Affinage

DUSP2

Dual specificity protein phosphatase 2 · UniProt Q05923

Length
314 aa
Mass
34.4 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP2 (PAC-1) is a mitogen-inducible, nuclear dual-specificity MAP kinase phosphatase originally cloned from human T cells and expressed predominantly in hematopoietic tissues (PMID:7681221). Its catalytic activity is conformationally gated: recombinant DUSP2 is essentially inactive alone and is allosterically activated upon association of its N-terminal kinase-binding domain with ERK2, a process coupled to a MAPK-induced rearrangement of the C-terminal phosphatase active site, with Arg294/Arg295 forming the phosphothreonine-binding pocket required for catalysis (PMID:12575935, PMID:16288922). Through this binding-dependent mechanism DUSP2 preferentially dephosphorylates ERK2 while showing distinct handling of other MAPKs, and it engages the atypical kinases ERK3 and ERK4 via a KIM/CD-domain interaction that both dephosphorylates them, blocking downstream MK5 activation, and reciprocally stabilizes DUSP2 protein (PMID:16288922, PMID:28252035). DUSP2 transcription is driven by the ERK/MAPK pathway itself, placing ERK2 upstream of PAC-1 induction and establishing a MAPK negative-feedback loop (PMID:8649402). Beyond MAPKs, DUSP2 directly binds and dephosphorylates STAT3 (Tyr705 and Ser727) and STAT1, and modulates NFAT phosphorylation, linking it to transcriptional control of inflammatory and effector programs (PMID:26479789, PMID:35836796, PMID:41883167). Genetic loss-of-function studies show DUSP2 is a positive regulator of inflammatory signaling via JNK/ERK crosstalk in arthritis models (PMID:16474395), a negative regulator of TH17 differentiation (PMID:26479789), a restrictor of STAT1-driven GSDMD pyroptosis in acute kidney injury (PMID:35836796), and an enforcer of T cell exhaustion downstream of type I interferon through NFAT (PMID:41883167). In cancer, DUSP2 acts as a tumor suppressor whose silencing—via hypoxia/HIF-1, HDAC recruitment to its promoter, transcription-factor repression, or oncogenic miRNA targeting—drives ERK or p38 reactivation, stemness, EMT, metastasis, VEGF-C secretion, and drug resistance (PMID:28652251, PMID:25596742, PMID:30042387, PMID:35689852). DUSP2 protein abundance is further controlled by ubiquitin-dependent proteasomal degradation through the E3 ligases TRIM21 and FBXO45 (PMID:37390887, PMID:40637745).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1993 High

    Established the existence and basic identity of DUSP2 by cloning a mitogen-induced nuclear phosphatase, defining where and when it is expressed.

    Evidence cDNA cloning from human T cells with transfection-based subcellular localization in COS-7 and stimulated T cells

    PMID:7681221

    Open questions at the time
    • Substrate specificity not yet defined
    • Catalytic mechanism unresolved
  2. 1995 Medium

    Defined DUSP2 as a MAP-kinase-directed dual-specificity phosphatase that downregulates signal transduction and mapped the gene, framing its negative-regulatory role.

    Evidence Genomic structure analysis and chromosomal mapping with functional description

    PMID:7590752

    Open questions at the time
    • Specific MAPK substrate preference not distinguished
    • No structural basis for specificity
  3. 1996 High

    Showed DUSP2 transcription is itself driven by the ERK/MAPK pathway, establishing a negative-feedback architecture rather than constitutive expression.

    Evidence Promoter-reporter assays with dominant-negative ERK2 and EMSA for E-box/AP-2 elements

    PMID:8649402

    Open questions at the time
    • Identity of trans-acting factors at E-box/AP-2 sites not resolved
    • Does not address protein-level feedback
  4. 2003 High

    Provided the structural and mechanistic basis for catalysis, showing the active site is reconfigured by N-/C-domain interaction coupled to MAPK binding.

    Evidence NMR solution structure of the C-terminal phosphatase domain with biochemical phosphatase assays

    PMID:12575935

    Open questions at the time
    • No full-length structure with bound ERK2
    • Dynamics of activation not directly visualized
  5. 2005 High

    Defined substrate specificity and the substrate-induced activation mechanism, showing DUSP2 is inactive alone and requires ERK2 binding plus an intact phosphothreonine pocket.

    Evidence In vitro reconstitution with recombinant proteins, binding assays, and Arg294/Arg295 mutagenesis

    PMID:16288922

    Open questions at the time
    • In-cell substrate repertoire beyond ERK2 not addressed
    • Quantitative selectivity over other DUSPs unknown
  6. 2006 High

    Revealed an unexpected in vivo role as a positive regulator of inflammation through MAPK crosstalk, complicating the simple negative-feedback model.

    Evidence Dusp2-/- mice in the K/BxN arthritis model with kinase activity and transcription-factor reporter assays

    PMID:16474395

    Open questions at the time
    • Molecular basis of JNK/ERK/p38 crosstalk not fully mechanistic
    • Cell-type-specific contributions not separated
  7. 2004 Medium

    Connected DUSP2 to receptor-driven feedback inhibition, showing it is recruited to ERK to terminate B-cell signaling.

    Evidence Co-IP of ERK with PAC-1 and phosphatase assays following BCR/FcgammaRIIb or ES-62 priming

    PMID:11390499 PMID:14607277

    Open questions at the time
    • Single-lab co-IP without reciprocal genetic validation
    • Recruitment mechanism not defined
  8. 2015 High

    Extended DUSP2 substrates beyond MAPKs to STAT3, defining a direct route by which it restrains TH17 differentiation.

    Evidence Reciprocal co-IP, direct dephosphorylation assays, and Dusp2-/- colitis model with flow cytometry

    PMID:26479789

    Open questions at the time
    • Whether STAT3 dephosphorylation is nuclear or cytoplasmic not resolved
    • Selectivity for Tyr705 vs Ser727 kinetics unquantified
  9. 2017 High

    Established DUSP2 regulation of the atypical kinases ERK3/ERK4 via KIM/CD docking, with reciprocal stabilization of DUSP2, broadening its substrate range.

    Evidence Co-IP, domain-mapped binding, dephosphorylation and protein-stability assays, MK5 activation readout

    PMID:28252035

    Open questions at the time
    • Physiological consequence of ERK3/ERK4 dephosphorylation in vivo unknown
    • Mechanism of ERK4-dependent DUSP2 stabilization not detailed
  10. 2017 Medium

    Defined DUSP2 as a hypoxia-suppressed tumor suppressor whose loss elevates COX-2/PGE2 to drive cancer stemness.

    Evidence DUSP2 knockdown/overexpression, COX-2/PGE2 pathway perturbation, stemness assays, genome-wide profiling

    PMID:28652251

    Open questions at the time
    • Direct link from DUSP2 phosphatase activity to COX-2 transcription not established
    • Single-lab loss-of-function
  11. 2017 Medium

    Linked DUSP2 loss to ERK reactivation and drug resistance/inflammation across tissue contexts, positioning it downstream of HIF-1.

    Evidence DUSP2 overexpression/knockdown rescue with HIF-1 manipulation in breast cancer and endometriotic stromal cell models

    PMID:25596742 PMID:28440564

    Open questions at the time
    • Direct substrate engagement (ERK vs STAT3) context-dependent and not always shown
    • Single-lab epistasis
  12. 2018 Medium

    Demonstrated post-transcriptional silencing of DUSP2 by oncogenic miRNAs that activates ERK to drive EMT and metastasis.

    Evidence 3'UTR luciferase, Ago2 co-IP, and DUSP2 rescue in pancreatic cancer; later extended to lymphoma miRNA clusters

    PMID:30042387 PMID:40537745

    Open questions at the time
    • Relative contribution of each miRNA in vivo unclear
    • Whether miRNA loss restores DUSP2 function physiologically untested
  13. 2020 Medium

    Identified a non-canonical route by which DUSP2 loss promotes EV-associated VEGF-C secretion and lymphovascular invasion in PDAC.

    Evidence Tissue-specific Dusp2 knockout mouse, EV isolation with VEGF-C quantification, lymphatic endothelial assays

    PMID:32341770

    Open questions at the time
    • Phosphatase substrate driving convertase/trafficking changes not identified
    • Single-lab mechanism
  14. 2022 High

    Showed DUSP2 restrains STAT1-driven GSDMD pyroptosis, defining a protective role in acute kidney injury and a STAT1 substrate.

    Evidence RTEC-specific Dusp2 conditional knockout, STAT1 phosphorylation and GSDMD transcription analysis, AAV rescue

    PMID:35836796

    Open questions at the time
    • Direct dephosphorylation of STAT1 by DUSP2 not shown in vitro
    • Tissue specificity of STAT1 vs STAT3 preference unexplained
  15. 2022 High

    Established epigenetic silencing of DUSP2 via HDAC1 recruitment to its promoter, linking chromatin state to ERK reactivation in metastasis.

    Evidence ChIP, co-IP of DNTTIP1-HDAC1, luciferase, and metastasis assays with chidamide rescue

    PMID:35689852

    Open questions at the time
    • Whether HDAC silencing operates in non-NPC contexts not tested
    • Upstream signal controlling DNTTIP1/HDAC1 recruitment unknown
  16. 2023 Medium

    Identified ubiquitin-dependent control of DUSP2 stability and a competitive AKT1/CSNK2A1 mechanism, embedding DUSP2 in a self-reinforcing degradation loop.

    Evidence Co-IP of DUSP2-CSNK2A1, AKT1-CSNK2A1, TRIM21-DUSP2 and ubiquitination/apoptosis assays in pancreatic cancer

    PMID:37390887

    Open questions at the time
    • TRIM21 ubiquitination site on DUSP2 not mapped
    • Single-lab multi-partner co-IP
  17. 2023 Medium

    Reinforced DUSP2 as a STAT3-pathway suppressor in autoimmune disease and tied additional transcription factors to its promoter repression.

    Evidence AAV-DUSP2 overexpression in lupus nephritis mice; E2F4 ChIP/luciferase at the DUSP2 promoter with p38 readout

    PMID:37479052 PMID:37483429

    Open questions at the time
    • Direct vs indirect STAT3 effects in vivo not separated
    • Generality of E2F4 repression across tissues untested
  18. 2024 Medium

    Placed DUSP2 as an intermediate in an RB/TRIM24-mTOR signaling axis driving castration-resistant prostate cancer progression.

    Evidence Motif mapping, co-IP of the RB-TRIM24-DUSP2 complex, mTOR pathway assays, PROTAC TRIM24 degradation

    PMID:38514847

    Open questions at the time
    • How DUSP2 phosphatase activity connects to mTOR not mechanistically defined
    • Single-lab ternary-complex evidence
  19. 2025 Medium

    Showed DUSP2 enforces T cell exhaustion downstream of type I interferon via NFAT dephosphorylation, identifying it as an immunotherapy target.

    Evidence scRNA-seq, Dusp2 genetic ablation, NFAT phosphorylation and T cell function assays, ICB treatment in vivo

    PMID:41883167

    Open questions at the time
    • Direct DUSP2-NFAT dephosphorylation kinetics not characterized
    • Single tumor model
  20. 2025 Medium

    Added FBXO45 as a second E3 ligase degrading DUSP2 to sustain ERK-driven glycolysis, and broadened the degradation/silencing landscape.

    Evidence Co-IP, ubiquitination assay, ERK1/2 and Seahorse glycolysis readouts, xenograft, plus NELFCD/PRMT5 promoter repression

    PMID:40302325 PMID:40637745

    Open questions at the time
    • Hierarchy/redundancy between TRIM21 and FBXO45 unknown
    • Degradation site on DUSP2 not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DUSP2 selects among ERK, STAT, and NFAT substrates in a given cell type, and how its many transcriptional/epigenetic/post-translational repressors are integrated, remains unresolved.
  • No unified model of substrate selection across contexts
  • Relative weight of transcriptional vs degradative control unquantified
  • No full-length DUSP2-substrate complex structure

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
CSNK2A1ERK2ERK3ERK4FBXO45STAT1STAT3TRIM21

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 DUSP2 (PAC-1) was cloned from human T cells as a mitogen-induced gene encoding a 32-kDa nuclear dual-specificity protein phosphatase; it localizes to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells, and is predominantly expressed in hematopoietic tissues. cDNA cloning, sequence analysis, transfection with subcellular localization by imaging Science High 7681221
1996 PAC-1 transcription is induced by the MAPK/ERK pathway downstream of mitogen stimulation and oncogenic Ras/Raf signaling; an interfering ERK-2 dominant-negative mutant blocked PMA- and v-ras-dependent PAC-1 transcription, placing ERK2 upstream of PAC-1 induction. Transcriptional regulation involves an E-box element and an AP-2-related site in a 200-bp promoter region. Promoter-reporter transfection, dominant-negative ERK-2 mutant, EMSA for E-box and AP-2 binding Molecular and cellular biology High 8649402
1995 The DUSP2 gene encodes a nuclear dual-specificity MAP kinase phosphatase with stringent substrate specificity for MAP kinase; it downregulates intracellular signal transduction through dephosphorylation/inactivation of MAP kinases. The gene was mapped to human chromosome 2p11.2-q11. Genomic structure analysis, somatic cell hybrid mapping, in situ hybridization, SSCP linkage analysis Genomics Medium 7590752
2003 The NMR solution structure of the PAC-1 C-terminal phosphatase domain revealed unique active-site geometry important for binding phosphorylated threonine and tyrosine of ERK2; structural and biochemical analyses demonstrated that dynamic interaction between the N-terminal kinase-binding domain and the C-terminal phosphatase domain is coupled to MAPK-induced conformational change of the phosphatase active site, essential for full enzymatic activity. NMR structure determination, biochemical phosphatase assays Structure High 12575935
2005 PAC-1 in vitro dephosphorylates ERK2 but not p38α or JNK2; recombinant PAC-1 is virtually inactive alone and requires association of its N-terminal domain with ERK2 for catalytic activation. p38α interacts with but does not activate PAC-1, whereas JNK2 neither binds nor activates PAC-1. Individual mutation of conserved Arg294 and Arg295 (phosphothreonine-binding pocket) to alanine or lysine causes near-complete loss of phosphatase activity even in the presence of ERK2. In vitro phosphatase assay with recombinant proteins, active-site mutagenesis, binding assays Journal of molecular biology High 16288922
2006 In Dusp2−/− mice, PAC-1 deficiency leads to increased JNK activity but unexpected impairment of ERK and p38 activity, reduced Elk1 transcriptional activity and reduced NFAT/AP-1 complex activity, resulting in considerably reduced inflammatory responses in the K/BxN model of rheumatoid arthritis and impaired effector immune cell function. Thus PAC-1 is a positive regulator of inflammatory signaling via JNK/ERK MAPK crosstalk. Dusp2 knockout mouse model (Dusp2−/−), K/BxN arthritis model, kinase activity assays, transcription factor reporter assays Nature immunology High 16474395
2001 The MAP kinase phosphatase PAC-1 (DUSP2) is recruited to and terminates ERK/MAP kinase signaling in B cells following BCR ligation primed by ES-62 (filarial nematode phosphorylcholine glycoprotein), representing a mechanism by which the parasite desensitizes B cell activation. Co-immunoprecipitation of Erk with PAC-1 after ES-62 priming and BCR ligation, phosphatase activity assay Journal of immunology Medium 11390499
2004 FcγRIIb-mediated negative regulation of BCR signaling involves rapid association of ERK with the MAP kinase phosphatase PAC-1 and dephosphorylation/inactivation of ERK; this provides a mechanism for immune-complex-mediated feedback inhibition of active antigen-driven B cell responses. Co-immunoprecipitation of ERK with PAC-1, phosphatase activity assay following FcγRIIb co-ligation Cellular signalling Medium 14607277
2015 DUSP2 directly associates with STAT3 and dephosphorylates it at both Tyr705 and Ser727, thereby attenuating STAT3 activity and negatively regulating TH17 cell differentiation. DUSP2-deficient mice showed enhanced TH17 differentiation and severe susceptibility to experimental colitis. Direct co-immunoprecipitation of DUSP2 with STAT3, dephosphorylation assay, Dusp2−/− mouse colitis model, flow cytometry for TH17 Nature immunology High 26479789
2017 DUSP2 regulates the atypical MAP kinases ERK3 and ERK4 by direct binding via the kinase interaction motif (KIM) in the DUSP2 N-terminus and the common docking (CD) domain in ERK3/ERK4 C-termini; this interaction leads to dephosphorylation of ERK3 and ERK4 and stabilization of DUSP2. ERK4 stabilizes DUSP2 in a kinase activity-dependent manner. DUSP2 expression inhibits ERK3/ERK4-mediated activation of downstream substrate MK5. Co-immunoprecipitation, direct binding assay, dephosphorylation assays, protein stability experiments, MK5 activation assay Scientific reports High 28252035
2017 Hypoxia-mediated downregulation of DUSP2 is critical for accumulation of cancer stem-like cells in colorectal cancer; reduced DUSP2 leads to overproduction of COX-2-derived prostaglandin E2, which promotes cancer stemness via EP2/EP4 signaling. Genome-wide profiling revealed DUSP2-regulated genes overlap with HDAC-controlled genes. DUSP2 knockdown/overexpression, genetic/pharmacological COX-2/PGE2 pathway inhibition, tumor growth and stemness assays, genome-wide expression profiling Cancer research Medium 28652251
2015 HIF-1 induces lapatinib resistance in ERBB2-positive breast cancer cells by inhibiting DUSP2, thereby maintaining ERK pathway activation in the presence of lapatinib. Overexpression of DUSP2 reverses hypoxia-mediated lapatinib resistance, demonstrating DUSP2 acts downstream of HIF-1 to suppress ERK signaling. DUSP2 overexpression/knockdown, HIF-1 stable overexpression, MEK inhibitor treatment, 3D culture apoptosis/growth assays Oncotarget Medium 25596742
2018 miR-361-3p promotes EMT and metastasis in pancreatic cancer by directly targeting DUSP2 mRNA (confirmed by luciferase assay and Ago2 co-IP), leading to ERK pathway activation; re-expression of DUSP2 reverses miR-361-3p-induced EMT, establishing a miR-361-3p/DUSP2/ERK axis. Luciferase reporter assay for 3'UTR targeting, Ago2 co-immunoprecipitation, DUSP2 rescue experiments, western blot for ERK phosphorylation Cell death & disease Medium 30042387
2020 Loss of DUSP2 in pancreatic cancer enhances proprotein convertase activity and vesicle trafficking to promote secretion of mature EV-associated VEGF-C, leading to lymphovascular invasion. Tissue-specific knockout of Dusp2 in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion. DUSP2 knockdown, tissue-specific Dusp2 knockout mouse, extracellular vesicle isolation and VEGF-C quantification, lymphatic endothelial cell functional assays Journal of extracellular vesicles Medium 32341770
2015 Salubrinal acts as an inhibitor of Dusp2 (PAC1) in immune cells; partial silencing of Dusp2 downregulates IL-1β and Cox2 expression, and salubrinal suppresses Dusp2 in LPS-activated macrophages and PMA/ionomycin-activated T lymphocytes and mast cells, reducing inflammatory gene expression and arthritic responses in CAIA mice. Genome-wide microarray, qPCR, RNA interference (Dusp2 partial silencing), CAIA mouse model with clinical/histological scoring Cellular signalling Medium 25619567
2014 P2Y13 receptor activation induces DUSP2 expression in cerebellar granule neurons, and the resultant DUSP2 activity dephosphorylates p38 MAPK, restoring its inactive form; cisplatin-induced sustained p38 activation correlates with progressive reduction in DUSP2 expression, suggesting DUSP2 acts to maintain p38 signaling homeostasis and neuronal survival. Microarray gene expression validated by qPCR, p38 phosphorylation assays following P2Y13 agonist treatment, knockdown of DUSP2 Biochimica et biophysica acta Medium 24851838
2022 DUSP2 acts as a nuclear phosphatase that deactivates STAT1, thereby restricting gasdermin D (GSDMD)-mediated pyroptosis in renal tubular epithelial cells during acute kidney injury. GSDMD is a transcriptional target of activated STAT1; RTEC-specific Dusp2 deletion sensitizes mice to AKI by promoting RTEC pyroptosis. AAV-mediated DUSP2 overexpression significantly ameliorates AKI. RTEC-specific Dusp2 conditional knockout mice, AKI model, STAT1 phosphorylation assay, GSDMD transcription analysis, AAV overexpression rescue Theranostics High 35836796
2022 DNTTIP1 suppresses DUSP2 gene expression by recruiting HDAC1 to the DUSP2 promoter, maintaining a deacetylated state of histone H3K27; downregulation of DUSP2 results in aberrant ERK activation and elevated MMP2 levels, promoting NPC metastasis. HDAC inhibitor chidamide restores DUSP2 expression by disrupting the DNTTIP1/HDAC1 complex. ChIP assay (HDAC1 at DUSP2 promoter), co-IP (DNTTIP1-HDAC1 interaction), luciferase reporter, western blot, in vitro/in vivo metastasis assays EBioMedicine High 35689852
2023 DUSP2 competes with AKT1 to bind casein kinase 2 alpha 1 (CSNK2A1), thereby inhibiting AKT1 phosphorylation and promoting apoptosis in pancreatic cancer. Activated AKT1 in turn induces TRIM21 E3 ubiquitin ligase to bind and mediate ubiquitination-dependent proteasomal degradation of DUSP2, forming a positive feedback loop that suppresses DUSP2. Co-immunoprecipitation (DUSP2-CSNK2A1, AKT1-CSNK2A1, TRIM21-DUSP2), ubiquitination assay, in vitro and in vivo apoptosis assays Cancer letters Medium 37390887
2017 Hypoxia-induced downregulation of DUSP2 promotes IL-6 expression in endometriotic stromal cells, which in turn activates STAT3 phosphorylation; DUSP2 overexpression suppresses IL-6 and phospho-STAT3 levels, and DUSP2 knockdown phenocopies hypoxia-induced IL-6 upregulation, establishing a DUSP2/IL-6/STAT3 axis in endometriosis. DUSP2 knockdown/overexpression, IL-6 quantification, STAT3 phosphorylation western blot, genome-wide expression profiling, BrdU proliferation assay American journal of reproductive immunology Medium 28440564
2019 Membrane cholesterol loss during aging activates a subset of receptor tyrosine kinases (RTKs), increasing p38 MAPK activity, which in turn upregulates DUSP2 expression and activity in the hippocampus; this forms a negative-feedback loop that keeps p38 MAPK activity within physiological range during normal aging. Membrane cholesterol manipulation (enrichment/depletion), western blot for p38 phosphorylation and DUSP2 levels in aged mouse hippocampus, RTK inhibitor experiments Frontiers in neurology Medium 31293510
2023 DUSP2 deletion by CRISPR/Cas9 in zebrafish promotes Mauthner cell axonal regeneration at early developmental stages; DUSP2 acts as a negative regulator of axon regeneration by mediating dephosphorylation of JNK, and DUSP2 knockout slightly increases phosphorylated JNK levels. Overexpression of DUSP2 retards M-cell axon regeneration. CRISPR/Cas9 knockout, single-cell electroporation for DUSP2 overexpression, western blot for phospho-JNK, axon regeneration imaging in Tg zebrafish Neural regeneration research Medium 36018180
2024 The RB/TRIM24 complex functions through DUSP2 as an intermediate bridge to activate the mTOR pathway in castration-resistant prostate cancer; TRIM24 transcriptional activity regulated at RB S249/T252 sites controls DUSP2 to promote mTOR signaling and prostate cancer progression. FXXXV motif mapping, co-immunoprecipitation (RB-TRIM24-DUSP2), mTOR pathway assays, PROTAC-mediated TRIM24 degradation Cell death and differentiation Medium 38514847
2023 DUSP2 inhibits STAT3 phosphorylation in vivo (AAV-DUSP2 overexpression in MRL/lpr lupus nephritis mice reduces STAT3 phosphorylation) and ameliorates lupus nephritis by reducing proteinuria, inflammatory cytokines (TNF-α, IL-6, IL-1β), and renal tissue injury. AAV-mediated DUSP2 overexpression in MRL/lpr mice, western blot for STAT3 phosphorylation, proteinuria and cytokine measurement, histopathology Open life sciences Medium 37483429
2023 E2F4 transcription factor binds to the DUSP2 promoter and suppresses DUSP2 expression (validated by dual-luciferase reporter and ChIP assay); DUSP2 knockdown upregulates p38 MAPK phosphorylation and promotes endothelial cell proliferation, migration, and angiogenesis under high-glucose conditions. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), western blot for p-p38 MAPK, cell proliferation/migration/tube formation assays Experimental cell research Medium 37479052
2025 FBXO45 interacts with and ubiquitinates DUSP2, leading to its proteasomal degradation and subsequent ERK1/2 activation and enhanced glycolysis in cervical cancer cells (confirmed by co-IP and western blot); negative correlation between FBXO45 and DUSP2 was confirmed in tissue microarrays. Co-immunoprecipitation (FBXO45-DUSP2), ubiquitination assay, western blot for DUSP2 levels and ERK1/2 phosphorylation, Seahorse glycolysis assay, mouse xenograft model Naunyn-Schmiedeberg's archives of pharmacology Medium 40637745
2025 NELFCD recruits PRMT5 to the DUSP2 promoter (confirmed by co-IP and ChIP), suppressing DUSP2 expression and consequently activating p38 MAPK signaling to promote colon cancer cell growth. Co-immunoprecipitation (NELFCD-PRMT5), ChIP (PRMT5 at DUSP2 promoter), RNA sequencing, DUSP2 promoter ChIP-seq, cell proliferation assays Frontiers in bioscience Medium 40302325
2003 A variant of PAC-1 (DUSP2) identified in LGL leukemia encodes a 170-amino acid truncated protein (clone 8) lacking the phosphatase active site; when expressed as a GST fusion, this variant has no intrinsic phosphatase activity in vitro but enhances the phosphatase activity of co-added dual-specificity phosphatase CL100. cDNA library screening, GST-fusion protein expression in E. coli, in vitro phosphatase assay Protein expression and purification Low 14680939
2025 IFN-I signaling in pre-exhausted T cells induces DUSP2 expression, which promotes NFAT dephosphorylation and nuclear accumulation; nuclear NFAT upregulates inhibitory receptors and antagonizes Bcl6-dependent transcriptional programs, reinforcing T cell exhaustion and impairing Tfh differentiation. Genetic ablation of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, enhancing ICB responsiveness in lung squamous carcinoma. Single-cell RNA sequencing, Dusp2 genetic ablation, NFAT phosphorylation assay, T cell functional assays, ICB treatment in Dusp2-KO mice Molecular therapy Medium 41883167
2025 Flavescensine 10 exhibits a potential interaction with DUSP2 and inhibits its expression, suppressing DUSP2-mediated mitochondrial apoptosis via the PI3K/Akt/JNK pathway in APAP-induced liver injury. In vitro hepatoprotection assay, in vivo APAP liver injury model, western blot for DUSP2, PI3K/Akt/JNK pathway analysis Acta pharmaceutica Sinica B Low 41909738
2025 Multiple oncogenic microRNA clusters (miR-17-92, miR-106a-363, miR-106b-25) directly target the DUSP2 mRNA 3'UTR (confirmed by reporter gene assay); specific miRNA inhibitors (miR-17-5p, miR-20b-5p, miR-106b-5p) increase DUSP2 mRNA levels in lymphoma cells, implicating miRNA-mediated DUSP2 suppression in MAPK pathway dysregulation in cancer. Reporter gene assay for 3'UTR interaction, pan-cancer expression correlation analysis, miRNA inhibitor treatment with qPCR BMC cancer Medium 40537745

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science (New York, N.Y.) 292 7681221
2006 Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nature immunology 219 16474395
2015 The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation. Nature immunology 134 26479789
2009 PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition. Journal of molecular biology 132 19281821
2009 Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3. Journal of medicinal chemistry 109 19708658
1999 Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways. The Journal of biological chemistry 101 10488112
1996 Critical residues of integrin alphaIIb subunit for binding of alphaIIbbeta3 (glycoprotein IIb-IIIa) to fibrinogen and ligand-mimetic antibodies (PAC-1, OP-G2, and LJ-CP3). The Journal of biological chemistry 81 8702512
2000 Developmental regulation of pituitary adenylate cyclase-activating polypeptide and PAC(1) receptor mRNA expression in the rat central nervous system. Brain research. Developmental brain research 79 10727727
2018 MiR-361-3p regulates ERK1/2-induced EMT via DUSP2 mRNA degradation in pancreatic ductal adenocarcinoma. Cell death & disease 77 30042387
1996 Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene. Molecular and cellular biology 73 8649402
2015 Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 70 26658840
2018 PACAP38 and PAC1 receptor blockade: a new target for headache? The journal of headache and pain 64 30088106
2017 Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness. Cancer research 58 28652251
2018 JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma. Haematologica 49 30213827
2013 ERO1α-dependent endoplasmic reticulum-mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1). Cell death & disease 44 24357799
2003 Solution structure of the MAPK phosphatase PAC-1 catalytic domain. Insights into substrate-induced enzymatic activation of MKP. Structure (London, England : 1993) 44 12575935
2001 ADP-ribosylation factor-dependent phospholipase D activation by VPAC receptors and a PAC(1) receptor splice variant. Molecular pharmacology 44 11353814
2015 Hypoxia/HIF1α induces lapatinib resistance in ERBB2-positive breast cancer cells via regulation of DUSP2. Oncotarget 42 25596742
2020 DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination. Journal of extracellular vesicles 40 32341770
2009 Integrin priming dynamics: mechanisms of integrin antagonist-promoted alphaIIbbeta3:PAC-1 molecular recognition. Biochemistry 40 19640007
2000 Cellular distribution of the splice variants of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC(1)-R) in the rat brain by in situ RT-PCR. Brain research. Molecular brain research 39 10648899
2015 Curcumin enhances the radiosensitivity of U87 cells by inducing DUSP-2 up-regulation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 38 25792385
2022 DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics 37 35836796
2001 A filarial nematode-secreted phosphorylcholine-containing glycoprotein uncouples the B cell antigen receptor from extracellular signal-regulated kinase-mitogen-activated protein kinase by promoting the surface Ig-mediated recruitment of Src homology 2 domain-containing tyrosine phosphatase-1 and Pac-1 mitogen-activated kinase-phosphatase. Journal of immunology (Baltimore, Md. : 1950) 35 11390499
2016 Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities. Current medicinal chemistry 34 26630918
2022 DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway. EBioMedicine 33 35689852
2005 New insights into the catalytic activation of the MAPK phosphatase PAC-1 induced by its substrate MAPK ERK2 binding. Journal of molecular biology 33 16288922
2000 Progesterone increases mRNA levels of pituitary adenylate cyclase-activating polypeptide (PACAP) and type I PACAP receptor (PAC(1)) in the rat hypothalamus. Brain research. Molecular brain research 33 10891585
2000 Mice with markedly reduced PACAP (PAC(1)) receptor expression by targeted deletion of the signal peptide. Journal of neurochemistry 33 11032869
2015 Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis. Cellular signalling 32 25619567
2010 Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1, a preferential small molecule activator of procaspase-3, in healthy dogs. Investigational new drugs 32 20499133
2017 Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis. American journal of reproductive immunology (New York, N.Y. : 1989) 29 28440564
2011 Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1). ACS combinatorial science 29 22007686
2014 Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery. Biochimica et biophysica acta 27 24851838
2017 Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2. Scientific reports 26 28252035
2023 DUSP2 recruits CSNK2A1 to suppress AKT1-mediated apoptosis resistance under hypoxic microenvironment in pancreatic cancer. Cancer letters 22 37390887
2001 Role of PAC(1) receptor in adrenal catecholamine secretion induced by PACAP and VIP in vivo. American journal of physiology. Regulatory, integrative and comparative physiology 20 11208582
2004 FcgammaRIIb-mediated negative regulation of BCR signalling is associated with the recruitment of the MAPkinase-phosphatase, Pac-1, and the 3'-inositol phosphatase, PTEN. Cellular signalling 19 14607277
2000 Desensitization, surface expression, and glycosylation of a functional, epitope-tagged type I PACAP (PAC(1)) receptor. Biochimica et biophysica acta 19 11118531
2018 miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by Targeting Dual-Specificity Phosphatases 2 (DUSP2). Medical science monitor : international medical journal of experimental and clinical research 18 30011263
1995 Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11. Genomics 18 7590752
2022 The SKA3-DUSP2 Axis Promotes Gastric Cancer Tumorigenesis and Epithelial-Mesenchymal Transition by Activating the MAPK/ERK Pathway. Frontiers in pharmacology 17 35295342
2019 Acquisition of class C β-lactamase PAC-1 by ST664 strains of Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy 17 31527025
2015 Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis. Journal of cellular and molecular medicine 17 25754465
2015 Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics. Journal of medicinal chemistry 16 25856364
2019 Immunohistochemical Characterization of Procaspase-3 Overexpression as a Druggable Target With PAC-1, a Procaspase-3 Activator, in Canine and Human Brain Cancers. Frontiers in oncology 15 30859090
2023 Calcitonin/PAC1 receptor splice variants: a blind spot in migraine research. Trends in pharmacological sciences 14 37543479
2020 Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation. Molecules (Basel, Switzerland) 13 32635530
2019 PACAP stimulates insulin secretion by PAC1 receptor and ion channels in β-cells. Cellular signalling 12 31085235
2019 Expression of Dual-Specificity Phosphatase 2 (DUSP2) in Patients with Serous Ovarian Carcinoma and in SKOV3 and OVCAR3 Cells In Vitro. Medical science monitor : international medical journal of experimental and clinical research 12 31889045
2014 PAC-1 and isatin derivatives are weak matrix metalloproteinase inhibitors. Biochimica et biophysica acta 12 25046380
2013 Increased PAC-1 expression among patients with multiple myeloma on concurrent thalidomide and warfarin. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 12 24030118
2000 Splice variants of PAC(1) receptor during early neural development of rats. Peptides 12 11035203
1995 The dual specificity phosphatase PAC-1 is transcriptionally induced in the rat brain following transient forebrain ischemia. Brain research. Molecular brain research 12 7723634
2022 PAC1, VPAC1, and VPAC2 Receptor Expression in Rat and Human Trigeminal Ganglia: Characterization of PACAP-Responsive Receptor Antibodies. International journal of molecular sciences 11 36430275
2013 Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: comparison with TPEN and PAC-1. Bioorganic & medicinal chemistry 11 23859779
2012 Activation of PAC(1) and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetized rat. British journal of pharmacology 11 22612450
1991 PAC 1: an epitope associated with two novel glycoprotein components of isolated postsynaptic densities and a novel cytoskeleton-associated polypeptide. Neuroscience 11 1721684
2024 Pharmacology of PACAP and VIP receptors in the spinal cord highlights the importance of the PAC1 receptor. British journal of pharmacology 10 38616050
2015 Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells. Experimental hematology 9 26257207
2002 Specific interaction between the hop1 intracellular loop 3 domain of the human PAC(1) receptor and ARF. Regulatory peptides 9 12409233
2023 Interfering with Dusp2 alleviates high glucose-induced vascular endothelial cell dysfunction by promoting p38 MAPK pathway activation. Experimental cell research 8 37479052
2017 Role of transglutaminase 2 in PAC1 receptor mediated protection against hypoxia-induced cell death and neurite outgrowth in differentiating N2a neuroblastoma cells. Biochemical pharmacology 8 28065858
2016 Molecular evidence of Zn chelation of the procaspase activating compound B-PAC-1 in B cell lymphoma. Oncotarget 8 26658105
2016 SM-1, a novel PAC-1 derivative, activates procaspase-3 and causes cancer cell apoptosis. Cancer chemotherapy and pharmacology 8 27488460
2024 C. elegans Afadin is required for epidermal morphogenesis and functionally interfaces with the cadherin-catenin complex and RhoGAP PAC-1/ARHGAP21. Developmental biology 7 38556137
2023 The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma. Melanoma research 7 37738028
2021 Apatinib combined with Keytruda treatment induces apoptosis of gastric carcinoma cells through CES4/miR-616-5p/DUSP2 axis. Basic & clinical pharmacology & toxicology 7 34365722
2016 PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells. Neuropeptides 7 27745706
2015 Synergistic antitumor activity of pro-apoptotic agent PAC-1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299. Asia-Pacific journal of clinical oncology 7 26620316
2005 Ligand-mimetic anti-alphaIIb beta3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells. Pathology oncology research : POR 7 16388318
2024 Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer. Cell death and differentiation 6 38514847
2023 DUSP2 deletion with CRISPR/Cas9 promotes Mauthner cell axonal regeneration at the early stage of zebrafish. Neural regeneration research 6 36018180
2017 PAC-1 and its derivative WF-210 Inhibit Angiogenesis by inhibiting VEGF/VEGFR pathway. European journal of pharmacology 6 29269017
2014 The dual-specificity phosphatase 2 (DUSP2) does not regulate obesity-associated inflammation or insulin resistance in mice. PloS one 6 25375135
2008 Cilostazol reduces PAC-1 expression on platelets in ischemic stroke. Journal of clinical neurology (Seoul, Korea) 6 19513289
2018 DUSP2 methylation is a candidate biomarker of outcome in head and neck cancer. Annals of translational medicine 5 30094257
2023 DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway. Open life sciences 4 37483429
2020 Proteomic changes in Trypanosoma cruzi epimastigotes treated with the proapoptotic compound PAC-1. Biochimica et biophysica acta. Proteins and proteomics 4 33285319
2019 Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism. Frontiers in neurology 4 31293510
2003 Characterization of a variant of PAC-1 in large granular lymphocyte leukemia. Protein expression and purification 4 14680939
1994 Expression of PAC 1, an epitope associated with two synapse-enriched glycoproteins and a neuronal cytoskeleton-associated polypeptide in developing forebrain neurons. Neuroscience 4 7512700
2023 Mathematical modeling predicts pathways to successful implementation of combination TRAIL-producing oncolytic virus and PAC-1 to treat granulosa cell tumors of the ovary. Cancer biology & therapy 3 38010777
2018 Pharmacokinetics, tissue distribution and plasma protein binding study of SM-1, a novel PAC-1 derivative. Journal of pharmaceutical and biomedical analysis 3 30273837
2008 Does structural commonality of metal complex formation by PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) denote mechanistic similarity? Signal transduction and medical aspects. Journal of receptor and signal transduction research 3 18569522
2025 The MAP kinase negative regulator DUSP2 (dual specificity phosphatase 2) is controlled by oncogenic microRNA cluster miR-17-92, miR-106a-363 and miR-106b-25. BMC cancer 2 40537745
2024 Circ-EIF3I Promotes Hepatocellular Carcinoma Progression Through Modulating miR-361-3p/DUSP2 Axis. DNA and cell biology 2 38513057
2023 First report of environmental bla PAC-1-carrying Aeromonas enteropelogenes. Microbiology spectrum 2 37909756
2022 First-in-human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan. Clinical and translational science 2 35621246
2011 [Effect of electro-needling at acupoints of the yangming meridian on the expression of PAC-1 and lower limb functions in acute cerebral infarction patients]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine 2 21608218
2025 PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors. ACS pharmacology & translational science 1 40242587
2025 Flavescensines A-L: Novel azaspiro[4.4] heterodimeric alkaloids from Sophora flavescens protect against liver injury by inhibiting DUSP2-mediated mitochondrial apoptosis. Acta pharmaceutica Sinica. B 1 41909738
2023 C. elegans Afadin is required for epidermal morphogenesis and functionally interfaces with the cadherin-catenin complex and RhoGAP PAC-1/ARHGAP21. bioRxiv : the preprint server for biology 1 37546884
2014 [Changes and significance of P-selectin and PAC-1 in coronary heart disease before and after stenting]. Zhonghua yi xue za zhi 1 24844962
2026 PACAP/PAC 1 modulates light-induced sleep via the ipRGC-VLPO pathway. Biochemical and biophysical research communications 0 41702189
2026 The phosphatase DUSP2 constrains lymphoid remodeling and immunotherapy response in lung squamous carcinoma. Molecular therapy : the journal of the American Society of Gene Therapy 0 41883167
2026 LGL-1 and the RhoGAP protein PAC-1 redundantly polarize the C. elegans embryonic epidermis. bioRxiv : the preprint server for biology 0 41890132
2026 LGL-1 and the RhoGAP protein PAC-1 redundantly polarize the Caenorhabditis elegans embryonic epidermis. The Journal of cell biology 0 42084878
2025 NELFCD Promotes Colon Cancer Progression by Regulating the DUSP2-p38 Axis. Frontiers in bioscience (Landmark edition) 0 40302325
2025 FBXO45 enhances cell viability and glycolysis in cervical cancer via DUSP2 ubiquitination-mediated ERK1/2 activation. Naunyn-Schmiedeberg's archives of pharmacology 0 40637745

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