Affinage

DUSP6

Dual specificity protein phosphatase 6 · UniProt Q16828

Length
381 aa
Mass
42.3 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP6 (MKP-3/Pyst1) is a cytoplasmic dual-specificity phosphatase that serves as the principal negative-feedback attenuator of ERK1/2 MAP kinase signaling downstream of FGF and other receptor tyrosine kinase inputs (PMID:8670865, PMID:17164422, PMID:12814546). It selectively dephosphorylates and inactivates ERK1/2 while displaying very low activity toward JNK, p38, and ERK5 (PMID:8670865, PMID:8910287, PMID:18280112), and forms a physical complex with MAP kinase in cells (PMID:8670865). DUSP6 is catalytically inert until ERK2 binds its N-terminal noncatalytic domain through a kinase interaction motif; this binding allosterically activates the phosphatase independently of ERK kinase activity by inducing closure of the Asp262 loop over the distorted active site, as resolved by crystallography and kinetic analysis (PMID:9596579, PMID:10048930). Cytoplasmic retention of both DUSP6 and its bound ERK2 substrate depends on a CRM1-dependent nuclear export signal in the N-terminal domain that functions independently of the kinase interaction motif (PMID:15269220). The enzyme is embedded in interlocking feedback circuits: ERK1/2 drives DUSP6 transcription through Ets-factor binding sites in the promoter and intron 1 (negative feedback) (PMID:18321244, PMID:18848526), while ERK-mediated phosphorylation of DUSP6 at Ser159/Ser197 targets it for proteasomal degradation (positive feedback on ERK activity) (PMID:15632084). Genetic ablation in mice and Drosophila elevates phospho-ERK and produces developmental and proliferative phenotypes, confirming its in vivo role in restraining the Ras/ERK pathway (PMID:17164422, PMID:18753132, PMID:14701731). Beyond ERK1/2, DUSP6 dephosphorylates Drp1-Ser616 to limit mitochondrial fission and apoptosis, an activity gated by SUMOylation at Lys234 (PMID:32232156), and also dephosphorylates SMAD2 (PMID:34475393). It additionally performs phosphatase-dependent and scaffolding functions independent of ERK catalysis, including interaction with FOXO1 to drive hepatic gluconeogenic gene expression (PMID:22848439) and scaffolding of CK2-dependent PR-B phosphorylation at a Wnt1 enhancer (PMID:23921636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Established that DUSP6 is a cytoplasmic dual-specificity phosphatase with selectivity for ERK over JNK/p38, defining its core enzymatic identity and substrate preference.

    Evidence Subcellular fractionation, in vitro and in vivo phosphatase assays, and co-IP in transfected COS/Cos-1 cells

    PMID:8626780 PMID:8670865 PMID:8910287

    Open questions at the time
    • Mechanism of ERK selectivity at the molecular level not yet resolved
    • Did not address how catalytic activity is regulated
  2. 1998 High

    Resolved that DUSP6 is catalytically dormant until ERK2 binds its noncatalytic N-terminus, revealing substrate-induced allosteric activation as the activation mechanism.

    Evidence In vitro binding and phosphatase assays with purified recombinant proteins and the D319N ERK2 mutant

    PMID:9596579

    Open questions at the time
    • Structural basis of allosteric activation not yet defined
    • Did not map the binding motif residues
  3. 1999 High

    Provided the structural mechanism of allosteric activation by showing ERK2 binding closes the Asp262 loop over a distorted active site to render the catalytic domain competent.

    Evidence 2.35 Å crystal structure of the catalytic domain with kinetic assays and D262A mutagenesis

    PMID:10048930

    Open questions at the time
    • No co-crystal of the full-length DUSP6-ERK2 complex
    • Conformational dynamics of the loop closure inferred rather than directly observed
  4. 2004 High

    Distinguished the CRM1-dependent nuclear export signal from the kinase interaction motif, explaining how DUSP6 enforces cytoplasmic retention of ERK2.

    Evidence GFP live-cell imaging, leptomycin B, domain mutagenesis, and co-IP in cells

    PMID:15269220

    Open questions at the time
    • Import pathway / shuttling regulators not identified
    • Physiological signals that modulate shuttling unknown
  5. 2003 High

    Demonstrated in vivo that FGF-MAPK signaling induces DUSP6 expression and that DUSP6 feeds back to suppress MAPK, establishing the developmental negative-feedback loop.

    Evidence Tissue manipulation, FGF protein application, FGFR/MEK inhibitors, and retroviral overexpression in chick embryos

    PMID:12814546

    Open questions at the time
    • Promoter elements mediating induction not yet mapped
    • Did not establish degradation-based feedback
  6. 2005 High

    Identified ERK-mediated Ser159/Ser197 phosphorylation as a degron signal, defining a positive-feedback arm where ERK destabilizes its own phosphatase.

    Evidence In vitro kinase assays, inducible cell lines, cycloheximide chase, and serine mutant analysis

    PMID:15632084

    Open questions at the time
    • E3 ligase for ERK-triggered degradation not identified in this study
    • Quantitative impact on overall ERK dynamics not modeled
  7. 2007 High

    Confirmed via mammalian and Drosophila genetics that DUSP6 is an indispensable in vivo negative regulator of FGFR/Ras-ERK signaling during development.

    Evidence Targeted Dusp6 knockout in mice with pERK IHC/qRT-PCR; Drosophila DMKP-3 null and epistasis analysis

    PMID:14701731 PMID:17164422

    Open questions at the time
    • Tissue-specific contributions only partly resolved
    • Compensation by other DUSPs not fully addressed
  8. 2008 High

    Mapped the transcriptional feedback to Ets-factor binding sites (promoter and intron 1) bound by Ets2, and showed tissue-wide pERK specificity in knockouts with proliferative/apoptotic consequences.

    Evidence ChIP, promoter-reporter mutagenesis, EGFP transgenics, and gene-targeted KO mice with cardiac phenotyping

    PMID:18321244 PMID:18753132 PMID:18848526

    Open questions at the time
    • Combinatorial control with repressors not yet integrated
    • Mechanism of proliferation/apoptosis effects downstream of pERK incompletely defined
  9. 2008 Medium

    Extended DUSP6 regulation beyond ERK by implicating mTOR-dependent Ser159 phosphorylation and 3'UTR-mediated mRNA stability control.

    Evidence PI3K/mTOR/MEK inhibitors with serine mutagenesis; 3'UTR luciferase and actinomycin D mRNA stability assays with TTP/PUM2 knockdown

    PMID:18223677 PMID:20665674

    Open questions at the time
    • mTOR-responsive kinase acting on Ser159 not identified
    • Single-lab findings without independent replication
  10. 2009 High

    Validated DUSP6 as a druggable target by identifying BCI, a small-molecule allosteric inhibitor that blocks ERK2-induced catalytic activation.

    Evidence Transgenic zebrafish chemical screen, molecular docking, and in vitro phosphatase assays

    PMID:19578332

    Open questions at the time
    • Exact BCI binding site confirmed only by docking
    • Selectivity across other DUSPs not fully characterized
  11. 2012 Medium

    Uncovered phosphatase-dependent non-ERK functions and additional upstream regulators, showing DUSP6 interacts with FOXO1 to drive gluconeogenesis and is repressed by miR-181a in T cells.

    Evidence Domain-mapping co-IP, adenoviral/in vivo liver rescue (FOXO1); miRNA reconstitution and siRNA with functional T-cell readouts (miR-181a)

    PMID:22784513 PMID:22848439 PMID:23023500

    Open questions at the time
    • No direct miR-181a/DUSP6 binding assay
    • FOXO1 interaction findings from a single lab
  12. 2013 Medium

    Revealed scaffolding (phosphatase-independent) activity in which DUSP6 organizes CK2-dependent phosphorylation of PR-B to activate Wnt1 target transcription.

    Evidence Co-IP/pulldown, common-docking domain mutagenesis, ChIP, and luciferase reporters in breast cancer cells

    PMID:23921636

    Open questions at the time
    • Single-lab finding without reciprocal validation
    • Structural basis of the scaffolding complex unknown
  13. 2014 Medium

    Extended transcriptional control to repressive inputs (MEF2A/D, p38-dependent) and demonstrated FOXO1-driven DUSP6 upregulation in glucocorticoid-induced hepatic lipid accumulation.

    Evidence ChIP-exo, RNA-seq, siRNA/dominant-negative FOXO1, and KO mouse metabolic phenotyping

    PMID:24946098 PMID:25217591

    Open questions at the time
    • Lineage-specific divergence of MEF2 regulation mechanistically unresolved
    • Single-lab findings
  14. 2020 High

    Defined a non-ERK substrate (Drp1-Ser616) and a stabilizing PTM, showing SUMOylation at Lys234 maintains DUSP6 stability/activity and that SENP1-driven deSUMOylation under oxidative stress promotes mitochondrial fragmentation.

    Evidence Co-IP, SUMOylation and phosphatase assays, K234R mutagenesis, and in vivo brain ischemia/reperfusion model

    PMID:32232156

    Open questions at the time
    • Selectivity of DUSP6 between ERK and Drp1 substrates not mechanistically partitioned
    • SUMO ligase identity not defined
  15. 2021 Medium

    Identified two E3 ligases (FBXO31, TRIM65) controlling DUSP6 turnover and additional substrate (SMAD2), expanding the degradation network and substrate repertoire.

    Evidence Co-IP, ubiquitylation assays, shRNA depletion, in vivo tumor/endometrial models (FBXO31, TRIM65); co-IP and osteoclastogenesis assays (SMAD2)

    PMID:33146694 PMID:34475393 PMID:34686346

    Open questions at the time
    • Relationship between FBXO31- and TRIM65-mediated degradation not reconciled
    • Single-lab findings per ligase
  16. 2022 Medium

    Placed DUSP6 in disease-context signaling axes, including JAK2-inhibitor resistance via a DUSP6-RSK1 axis and neutrophil p38-C/EBPβ-driven DUSP6 maintaining p-p38 after myocardial infarction.

    Evidence scRNA-seq, PDX and MPN mouse models, pharmacological DUSP6 inhibition; neutrophil-specific conditional KO and co-culture

    PMID:36335128 PMID:36581736

    Open questions at the time
    • Direct enzymatic targets in these contexts not all defined
    • Single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DUSP6 partitions its catalytic and scaffolding activities among ERK1/2, Drp1, SMAD2, and protein complexes such as PR-B/CK2 within a single cell remains unresolved.
  • No unified model for substrate selection beyond ERK
  • Spatial/temporal regulation of non-ERK substrate engagement unknown
  • Structural basis of scaffolding complexes not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3
Partners
DNM1LFBXO31FOXO1MAPK1MAPK3PKN2SMAD2TRIM65

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MKP-3/DUSP6 is catalytically activated by direct binding to ERK2; activation requires ERK2 binding to the noncatalytic N-terminus of MKP-3 and is independent of ERK2 kinase activity. The gain-of-function ERK2 mutant D319N, JNK/SAPK, and p38 did not bind MKP-3 or activate it. In vitro binding and phosphatase activity assays with purified recombinant proteins; mutagenesis (Sevenmaker D319N ERK2) Science High 9596579
1996 Pyst1/DUSP6 is a cytoplasmic (not nuclear) dual-specificity phosphatase that selectively dephosphorylates and inactivates ERK/MAP kinase but displays very low activity toward JNK/SAPK and p38 in vitro and in vivo; it forms a physical complex with endogenous MAP kinase in cells. Subcellular fractionation/immunofluorescence in transfected Cos-1 cells; in vitro phosphatase assay; co-immunoprecipitation; in vivo kinase assays The EMBO journal High 8670865
1996 MKP-3/DUSP6 is a cytosolic dual-specificity phosphatase that blocks ERK2 phosphorylation and enzymatic activation when expressed in COS-7 cells; subcellular localization in sympathetic neurons is cytosolic with nuclear exclusion. Transfection in COS-7 cells with kinase assays; in situ hybridization; epitope-tag immunolocalization in neurons The Journal of biological chemistry High 8626780
1996 MKP-3/DUSP6 selectively inactivates ERK1 but only partially inhibits JNK/SAPK and p38 upon co-expression in COS-7 cells, demonstrating reciprocal selectivity compared to M3/6 phosphatase. Co-transfection in COS-7 cells; kinase activity assays; dose-response co-transfection The Journal of biological chemistry High 8910287
1999 Crystal structure of the Pyst1/DUSP6 catalytic domain at 2.35 Å reveals a protein tyrosine phosphatase fold with a distorted active site; kinetic analysis shows the catalytic domain is sufficient to dephosphorylate ERK2 and is allosterically activated by inactive ERK2; mutation of Asp262 (5.5 Å from active site) abolishes catalysis in the ERK2-dependent high-activity conformation but not the low-activity form, indicating ERK2 induces closure of the Asp262 loop over the active site. X-ray crystallography (2.35 Å); kinetic assays with pNPP substrate; site-directed mutagenesis (D262A) Nature structural biology High 10048930
2004 The cytoplasmic localization of MKP-3/DUSP6 is mediated by a CRM1-dependent nuclear export signal (NES) in its N-terminal noncatalytic domain; MKP-3 undergoes active nuclear-cytoplasmic shuttling. The NES and kinase interaction motif (KIM) function independently: KIM mutations abolish ERK2 binding without affecting localization, and NES mutations do not affect ERK2 binding or phosphatase activity. MKP-3 requires both a functional KIM and NES to cause cytoplasmic retention of ERK2. GFP-fusion live-cell imaging; leptomycin B treatment; domain deletion and point mutations; co-immunoprecipitation; FRAP/nuclear translocation assays The Journal of biological chemistry High 15269220
2005 ERK2 phosphorylates MKP-3/DUSP6 on serines 159 and 197 in vitro and in vivo, promoting its proteasomal degradation in a MEK1/2-ERK1/2-dependent manner; double S159A/S197A mutants have ~3-fold longer half-life; this phosphorylation does not affect MKP-3 catalytic activity, constituting a positive feedback loop of ERKs on their own activity. In vitro phosphorylation assays with GST-MKP-3 fusion proteins; tetracycline-inducible cell lines; cycloheximide chase; proteasome inhibitor experiments; single and double serine mutant analysis Molecular and cellular biology High 15632084
2007 In mouse embryos, FGFR signaling is required for Dusp6 transcription; targeted inactivation of Dusp6 increases pERK levels and pERK target expression, demonstrating that DUSP6 acts as an in vivo negative feedback regulator of FGFR-ERK signaling during development. Conditional/targeted gene knockout in mice; immunohistochemistry for pERK; qRT-PCR; histological phenotype analysis Development High 17164422
2003 Pyst1/MKP3 expression in chick embryo neural plate and limb bud is induced downstream of FGF signaling via the MAPK cascade (blocked by FGFR inhibitor SU5402 or MEK inhibitor PD184352); overexpression of Pyst1 reduces activated MAPK levels, alters neural plate morphology, and retards limb bud outgrowth, demonstrating a negative feedback loop on FGF-MAPK signaling in vivo. Tissue transplantation/ablation; FGF protein application; pharmacological inhibitors (SU5402, PD184352); retroviral overexpression in chick embryos Current biology High 12814546
2008 FGF-induced DUSP6/MKP-3 transcription is driven by ERK1/2 signaling acting through a conserved Ets-factor binding site in the DUSP6 promoter; Ets2, a known ERK target, binds the endogenous DUSP6 promoter. The DUSP6 promoter-EGFP reporter recapitulates endogenous expression in chick neural plate dependent on FGFR, MAPK, and Ets-binding site integrity. Pharmacological inhibitors; promoter-reporter assays; ChIP; EGFP transgenic embryo experiments; mutagenesis of Ets-binding site The Biochemical journal High 18321244
2008 Dusp6-null mice show increased basal ERK1/2 phosphorylation in multiple tissues (heart, spleen, kidney, brain, fibroblasts) but no change in ERK5, p38, or JNK activation; loss of Dusp6 increases myocyte proliferation during cardiac development, resulting in cardiac hypercellularity protective against pressure overload and MI. Dusp6-/- MEFs show reduced apoptosis. Gene-targeted knockout mouse; western blotting; histology; cardiomyocyte proliferation assays; pressure-overload and MI models; MEF apoptosis assays The Journal of biological chemistry High 18753132
2007 DUSP6/MKP3 binds ERK1/2 in yeast and human cells but fails to bind ERK5; recombinant ERK2 activates DUSP6 catalytically whereas ERK5 cannot; DUSP6 dephosphorylates co-expressed ERK2 but not ERK5; DUSP6 blocks MEK1-driven ERK1/2 target transcription but not MEK5-driven ERK5 target transcription, confirming strict ERK1/2 specificity. Yeast two-hybrid; co-immunoprecipitation in human cells; in vitro catalytic activation assay; co-expression dephosphorylation assay; transcriptional reporter assays Cellular signalling High 18280112
2009 BCI (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one is a small-molecule allosteric inhibitor of Dusp6 identified by zebrafish chemical screen; docking simulations predicted an allosteric binding site within the phosphatase domain; in vitro studies support a model in which BCI inhibits Dusp6 catalytic activation by blocking ERK2 substrate-induced activation. Transgenic zebrafish chemical screen; molecular docking; in vitro phosphatase activity assays with ERK2 Nature chemical biology High 19578332
2008 The PI3K/mTOR pathway contributes to serum-induced phosphorylation and proteasomal degradation of DUSP6; amino acids and insulin/IGF-1 (mTOR agonists that do not activate ERK) also induce DUSP6 phosphorylation and degradation, requiring basal MEK activity; mutagenesis identified serine 159 as the specific mTOR pathway target on DUSP6. Pharmacological inhibitors (PI3K, mTOR, MEK); tetracycline-inducible cell lines; serine mutagenesis; cycloheximide chase; western blotting Oncogene Medium 18223677
2011 DUSP6 mRNA stability is regulated by MEK/ERK signaling via the 3'UTR; hypoxia (HIF-1-dependent) also increases DUSP6 mRNA stability via the 3'UTR, requiring basal ERK activity; Tristetraprolin (TTP) and PUM2 reduce DUSP6 mRNA stability and expression. Luciferase 3'UTR reporter assays; mRNA stability assays with actinomycin D; pharmacological inhibitors; siRNA knockdown Journal of cellular physiology Medium 20665674
2020 DUSP6 dephosphorylates Drp1 at serine 616 independently of its known substrates ERK1/2, keeping Drp1-S616 phosphorylation low under normal conditions and preventing mitochondrial fragmentation and apoptosis. DUSP6 is SUMOylated at lysine 234 by SUMO1/2/3; SUMOylation maintains DUSP6 stability and catalytic function. Under oxidative stress, SENP1 is upregulated, causing deSUMOylation and DUSP6 degradation via ubiquitin-proteasome, leading to Drp1-S616 hyperphosphorylation and mitochondrial fragmentation; overexpression of WT but not the SUMOylation-deficient DUSP6-K234R mutant is protective. Co-immunoprecipitation; SUMOylation assays; phosphatase activity assays; site-directed mutagenesis (K234R); cell-based apoptosis assays; in vivo brain ischemia/reperfusion model Science advances High 32232156
2012 MKP-3/DUSP6 interacts with FOXO1 via residues 200–260 of MKP-3 and residues 360–456 of FOXO1; MKP-3 phosphatase activity (not the interaction itself) is required for FOXO1 nuclear translocation and gluconeogenic gene (G6Pase) transcription; ERK-phosphorylation-deficient FOXO1 loses interaction with MKP-3. Adenoviral overexpression; mutagenesis of MKP-3 and FOXO1; co-immunoprecipitation; glucose output assays; in vivo liver knockdown rescue experiments PloS one Medium 22848439
2012 DUSP6 depletion in AML cells harboring FLT3-ITD reduces ERK1/2 dephosphorylation and attenuates FLT3-ITD-dependent cell proliferation; high DUSP6 expression in FLT3-ITD cells is causally dependent on FLT3-ITD kinase activity and ERK signaling (shown by pharmacological inhibition and siRNA knockdown). siRNA/shRNA knockdown; pharmacological FLT3 and ERK inhibitors; proliferation assays; western blotting Cell communication and signaling Medium 22784513
2013 PR-B interacts with DUSP6 via a common docking (CD) domain in PR-B N-terminus; DUSP6 acts as a scaffold for CK2-dependent phosphorylation of PR-B at Ser81, which is required for recruitment of a PR-B/DUSP6/CK2 transcriptional complex to the Wnt1 enhancer and expression of STAT5A and Wnt1 target genes in breast cancer cells. Binding studies (Co-IP/pulldown); CD domain mutagenesis; ChIP; luciferase reporter assays; western blotting Nucleic acids research Medium 23921636
2018 PKN2 phosphorylates and activates DUSP6 through direct association, as confirmed by co-immunoprecipitation and kinase activity assay; activated DUSP6 suppresses ERK1/2 activation, thereby reducing IL-4 and IL-10 expression from colon cancer cells and inhibiting M2 macrophage polarization. Co-immunoprecipitation; kinase activity assay; luciferase assay; ChIP-qPCR; siRNA knockdown; in vitro/in vivo tumor models Molecular cancer Medium 29368606
2008 DUSP6 transcription in human pancreatic cancer cells is regulated by MAPK1/ERK2 through an ETS transcription factor binding site in intron 1, with ETS2 specifically associating with this region; this constitutes a feedback loop where MAPK1 drives its own negative regulator's expression. Promoter-reporter assays; ChIP; pharmacological inhibitor experiments; mutagenesis of ETS binding site Biochemical and biophysical research communications Medium 18848526
2010 DUSP6 overexpression in corneal epithelial cells prevents ERK1/2 phosphorylation and reduces proliferation rates by >50%; this establishes a functional link between DUSP6-mediated ERK dephosphorylation and control of epithelial cell proliferation. Lentiviral overexpression; immunoblotting; [3H]-thymidine proliferation assays Molecular vision Medium 20806045
2020 The transcriptional repressor CIC directly represses DUSP6 transcription by binding three cis-regulatory elements (CREs) in the DUSP6 promoter. ERK1/2 activates p90RSK, which phosphorylates CIC at S173 and S301, creating a 14-3-3 recognition motif that promotes nuclear export of CIC, thereby derepressing DUSP6 transcription. ChIP; promoter-reporter assays; mutagenesis; co-immunoprecipitation; 14-3-3 binding assays iScience Medium 33103082
2012 miR-181a directly represses DUSP6 protein expression in naive CD4+ T cells; age-associated decline in miR-181a increases DUSP6 protein, which dephosphorylates ERK after TCR stimulation, impairing T cell activation. Reconstitution of miR-181a or siRNA knockdown of DUSP6 restores ERK phosphorylation and T cell responses; allosteric DUSP6 inhibition (BCI) similarly improves TCR-induced ERK signaling. miRNA reconstitution; siRNA knockdown; western blotting; flow cytometry; proliferation and activation marker assays; pharmacological inhibition Nature medicine Medium 23023500
2018 DUSP6 deficiency in T cells leads to enhanced JNK and p38 phosphorylation but impaired glycolysis; DUSP6-/- T cells cannot induce phosphofructokinase activity and rely on fatty acid oxidation; JNK/p38 inhibitors reduce IL-21 production but do not restore glycolysis, indicating DUSP6 connects TCR signaling to metabolic commitment toward glycolysis separately from TFH cytokine regulation. DUSP6-/- mouse model; metabolic assays (glycolysis, phosphofructokinase activity, fatty acid oxidation); phospho-kinase western blotting; pharmacological JNK/p38 inhibitors; in vivo immunization PNAS Medium 30087184
2021 DUSP6 directly dephosphorylates SMAD2, and immunoprecipitation confirmed this interaction; DUSP6-mediated ERK2 and SMAD2 dephosphorylation regulates nuclear translocation of NFATC1 and inhibits osteoclast differentiation. Co-immunoprecipitation; western blotting; ERK2-deficient BMM analysis; DUSP6 overexpression and siRNA knockdown; in vitro osteoclastogenesis Cell death & disease Medium 34475393
2022 In neutrophils, DUSP6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector maintaining p-p38 activity by downregulating pERK and p38-targeting phosphatases DUSP1/DUSP16; neutrophil-specific Dusp6 knockout attenuates cardiac damage after myocardial infarction. Rat nonsense-mutation strain; bone marrow transplantation; neutrophil-specific conditional KO mice; neutrophil-cardiomyocyte co-culture; western blotting; cardiac functional measurements Nature communications Medium 36335128
2022 DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression; ectopic DUSP6 expression exacerbated disease in PDX models; pharmacological DUSP6 inhibition reduced S6 kinase and JAK-STAT signaling and suppressed inflammatory cytokine production, defining a DUSP6-RSK1 axis. Single-cell RNA-seq; DUSP6 ectopic expression in PDX models; pharmacological DUSP6 inhibition; Jak2V617F and MPLW515L MPN mouse models; western blotting for S6 and JAK-STAT pathway components Nature cancer Medium 36581736
2021 FBXO31 is the substrate receptor of CRL1 ubiquitin ligase that promotes ubiquitylation-mediated degradation of DUSP6; depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and paradoxically activates PI3K-AKT signaling; BCI treatment of FBXO31-depleted cells suppresses AKT activation and prevents tumor formation, indicating tumor suppressor activity of FBXO31 is DUSP6-dependent. Co-immunoprecipitation; ubiquitylation assays; shRNA depletion; western blotting; mouse orthotopic tumor model; pharmacological inhibition with BCI Cell reports Medium 34686346
2021 TRIM65 promotes ubiquitination and degradation of DUSP6, resulting in ERK1/2 activation and C-myc induction in endometrial stromal cells; C-myc in turn promotes TRIM65 expression, creating a feedback loop; ERK1/2 inhibition reverses these effects in vivo. Co-immunoprecipitation; ubiquitylation assay; dual luciferase assay; ChIP; western blotting; in vivo mouse EM model The Journal of clinical endocrinology and metabolism Medium 33146694
2014 MEF2D functions as a p38MAPK-dependent transcriptional repressor of Dusp6 in skeletal myoblasts; MEF2A binds the Dusp6 genomic locus (identified by ChIP-exo); siRNA targeting MEF2A/D reveals divergent regulation of Dusp6 in cardiac versus skeletal myogenic lineages. ChIP-exo; RNA-seq of MEF2A-depleted cells; siRNA knockdown; promoter-reporter assays; pharmacological p38 inhibition Nucleic acids research Medium 25217591
2018 DUSP6 promotes endothelial inflammation by facilitating TNF-α-induced ICAM-1 expression through canonical NF-κB-mediated transcription, independently of ERK signaling; DUSP6 knockout mice show reduced ICAM-1 in aorta/vein and reduced neutrophil recruitment and susceptibility to lung injury in sepsis models. DUSP6 knockout mice; RNAi in HUVECs; ICAM-1 reporter assays; NF-κB pathway analysis; LPS/TNF-α sepsis model The FEBS journal Medium 29493888
2011 In oligodendrocytes, DUSP6 overexpression increases AMPA receptor-induced inward currents and cytosolic calcium overload, while blocking DUSP6 expression (enhancing ERK1/2 phosphorylation) significantly reduces AMPA receptor-induced oligodendrocyte death; ERK pathway inhibition (UO126) potentiates excitotoxic death and increases mitochondrial dysfunction, demonstrating that DUSP6-controlled ERK levels regulate AMPA receptor permeability and oligodendroglial excitotoxicity. Microarray and qPCR; DUSP6 knockdown; pharmacological MAPK/ERK inhibition (UO126); patch-clamp electrophysiology; calcium imaging; cell death assays; in vivo optic nerve analysis The Journal of biological chemistry Medium 21300799
2013 MKP-3/DUSP6 is required for normal resolution of acute postoperative pain; MKP-3 knockout mice develop persistent mechanical allodynia with sustained spinal pERK and p-p38 (in neurons and microglia); pharmacological inhibition of ERK or p38 reduced persistent allodynia in KO mice, demonstrating DUSP6 normally terminates MAPK activity to resolve pain. MKP-3 KO mice; paw incision pain model; behavioral allodynia assays; western blotting for pERK/p-p38; pharmacological MAPK inhibitors; immunofluorescence The Journal of neuroscience Medium 24155322
2019 In DBA/2J mice, a Met62Ile substitution in DUSP6 reduces the interaction between DUSP6 and ERK, resulting in increased ERK phosphorylation and activity; this hypomorphic allele acts as a genetic modifier of body mass in muscular dystrophy through enhanced ERK activity. Whole-genome sequencing; RNA-seq; co-immunoprecipitation to measure ERK binding; pharmacological DUSP6 inhibition in myoblasts; ERK phosphorylation assays Human molecular genetics Medium 30289454
2000 Nitric oxide downregulates MKP-3/DUSP6 by destabilizing its mRNA, leading to decreased MKP-3 protein levels and protection of ERK1/2 from TNFα-induced dephosphorylation in endothelial cells; this protects Bcl-2 from proteolysis and prevents cytochrome c release. NO does not affect MKP-3 phosphatase activity directly. Northern blotting; western blotting; NO donor treatment; MKP-3 overexpression; Bcl-2/cytochrome c measurements The Journal of biological chemistry Medium 10846176
2014 FOXO1-dependent upregulation of MKP-3/DUSP6 mediates glucocorticoid-induced hepatic lipid accumulation; dexamethasone increases MKP-3 protein in hepatoma cells and mouse liver via FOXO1 (FOXO1 knockdown or dominant-negative FOXO1 blocks this); MKP-3 deficient mice are protected from glucocorticoid-induced metabolic side effects. FOXO1 siRNA knockdown; dominant-negative FOXO1 overexpression; MKP-3 KO mice; western blotting; metabolic phenotyping Molecular and cellular endocrinology Medium 24946098
2004 Drosophila MKP-3 (DMKP-3) specifically binds DERK via its N-terminal ERK-binding domain and suppresses Ras/DERK pathway signaling in vivo; DMKP-3 null mutants show embryonic lethality, severe oogenesis defects, extra photoreceptor cells and wing veins phenocopying gain-of-function DERK mutants; genetic interactions confirm DMKP-3 is indispensable for DERK signaling regulation. Drosophila genetics (null mutants, hypomorphs, overexpression transgenes); genetic interaction analysis with Ras/ERK pathway mutants; in vivo epistasis Molecular and cellular biology High 14701731

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science (New York, N.Y.) 439 9596579
1996 Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. The EMBO journal 359 8670865
1996 MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. The Journal of biological chemistry 320 8626780
1996 The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. The Journal of biological chemistry 319 8910287
2012 Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nature medicine 297 23023500
2007 Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development (Cambridge, England) 235 17164422
2009 Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nature chemical biology 209 19578332
2013 Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. American journal of human genetics 202 23643382
2003 Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. The American journal of pathology 191 12759238
2008 Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. The Biochemical journal 166 18321244
2010 Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 160 20097731
2008 DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. The Journal of biological chemistry 152 18753132
2003 Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos. Current biology : CB 150 12814546
1999 Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nature structural biology 140 10048930
2018 PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway. Molecular cancer 122 29368606
2005 Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Molecular and cellular biology 118 15632084
2005 Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of human genetics 113 15824892
2004 Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. The Journal of biological chemistry 112 15269220
2000 Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis. The Journal of biological chemistry 112 10846176
1998 Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. Journal of cell science 110 9788880
2018 Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer. Cancer biology & medicine 107 29545965
2005 Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 103 15832194
2009 Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis. The American journal of pathology 98 19608870
2011 Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 87 21499306
2007 DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. Cellular signalling 76 18280112
2017 Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6. Cellular immunology 75 28242024
2017 Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance. Cancer letters 74 29050982
2014 Global MEF2 target gene analysis in cardiac and skeletal muscle reveals novel regulation of DUSP6 by p38MAPK-MEF2 signaling. Nucleic acids research 70 25217591
2011 Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype. International journal of cancer 70 21387288
1998 Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenetics and cell genetics 70 9858808
2020 DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Science advances 68 32232156
2008 Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene 67 18223677
2019 Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK. Clinical cancer research : an official journal of the American Association for Cancer Research 65 30936125
2011 Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia. Journal of cellular physiology 65 20665674
2000 Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells. The Biochemical journal 61 11104676
2018 Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development (Cambridge, England) 59 29444893
2014 Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity. Diabetes 58 24722245
2019 Long non-coding RNA TUG1 promotes airway remodelling by suppressing the miR-145-5p/DUSP6 axis in cigarette smoke-induced COPD. Journal of cellular and molecular medicine 56 31557398
2017 DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers. PloS one 55 28910386
2018 DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 51 30087184
2013 DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells. Endocrine-related cancer 50 23132790
2002 Expression of the ERK-specific MAP kinase phosphatase PYST1/MKP3 in mouse embryos during morphogenesis and early organogenesis. Mechanisms of development 50 11960712
2022 DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression. Nature cancer 48 36581736
2010 Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. The Journal of biological chemistry 47 20554528
2013 A missense mutation in DUSP6 is associated with Class III malocclusion. Journal of dental research 45 23965468
2008 Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells. Biochemical and biophysical research communications 44 18848526
2001 Two kinds of mitogen-activated protein kinase phosphatases, MKP-1 and MKP-3, are differentially activated by acute and chronic methamphetamine treatment in the rat brain. Journal of neurochemistry 44 11701771
2021 Hydrogen sulfide exposure induces pyroptosis in the trachea of broilers via the regulatory effect of circRNA-17828/miR-6631-5p/DUSP6 crosstalk on ROS production. Journal of hazardous materials 43 34098264
2015 Hepatitis C virus-induced reduction in miR-181a impairs CD4(+) T-cell responses through overexpression of DUSP6. Hepatology (Baltimore, Md.) 43 25477247
2010 p-MAPK1/3 and DUSP6 regulate epididymal cell proliferation and survival in a region-specific manner in mice. Biology of reproduction 43 20650883
2013 A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells. Nucleic acids research 41 23921636
2012 Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells: FLT3 ITD sustains high levels of DUSP6 expression. Cell communication and signaling : CCS 41 22784513
2022 Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction. Nature communications 40 36335128
2011 CD40-modulated dual-specificity phosphatases MAPK phosphatase (MKP)-1 and MKP-3 reciprocally regulate Leishmania major infection. Journal of immunology (Baltimore, Md. : 1950) 40 21471446
2014 TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6. Neoplasia (New York, N.Y.) 37 25499223
2004 MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development. Molecular and cellular biology 37 14701731
2012 Ischemia/reperfusion-induced MKP-3 impairs endothelial NO formation via inactivation of ERK1/2 pathway. PloS one 36 22848708
2011 Dual-specific phosphatase-6 (Dusp6) and ERK mediate AMPA receptor-induced oligodendrocyte death. The Journal of biological chemistry 36 21300799
2008 Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development. Developmental dynamics : an official publication of the American Association of Anatomists 33 18058922
2019 Tripartite motif-containing protein 7 regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway. Biochemical and biophysical research communications 31 30850165
2014 FOXO1-dependent up-regulation of MAP kinase phosphatase 3 (MKP-3) mediates glucocorticoid-induced hepatic lipid accumulation in mice. Molecular and cellular endocrinology 31 24946098
2013 DUSP6 regulates drug sensitivity by modulating DNA damage response. British journal of cancer 31 23839489
2021 Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis. Cell reports 29 34686346
2020 CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop. iScience 28 33103082
2019 DUSP6 Inhibitor (E/Z)-BCI Hydrochloride Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Murine Macrophage Cells via Activating the Nrf2 Signaling Axis and Inhibiting the NF-κB Pathway. Inflammation 28 30506106
2023 N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer. Cancer letters 27 36806557
2021 DUSP6 expression is associated with osteoporosis through the regulation of osteoclast differentiation via ERK2/Smad2 signaling. Cell death & disease 27 34475393
2020 Overexpression of DUSP6 enhances chemotherapy-resistance of ovarian epithelial cancer by regulating the ERK signaling pathway. Journal of Cancer 27 32231719
2018 Dual specificity phosphatase DUSP6 promotes endothelial inflammation through inducible expression of ICAM-1. The FEBS journal 27 29493888
2021 NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene 26 34689179
2013 Lef1 regulates Dusp6 to influence neuromast formation and spacing in the zebrafish posterior lateral line primordium. Development (Cambridge, England) 26 23637337
2020 MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance. The Journal of investigative dermatology 25 32888955
2019 Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer. International journal of molecular sciences 25 31027181
2011 The genetic association of DUSP6 with bipolar disorder and its effect on ERK activity. Progress in neuro-psychopharmacology & biological psychiatry 25 22155192
2000 Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler. Molecular psychiatry 25 11035444
2012 MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells. Molecular and cellular endocrinology 24 22521266
2022 Cynarin attenuates LPS-induced endothelial inflammation via upregulation of the negative regulator MKP-3. Animal cells and systems 23 35784390
2018 ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma. Cancers 23 30577494
2015 MicroRNA-145 inhibits human papillary cancer TPC1 cell proliferation by targeting DUSP6. International journal of clinical and experimental medicine 23 26309510
2014 p53 protein-mediated up-regulation of MAP kinase phosphatase 3 (MKP-3) contributes to the establishment of the cellular senescent phenotype through dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). The Journal of biological chemistry 23 25414256
2021 Upregulation of DUSP6 impairs infectious bronchitis virus replication by negatively regulating ERK pathway and promoting apoptosis. Veterinary research 22 33431056
2021 Short-Chain Fatty Acid Decreases the Expression of CEBPB to Inhibit miR-145-Mediated DUSP6 and Thus Further Suppresses Intestinal Inflammation. Inflammation 22 34792688
2019 Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes. Oncotarget 22 31164954
2019 Dusp6 inhibits epithelial-mesenchymal transition in endometrial adenocarcinoma via ERK signaling pathway. Radiology and oncology 22 31553703
2012 Mapping MKP-3/FOXO1 interaction and evaluating the effect on gluconeogenesis. PloS one 22 22848439
2022 Insights into the role of P2X7R/DUSP6/ERK1/2 and SIRT2/MDM2 signaling in the nephroprotective effect of berberine against cisplatin-induced renal fibrosis in rats. Life sciences 21 36208663
2018 P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling. Frontiers in molecular neuroscience 21 29375309
2013 DUSP6, a tumor suppressor, is involved in differentiation and apoptosis in esophageal squamous cell carcinoma. Oncology letters 21 24260056
2020 DUSP6 protects murine podocytes from high glucose‑induced inflammation and apoptosis. Molecular medicine reports 20 32705203
2019 Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer. International journal of molecular sciences 20 31238530
2012 Increased levels of DUSP6 phosphatase stimulate tumourigenesis in a molecularly distinct melanoma subtype. Pigment cell & melanoma research 20 22171919
2010 DUSP5 and DUSP6 modulate corneal epithelial cell proliferation. Molecular vision 20 20806045
2018 The testosterone metabolite 3α-androstanediol inhibits oxidative stress-induced ERK phosphorylation and neurotoxicity in SH-SY5Y cells through an MKP3/DUSP6-dependent mechanism. Neuroscience letters 19 30552945
2015 Silencing of DUSP6 gene by RNAi-mediation inhibits proliferation and growth in MDA-MB-231 breast cancer cells: an in vitro study. International journal of clinical and experimental medicine 19 26379838
2004 Effect of hypoxia on the expression and activity of mitogen-activated protein (MAP) kinase-phosphatase-1 (MKP-1) and MKP-3 in neuronal nuclei of newborn piglets: the role of nitric oxide. Neuroscience 18 15541888
2021 TRIM65 Promotes Invasion of Endometrial Stromal Cells by Activating ERK1/2/C-myc Signaling via Ubiquitination of DUSP6. The Journal of clinical endocrinology and metabolism 17 33146694
2020 Mice lacking DUSP6/8 have enhanced ERK1/2 activity and resistance to diet-induced obesity. Biochemical and biophysical research communications 17 32917360
2022 A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction. Disease models & mechanisms 16 36478044
2019 Dusp6 is a genetic modifier of growth through enhanced ERK activity. Human molecular genetics 16 30289454
2013 Spinal mitogen-activated protein kinase phosphatase-3 (MKP-3) is necessary for the normal resolution of mechanical allodynia in a mouse model of acute postoperative pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 24155322

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