n      \"pmids\": [\"21084841\", \"22430215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for stabilization vs. canonical ERK feedback not fully separated\", \"E3 ligase mediating degradation unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic loss-of-function in mice established non-redundant roles in cell-cycle progression, apoptosis, and CD4+ T-cell proliferation control.\",\n      \"evidence\": \"DUSP4 knockout MEFs and mice with adenoviral rescue, cell-cycle analysis, and STAT5 phosphorylation readouts\",\n      \"pmids\": [\"21317287\", \"22101742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate for STAT5 regulation in T cells unclear\", \"Tissue-specific requirements not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined DUSP4 as an epigenetically silenced tumor suppressor whose loss activates Ras-ERK and modulates chemosensitivity in basal-like breast cancer.\",\n      \"evidence\": \"Gain/loss-of-function in breast cancer cell lines, promoter methylation analysis, MEK-inhibitor combination, and xenografts\",\n      \"pmids\": [\"22683778\", \"20124482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of selective promoter methylation unknown\", \"Whether ERK is the sole driver of chemoresistance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the tumor-suppressor mechanism to dual MEK/ERK and JNK control of cancer stem-cell populations and inflammatory cytokine output via ETS-1 and c-JUN.\",\n      \"evidence\": \"Knockdown/overexpression in BLBC lines, mammosphere and flow-cytometry assays, MEK-inhibitor rescue, and xenografts\",\n      \"pmids\": [\"23966295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ERK vs JNK arms not quantified\", \"Direct transcription-factor dephosphorylation not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed C-terminal serine phosphorylation as the stability determinant in macrophages and broadened DUSP4 function into neuronal differentiation and inflammatory regulation.\",\n      \"evidence\": \"Phospho-site mutagenesis with half-life and ubiquitination assays in macrophages; knockdown/rescue in ES-derived neurons; G9a-inhibition autophagy studies\",\n      \"pmids\": [\"25204653\", \"25397900\", \"25027955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway independent of ubiquitination not mechanistically explained\", \"Calcium-pathway substrates not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated catalytic JNK dephosphorylation drives apoptosis in lymphoma and uncovered a novel GR–JNK1–DUSP4 complex controlling glucocorticoid receptor translocation, expanding the substrate repertoire beyond free MAPKs.\",\n      \"evidence\": \"Phosphatase-dead mutant rescue and methylation analysis in DLBCL; co-immunoprecipitation, IP-phosphatase activity assay, and GR-Ser226 readouts\",\n      \"pmids\": [\"25847947\", \"28283554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly of the GR-JNK1 complex unresolved\", \"Direct GR dephosphorylation vs JNK-mediated indirect effect not fully separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established DUSP4 loss at 8p as a driver of invasive progression and showed broad phosphoprotein-level suppression of ERK, p38, JNK, RB, and NF-κB upon DUSP4 induction.\",\n      \"evidence\": \"Re-expression in pancreatic and TNBC lines, invasion/anoikis assays, phosphoprotein microarray, and orthotopic xenografts\",\n      \"pmids\": [\"26941286\", \"27393618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect targets among the 172 phosphoproteins not distinguished\", \"Mechanism of cell-cycle arrest not assigned to a specific substrate\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic interaction studies revealed cooperative tumor suppression with Dok2 in lung tumorigenesis, reinforcing DUSP4 as a MAPK-restraining suppressor.\",\n      \"evidence\": \"Compound heterozygous Dok2/Dusp4 mouse knockout with tumor monitoring and restoration experiments\",\n      \"pmids\": [\"30475228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of Dok2-DUSP4 cooperation unresolved\", \"Whether the interaction is physical or pathway-level unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined DUSP4 as a feedback tuner across diverse physiological circuits—circadian VIP/ERK signaling in the SCN, diabetic podocyte protection via p38/JNK/Nox4, and PDGF-driven ERK/STAT3/p53 induction.\",\n      \"evidence\": \"Ex vivo SCN slice culture; DUSP4-/- diabetic mice and podocyte overexpression with PKC-δ inhibition; PDGF stimulation with regulator knockdowns\",\n      \"pmids\": [\"30710088\", \"30862678\", \"31526568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct p38/JNK dephosphorylation in podocytes not enzymatically demonstrated\", \"Tissue-specific upstream inducers incompletely mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked chromatin regulation (ARID1A, histone acetylation) to DUSP4 silencing and uncovered context-dependent, non-canonical ERK regulation in melanoma where DUSP4 loss acts through DUSP6.\",\n      \"evidence\": \"ChIP-seq/RNA-seq with ARID1A loss and ectopic DUSP4 rescue; DUSP4/DUSP6 double-knockout epistasis and kinase translocation reporters in melanoma; metabolic KO mouse phenotyping\",\n      \"pmids\": [\"38071325\", \"35189148\", \"35580987\", \"35745205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of direct ERK-phosphatase model with DUSP6-dependent paradoxical effect unresolved\", \"Mechanism of DUSP6 post-transcriptional upregulation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the substrate landscape to non-MAPK proteins, showing DUSP4 binds and dephosphorylates HSP90β to activate JAK-STAT3, dephosphorylates ALDOB to restrict G6PD/ROS metabolism, and scaffolds a TBK1-ERK1/2-IRF3 complex governing type I interferon and antimicrobial defense.\",\n      \"evidence\": \"Co-IP/pulldown with phospho-site mapping and ATPase assays for HSP90β; IP-MS and enzyme assays for ALDOB; reciprocal Co-IP and DUSP4-/- infection models for the TBK1-IRF3 complex\",\n      \"pmids\": [\"37141098\", \"38843658\", \"38383887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these non-MAPK activities share a common recognition motif unknown\", \"Structural basis of substrate selection unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected DUSP4 to cancer metabolism and immune modulation through new substrates, dephosphorylating PGK1-associated ERK to alter glycolysis/ROS and CDK7 to drive CXCL16 expression and CD8+ T-cell infiltration while suppressing ferroptosis.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP, mitochondrial fractionation, ferroptosis and metabolic assays, and in vivo tumor models in ovarian and MSI colorectal cancers\",\n      \"pmids\": [\"40082940\", \"40847010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDK7 dephosphorylation requires reconstitution\", \"Substrate findings from single labs await independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DUSP4 achieves substrate selection across its expanding set of canonical (ERK/JNK) and non-canonical (HSP90β, ALDOB, CDK7, PGK1, TBK1-IRF3) targets and how this selectivity is partitioned between tumor-suppressive and context-dependent oncogenic outcomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model defines substrate recognition\", \"Whether non-MAPK substrates are dephosphorylated by the same catalytic mechanism is unestablished\", \"Determinants distinguishing tumor-suppressor vs DUSP6-mediated paradoxical roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 4, 20]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 20, 25, 36, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 13, 20, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 37]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 24]}\n    ],\n    \"complexes\": [\n      \"GR-JNK1-DUSP4 complex\",\n      \"TBK1-ERK1/2-IRF3 complex\"\n    ],\n    \"partners\": [\n      \"ERK1/2\",\n      \"JNK1\",\n      \"GR\",\n      \"HSP90B1\",\n      \"ALDOB\",\n      \"TBK1\",\n      \"IRF3\",\n      \"CDK7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}