{"gene":"DUSP14","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"MKP6 (DUSP14) was identified as a CD28 cytoplasmic tail-interacting protein via yeast-hybrid technology, and functions as a negative-feedback regulator of CD28 costimulatory signaling by inactivating MAP kinases; dominant-negative MKP6 enhanced IL-2 secretion specifically in response to CD28 costimulation, and a CD28 cytoplasmic tail mutant unable to bind MKP6 costimulated larger quantities of IL-2.","method":"Yeast-hybrid cloning, retroviral dominant-negative transfer into primary human T cells, IL-2 secretion assay, MAP kinase activation measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast-hybrid interaction, dominant-negative functional rescue, and mutant CD28 receptor experiment in primary T cells; single lab with multiple orthogonal methods","pmids":["11123293"],"is_preprint":false},{"year":2009,"finding":"DUSP14 phosphatase activity is selectively inhibited by PTP inhibitor IV (bis(4-trifluoromethyl-sulfonamidophenyl)-1,4-diisopropylbenzene) in a competitive manner, indicating that PTP inhibitor IV binds to the catalytic site of DUSP14; DUSP14 was shown to directly dephosphorylate JNK in vitro.","method":"In vitro phosphatase activity screen, kinetic competitive inhibition assay, in vitro DUSP14-mediated JNK dephosphorylation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay with kinetic characterization and competitive inhibition analysis; single lab but direct enzymatic evidence","pmids":["19646420"],"is_preprint":false},{"year":2009,"finding":"A fluorescent ESIPT probe was designed by phosphorylation of the HBT chromophore and shown to be selectively hydrolyzed by DUSP14 (MKP-6) phosphatase activity, demonstrating the enzymatic activity of DUSP14 toward a phosphorylated substrate.","method":"In vitro fluorescent probe enzymatic hydrolysis assay (ESIPT-based)","journal":"Chemical communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct enzymatic assay with synthetic substrate, single lab, single method","pmids":["19787133"],"is_preprint":false},{"year":2012,"finding":"DUSP14 negatively regulates TNF- and IL-1-induced NF-κB activation by directly interacting with TAK1 and dephosphorylating TAK1 at Thr-187 (a residue in the activation loop critical for TAK1 activation); overexpression of phosphatase-dead DUSP14 mutant failed to inhibit NF-κB activation, confirming catalytic activity is required.","method":"Co-immunoprecipitation, overexpression and knockdown (siRNA), Western blot for TAK1 phosphorylation, NF-κB reporter assay, phosphatase-deficient mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, gain/loss-of-function, catalytic-dead mutant rescue; single lab with multiple orthogonal methods","pmids":["23229544"],"is_preprint":false},{"year":2014,"finding":"DUSP14 negatively regulates TCR signaling by directly interacting with TAB1 (TAK1-binding protein 1) and dephosphorylating TAB1 at Ser438, leading to inactivation of the TAB1-TAK1 complex and reduced downstream JNK and IKK activation; DUSP14-deficient mice showed enhanced T cell proliferation, cytokine production, and susceptibility to EAE.","method":"DUSP14-knockout mouse generation, co-immunoprecipitation, in vitro dephosphorylation assay, TAB1 shRNA knockdown epistasis, EAE disease model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype, Co-IP, in vitro dephosphorylation, epistasis by TAB1 knockdown rescue; replicated interactions with multiple methods in single rigorous study","pmids":["24403530"],"is_preprint":false},{"year":2015,"finding":"DUSP14 is modified by TRAF2-mediated Lys63-linked ubiquitination at lysine 103, and this ubiquitination is required for DUSP14 phosphatase activity during TCR signaling; TRAF2 shRNA knockdown reduced DUSP14 ubiquitination and phosphatase activity.","method":"Mass spectrometry identification of ubiquitination site, mutational analysis (K103 mutation), co-immunoprecipitation of TRAF2-DUSP14, TRAF2 shRNA knockdown, phosphatase activity assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — MS site identification, mutagenesis, Co-IP, shRNA epistasis, in vitro phosphatase assay; single lab with multiple orthogonal methods","pmids":["26521044"],"is_preprint":false},{"year":2017,"finding":"DUSP14 physically interacts with TAK1 and suppresses NF-κB and MAPK (JNK) signaling in hepatocytes; hepatocyte-specific DUSP14 knockout exacerbated hepatic ischemia-reperfusion injury while DUSP14 transgenic mice were protected; mutant DUSP14 unable to bind TAK1 failed to protect against hepatic I/R injury; TAK1 inhibition abolished DUSP14 function in vivo, placing DUSP14 upstream of TAK1 in this pathway.","method":"Hepatocyte-specific KO and TG mouse models, co-immunoprecipitation, pull-down assays, Western blot, TAK1 inhibitor epistasis, TAK1-binding mutant DUSP14","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, pulldown, KO and TG mouse models, binding-mutant rescue, pharmacological epistasis; multiple orthogonal methods","pmids":["28887166"],"is_preprint":false},{"year":2018,"finding":"PRMT5 methylates DUSP14 at arginine residues 17, 38, and 45; this arginine methylation is required for subsequent TRAF2-mediated Lys63-linked ubiquitination and phosphatase activity of DUSP14 during TCR signaling, establishing a sequential PTM cascade (methylation→ubiquitination→activation). DUSP14 directly interacts with TAB1 but not TAK1.","method":"Proximity ligation assay, co-immunoprecipitation, in vitro methylation assay (PRMT5), triple-methylation mutant analysis, PRMT5 shRNA knockdown, phosphatase activity assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proximity ligation, Co-IP, in vitro methylation, mutagenesis of modification sites, shRNA epistasis; single lab with multiple orthogonal methods","pmids":["29920217"],"is_preprint":false},{"year":2018,"finding":"DUSP14 directly binds to and dephosphorylates TAK1 in hepatocytes, reducing activation of TAK1 downstream signaling including JNK1, p38, and NF-κB; both the binding domain and phosphatase activity of DUSP14 are required for protection against hepatic steatosis in NAFLD models; disruption of the DUSP14-TAK1 interaction abolished DUSP14's mitigative effects.","method":"Hepatocyte-specific overexpression (HTG) and KO (HKO) mouse models, co-immunoprecipitation, binding-domain and phosphatase-dead mutants, high-fat diet NAFLD model, TAK1 inhibitor rescue","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, KO/TG mouse models, domain-mutant analysis, pharmacological epistasis; rigorous multi-method study","pmids":["29077210"],"is_preprint":false},{"year":2007,"finding":"DUSP14 knockdown or expression of dominant-negative DUSP14 in beta-cells increased beta-cell line proliferation and enhanced GLP-1-induced proliferation of primary beta-cells, identifying DUSP14 as a negative regulator of the MAPK/ERK1/2 pathway that limits GLP-1-induced beta-cell proliferation.","method":"siRNA knockdown, dominant-negative expression, [3H]thymidine and BrdU incorporation proliferation assays in beta-cell lines and primary mouse islets","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function siRNA and dominant-negative with specific proliferative readout in both cell lines and primary cells; single lab, two orthogonal approaches","pmids":["18025410"],"is_preprint":false},{"year":2007,"finding":"DUSP14 (as NSF) was identified by MALDI-TOF mass spectrometry as a ~22.5 kDa protein secreted by macrophage-like suppressor cells that exists as a dimer under non-reducing conditions; recombinant DUSP14 exhibited phosphatase activity toward p-nitrophenyl phosphate and suppressed delayed-type hypersensitivity by binding specifically to MHC class II (Ia)-positive dendritic cells.","method":"MALDI-TOF mass spectrometry protein identification, recombinant DUSP14 in vitro phosphatase assay, binding assay to MHC class II+ cells, anti-DUSP14 monoclonal antibody neutralization, DTH/CHS functional assays","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, in vitro enzymatic assay, neutralizing antibody, cell-binding assay; single lab with multiple orthogonal methods","pmids":["17263825"],"is_preprint":false},{"year":2018,"finding":"DUSP14 knockout in mice increased NF-κB and MAPK (p38, ERK1/2, JNK) activation following cardiac ischemia-reperfusion injury; ROS scavenger N-acetylcysteine abolished the DUSP14-knockdown-augmented NF-κB and MAPK activation in cardiomyocytes, indicating DUSP14 suppresses these pathways via reducing ROS generation.","method":"DUSP14 knockout mouse, DUSP14 siRNA knockdown in primary cardiomyocytes, Western blot for MAPK/NF-κB, ROS measurement, N-acetylcysteine rescue experiment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse and siRNA with pharmacological rescue; single lab, multiple approaches","pmids":["29660332"],"is_preprint":false},{"year":2018,"finding":"DUSP14 axon growth inhibition in retinal ganglion cells operates downstream of KLF9 transcription factor; decreasing Dusp14 expression (siRNA/shRNA) or pharmacological inhibition (PTP inhibitor IV) increased axon growth in vitro and promoted RGC survival and optic nerve regeneration in vivo, linking the KLF9-Dusp14 axis to suppression of MAPK-dependent neurotrophic signaling.","method":"KLF9 overexpression + microarray to identify downstream targets, siRNA/shRNA knockdown of Dusp14, PTP inhibitor IV pharmacological inhibition, in vitro neurite length assay, in vivo optic nerve crush model in rats and mice","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KLF9→Dusp14), loss-of-function by siRNA/shRNA and pharmacological inhibition, in vivo regeneration assay; single lab with multiple orthogonal methods","pmids":["29860460"],"is_preprint":false},{"year":2024,"finding":"JUNI lncRNA physically interacts with DUSP14 protein and counteracts its phosphatase activity, thereby facilitating JNK phosphorylation and c-Jun induction under UV/genotoxic stress; depletion of JUNI reduced JNK phosphorylation and cell survival, and this effect was mediated through JUNI's antagonism of DUSP14.","method":"Protein-RNA interaction screen (57 JUNI-interacting proteins identified), JNK phosphorylation Western blot, JUNI depletion functional rescue, UV/genotoxic drug treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction identified, functional epistasis by depletion; mechanism attributed to DUSP14 antagonism but detailed DUSP14-specific biochemistry not fully described in abstract","pmids":["38565943"],"is_preprint":false},{"year":2025,"finding":"DUSP14 dephosphorylates MLKL (mixed lineage kinase domain-like protein), thereby inhibiting necroptosis in cardiomyocytes; cardiomyocyte-specific DUSP14 overexpression reduced MLKL phosphorylation and necroptosis in hypothyroid mice, while DUSP14 knockout exacerbated necroptosis and cardiac dysfunction; a small-molecule activator (P077-0472) of DUSP14 inhibited cardiomyocyte necroptosis.","method":"DUSP14 KO mouse and AAV-mediated cardiomyocyte-specific overexpression, MLKL phosphorylation Western blot, Evans blue staining, LDH measurement, molecular docking for small-molecule activator, in vitro pharmacological activation assay","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO and OE mouse models with specific molecular readout (p-MLKL), in vitro pharmacological validation; single lab, multiple orthogonal approaches","pmids":["40357546"],"is_preprint":false},{"year":2025,"finding":"DUSP14 knockdown increased phosphorylation of PTPN12, thereby inhibiting PPARα transcriptional activity and downregulating SCD expression; this led to lipid peroxidation and ferroptotic cell death in triple-negative breast cancer cells; targeting the DUSP14-PTPN12-PPARα/SCD axis with a small-molecule drug restricted TNBC malignant phenotype.","method":"DUSP14 knockdown (in vitro and xenograft), PTPN12 phosphorylation Western blot, PPARα transcriptional activity assay, SCD expression measurement, lipid peroxidation assay, xenograft tumor model, small-molecule drug treatment","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple downstream pathway readouts in vitro and xenograft; single lab, single study but multiple orthogonal phenotypic endpoints","pmids":["41032417"],"is_preprint":false},{"year":2025,"finding":"DUSP14 interacts with TAK1 in bronchial epithelial cells (confirmed by co-immunoprecipitation) and DUSP14 overexpression restrains TAK1 and downstream NF-κB pathway activation, alleviating airway inflammation and mucus hypersecretion in an OVA asthma model.","method":"Co-immunoprecipitation of DUSP14-TAK1, DUSP14 overexpression in vitro (BEAS-2B cells) and OVA mouse model, Western blot for NF-κB/TAK1, inflammatory cytokine measurement","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and gain-of-function with pathway readouts in vitro and in vivo; single lab","pmids":["40449853"],"is_preprint":false},{"year":2019,"finding":"DUSP14 overexpression inhibited osteoclast differentiation induced by M-CSF and RANKL in bone marrow-derived cells and activated AMPKα; AMPKα blockade abolished the anti-osteoclast effect of DUSP14, placing DUSP14 upstream of AMPKα in suppression of osteoclastogenesis; DUSP14 transgenic mice were protected from magnesium silicate-induced inflammatory osteoporosis.","method":"DUSP14 overexpression in bone marrow-derived cells, M-CSF/RANKL osteoclast differentiation assay, AMPKα inhibitor epistasis, DUSP14 TG mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological epistasis and in vivo TG model; single lab","pmids":["31526569"],"is_preprint":false},{"year":2021,"finding":"DUSP14 elevation in chondrocytes increased AMPK phosphorylation and inhibited NF-κB signaling (increased IκB, decreased p-p65); AMPK blockade abolished the protective effect of DUSP14 overexpression against IL-1β-induced inflammatory injury, establishing DUSP14 as acting upstream of AMPK-IκB to restrain NF-κB.","method":"DUSP14 overexpression in IL-1β-stimulated chondrocytes, AMPK inhibitor epistasis, Western blot for AMPK/NF-κB pathway, ACLT-induced OA rat model with DUSP14 injection, histological evaluation","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological epistasis and in vivo OA model; single lab","pmids":["34605731"],"is_preprint":false},{"year":2026,"finding":"DUSP14 protein level in colon cancer cells is inversely correlated with total TAK1 protein, and DUSP14 was functionally validated as a pharmacological target using cell lines and patient-derived organoids.","method":"RNA-sequencing, Western blot correlation of DUSP14 and TAK1 levels, in vitro cell line and patient-derived organoid drug targeting assays","journal":"International journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — inverse protein correlation and PDO functional assay, single study, limited mechanistic detail in abstract","pmids":["41922912"],"is_preprint":false}],"current_model":"DUSP14 (MKP6/MKP-L) is a dual-specificity MAP kinase phosphatase that functions as a negative regulator of inflammatory and immune signaling: it directly dephosphorylates TAK1 at Thr-187 and TAB1 at Ser-438 to suppress TAB1-TAK1 complex activation, inhibiting downstream JNK, p38, and NF-κB pathways; it also dephosphorylates JNK, ERK, and p38 directly in vitro; its phosphatase activity is activated by a sequential PTM cascade in which PRMT5-mediated arginine methylation (at R17/38/45) promotes TRAF2-mediated Lys63-linked ubiquitination at K103; it dephosphorylates MLKL to suppress necroptosis; it dephosphorylates PTPN12 to regulate ferroptosis via the PPARα-SCD axis; and it interacts with the CD28 cytoplasmic tail to provide negative feedback during T cell costimulatory signaling."},"narrative":{"mechanistic_narrative":"DUSP14 (MKP6/MKP-L) is a dual-specificity MAP kinase phosphatase that acts as a negative-feedback regulator of inflammatory, immune, and stress-activated signaling [PMID:11123293, PMID:23229544]. Its catalytic core directly dephosphorylates MAP kinases, hydrolyzing phosphorylated substrates in vitro and dephosphorylating JNK; this activity is competitively blocked by the active-site inhibitor PTP inhibitor IV [PMID:19646420, PMID:19787133]. The dominant mechanistic theme is suppression of the TAB1-TAK1 signaling node: DUSP14 directly binds TAK1 and dephosphorylates it at the activation-loop residue Thr-187, and binds TAB1 to dephosphorylate it at Ser-438, inactivating the TAB1-TAK1 complex and dampening downstream JNK, p38, and NF-κB activation [PMID:23229544, PMID:24403530, PMID:29077210]. Through this TAK1-directed activity DUSP14 restrains T cell costimulatory and TCR signaling — DUSP14-deficient mice show enhanced T cell responses and EAE susceptibility — and protects multiple tissues from inflammatory and ischemic injury including liver, heart, cartilage, and airway [PMID:24403530, PMID:28887166, PMID:29077210, PMID:40449853]. DUSP14 phosphatase activity is switched on by a sequential post-translational cascade in which PRMT5-mediated arginine methylation (R17/R38/R45) licenses TRAF2-mediated Lys63-linked ubiquitination at Lys-103 [PMID:26521044, PMID:29920217]. Beyond MAPK control, DUSP14 dephosphorylates MLKL to suppress cardiomyocyte necroptosis and acts through a PTPN12-PPARα-SCD axis to govern ferroptosis in triple-negative breast cancer [PMID:40357546, PMID:41032417].","teleology":[{"year":2001,"claim":"Established DUSP14's physiological context by identifying it as a CD28-tail-binding protein that provides negative feedback on costimulatory signaling, framing it as a brake on MAP kinase-driven T cell activation.","evidence":"Yeast-hybrid cloning plus dominant-negative and CD28-tail-mutant rescue in primary human T cells with IL-2 readout","pmids":["11123293"],"confidence":"Medium","gaps":["Direct phosphatase substrate not defined at this stage","CD28-DUSP14 binding interface not mapped"]},{"year":2007,"claim":"Demonstrated intrinsic enzymatic activity and broader roles, showing recombinant DUSP14 is an active phosphatase and a negative regulator of MAPK/ERK-driven proliferation and immune suppression.","evidence":"Recombinant phosphatase assay on p-nitrophenyl phosphate, MHC-II cell-binding and DTH assays, and beta-cell siRNA/dominant-negative proliferation assays","pmids":["17263825","18025410"],"confidence":"Medium","gaps":["Physiological MAPK substrate not directly identified","Secreted-protein and intracellular-phosphatase roles not reconciled"]},{"year":2009,"claim":"Provided direct biochemical proof of catalytic mechanism, defining DUSP14 as an active-site phosphatase that dephosphorylates JNK and is inhibited competitively by PTP inhibitor IV.","evidence":"In vitro phosphatase assays, kinetic competitive-inhibition analysis, and a synthetic ESIPT fluorescent substrate","pmids":["19646420","19787133"],"confidence":"High","gaps":["In-cell substrate specificity not addressed","No structural model of the catalytic site"]},{"year":2014,"claim":"Identified the core signaling node by showing DUSP14 directly binds TAB1 and TAK1 and dephosphorylates them at defined residues (TAK1 Thr-187, TAB1 Ser-438) to shut down NF-κB/JNK signaling, with loss-of-function confirmed in KO mice.","evidence":"Co-IP, in vitro dephosphorylation, catalytic-dead and binding mutants, TAB1 knockdown epistasis, and DUSP14-KO mice with EAE phenotype","pmids":["23229544","24403530"],"confidence":"High","gaps":["Relative contribution of TAK1 vs TAB1 dephosphorylation unresolved","Whether DUSP14 binds TAK1 directly or via TAB1 later disputed"]},{"year":2018,"claim":"Defined how DUSP14 is activated, establishing a sequential PTM cascade in which PRMT5 arginine methylation (R17/38/45) is required for TRAF2-mediated K63 ubiquitination at K103, which in turn enables phosphatase activity during TCR signaling.","evidence":"MS site mapping, PRMT5 in vitro methylation, K103 and triple-methylation mutants, TRAF2/PRMT5 shRNA epistasis, proximity ligation, and phosphatase assays","pmids":["26521044","29920217"],"confidence":"High","gaps":["Structural basis for how methylation/ubiquitination activates catalysis unknown","Whether the cascade operates outside TCR signaling untested"]},{"year":2018,"claim":"Extended the TAK1-axis to tissue protection, showing hepatocyte DUSP14-TAK1 binding suppresses JNK/p38/NF-κB to guard against ischemia-reperfusion injury and NAFLD steatosis, requiring both binding and catalytic activity.","evidence":"Hepatocyte-specific KO and transgenic mice, Co-IP/pulldown, binding-domain and phosphatase-dead mutants, and TAK1 inhibitor epistasis","pmids":["28887166","29077210"],"confidence":"High","gaps":["Upstream signals controlling hepatic DUSP14 activity not defined","Contribution of ROS reduction vs direct dephosphorylation not separated"]},{"year":2025,"claim":"Broadened the substrate repertoire beyond MAPK signaling, showing DUSP14 dephosphorylates MLKL to block necroptosis and acts via PTPN12-PPARα-SCD to control ferroptosis, expanding its role into regulated cell death.","evidence":"DUSP14 KO/overexpression mice with p-MLKL readout and small-molecule activator, plus DUSP14 knockdown with PTPN12/PPARα/SCD and lipid-peroxidation readouts in TNBC xenografts","pmids":["40357546","41032417"],"confidence":"High","gaps":["Direct dephosphorylation of MLKL/PTPN12 vs indirect effects not fully resolved","Phospho-residues targeted on these substrates not mapped"]},{"year":null,"claim":"How DUSP14 substrate selection is partitioned across its many substrates (TAK1, TAB1, JNK, MLKL, PTPN12) in different tissues, and the structural basis for its PTM-dependent activation, remain open.","evidence":"No single study reconciles substrate choice across cell types","pmids":[],"confidence":"Medium","gaps":["No structure of DUSP14 in complex with any substrate","Tissue-specific determinants of substrate preference unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,4,8,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,15]}],"complexes":[],"partners":["TAK1","TAB1","TRAF2","PRMT5","CD28","MLKL","PTPN12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95147","full_name":"Dual specificity protein phosphatase 14","aliases":["MKP-1-like protein tyrosine phosphatase","MKP-L","Mitogen-activated protein kinase phosphatase 6","MAP kinase phosphatase 6","MKP-6"],"length_aa":198,"mass_kda":22.3,"function":"Involved in the inactivation of MAP kinases. Dephosphorylates ERK, JNK and p38 MAP-kinases. Plays a negative role in TCR signaling by dephosphorylating MAP3K7 adapter TAB1 leading to its inactivation (PubMed:24403530)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O95147/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DUSP14","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DUSP14","total_profiled":1310},"omim":[{"mim_id":"611446","title":"DUAL-SPECIFICITY PHOSPHATASE 18; DUSP18","url":"https://www.omim.org/entry/611446"},{"mim_id":"606618","title":"DUAL-SPECIFICITY PHOSPHATASE 14; DUSP14","url":"https://www.omim.org/entry/606618"},{"mim_id":"300678","title":"DUAL-SPECIFICITY PHOSPHATASE 21; DUSP21","url":"https://www.omim.org/entry/300678"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":44.5}],"url":"https://www.proteinatlas.org/search/DUSP14"},"hgnc":{"alias_symbol":["MKP-L","MKP6"],"prev_symbol":[]},"alphafold":{"accession":"O95147","domains":[{"cath_id":"3.90.190.10","chopping":"24-150","consensus_level":"high","plddt":97.3731,"start":24,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95147","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95147-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95147-F1-predicted_aligned_error_v6.png","plddt_mean":89.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DUSP14","jax_strain_url":"https://www.jax.org/strain/search?query=DUSP14"},"sequence":{"accession":"O95147","fasta_url":"https://rest.uniprot.org/uniprotkb/O95147.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95147/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95147"}},"corpus_meta":[{"pmid":"11123293","id":"PMC_11123293","title":"Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11123293","citation_count":88,"is_preprint":false},{"pmid":"22993413","id":"PMC_22993413","title":"Unrestrained p38 MAPK activation in Dusp1/4 double-null mice induces cardiomyopathy.","date":"2012","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/22993413","citation_count":87,"is_preprint":false},{"pmid":"19787133","id":"PMC_19787133","title":"A highly selective fluorescent ESIPT probe for the dual specificity phosphatase MKP-6.","date":"2009","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19787133","citation_count":86,"is_preprint":false},{"pmid":"18025410","id":"PMC_18025410","title":"Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14.","date":"2007","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18025410","citation_count":80,"is_preprint":false},{"pmid":"30335891","id":"PMC_30335891","title":"Evaluation of exosomal miR-9 and miR-155 targeting PTEN and DUSP14 in highly metastatic breast cancer and their effect on low metastatic cells.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30335891","citation_count":68,"is_preprint":false},{"pmid":"28887166","id":"PMC_28887166","title":"Dusp14 protects against hepatic ischaemia-reperfusion injury via Tak1 suppression.","date":"2017","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/28887166","citation_count":65,"is_preprint":false},{"pmid":"24403530","id":"PMC_24403530","title":"Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24403530","citation_count":59,"is_preprint":false},{"pmid":"29077210","id":"PMC_29077210","title":"Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver.","date":"2018","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29077210","citation_count":50,"is_preprint":false},{"pmid":"23229544","id":"PMC_23229544","title":"The dual-specificity phosphatase DUSP14 negatively regulates tumor necrosis factor- and interleukin-1-induced nuclear factor-κB activation by dephosphorylating the protein kinase TAK1.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23229544","citation_count":49,"is_preprint":false},{"pmid":"29860460","id":"PMC_29860460","title":"The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth and Regeneration.","date":"2018","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/29860460","citation_count":45,"is_preprint":false},{"pmid":"30693516","id":"PMC_30693516","title":"Iron overload threatens the growth of osteoblast cells via inhibiting the PI3K/AKT/FOXO3a/DUSP14 signaling pathway.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30693516","citation_count":39,"is_preprint":false},{"pmid":"32096190","id":"PMC_32096190","title":"MiR-155-5p accelerates cerebral ischemia-reperfusion injury via targeting DUSP14 by regulating NF-κB and MAPKs signaling pathways.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32096190","citation_count":39,"is_preprint":false},{"pmid":"32633405","id":"PMC_32633405","title":"Neuroprotective effect of DUSP14 overexpression against isoflurane-induced inflammatory response, pyroptosis and cognitive impairment in aged rats through inhibiting the NLRP3 inflammasome.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32633405","citation_count":32,"is_preprint":false},{"pmid":"29660332","id":"PMC_29660332","title":"DUSP14 knockout accelerates cardiac ischemia reperfusion (IR) injury through activating NF-κB and MAPKs signaling pathways modulated by ROS generation.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29660332","citation_count":30,"is_preprint":false},{"pmid":"30638656","id":"PMC_30638656","title":"DUSP14 rescues cerebral ischemia/reperfusion (IR) injury by reducing inflammation and apoptosis via the activation of Nrf-2.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30638656","citation_count":28,"is_preprint":false},{"pmid":"26521044","id":"PMC_26521044","title":"TRAF2-mediated Lys63-linked ubiquitination of 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development of pulmonary tuberculosis.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26938665","citation_count":14,"is_preprint":false},{"pmid":"19646420","id":"PMC_19646420","title":"PTP inhibitor IV protects JNK kinase activity by inhibiting dual-specificity phosphatase 14 (DUSP14).","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19646420","citation_count":13,"is_preprint":false},{"pmid":"33708977","id":"PMC_33708977","title":"Eriocitrin attenuates ischemia reperfusion-induced oxidative stress and inflammation in rats with acute kidney injury by regulating the dual-specificity phosphatase 14 (DUSP14)-mediated Nrf2 and nuclear factor-κB (NF-κB) pathways.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33708977","citation_count":13,"is_preprint":false},{"pmid":"39209069","id":"PMC_39209069","title":"Silencing miR-155-5p alleviates hippocampal damage in kainic acid-induced epileptic rats via the Dusp14/MAPK pathway.","date":"2024","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/39209069","citation_count":10,"is_preprint":false},{"pmid":"17263825","id":"PMC_17263825","title":"Novel function of DUSP14/MKP6 (dual specific phosphatase 14) as a nonspecific regulatory molecule for delayed-type hypersensitivity.","date":"2007","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17263825","citation_count":10,"is_preprint":false},{"pmid":"34605731","id":"PMC_34605731","title":"Enhancement of DUSP14 (dual specificity phosphatase 14) limits osteoarthritis progression by alleviating chondrocyte injury, inflammation and metabolic homeostasis.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34605731","citation_count":8,"is_preprint":false},{"pmid":"39039652","id":"PMC_39039652","title":"Inhibiting TRIM8 alleviates adipocyte inflammation and insulin resistance by regulating the DUSP14/MAPKs pathway.","date":"2024","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/39039652","citation_count":7,"is_preprint":false},{"pmid":"35927915","id":"PMC_35927915","title":"Sevoflurane Post-treatment Mitigates Oxygen-glucose Deprivationinduced Pyroptosis of Hippocampal Neurons by Regulating the Mafb/DUSP14 Axis.","date":"2022","source":"Current neurovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/35927915","citation_count":5,"is_preprint":false},{"pmid":"39484777","id":"PMC_39484777","title":"Exosomal Delivery of miR-155 Inhibitor can Suppress Migration, Invasion, and Angiogenesis Via PTEN and DUSP14 in Triple-negative Breast Cancer.","date":"2025","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39484777","citation_count":5,"is_preprint":false},{"pmid":"38644862","id":"PMC_38644862","title":"miR-199a-5p targets DUSP14 to regulate cell proliferation, invasion and stemness in non-small 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axis.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38565943","citation_count":4,"is_preprint":false},{"pmid":"40357546","id":"PMC_40357546","title":"Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure.","date":"2025","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/40357546","citation_count":2,"is_preprint":false},{"pmid":"41032417","id":"PMC_41032417","title":"DUSP14 suppresses ferroptosis and promotes tumor progression of triple-negative breast cancer.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41032417","citation_count":2,"is_preprint":false},{"pmid":"40449853","id":"PMC_40449853","title":"DUSP14 attenuates airway inflammation and mucus hypersecretion in allergic asthma by regulating TAK1 activity.","date":"2025","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40449853","citation_count":2,"is_preprint":false},{"pmid":"38767414","id":"PMC_38767414","title":"A Negative Regulatory Feedback Loop within the JAK-STAT Pathway Mediated by the Protein Tyrosine Phosphatase DUSP14 in Shrimp.","date":"2024","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/38767414","citation_count":1,"is_preprint":false},{"pmid":"41922912","id":"PMC_41922912","title":"Globo-H diagnostic stratification and identification of DUSP14 as a candidate target in colorectal cancer.","date":"2026","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41922912","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22640,"output_tokens":5594,"usd":0.075915,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14194,"output_tokens":3100,"usd":0.074235,"stage2_stop_reason":"end_turn"},"total_usd":0.15015,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MKP6 (DUSP14) was identified as a CD28 cytoplasmic tail-interacting protein via yeast-hybrid technology, and functions as a negative-feedback regulator of CD28 costimulatory signaling by inactivating MAP kinases; dominant-negative MKP6 enhanced IL-2 secretion specifically in response to CD28 costimulation, and a CD28 cytoplasmic tail mutant unable to bind MKP6 costimulated larger quantities of IL-2.\",\n      \"method\": \"Yeast-hybrid cloning, retroviral dominant-negative transfer into primary human T cells, IL-2 secretion assay, MAP kinase activation measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast-hybrid interaction, dominant-negative functional rescue, and mutant CD28 receptor experiment in primary T cells; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11123293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DUSP14 phosphatase activity is selectively inhibited by PTP inhibitor IV (bis(4-trifluoromethyl-sulfonamidophenyl)-1,4-diisopropylbenzene) in a competitive manner, indicating that PTP inhibitor IV binds to the catalytic site of DUSP14; DUSP14 was shown to directly dephosphorylate JNK in vitro.\",\n      \"method\": \"In vitro phosphatase activity screen, kinetic competitive inhibition assay, in vitro DUSP14-mediated JNK dephosphorylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay with kinetic characterization and competitive inhibition analysis; single lab but direct enzymatic evidence\",\n      \"pmids\": [\"19646420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A fluorescent ESIPT probe was designed by phosphorylation of the HBT chromophore and shown to be selectively hydrolyzed by DUSP14 (MKP-6) phosphatase activity, demonstrating the enzymatic activity of DUSP14 toward a phosphorylated substrate.\",\n      \"method\": \"In vitro fluorescent probe enzymatic hydrolysis assay (ESIPT-based)\",\n      \"journal\": \"Chemical communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct enzymatic assay with synthetic substrate, single lab, single method\",\n      \"pmids\": [\"19787133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DUSP14 negatively regulates TNF- and IL-1-induced NF-κB activation by directly interacting with TAK1 and dephosphorylating TAK1 at Thr-187 (a residue in the activation loop critical for TAK1 activation); overexpression of phosphatase-dead DUSP14 mutant failed to inhibit NF-κB activation, confirming catalytic activity is required.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown (siRNA), Western blot for TAK1 phosphorylation, NF-κB reporter assay, phosphatase-deficient mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, gain/loss-of-function, catalytic-dead mutant rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23229544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DUSP14 negatively regulates TCR signaling by directly interacting with TAB1 (TAK1-binding protein 1) and dephosphorylating TAB1 at Ser438, leading to inactivation of the TAB1-TAK1 complex and reduced downstream JNK and IKK activation; DUSP14-deficient mice showed enhanced T cell proliferation, cytokine production, and susceptibility to EAE.\",\n      \"method\": \"DUSP14-knockout mouse generation, co-immunoprecipitation, in vitro dephosphorylation assay, TAB1 shRNA knockdown epistasis, EAE disease model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype, Co-IP, in vitro dephosphorylation, epistasis by TAB1 knockdown rescue; replicated interactions with multiple methods in single rigorous study\",\n      \"pmids\": [\"24403530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUSP14 is modified by TRAF2-mediated Lys63-linked ubiquitination at lysine 103, and this ubiquitination is required for DUSP14 phosphatase activity during TCR signaling; TRAF2 shRNA knockdown reduced DUSP14 ubiquitination and phosphatase activity.\",\n      \"method\": \"Mass spectrometry identification of ubiquitination site, mutational analysis (K103 mutation), co-immunoprecipitation of TRAF2-DUSP14, TRAF2 shRNA knockdown, phosphatase activity assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS site identification, mutagenesis, Co-IP, shRNA epistasis, in vitro phosphatase assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26521044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DUSP14 physically interacts with TAK1 and suppresses NF-κB and MAPK (JNK) signaling in hepatocytes; hepatocyte-specific DUSP14 knockout exacerbated hepatic ischemia-reperfusion injury while DUSP14 transgenic mice were protected; mutant DUSP14 unable to bind TAK1 failed to protect against hepatic I/R injury; TAK1 inhibition abolished DUSP14 function in vivo, placing DUSP14 upstream of TAK1 in this pathway.\",\n      \"method\": \"Hepatocyte-specific KO and TG mouse models, co-immunoprecipitation, pull-down assays, Western blot, TAK1 inhibitor epistasis, TAK1-binding mutant DUSP14\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, pulldown, KO and TG mouse models, binding-mutant rescue, pharmacological epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"28887166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT5 methylates DUSP14 at arginine residues 17, 38, and 45; this arginine methylation is required for subsequent TRAF2-mediated Lys63-linked ubiquitination and phosphatase activity of DUSP14 during TCR signaling, establishing a sequential PTM cascade (methylation→ubiquitination→activation). DUSP14 directly interacts with TAB1 but not TAK1.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, in vitro methylation assay (PRMT5), triple-methylation mutant analysis, PRMT5 shRNA knockdown, phosphatase activity assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proximity ligation, Co-IP, in vitro methylation, mutagenesis of modification sites, shRNA epistasis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29920217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DUSP14 directly binds to and dephosphorylates TAK1 in hepatocytes, reducing activation of TAK1 downstream signaling including JNK1, p38, and NF-κB; both the binding domain and phosphatase activity of DUSP14 are required for protection against hepatic steatosis in NAFLD models; disruption of the DUSP14-TAK1 interaction abolished DUSP14's mitigative effects.\",\n      \"method\": \"Hepatocyte-specific overexpression (HTG) and KO (HKO) mouse models, co-immunoprecipitation, binding-domain and phosphatase-dead mutants, high-fat diet NAFLD model, TAK1 inhibitor rescue\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, KO/TG mouse models, domain-mutant analysis, pharmacological epistasis; rigorous multi-method study\",\n      \"pmids\": [\"29077210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DUSP14 knockdown or expression of dominant-negative DUSP14 in beta-cells increased beta-cell line proliferation and enhanced GLP-1-induced proliferation of primary beta-cells, identifying DUSP14 as a negative regulator of the MAPK/ERK1/2 pathway that limits GLP-1-induced beta-cell proliferation.\",\n      \"method\": \"siRNA knockdown, dominant-negative expression, [3H]thymidine and BrdU incorporation proliferation assays in beta-cell lines and primary mouse islets\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function siRNA and dominant-negative with specific proliferative readout in both cell lines and primary cells; single lab, two orthogonal approaches\",\n      \"pmids\": [\"18025410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DUSP14 (as NSF) was identified by MALDI-TOF mass spectrometry as a ~22.5 kDa protein secreted by macrophage-like suppressor cells that exists as a dimer under non-reducing conditions; recombinant DUSP14 exhibited phosphatase activity toward p-nitrophenyl phosphate and suppressed delayed-type hypersensitivity by binding specifically to MHC class II (Ia)-positive dendritic cells.\",\n      \"method\": \"MALDI-TOF mass spectrometry protein identification, recombinant DUSP14 in vitro phosphatase assay, binding assay to MHC class II+ cells, anti-DUSP14 monoclonal antibody neutralization, DTH/CHS functional assays\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, in vitro enzymatic assay, neutralizing antibody, cell-binding assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17263825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DUSP14 knockout in mice increased NF-κB and MAPK (p38, ERK1/2, JNK) activation following cardiac ischemia-reperfusion injury; ROS scavenger N-acetylcysteine abolished the DUSP14-knockdown-augmented NF-κB and MAPK activation in cardiomyocytes, indicating DUSP14 suppresses these pathways via reducing ROS generation.\",\n      \"method\": \"DUSP14 knockout mouse, DUSP14 siRNA knockdown in primary cardiomyocytes, Western blot for MAPK/NF-κB, ROS measurement, N-acetylcysteine rescue experiment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse and siRNA with pharmacological rescue; single lab, multiple approaches\",\n      \"pmids\": [\"29660332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DUSP14 axon growth inhibition in retinal ganglion cells operates downstream of KLF9 transcription factor; decreasing Dusp14 expression (siRNA/shRNA) or pharmacological inhibition (PTP inhibitor IV) increased axon growth in vitro and promoted RGC survival and optic nerve regeneration in vivo, linking the KLF9-Dusp14 axis to suppression of MAPK-dependent neurotrophic signaling.\",\n      \"method\": \"KLF9 overexpression + microarray to identify downstream targets, siRNA/shRNA knockdown of Dusp14, PTP inhibitor IV pharmacological inhibition, in vitro neurite length assay, in vivo optic nerve crush model in rats and mice\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KLF9→Dusp14), loss-of-function by siRNA/shRNA and pharmacological inhibition, in vivo regeneration assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29860460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JUNI lncRNA physically interacts with DUSP14 protein and counteracts its phosphatase activity, thereby facilitating JNK phosphorylation and c-Jun induction under UV/genotoxic stress; depletion of JUNI reduced JNK phosphorylation and cell survival, and this effect was mediated through JUNI's antagonism of DUSP14.\",\n      \"method\": \"Protein-RNA interaction screen (57 JUNI-interacting proteins identified), JNK phosphorylation Western blot, JUNI depletion functional rescue, UV/genotoxic drug treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction identified, functional epistasis by depletion; mechanism attributed to DUSP14 antagonism but detailed DUSP14-specific biochemistry not fully described in abstract\",\n      \"pmids\": [\"38565943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUSP14 dephosphorylates MLKL (mixed lineage kinase domain-like protein), thereby inhibiting necroptosis in cardiomyocytes; cardiomyocyte-specific DUSP14 overexpression reduced MLKL phosphorylation and necroptosis in hypothyroid mice, while DUSP14 knockout exacerbated necroptosis and cardiac dysfunction; a small-molecule activator (P077-0472) of DUSP14 inhibited cardiomyocyte necroptosis.\",\n      \"method\": \"DUSP14 KO mouse and AAV-mediated cardiomyocyte-specific overexpression, MLKL phosphorylation Western blot, Evans blue staining, LDH measurement, molecular docking for small-molecule activator, in vitro pharmacological activation assay\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and OE mouse models with specific molecular readout (p-MLKL), in vitro pharmacological validation; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"40357546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUSP14 knockdown increased phosphorylation of PTPN12, thereby inhibiting PPARα transcriptional activity and downregulating SCD expression; this led to lipid peroxidation and ferroptotic cell death in triple-negative breast cancer cells; targeting the DUSP14-PTPN12-PPARα/SCD axis with a small-molecule drug restricted TNBC malignant phenotype.\",\n      \"method\": \"DUSP14 knockdown (in vitro and xenograft), PTPN12 phosphorylation Western blot, PPARα transcriptional activity assay, SCD expression measurement, lipid peroxidation assay, xenograft tumor model, small-molecule drug treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple downstream pathway readouts in vitro and xenograft; single lab, single study but multiple orthogonal phenotypic endpoints\",\n      \"pmids\": [\"41032417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUSP14 interacts with TAK1 in bronchial epithelial cells (confirmed by co-immunoprecipitation) and DUSP14 overexpression restrains TAK1 and downstream NF-κB pathway activation, alleviating airway inflammation and mucus hypersecretion in an OVA asthma model.\",\n      \"method\": \"Co-immunoprecipitation of DUSP14-TAK1, DUSP14 overexpression in vitro (BEAS-2B cells) and OVA mouse model, Western blot for NF-κB/TAK1, inflammatory cytokine measurement\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and gain-of-function with pathway readouts in vitro and in vivo; single lab\",\n      \"pmids\": [\"40449853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP14 overexpression inhibited osteoclast differentiation induced by M-CSF and RANKL in bone marrow-derived cells and activated AMPKα; AMPKα blockade abolished the anti-osteoclast effect of DUSP14, placing DUSP14 upstream of AMPKα in suppression of osteoclastogenesis; DUSP14 transgenic mice were protected from magnesium silicate-induced inflammatory osteoporosis.\",\n      \"method\": \"DUSP14 overexpression in bone marrow-derived cells, M-CSF/RANKL osteoclast differentiation assay, AMPKα inhibitor epistasis, DUSP14 TG mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological epistasis and in vivo TG model; single lab\",\n      \"pmids\": [\"31526569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DUSP14 elevation in chondrocytes increased AMPK phosphorylation and inhibited NF-κB signaling (increased IκB, decreased p-p65); AMPK blockade abolished the protective effect of DUSP14 overexpression against IL-1β-induced inflammatory injury, establishing DUSP14 as acting upstream of AMPK-IκB to restrain NF-κB.\",\n      \"method\": \"DUSP14 overexpression in IL-1β-stimulated chondrocytes, AMPK inhibitor epistasis, Western blot for AMPK/NF-κB pathway, ACLT-induced OA rat model with DUSP14 injection, histological evaluation\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological epistasis and in vivo OA model; single lab\",\n      \"pmids\": [\"34605731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP14 protein level in colon cancer cells is inversely correlated with total TAK1 protein, and DUSP14 was functionally validated as a pharmacological target using cell lines and patient-derived organoids.\",\n      \"method\": \"RNA-sequencing, Western blot correlation of DUSP14 and TAK1 levels, in vitro cell line and patient-derived organoid drug targeting assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — inverse protein correlation and PDO functional assay, single study, limited mechanistic detail in abstract\",\n      \"pmids\": [\"41922912\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DUSP14 (MKP6/MKP-L) is a dual-specificity MAP kinase phosphatase that functions as a negative regulator of inflammatory and immune signaling: it directly dephosphorylates TAK1 at Thr-187 and TAB1 at Ser-438 to suppress TAB1-TAK1 complex activation, inhibiting downstream JNK, p38, and NF-κB pathways; it also dephosphorylates JNK, ERK, and p38 directly in vitro; its phosphatase activity is activated by a sequential PTM cascade in which PRMT5-mediated arginine methylation (at R17/38/45) promotes TRAF2-mediated Lys63-linked ubiquitination at K103; it dephosphorylates MLKL to suppress necroptosis; it dephosphorylates PTPN12 to regulate ferroptosis via the PPARα-SCD axis; and it interacts with the CD28 cytoplasmic tail to provide negative feedback during T cell costimulatory signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DUSP14 (MKP6/MKP-L) is a dual-specificity MAP kinase phosphatase that acts as a negative-feedback regulator of inflammatory, immune, and stress-activated signaling [#0, #3]. Its catalytic core directly dephosphorylates MAP kinases, hydrolyzing phosphorylated substrates in vitro and dephosphorylating JNK; this activity is competitively blocked by the active-site inhibitor PTP inhibitor IV [#1, #2]. The dominant mechanistic theme is suppression of the TAB1-TAK1 signaling node: DUSP14 directly binds TAK1 and dephosphorylates it at the activation-loop residue Thr-187, and binds TAB1 to dephosphorylate it at Ser-438, inactivating the TAB1-TAK1 complex and dampening downstream JNK, p38, and NF-\\u03baB activation [#3, #4, #8]. Through this TAK1-directed activity DUSP14 restrains T cell costimulatory and TCR signaling — DUSP14-deficient mice show enhanced T cell responses and EAE susceptibility — and protects multiple tissues from inflammatory and ischemic injury including liver, heart, cartilage, and airway [#4, #6, #8, #16]. DUSP14 phosphatase activity is switched on by a sequential post-translational cascade in which PRMT5-mediated arginine methylation (R17/R38/R45) licenses TRAF2-mediated Lys63-linked ubiquitination at Lys-103 [#5, #7]. Beyond MAPK control, DUSP14 dephosphorylates MLKL to suppress cardiomyocyte necroptosis and acts through a PTPN12-PPAR\\u03b1-SCD axis to govern ferroptosis in triple-negative breast cancer [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established DUSP14's physiological context by identifying it as a CD28-tail-binding protein that provides negative feedback on costimulatory signaling, framing it as a brake on MAP kinase-driven T cell activation.\",\n      \"evidence\": \"Yeast-hybrid cloning plus dominant-negative and CD28-tail-mutant rescue in primary human T cells with IL-2 readout\",\n      \"pmids\": [\"11123293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase substrate not defined at this stage\", \"CD28-DUSP14 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated intrinsic enzymatic activity and broader roles, showing recombinant DUSP14 is an active phosphatase and a negative regulator of MAPK/ERK-driven proliferation and immune suppression.\",\n      \"evidence\": \"Recombinant phosphatase assay on p-nitrophenyl phosphate, MHC-II cell-binding and DTH assays, and beta-cell siRNA/dominant-negative proliferation assays\",\n      \"pmids\": [\"17263825\", \"18025410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological MAPK substrate not directly identified\", \"Secreted-protein and intracellular-phosphatase roles not reconciled\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided direct biochemical proof of catalytic mechanism, defining DUSP14 as an active-site phosphatase that dephosphorylates JNK and is inhibited competitively by PTP inhibitor IV.\",\n      \"evidence\": \"In vitro phosphatase assays, kinetic competitive-inhibition analysis, and a synthetic ESIPT fluorescent substrate\",\n      \"pmids\": [\"19646420\", \"19787133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell substrate specificity not addressed\", \"No structural model of the catalytic site\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the core signaling node by showing DUSP14 directly binds TAB1 and TAK1 and dephosphorylates them at defined residues (TAK1 Thr-187, TAB1 Ser-438) to shut down NF-\\u03baB/JNK signaling, with loss-of-function confirmed in KO mice.\",\n      \"evidence\": \"Co-IP, in vitro dephosphorylation, catalytic-dead and binding mutants, TAB1 knockdown epistasis, and DUSP14-KO mice with EAE phenotype\",\n      \"pmids\": [\"23229544\", \"24403530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of TAK1 vs TAB1 dephosphorylation unresolved\", \"Whether DUSP14 binds TAK1 directly or via TAB1 later disputed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined how DUSP14 is activated, establishing a sequential PTM cascade in which PRMT5 arginine methylation (R17/38/45) is required for TRAF2-mediated K63 ubiquitination at K103, which in turn enables phosphatase activity during TCR signaling.\",\n      \"evidence\": \"MS site mapping, PRMT5 in vitro methylation, K103 and triple-methylation mutants, TRAF2/PRMT5 shRNA epistasis, proximity ligation, and phosphatase assays\",\n      \"pmids\": [\"26521044\", \"29920217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how methylation/ubiquitination activates catalysis unknown\", \"Whether the cascade operates outside TCR signaling untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the TAK1-axis to tissue protection, showing hepatocyte DUSP14-TAK1 binding suppresses JNK/p38/NF-\\u03baB to guard against ischemia-reperfusion injury and NAFLD steatosis, requiring both binding and catalytic activity.\",\n      \"evidence\": \"Hepatocyte-specific KO and transgenic mice, Co-IP/pulldown, binding-domain and phosphatase-dead mutants, and TAK1 inhibitor epistasis\",\n      \"pmids\": [\"28887166\", \"29077210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling hepatic DUSP14 activity not defined\", \"Contribution of ROS reduction vs direct dephosphorylation not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the substrate repertoire beyond MAPK signaling, showing DUSP14 dephosphorylates MLKL to block necroptosis and acts via PTPN12-PPAR\\u03b1-SCD to control ferroptosis, expanding its role into regulated cell death.\",\n      \"evidence\": \"DUSP14 KO/overexpression mice with p-MLKL readout and small-molecule activator, plus DUSP14 knockdown with PTPN12/PPAR\\u03b1/SCD and lipid-peroxidation readouts in TNBC xenografts\",\n      \"pmids\": [\"40357546\", \"41032417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation of MLKL/PTPN12 vs indirect effects not fully resolved\", \"Phospho-residues targeted on these substrates not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DUSP14 substrate selection is partitioned across its many substrates (TAK1, TAB1, JNK, MLKL, PTPN12) in different tissues, and the structural basis for its PTM-dependent activation, remain open.\",\n      \"evidence\": \"No single study reconciles substrate choice across cell types\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of DUSP14 in complex with any substrate\", \"Tissue-specific determinants of substrate preference unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 4, 8, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TAK1\", \"TAB1\", \"TRAF2\", \"PRMT5\", \"CD28\", \"MLKL\", \"PTPN12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}