Affinage

DUSP4

Dual specificity protein phosphatase 4 · UniProt Q13115

Length
394 aa
Mass
43.0 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP4 (MKP-2/HVH2) is a nuclear dual-specificity phosphatase that serves as a feedback inhibitor of MAPK signaling by dephosphorylating activated ERK1/2, JNK, and p38 on both phosphothreonine and phosphotyrosine residues, thereby regulating cell proliferation, apoptosis, differentiation, innate immunity, and metabolic gene expression (PMID:7535768, PMID:8545112, PMID:8626452). DUSP4 is transcriptionally induced by MEK/ERK, AMPK/EGR1, and STAT3/p53 pathways, and its protein is stabilized by ERK-mediated C-terminal serine phosphorylation that protects it from ubiquitin-independent proteasomal degradation, establishing a self-limiting negative-feedback loop on nuclear ERK activity (PMID:21084841, PMID:25204653, PMID:22430215, PMID:16849326). Beyond canonical MAPK substrates, DUSP4 dephosphorylates HSP90β (T214/Y216) to promote JAK-STAT3 signaling (PMID:37141098), ALDOB to modulate pentose phosphate pathway flux (PMID:38843658), and participates in a TBK1–ERK1/2–IRF3 complex controlling type I interferon production during innate antiviral responses (PMID:38383887). Loss of DUSP4 drives MAPK hyperactivation linked to cancer stem cell expansion, chemotherapy resistance, and diabetic organ injury, while its epigenetic silencing by promoter methylation or loss of ARID1A-dependent histone acetylation is a recurrent feature in aggressive cancers (PMID:22683778, PMID:23966295, PMID:30862678, PMID:38071325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    The founding question—what enzymatic activity does DUSP4 possess and what are its substrates—was answered by demonstrating that purified DUSP4 dephosphorylates both phosphothreonine and phosphotyrosine on activated ERK1/2 in vitro, establishing it as a nuclear dual-specificity MAPK phosphatase.

    Evidence Recombinant/purified protein in vitro phosphatase assays, immunofluorescence for nuclear localization, reporter assays in NIH3T3 and COS-1 cells

    PMID:7535768 PMID:8545112

    Open questions at the time
    • Crystal structure of DUSP4 catalytic domain not yet determined
    • Relative affinity for ERK vs JNK vs p38 not quantified in vitro
  2. 1996 High

    In vivo substrate selectivity was defined: DUSP4 dephosphorylates ERK and JNK but not p38 in T cells, and the ERK2 sevenmaker mutation confers resistance, demonstrating a direct enzyme-substrate docking requirement.

    Evidence In vivo phosphatase specificity assays in T cells with ERK2 D319N gain-of-function mutant

    PMID:8626452

    Open questions at the time
    • Structural basis of substrate selectivity unknown
    • Later studies showed DUSP4 can target p38 in other cell types, suggesting context-dependent specificity
  3. 2002 High

    The autoinhibitory role of the C-terminal domain was established: truncation markedly increased phosphatase activity without altering substrate affinity, revealing an intramolecular regulatory mechanism.

    Evidence C-terminal deletion mutagenesis with in vitro and in vivo phosphatase activity assays

    PMID:12083364

    Open questions at the time
    • Molecular contacts mediating autoinhibition not mapped
    • Whether post-translational modifications relieve autoinhibition was unresolved at this point
  4. 2006 High

    DUSP4 was placed downstream of AMPK/EGR1 signaling and shown to suppress hepatic gluconeogenesis by inhibiting p38-dependent PEPCK and G6Pase expression, extending its role beyond MAPK feedback to metabolic gene regulation.

    Evidence Reporter assays, siRNA knockdown, glucose production assay, constitutively active p38 rescue in hepatocytes

    PMID:16849326

    Open questions at the time
    • Whether DUSP4 directly dephosphorylates p38 in hepatocytes or acts indirectly was not fully resolved
    • Physiological significance in vivo not tested in liver-specific KO
  5. 2010 High

    The feedback stabilization mechanism was elucidated: ERK phosphorylates DUSP4 on C-terminal serines (Ser386/Ser391 and Thr361/Thr363/Ser390/Ser395), stabilizing the protein against proteasomal degradation without altering catalytic activity, closing the ERK-DUSP4 negative-feedback loop.

    Evidence In vitro kinase assays, site-directed mutagenesis, proteasome inhibitor treatment, half-life measurements in multiple cell systems

    PMID:21084841 PMID:22430215

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting DUSP4 was unknown at this time
    • Degradation was later shown to be ubiquitin-independent, raising questions about the proteasomal targeting mechanism
  6. 2011 High

    Genetic loss-of-function studies in knockout MEFs and mice established that DUSP4 is essential for proper cell cycle progression (G2/M), JNK-dependent apoptosis control, and CD4+ T cell homeostasis via IL-2/STAT5 signaling.

    Evidence DUSP4 KO mouse-derived MEFs with adenoviral rescue, KO mice with T cell proliferation assays, phospho-STAT5 analysis

    PMID:21317287 PMID:22101742

    Open questions at the time
    • How DUSP4 influences STAT5 phosphorylation—directly or through MAPK-dependent intermediates—was not resolved
    • Conditional tissue-specific knockouts not employed
  7. 2012 High

    DUSP4 was established as a tumor suppressor in basal-like breast cancer: its silencing by promoter methylation activates Ras-ERK signaling, confers chemoresistance, and expands cancer stem cells through MEK/JNK-dependent ETS-1 and c-JUN activation.

    Evidence DUSP4 overexpression/depletion in BLBC cell lines, promoter methylation analysis, mammosphere and CSC marker assays, xenograft models with MEK inhibitor

    PMID:22683778 PMID:23966295

    Open questions at the time
    • Whether DUSP4 loss is driver or passenger in tumor evolution not genetically resolved
    • Relative contribution of ERK vs JNK arms to CSC phenotype not fully separated
  8. 2014 High

    The proteasomal degradation mechanism was refined: DUSP4 turnover is proteasome-dependent but independent of polyubiquitination, and phosphomimetic C-terminal serine mutations dramatically extend half-life.

    Evidence Pulse-chase half-life assays, ubiquitination assays, phosphomimetic and phospho-dead mutagenesis

    PMID:25204653

    Open questions at the time
    • Ubiquitin-independent proteasomal targeting mechanism (e.g., default degradation signal) not identified
    • Whether HUWE1 (later implicated) acts in a ubiquitin-dependent manner in other contexts was unresolved
  9. 2015 High

    Phosphatase-dead mutant experiments demonstrated that DUSP4's enzymatic activity is required for JNK dephosphorylation and apoptosis induction in DLBCL, and that DUSP4 modulates corticosteroid sensitivity through a complex with JNK1 and glucocorticoid receptor.

    Evidence WT vs phosphatase-dead DUSP4 expression in DLBCL, co-immunoprecipitation of DUSP4–JNK1–GR complex, GR nuclear translocation assays

    PMID:25847947 PMID:28283554

    Open questions at the time
    • Whether DUSP4 directly dephosphorylates GR-Ser226 or acts exclusively through JNK1 not fully distinguished
    • Structural basis of the ternary complex unknown
  10. 2019 High

    DUSP4's physiological roles expanded to diabetic nephropathy (p38/JNK-dependent podocyte death under PKC-δ regulation) and circadian clock resetting (ERK negative regulation in the SCN), demonstrating tissue-specific functions beyond cancer.

    Evidence DUSP4 KO diabetic mouse model with podocyte analysis, PKC-δ inhibitor epistasis; SCN organotypic culture with VIP stimulation

    PMID:30710088 PMID:30862678

    Open questions at the time
    • DUSP4 regulation by PKC-δ—direct phosphorylation or transcriptional—not fully delineated
    • Circadian role based on correlative expression data, no KO circadian behavioral phenotype shown
  11. 2022 High

    CRISPR paralog screens revealed that DUSP4 and DUSP6 are synthetic lethal partners specifically in BRAF/NRAS-mutant cells, and that DUSP4 depletion alone triggers oncogene overdose via toxic ERK hyperactivation in melanoma.

    Evidence CRISPR paralog targeting library across cancer cell line panels, single vs dual KO comparisons, MITF downregulation as lineage readout

    PMID:34857952 PMID:35580987

    Open questions at the time
    • Therapeutic window for dual DUSP4/DUSP6 inhibition not assessed in vivo
    • Whether ERK overdose threshold varies across tumor lineages is unknown
  12. 2023 High

    Non-canonical substrates were identified: DUSP4 dephosphorylates HSP90β at T214/Y216 to promote its ATPase activity and stabilize JAK-STAT3 signaling, and participates in a TBK1–ERK1/2–IRF3 complex controlling type I IFN production, revealing pro-tumorigenic and innate immune roles beyond MAPK feedback.

    Evidence Co-IP and site-specific dephosphorylation of HSP90β, ATPase assays, DUSP4 KO mouse tumorigenesis and viral challenge models, CoIP of quaternary complex

    PMID:37141098 PMID:38383887

    Open questions at the time
    • Structural basis of HSP90β recognition by DUSP4 unknown
    • Relative contribution of MAPK vs HSP90β dephosphorylation to esophageal tumorigenesis not separated
    • Whether TBK1 is a direct DUSP4 substrate or dephosphorylated via ERK not resolved
  13. 2024 Medium

    DUSP4 was shown to dephosphorylate ALDOB, thereby inhibiting G6PD activity and pentose phosphate pathway flux, linking DUSP4 to metabolic reprogramming and therapeutic sensitivity in HER2+ breast cancer.

    Evidence IP-MS substrate identification, phosphoproteomic analysis, G6PD activity and ROS assays, in vivo therapeutic response

    PMID:38843658

    Open questions at the time
    • ALDOB phosphorylation site(s) targeted by DUSP4 not mapped
    • Awaits independent replication
    • Whether this is direct dephosphorylation or mediated through ERK inactivation not fully excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for DUSP4's expanding non-MAPK substrate repertoire, the identity of the E3 ligase or degron controlling its ubiquitin-independent proteasomal degradation, and whether therapeutic targeting of DUSP4 (or DUSP4/DUSP6 dual inhibition) has a viable therapeutic window in MAPK-driven cancers.
  • No crystal structure of full-length DUSP4 available
  • Proteasomal degradation mechanism (ubiquitin-independent) not mechanistically explained
  • In vivo safety and efficacy of DUSP4-targeted strategies not evaluated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
ALDOBERK1ERK2GRHSP90AB1IRF3JNK1TBK1
Complex memberships
DUSP4–JNK1–GRDUSP4–TBK1–ERK1/2–IRF3

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 DUSP4 (HVH2) was cloned and shown to be a dual-specificity phosphatase that selectively dephosphorylates activated ERK1 and ERK2 on both threonine and tyrosine residues in vitro, and localizes to the cell nucleus. Transfection into NIH3T3 cells inhibited v-src and MEK-induced SRE-containing promoter transcription. In vitro phosphatase assay with recombinant protein, immunofluorescence (epitope-tagged), transfection/reporter assay The Journal of biological chemistry High 7535768
1995 DUSP4 (TYP1) purified protein efficiently inactivates recombinant ERK2 in vitro by concomitant dephosphorylation of both phosphothreonine and phosphotyrosine residues, and also inhibits p54 JNK when transfected into COS-1 cells. The protein is nuclear and stabilized by EGF treatment. In vitro phosphatase assay with purified protein, transfection/overexpression in COS-1 cells, northern analysis Oncogene High 8545112
1996 MKP-2 (DUSP4) has unique in vivo substrate specificity, dephosphorylating ERK and JNK but not p38 in T cells. The ERK2 sevenmaker gain-of-function mutation (D319N) confers significantly reduced sensitivity to DUSP4 dephosphorylation in vivo. In vivo substrate specificity assays in T cells using phorbol ester stimulation, mutagenesis (D319N ERK2 allele) The Journal of biological chemistry High 8626452
1997 DUSP4 (MKP2) gene was chromosomally localized to 8p11-p12 by fluorescence in situ hybridization and radiation hybrid mapping. Fluorescence in situ hybridization (FISH), radiation hybrid mapping Genomics High 9205128
2002 The C-terminal domain of MKP-2 (DUSP4) exerts an inhibitory effect on its phosphatase activity; C-terminal truncations of MKP-2 show substantially greater phosphatase activity both in vivo and in vitro toward MAPK substrates, without significantly changing substrate affinity or substrate-mediated catalytic activation. C-terminal deletion mutagenesis, in vivo and in vitro phosphatase activity assays Molecular and cellular biochemistry High 12083364
2003 I1-imidazoline receptor stimulation with moxonidine induces MKP-2 (DUSP4) expression in PC12 cells; this induction reverses NGF-induced ERK activation, and is blocked by an I1-antagonist or a phospholipase C inhibitor, placing MKP-2 downstream of I1-receptor/phospholipase C signaling. Pharmacological stimulation, immunoblotting for phospho-ERK and MKP-2, antagonist blocking experiments Brain research Medium 12865160
2006 AMPK activation induces DUSP4 expression in hepatocytes via the transcription factor EGR1 (which directly binds the DUSP4 promoter). DUSP4 in turn inhibits promoter activity and expression of gluconeogenic genes G6Pase and PEPCK, and depletion of EGR1 or DUSP4 by siRNA partially abrogates AICAR-mediated inhibition of PEPCK and glucose production. Constitutively active p38 rescues DUSP4-mediated PEPCK repression. Reporter gene assays, siRNA knockdown, real-time PCR, glucose production assay, constitutively active kinase rescue experiment The Journal of biological chemistry High 16849326
2010 ERK phosphorylates MKP-2 (DUSP4) on Ser386 and Ser391 at its C-terminus, leading to stabilization of MKP-2 protein. Blockage of ERK activation enhances proteasomal degradation of MKP-2, while phosphorylation has no effect on MKP-2 phosphatase activity. In vitro kinase assay, site-directed mutagenesis (Ser386/Ser391), proteasome inhibitor treatment, immunoblotting Cell cycle (Georgetown, Tex.) High 21084841
2010 Oncogenic KRAS(G12V) and BRAF(V600E) induce nuclear DUSP4 expression in an MEK-dependent manner, resulting in nuclear ERK dephosphorylation and restriction of pERK to the cytoplasm. MEK-dependent phosphorylation of T361, T363, S390, and S395 residues of DUSP4 stabilizes the protein. Expression of oncogenic constructs in intestinal epithelial cells, MEK inhibitor treatment, vanadate treatment, immunofluorescence for pERK localization, site-directed mutagenesis Oncogene High 22430215
2011 DUSP4 (MKP-2) deletion in MEFs leads to enhanced sustained ERK phosphorylation after PDGF stimulation, G2/M cell cycle block with cyclin B accumulation and enhanced cdc2 phosphorylation, and increased apoptosis upon JNK activation. Adenoviral re-expression of MKP-2 reverses the proliferation defect and selectively inhibits JNK signaling. MKP-2 knockout mouse-derived MEFs, adenoviral rescue, cell cycle analysis, immunoblotting for MAPK substrates and apoptosis markers The Journal of biological chemistry High 21317287
2011 DUSP4 deficiency in mice leads to hyperproliferation of CD4+ T cells but not CD8+ T cells upon activation. Mechanistic studies showed this involves enhanced CD25 expression and increased STAT5 phosphorylation, placing DUSP4 as a suppressor of CD4+ T cell proliferation through regulation of IL-2/STAT5 signaling. DUSP4 knockout mice, T-cell proliferation assays, immunization, phospho-STAT5 immunoblotting, CD25 expression analysis European journal of immunology High 22101742
2012 DUSP4 depletion in basal-like breast cancer (BLBC) activates Ras-ERK signaling and attenuates apoptotic response to chemotherapy. DUSP4 overexpression increases chemotherapy-induced apoptosis. DUSP4 promoter methylation is elevated in BLBC, reducing its expression. DUSP4 overexpression/depletion in cell lines, chemotherapy response assays, promoter methylation analysis, xenograft model with MEK inhibitor combination Nature medicine High 22683778
2013 DUSP4 loss increases mammosphere formation and expression of CSC-promoting cytokines IL-6 and IL-8 in BLBC through loss of control of MEK and JNK pathways, involving downstream activation of ETS-1 and c-JUN transcription factors. Enforced DUSP4 expression reduces CD44+/CD24- CSC population in a MEK-dependent manner. DUSP4 knockdown/overexpression, mammosphere formation assay, flow cytometry for CSC markers, xenograft tumor formation, MEK inhibitor epistasis Cancer research High 23966295
2014 ERK-mediated phosphorylation of two C-terminal serine residues of MKP-2 (DUSP4) by the ERK pathway regulates stability. Mutation of these serines to alanine decreases half-life; mutation to aspartate dramatically increases half-life. Degradation of MKP-2 is proteasome-dependent but independent of polyubiquitination. Site-directed mutagenesis of C-terminal serines, pulse-chase/half-life assays, ERK pathway inhibitors, proteasome inhibitors, ubiquitination assays The Journal of biological chemistry High 25204653
2014 DUSP4 regulates neuronal differentiation and ERK1/2 phosphorylation in embryonic stem cell-derived neurons. DUSP4 knockdown markedly enhances ERK activation and reduces neurite outgrowth and neuron-specific marker expression. The DUSP4-ERK pathway balances calcium signaling by regulating CaMKI phosphorylation and Cav1.2 expression and plasma membrane localization. DUSP4 knockdown/rescue in ESC-derived neurons, immunoblotting for pERK and CaMKI, Cav1.2 localization Stem cells and development Medium 25397900
2015 Ectopic expression of wild-type DUSP4, but not a phosphatase-deficient mutant, dephosphorylates JNK and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo, establishing DUSP4's role in suppressing JNK-dependent survival. Wild-type vs phosphatase-dead DUSP4 mutant expression, JNK phosphorylation immunoblotting, apoptosis assays, dominant-negative JNK, xenograft model The Journal of experimental medicine High 25847947
2015 DUSP4 deficiency in idiopathic CD4 lymphopenia (ICL) causes increased DUSP4 expression that dampens TCR-induced ERK activation. siRNA-mediated DUSP4 normalization restores ERK activation and increases expression of costimulatory molecules CD27 and CD40L. Repeated TCR stimulation of normal CD4+ T cells leads to DUSP4 overexpression and defective signaling. siRNA knockdown of DUSP4 in primary T cells from ICL patients, phospho-ERK immunoblotting, FACS for surface markers Blood Medium 25733583
2015 DUSP4 loss in DUSP4-/- mice leads to hyperactivation of p38 in endothelial cells under hypoxia/reoxygenation and in hearts after ischemia/reperfusion, causing increased apoptosis and larger infarct size. DUSP4 gene silencing augments p38-dependent apoptosis, rescued by p38 inhibitor. DUSP4 KO mouse isolated hearts (Langendorff), siRNA knockdown in endothelial cells, H/R model, TUNEL, caspase-3 cleavage, p38 inhibitor rescue Free radical biology & medicine High 26184564
2016 DUSP4 restoration in pancreatic cancer cells suppresses invasiveness and anoikis resistance via ERK inactivation. MEK inhibition is effective in an orthotopic xenograft model, supporting an ERK-dependent mechanism for DUSP4's invasion-suppressor role. DUSP4 re-expression in pancreatic cancer cells, invasion and anoikis assays, MEK inhibitor orthotopic xenograft model Cancer research High 26941286
2017 DUSP4 regulates corticosteroid sensitivity via dephosphorylation of JNK1 and glucocorticoid receptor (GR) Ser226. Coimmunoprecipitation reveals DUSP4 forms a complex with GR and JNK1. DUSP4 knockdown enhances JNK1 and GR-Ser226 phosphorylation and reduces GR nuclear translocation. Formoterol enhances DUSP4 phosphatase activity and restores corticosteroid sensitivity. siRNA knockdown, coimmunoprecipitation (GR-JNK1-DUSP4 complex), phospho-JNK1/GR-Ser226 immunoblotting, imaging flow cytometry for GR nuclear translocation, fluorescence-based phosphatase activity assay on immunoprecipitated DUSP4 Molecular pharmacology High 28283554
2019 DUSP4 modulates ERK1/2 signaling in the suprachiasmatic nucleus (SCN) downstream of VIP receptor activation. ERK1/2 signaling and its negative regulation by DUSP4 are critical elements of VIP-directed circadian re-programming in the SCN circuit. SCN slice organotypic culture, VIP treatment, transcriptional profiling, analysis of DUSP4 as negative regulator of ERK in circadian context Nature communications Medium 30710088
2019 Diabetes-induced DUSP4 reduction (mediated by PKC-δ) enhances p38 and JNK activity in podocytes. DUSP4 overexpression prevents high-glucose-induced p38, JNK, caspase 3/7 activation and NOX4 expression. DUSP4 knockout in diabetic mice exacerbates albuminuria, mesangial expansion, and podocyte death with sustained p38/JNK activation. DUSP4 overexpression in cultured podocytes, DUSP4 KO diabetic mouse model, immunoblotting for pJNK/pp38, PKC-δ inhibitor epistasis Diabetes High 30862678
2019 DUSP4 expression is induced by PDGF-BB in an ERK1/2-, STAT3-, and p53-dependent manner. ERK1/2 inhibition reduces DUSP4 mRNA levels; STAT3 maintains p53 expression; p53 has binding sites in the DUSP4 promoter and promotes its expression. Pharmacological inhibitors of ERK1/2, STAT3, p53; promoter binding analysis; immunoblotting Biochemical and biophysical research communications Medium 31526568
2021 Dual inactivation of DUSP4 and DUSP6 (but not either alone) selectively impairs growth in NRAS and BRAF mutant cancer cells through hyperactivation of MAPK signaling. Cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4/DUSP6 dual perturbation. CRISPR paralog targeting library screen, single vs. dual knockout comparisons in panels of cancer cell lines with defined BRAF/NRAS mutation status Nature genetics High 34857952
2023 DUSP4 directly binds HSP90β and promotes its ATPase activity by dephosphorylating HSP90β on T214 and Y216, stabilizing JAK1/2-STAT3 signaling and promoting p-STAT3(Y705) nuclear translocation in esophageal squamous cell carcinoma. Dusp4 knockout in mice inhibits 4-NQO-induced esophageal tumorigenesis. Co-IP, dephosphorylation of HSP90β (T214/Y216), ATPase activity assay, STAT3 nuclear translocation immunoblotting, DUSP4 KO mouse carcinogenesis model, PDX tumor model Cell reports High 37141098
2023 DUSP4 modulates innate immune signaling by regulating TBK1 and ERK1/2 activation within a signaling complex containing DUSP4, TBK1, ERK1/2, and IRF3, thereby controlling type I IFN production downstream of RIG-I and STING. DUSP4-deficient mice are more resistant to RNA and DNA virus infections but more susceptible to malaria. DUSP4 KO mice, co-immunoprecipitation of DUSP4-TBK1-ERK1/2-IRF3 complex, viral challenge experiments, innate immune signaling readouts Cell death and differentiation High 38383887
2023 ARID1A loss downregulates DUSP4 expression through decreased histone acetylation (H3K27Ac, H3K9Ac) at DUSP4 regulatory regions, leading to MAPK pathway activation. Ectopic DUSP4 expression in ARID1A-deficient cells decreases cell proliferation. RNA-seq in isogenic ARID1A KO cells, ChIP-seq for histone marks at DUSP4 locus, ectopic DUSP4 expression, in vivo MEK inhibitor treatment Journal of biomedical science High 38071325
2024 DUSP4 interacts with ALDOB and inhibits G6PD activity through ALDOB dephosphorylation, thereby disrupting the pentose phosphate pathway/ROS metabolism and enhancing therapeutic sensitivity in HER2-positive breast cancer. Co-IP and mass spectrometry (IP-MS), phosphoproteomic analysis, G6PD activity assay, DUSP4 KO cells, in vitro and in vivo therapeutic response assays Translational oncology Medium 38843658
2020 DUSP4 inhibits autophagic cell death in HNSCC through ERK inactivation. G9a inhibition (genetic or pharmacological) induces DUSP4 expression, leading to autophagic cell death via a DUSP4-dependent ERK inactivation pathway. G9a knockdown/inhibitor, Affymetrix microarray, DUSP4 overexpression/knockdown, autophagy markers (immunoblot, EM), orthotopic tumor model Molecular cancer Medium 25027955
2008 In zebrafish, dusp4 (MAP kinase inhibitor) is essential for early endoderm specification; morpholino knockdown causes loss of sox17 expression (but not other endoderm markers) and loss of foregut and pancreatic endoderm, placing DUSP4 in a specific endoderm specification pathway. Morpholino antisense knockdown in zebrafish, in situ hybridization for endoderm markers, transplantation assays Proceedings of the National Academy of Sciences of the United States of America Medium 18719100
2020 DUSP4 promotes esophageal tumorigenesis when overexpressed; in the DUSP4/GSK3β/SNAI1 pathway, ΔNp63α induces DUSP4 expression, which activates GSK3β leading to SNAI1-driven EMT. bFGF reverses this by blocking DUSP4/GSK3β/SNAI1 signaling. Transcriptomic analysis, forced DUSP4 expression, GSK3β/SNAI1 pathway epistasis, bFGF rescue both in vitro and in vivo Cell death & disease Medium 32528070
2022 DUSP4 depletion in BRAF/NRAS-mutant melanoma leads to toxic ERK hyperactivation (oncogene overdose) associated with downregulation of lineage-defining genes including MITF, establishing DUSP4 as a gatekeeper of oncogene overdose. DUSP4 siRNA/CRISPR depletion in drug-naïve and drug-resistant melanoma lines, ERK activity measurement, MITF immunoblotting, drug response assays Life science alliance Medium 35580987
2023 DOCK1 deficiency in trophoblasts leads to accumulation of DUSP4 by disrupting its ubiquitin-mediated degradation (possibly via E3 ligase HUWE1), causing ERK pathway inactivation and impaired EVT migration/invasion. TBOPP (DOCK1 inhibitor) causes miscarriage in mice via DUSP4/ERK inactivation. Co-IP for DOCK1-HUWE1-DUSP4, ubiquitination assays, DOCK1 KD/KO in trophoblasts, in vivo mouse miscarriage model Life science alliance Medium 37967942
2025 DUSP4 overexpression reduces phosphorylation of PGK1 at Ser203 by dephosphorylating p-ERK, disrupting the ERK-PGK1 interaction and decreasing PGK1 mitochondrial localization, leading to reduced glycolysis (lactate production) and increased ROS levels in ovarian cancer cells. Phosphoproteomic profiling (LC-MS/MS), DUSP4 overexpression, co-IP of ERK-PGK1, mitochondrial fractionation, lactate/ROS assays, in vivo xenograft Cancer cell international Medium 40082940

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 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. The Journal of biological chemistry 390 8626452
2012 Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nature medicine 219 22683778
2009 An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 194 19525976
1995 Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. The Journal of biological chemistry 174 7535768
2010 Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes, chromosomes & cancer 172 20725992
2013 Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer research 133 23966295
2021 Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers. Nature genetics 115 34857952
2018 MiR-122-5p inhibits cell migration and invasion in gastric cancer by down-regulating DUSP4. Cancer biology & therapy 75 29509059
2012 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. Oncogene 75 22430215
2006 Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase. The Journal of biological chemistry 68 16849326
2010 Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer research 63 20124482
1995 Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. Oncogene 58 8545112
2015 DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma. The Journal of experimental medicine 56 25847947
2014 Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma. Molecular cancer 56 25027955
2012 Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation. International journal of cancer 56 22965873
2017 IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition. Cancer research 53 28400477
2011 DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development. European journal of immunology 52 22101742
2011 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. The Journal of biological chemistry 50 21317287
2019 Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling. Nature communications 48 30710088
2022 Genome-Wide CRISPR/Cas9 Library Screening Identified that DUSP4 Deficiency Induces Lenvatinib Resistance in Hepatocellular Carcinoma. International journal of biological sciences 46 35864956
2016 Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma. Cancer research 45 26941286
2016 Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4/ERK pathway. Journal of cellular and molecular medicine 43 27957827
2020 ΔNp63α-induced DUSP4/GSK3β/SNAI1 pathway in epithelial cells drives endometrial fibrosis. Cell death & disease 42 32528070
2015 DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia. Blood 42 25733583
2017 DUSP4 promotes doxorubicin resistance in gastric cancer through epithelial-mesenchymal transition. Oncotarget 41 29212207
2015 Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress. Free radical biology & medicine 40 26184564
2019 Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy. Diabetes 39 30862678
2013 Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer. Medical oncology (Northwood, London, England) 37 23749251
2020 Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness. Cell death & disease 34 32188842
2014 DUSP4 regulates neuronal differentiation and calcium homeostasis by modulating ERK1/2 phosphorylation. Stem cells and development 32 25397900
2008 Transcriptional profiling of endogenous germ layer precursor cells identifies dusp4 as an essential gene in zebrafish endoderm specification. Proceedings of the National Academy of Sciences of the United States of America 32 18719100
2016 Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency. Scientific reports 30 27604655
2020 MiR-122-5p protects against acute lung injury via regulation of DUSP4/ERK signaling in pulmonary microvascular endothelial cells. Life sciences 29 32470454
2017 DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer. Oncotarget 28 29100381
2020 DUSP4 is involved in the enhanced proliferation and survival of DUSP4-overexpressing cancer cells. Biochemical and biophysical research communications 27 32505357
2012 Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury. American journal of physiology. Lung cellular and molecular physiology 27 22683570
2019 Unraveling the role of H3K4 trimethylation and lncRNA HOTAIR in SATB1 and DUSP4-dependent survival of virulent Mycobacterium tuberculosis in macrophages. Tuberculosis (Edinburgh, Scotland) 26 32090865
2016 Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast cancer research and treatment 26 27393618
1997 Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7). Genomics 25 9205128
2019 Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. British journal of cancer 24 31839677
2018 Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. The Journal of clinical investigation 24 30475228
2017 Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 28554129
2010 Post-translational regulation of mitogen-activated protein kinase phosphatase-2 (MKP-2) by ERK. Cell cycle (Georgetown, Tex.) 23 21084841
2023 DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β. Cell reports 22 37141098
2019 miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression. Journal of Cancer 22 31258782
2019 Estradiol inhibits fMLP-induced neutrophil migration and superoxide production by upregulating MKP-2 and dephosphorylating ERK. International immunopharmacology 22 31401382
2019 GFAP alternative splicing regulates glioma cell-ECM interaction in a DUSP4-dependent manner. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 31480854
2014 Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd²⁺-induced apoptosis. Free radical biology & medicine 21 24973647
2022 Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females. Cells 18 36497141
2016 DUSP4/MKP2 overexpression is associated with BRAF(V600E) mutation and aggressive behavior of papillary thyroid cancer. OncoTargets and therapy 18 27143921
2014 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. The Journal of biological chemistry 17 25204653
2012 MKP-2: out of the DUSP-bin and back into the limelight. Biochemical Society transactions 17 22260697
2024 DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response. Cell death and differentiation 16 38383887
2020 DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex. Neurobiology of disease 16 32890776
2023 ARID1A loss activates MAPK signaling via DUSP4 downregulation. Journal of biomedical science 15 38071325
2022 DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation of MITF. Life science alliance 15 35580987
2013 MAPK phosphatase-2 (MKP-2) is induced by hCG and plays a role in the regulation of CYP11A1 expression in MA-10 Leydig cells. Endocrinology 15 23471219
2003 The I(1)-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase. Brain research 15 12865160
2023 ADSC secretome constrains NK cell activity by attenuating IL-2-mediated JAK-STAT and AKT signaling pathway via upregulation of CIS and DUSP4. Stem cell research & therapy 14 37964351
2014 Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity. Oncotarget 13 24658355
2002 The carboxyl-terminal domains of MKP-1 and MKP-2 have inhibitory effects on their phosphatase activity. Molecular and cellular biochemistry 13 12083364
2022 SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Frontiers in physiology 12 35923224
2021 miR‑122‑5p suppresses the oncogenesis of PTC by inhibiting DUSP4 expression. Molecular medicine reports 12 33760201
2021 DUSP4 alleviates LPS-induced chondrocyte injury in knee osteoarthritis via the MAPK signaling pathway. Experimental and therapeutic medicine 12 34650647
2017 Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity. Molecular pharmacology 12 28283554
2012 MEK inhibition as a strategy for targeting residual breast cancer cells with low DUSP4 expression. Breast cancer research : BCR 12 23127286
2022 Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients 11 35745205
2021 The microRNA-429/DUSP4 axis regulates the sensitivity of colorectal cancer cells to nintedanib. Molecular medicine reports 11 33495832
2020 DUSP4 directly deubiquitinates and stabilizes Smad4 protein, promoting proliferation and metastasis of colorectal cancer cells. Aging 11 32897241
2023 DUSP4 inhibits autophagic cell death and apoptosis in colorectal cancer by regulating BCL2-Beclin1/Bax signaling. Molecular biology reports 10 36705792
2022 Reduction of DUSP4 contributes to podocytes oxidative stress, insulin resistance and diabetic nephropathy. Biochemical and biophysical research communications 10 35940125
2015 Ethanolic extract of Allium cepa stimulates glucose transporter typ 4-mediated glucose uptake by the activation of insulin signaling. Planta medica 9 25654406
2022 Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer. Breast cancer research : BCR 8 35850776
2022 DUSP4 Silencing Enhances the Sensitivity of Breast Cancer Cells to Doxorubicin through the Activation of the JNK/c-Jun Signalling Pathway. Molecules (Basel, Switzerland) 8 36234680
2021 DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 33621155
2021 DUSP4 promotes the carcinogenesis of CCRCC via negative regulation of autophagic death. Bioscience, biotechnology, and biochemistry 8 34143206
2021 Lysine-Specific Histone Demethylase 1 Promotes Oncogenesis of the Esophageal Squamous Cell Carcinoma by Upregulating DUSP4. Biochemistry. Biokhimiia 8 34937541
2020 Dusp4 Contributes to Anesthesia Neurotoxicity via Mediated Neural Differentiation in Primates. Frontiers in cell and developmental biology 8 32974341
2019 Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner. Biochemical and biophysical research communications 8 31526568
2020 Aberrant expression of DUSP4 is a specific phenomenon in betel quid-related oral cancer. Medical molecular morphology 7 32951127
2013 T cell hypo-responsiveness against Leishmania major in MAP kinase phosphatase (MKP) 2 deficient C57BL/6 mice does not alter the healer disease phenotype. PLoS neglected tropical diseases 7 23437409
2023 DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway. Life science alliance 6 37967942
2021 SAHA could inhibit TGF-β1/p38 pathway in MI-induced cardiac fibrosis through DUSP4 overexpression. Heart and vessels 6 34236463
2021 Transcriptional regulation of human DUSP4 gene by cancer-related transcription factors. Journal of cellular biochemistry 6 34254709
2022 Silencing circFTO inhibits malignant phenotype through modulating DUSP4 expression in clear cell renal cell carcinoma. Cell death discovery 5 36127345
2021 Nicotine-derived NNK induces the stemness enrichment of CRC cells through regulating the balance of DUSP4-ERK1/2 feedback loop. Ecotoxicology and environmental safety 5 33662786
2024 DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB. Translational oncology 4 38843658
2023 Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis. BMC cancer 4 37946160
2022 Long non-coding RNA AFAP1-AS1 promotes thyroid cancer progression by sponging miR-204-3p and upregulating DUSP4. Journal of biochemistry 4 34652441
2022 DUSP4 Inactivation Leads to Reduced Extracellular Signal‒Regulated Kinase Activity through Upregulation of DUSP6 in Melanoma Cells. The Journal of investigative dermatology 4 35189148
2022 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. Frontiers in pharmacology 4 35496267
2022 TAT-Beclin 1 represses the carcinogenesis of DUSP4-positive PTC by enhancing autophagy. Molecular biology reports 4 36474060
2020 Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4. Cancers 4 31936698
2020 Expression of DUSP4 transcript variants as a potential biomarker for colorectal cancer. Biomarkers in medicine 4 32613839
1977 [Structures of oncornaviruses of C-typ-negativ staining technique by electron microscopy (author's transl)]. Archiv fur Geschwulstforschung 4 72553
2025 The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells. Respiratory research 3 40241046
2025 Exosomal miR-122-5p for regulation of secretory functions of fibroblasts and promotion of breast cancer metastasis by targeting MKP-2: an experimental study. Cancer biology & therapy 3 40320567
2025 DUSP4 inhibited tumor cell proliferation by downregulating glycolysis via p-ERK/p-PGK1 signaling in ovarian cancer. Cancer cell international 2 40082940
2024 Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer's Disease. Biomolecules 2 38254666
2022 Investigating the Role of DUSP4 in Uveal Melanoma. Translational vision science & technology 2 36576731