{"gene":"DUSP26","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"DUSP26 forms a physical complex with p38 MAPK and effectively dephosphorylates p38, promoting survival of anaplastic thyroid cancer cells by inhibiting p38-mediated apoptosis.","method":"Co-immunoprecipitation, in vitro phosphatase assay, overexpression/knockdown in ATC cell lines","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vitro phosphatase assay, replicated across multiple ATC cell lines and primary tumor samples","pmids":["16924234"],"is_preprint":false},{"year":2006,"finding":"DUSP26 interacts with HSF4b (identified by yeast two-hybrid) and controls ERK activity, leading to phosphorylation/dephosphorylation of HSF4b and altering its DNA-binding ability.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase/phosphatase assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification plus functional phosphatase assays, single lab","pmids":["16581800"],"is_preprint":false},{"year":2008,"finding":"DUSP26 associates with KIF3 motor subunit Kif3a (identified by yeast two-hybrid) and also with Kap3; DUSP26 dephosphorylates Kap3, promoting N-cadherin/beta-catenin distribution to cell-cell junctions and increased cell-cell adhesiveness; this requires catalytic activity.","method":"Yeast two-hybrid, co-immunoprecipitation, colocalization, in vitro dephosphorylation assay, catalytically inactive mutant analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro phosphatase assay, mutagenesis) in single lab","pmids":["19043453"],"is_preprint":false},{"year":2009,"finding":"NSC-87877 competitively inhibits DUSP26 phosphatase activity in vitro and blocks DUSP26-mediated dephosphorylation of p38.","method":"In vitro phosphatase assay, kinetic inhibition analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro kinetic assay but single lab, single study","pmids":["19233143"],"is_preprint":false},{"year":2010,"finding":"DUSP26 does not dephosphorylate ERK, JNK, or p38 MAPKs in epithelial cells as measured by in vitro phosphatase assays and overexpression; its growth-suppressive effects on MCF10A cells depend on phosphatase activity but not MAPK dephosphorylation.","method":"In vitro phosphatase assay, overexpression and knockdown in epithelial cell lines, 3D culture","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro assay plus cell-based functional experiments with multiple lines; contradicts some earlier reports","pmids":["20347885"],"is_preprint":false},{"year":2014,"finding":"Adenylate kinase 2 (AK2) forms a complex with DUSP26, stimulates DUSP26 phosphatase activity independently of AK enzymatic activity, and the AK2/DUSP26 complex dephosphorylates FADD at Ser194, suppressing cell proliferation.","method":"Co-immunoprecipitation, in vitro phosphatase reconstitution, xenograft assay, AK2-deficient MEFs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of complex activity, Co-IP, in vivo xenograft, MEF genetic model, multiple orthogonal methods","pmids":["24548998"],"is_preprint":false},{"year":2015,"finding":"DUSP26 inhibition by NSC-87877 or shRNA knockdown in neuroblastoma cells increases p53 phosphorylation (Ser37, Ser46) and activates p38 downstream effectors (HSP27, MAPKAPK2), inducing apoptosis; p53 knockdown or p38 inhibition partially reverses this cytotoxicity.","method":"shRNA knockdown, pharmacological inhibition (NSC-87877, SB203580), Western blot, intrarenal mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (shRNA rescue) plus pharmacological validation in vitro and in vivo, single lab","pmids":["26247726"],"is_preprint":false},{"year":2016,"finding":"DUSP26 phosphatase activity is required for increased Aβ42 generation; DUSP26 induces JNK activation and stimulates anterograde axonal transport of C99-positive vesicles, shifting γ-secretase/C99 localization from cell body to axons under hypoxia.","method":"Genome-wide functional cDNA screen, live-cell vesicle trafficking assay, JNK inhibitor (SP600125), NSC-87877, catalytically inactive mutant","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen identification, trafficking assay, pharmacological and genetic validation, single lab","pmids":["26924229"],"is_preprint":false},{"year":2008,"finding":"NEAP/DUSP26 (phosphatase-competent form) suppresses EGFR expression in PC12 cells by decreasing EGFR promoter activity through downregulation of the Akt pathway and Wilms' tumor gene product (WT1); catalytic activity is required.","method":"Overexpression of WT and C152S mutant, EGFR promoter reporter assay, RNAi knockdown, EGFR inhibitor rescue","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assays, mutant analysis, and rescue experiments; single lab","pmids":["19014381"],"is_preprint":false},{"year":2017,"finding":"NEAP/DUSP26 directly dephosphorylates TrkA and FGFR1 in vitro; morpholino knockdown of NEAP in zebrafish causes hyper-phosphorylation of TrkA and FGFR1 and defects in retinal differentiation and cranial motor neurons.","method":"In vitro dephosphorylation assay, RNAi knockdown in PC12 cells, zebrafish morpholino knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphatase assay combined with in vivo morpholino genetic model, single lab","pmids":["28701747"],"is_preprint":false},{"year":2021,"finding":"DUSP26 antagonizes MDM2-mediated ubiquitination and degradation of DPP4 in human valvular interstitial cells, thereby stabilizing DPP4 and promoting aortic valve calcification.","method":"Immunoprecipitation, LC-MS/MS, functional calcification assays, adeno-associated virus shRNA in ApoE-/- mice","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS identification of DPP4 interaction, in vivo AAV silencing model, single lab","pmids":["34179958"],"is_preprint":false},{"year":2022,"finding":"DUSP26 is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence; loss of DUSP26 increases ROS, reduces ATP production and mitochondrial motility, releases HtrA2 into cytoplasm, and activates p38 MAPK, leading to dopaminergic neuronal death in mouse substantia nigra.","method":"Subcellular fractionation, live imaging for mitochondrial targeting, Dusp26 knockout mouse model, ROS/ATP measurements","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by fractionation and imaging with functional consequence, validated in KO mouse model with defined neurodegeneration phenotype","pmids":["35313355"],"is_preprint":false},{"year":2024,"finding":"DUSP26 dephosphorylates FAK and negatively regulates the FAK-ERK signaling pathway in cardiomyocytes; DUSP26 overexpression improves mitochondrial fusion and cardiac function in diabetic db/db mice, and pharmacological FAK activation partially offsets these benefits.","method":"Overexpression in db/db mouse model, echocardiography, mitochondrial function assays, FAK activator rescue experiment","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression with pharmacological rescue epistasis, single lab","pmids":["39510451"],"is_preprint":false},{"year":2026,"finding":"DUSP26 directly binds p53 and dephosphorylates it at serine 312, dampening p53 transcriptional activity toward cell death genes and protecting kidney tubular cells from acute kidney injury.","method":"Co-immunoprecipitation, in vitro dephosphorylation assay with site-specific p53 antibodies, proximal tubule-specific knock-in mouse, pharmacological inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical demonstration of dephosphorylation at defined site, validated in cell-type-specific knock-in mouse model with multiple orthogonal approaches","pmids":["41748589"],"is_preprint":false},{"year":2026,"finding":"DUSP26 dephosphorylates HDAC1, HDAC2, and HDAC8 (identified by mass spectrometry-based proteomics), inactivating them and maintaining chondrocyte integrity; DUSP26 overexpression protects against IL-1β-induced cartilage degradation.","method":"Mass spectrometry proteomics, adenovirus-mediated overexpression and shRNA silencing, in vitro chondrocyte inflammatory model","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of substrates with genetic gain/loss-of-function validation, single lab","pmids":["41789628"],"is_preprint":false},{"year":2026,"finding":"PRMT9 directly interacts with DUSP26 and methylates it at arginine R29, promoting its polyubiquitination by Trim32 and proteasomal degradation, thereby reducing DUSP26 levels and exacerbating mitochondrial dysfunction in dopaminergic neurons.","method":"Co-immunoprecipitation, arginine methylation assay, ubiquitination assay, Trim32 identification, PRMT9 overexpression/KO in MPTP mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of methylation site and E3 ligase, validated in in vivo PD model, single lab","pmids":["42261762"],"is_preprint":false},{"year":2024,"finding":"DUSP26 overexpression in prostate cancer PC3 cells impairs TAK1, p38, and JNK phosphorylation, suppressing proliferation, migration, and invasion; TAK1 inhibitor treatment attenuates the effect of DUSP26.","method":"Overexpression and siRNA knockdown, Western blot, subcutaneous xenograft, RNA-seq, pharmacological TAK1 inhibition rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by pharmacological rescue, combined with in vivo xenograft, single lab","pmids":["39222869"],"is_preprint":false}],"current_model":"DUSP26 is an atypical dual-specificity phosphatase that localizes to the mitochondrial outer membrane (via an N-terminal targeting sequence) and dephosphorylates multiple substrates including p38 MAPK, FADD (stimulated by the activator AK2), p53 at Ser312, TrkA, FGFR1, Kap3 (a KIF3 motor subunit), FAK, and HDACs 1/2/8, thereby regulating cell survival, proliferation, apoptosis, intracellular transport, mitochondrial homeostasis, and neuronal integrity; its activity is subject to post-translational regulation through PRMT9-mediated arginine methylation at R29, which triggers Trim32-dependent polyubiquitination and proteasomal degradation."},"narrative":{"mechanistic_narrative":"DUSP26 is an atypical dual-specificity phosphatase that dephosphorylates a broad panel of substrates to control cell survival, proliferation, apoptosis, and mitochondrial and neuronal homeostasis across diverse tissues [PMID:16924234, PMID:24548998, PMID:35313355, PMID:41748589]. In its best-defined survival role, DUSP26 forms a complex with and dephosphorylates p38 MAPK to suppress p38-mediated apoptosis in anaplastic thyroid cancer cells [PMID:16924234], and its activity is potentiated by adenylate kinase 2 (AK2), which binds DUSP26 and stimulates dephosphorylation of FADD at Ser194 to restrain proliferation [PMID:24548998]. DUSP26 directly binds and dephosphorylates p53 at Ser312 to dampen p53-driven cell-death transcription and protect renal tubular cells [PMID:41748589], and it inactivates HDAC1, HDAC2, and HDAC8 to maintain chondrocyte integrity [PMID:41789628]. The enzyme also acts on receptor and cytoskeletal substrates, dephosphorylating TrkA and FGFR1 with consequences for retinal and motor-neuron development [PMID:28701747], the KIF3 motor subunit Kap3 to promote N-cadherin/beta-catenin junctional localization and cell-cell adhesion [PMID:19043453], and FAK to negatively regulate FAK-ERK signaling [PMID:39510451]. DUSP26 is targeted to the mitochondrial outer membrane via an N-terminal targeting sequence, where its loss elevates ROS, reduces ATP and mitochondrial motility, and triggers dopaminergic neuronal death [PMID:35313355]; its abundance is controlled by PRMT9-mediated arginine methylation at R29 that licenses Trim32-dependent polyubiquitination and proteasomal degradation [PMID:42261762]. The small molecule NSC-87877 competitively inhibits its catalytic activity [PMID:19233143]. Substrate selectivity is context-dependent: in epithelial cells DUSP26 does not dephosphorylate ERK, JNK, or p38, yet still suppresses growth in a phosphatase-activity-dependent manner [PMID:20347885].","teleology":[{"year":2006,"claim":"Established the first DUSP26 substrate and a pro-survival function, answering whether this atypical phosphatase had a defined MAPK target relevant to cancer.","evidence":"Reciprocal Co-IP and in vitro phosphatase assay with overexpression/knockdown across anaplastic thyroid cancer lines and primary tumors","pmids":["16924234"],"confidence":"High","gaps":["Did not define the structural basis of p38 recognition","Substrate specificity later found to be cell-context dependent"]},{"year":2006,"claim":"Identified a transcription-factor-linked interaction, showing DUSP26 can influence ERK activity and HSF4b DNA-binding.","evidence":"Yeast two-hybrid, Co-IP, in vitro kinase/phosphatase assays","pmids":["16581800"],"confidence":"Medium","gaps":["Direct phosphatase target within the HSF4b axis not pinpointed","Single-lab finding without in vivo validation"]},{"year":2008,"claim":"Extended DUSP26 substrates beyond signaling kinases to cytoskeletal transport and to transcriptional control of EGFR, broadening its functional scope.","evidence":"Y2H, Co-IP, colocalization, in vitro dephosphorylation of Kap3, catalytic-mutant analysis; separately EGFR promoter reporter and C152S mutant in PC12 cells","pmids":["19043453","19014381"],"confidence":"High","gaps":["Phospho-sites on Kap3 not mapped","Mechanistic link between phosphatase activity and WT1/EGFR promoter regulation indirect"]},{"year":2009,"claim":"Provided a pharmacological tool, establishing that NSC-87877 competitively inhibits DUSP26 and blocks p38 dephosphorylation.","evidence":"In vitro phosphatase assay with kinetic inhibition analysis","pmids":["19233143"],"confidence":"Medium","gaps":["Selectivity against other phosphatases not established","No cellular potency or off-target profile in this study"]},{"year":2010,"claim":"Challenged the universality of MAPK targeting by showing DUSP26 does not dephosphorylate ERK/JNK/p38 in epithelial cells yet still suppresses growth, establishing context-dependent substrate selection.","evidence":"In vitro phosphatase assay, overexpression/knockdown, and 3D culture in epithelial lines","pmids":["20347885"],"confidence":"Medium","gaps":["The relevant epithelial substrate driving growth suppression not identified","Contradicts MAPK-dependent models without reconciling mechanism"]},{"year":2014,"claim":"Revealed allosteric regulation of DUSP26, showing AK2 stimulates its phosphatase activity independent of kinase function and redirects it to FADD-Ser194.","evidence":"Co-IP, in vitro reconstitution, xenograft, AK2-deficient MEFs","pmids":["24548998"],"confidence":"High","gaps":["Structural basis of AK2-induced activation not resolved","How AK2 dictates substrate choice unclear"]},{"year":2015,"claim":"Defined a DUSP26-p53/p38 survival axis in neuroblastoma, linking enzyme inhibition to apoptosis induction.","evidence":"shRNA, NSC-87877 and SB203580 epistasis, Western blot, intrarenal mouse model","pmids":["26247726"],"confidence":"Medium","gaps":["Whether p53 effects were direct not addressed here","p53/p38 contributions only partially separable"]},{"year":2016,"claim":"Connected DUSP26 catalytic activity to amyloidogenic axonal transport, implicating it in JNK-driven C99 vesicle trafficking under hypoxia.","evidence":"Genome-wide cDNA screen, live-cell trafficking assay, JNK inhibitor and catalytic-dead mutant","pmids":["26924229"],"confidence":"Medium","gaps":["Direct phosphatase substrate in the JNK/transport pathway not identified","Mechanism of anterograde bias unresolved"]},{"year":2017,"claim":"Demonstrated direct receptor tyrosine kinase substrates (TrkA, FGFR1) and an in vivo developmental requirement.","evidence":"In vitro dephosphorylation, PC12 RNAi, zebrafish morpholino knockdown","pmids":["28701747"],"confidence":"Medium","gaps":["Specific phospho-tyrosines on TrkA/FGFR1 not mapped","Morpholino specificity not genetically confirmed"]},{"year":2021,"claim":"Uncovered a non-canonical, phosphatase-independent stabilizing role, with DUSP26 antagonizing MDM2-mediated DPP4 degradation to drive valve calcification.","evidence":"Co-IP, LC-MS/MS, calcification assays, AAV-shRNA in ApoE-/- mice","pmids":["34179958"],"confidence":"Medium","gaps":["Whether catalytic activity contributes not resolved","Mechanism of MDM2 antagonism unclear"]},{"year":2022,"claim":"Localized DUSP26 to the mitochondrial outer membrane via an N-terminal targeting sequence and tied its loss to mitochondrial dysfunction and dopaminergic neurodegeneration.","evidence":"Subcellular fractionation, live imaging, Dusp26 knockout mouse, ROS/ATP assays","pmids":["35313355"],"confidence":"High","gaps":["Direct mitochondrial substrate not defined","HtrA2 release mechanism downstream of DUSP26 loss unresolved"]},{"year":2024,"claim":"Added FAK and TAK1-p38-JNK axes as functional targets, linking DUSP26 to cardiac mitochondrial fusion and prostate cancer suppression.","evidence":"In vivo overexpression in db/db mice with FAK-activator rescue; PC3 overexpression/siRNA, xenograft, RNA-seq, TAK1 inhibitor rescue","pmids":["39510451","39222869"],"confidence":"Medium","gaps":["Direct vs indirect dephosphorylation of TAK1 not distinguished","Single-lab in vivo models"]},{"year":2026,"claim":"Provided direct, site-specific substrate definitions (p53-Ser312 and HDAC1/2/8) with cell-type-specific genetic models, anchoring DUSP26's protective roles in kidney and cartilage.","evidence":"Co-IP, site-specific in vitro dephosphorylation, proximal-tubule knock-in mouse; MS proteomics with adenoviral gain/loss in chondrocytes","pmids":["41748589","41789628"],"confidence":"High","gaps":["Structural recognition of these substrates not solved","HDAC substrate work is single-lab"]},{"year":2026,"claim":"Established post-translational control of DUSP26 abundance via PRMT9 methylation at R29 driving Trim32-dependent degradation in a Parkinson's model.","evidence":"Co-IP, methylation and ubiquitination assays, PRMT9 OE/KO in MPTP mice","pmids":["42261762"],"confidence":"Medium","gaps":["How R29 methylation recruits Trim32 mechanistically unclear","Single-lab biochemical model"]},{"year":null,"claim":"It remains unresolved how DUSP26 selects among its many reported substrates in different cell types and which determinants (localization, AK2 binding, methylation state) govern this specificity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Substrate repertoire varies by tissue without a unifying selectivity rule","Catalytic vs scaffolding contributions not separated across functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,9,12,13,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,5,13]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,12,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[11]}],"complexes":[],"partners":["MAPK14","AK2","FADD","TP53","KIF3A","KAP3","PRMT9","TRIM32"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BV47","full_name":"Dual specificity protein phosphatase 26","aliases":["Dual specificity phosphatase SKRP3","Low-molecular-mass dual-specificity phosphatase 4","DSP-4","LDP-4","Mitogen-activated protein kinase phosphatase 8","MAP kinase phosphatase 8","MKP-8","Novel amplified gene in thyroid anaplastic cancer"],"length_aa":211,"mass_kda":23.9,"function":"Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK)","subcellular_location":"Cytoplasm; Nucleus; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q9BV47/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DUSP26","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DUSP26","total_profiled":1310},"omim":[{"mim_id":"618368","title":"DUAL-SPECIFICITY PHOSPHATASE 26; DUSP26","url":"https://www.omim.org/entry/618368"},{"mim_id":"103020","title":"ADENYLATE KINASE 2; AK2","url":"https://www.omim.org/entry/103020"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":394.8},{"tissue":"tongue","ntpm":190.8}],"url":"https://www.proteinatlas.org/search/DUSP26"},"hgnc":{"alias_symbol":["MGC1136","DUSP24","NEAP"],"prev_symbol":[]},"alphafold":{"accession":"Q9BV47","domains":[{"cath_id":"3.90.190.10","chopping":"44-209","consensus_level":"high","plddt":94.6556,"start":44,"end":209}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV47","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV47-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV47-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DUSP26","jax_strain_url":"https://www.jax.org/strain/search?query=DUSP26"},"sequence":{"accession":"Q9BV47","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BV47.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BV47/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV47"}},"corpus_meta":[{"pmid":"16924234","id":"PMC_16924234","title":"A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16924234","citation_count":84,"is_preprint":false},{"pmid":"24548998","id":"PMC_24548998","title":"The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24548998","citation_count":65,"is_preprint":false},{"pmid":"16581800","id":"PMC_16581800","title":"Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16581800","citation_count":64,"is_preprint":false},{"pmid":"34179958","id":"PMC_34179958","title":"DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells.","date":"2021","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/34179958","citation_count":57,"is_preprint":false},{"pmid":"19233143","id":"PMC_19233143","title":"NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26).","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19233143","citation_count":50,"is_preprint":false},{"pmid":"19043453","id":"PMC_19043453","title":"Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19043453","citation_count":43,"is_preprint":false},{"pmid":"26247726","id":"PMC_26247726","title":"NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/26247726","citation_count":32,"is_preprint":false},{"pmid":"20347885","id":"PMC_20347885","title":"DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20347885","citation_count":26,"is_preprint":false},{"pmid":"35278641","id":"PMC_35278641","title":"Falnidamol and cisplatin combinational treatment inhibits non-small cell lung cancer (NSCLC) by targeting DUSP26-mediated signal pathways.","date":"2022","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35278641","citation_count":25,"is_preprint":false},{"pmid":"33466673","id":"PMC_33466673","title":"A Review of DUSP26: Structure, Regulation and Relevance in Human Disease.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33466673","citation_count":24,"is_preprint":false},{"pmid":"31155289","id":"PMC_31155289","title":"DUSP26 regulates podocyte oxidative stress and fibrosis in a mouse model with diabetic nephropathy through the mediation of ROS.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31155289","citation_count":21,"is_preprint":false},{"pmid":"26924229","id":"PMC_26924229","title":"Dual-specificity phosphatase 26 (DUSP26) stimulates Aβ42 generation by promoting amyloid precursor protein axonal transport during hypoxia.","date":"2016","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26924229","citation_count":20,"is_preprint":false},{"pmid":"19014381","id":"PMC_19014381","title":"NEAP causes down-regulation of EGFR, subsequently induces the suppression of NGF-induced differentiation in PC12 cells.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19014381","citation_count":17,"is_preprint":false},{"pmid":"28701747","id":"PMC_28701747","title":"NEAP/DUSP26 suppresses receptor tyrosine kinases and regulates neuronal development in zebrafish.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28701747","citation_count":15,"is_preprint":false},{"pmid":"23271903","id":"PMC_23271903","title":"Higher estimates of daily dietary net endogenous acid production (NEAP) in the elderly as compared to the young in a healthy, free-living elderly population of Pakistan.","date":"2012","source":"Clinical interventions in aging","url":"https://pubmed.ncbi.nlm.nih.gov/23271903","citation_count":12,"is_preprint":false},{"pmid":"39510451","id":"PMC_39510451","title":"Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39510451","citation_count":10,"is_preprint":false},{"pmid":"35313355","id":"PMC_35313355","title":"Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35313355","citation_count":9,"is_preprint":false},{"pmid":"35932862","id":"PMC_35932862","title":"Phytoplankton habitats and size distribution during a neap-spring transition in the highly turbid macrotidal Chikugo River estuary.","date":"2022","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/35932862","citation_count":6,"is_preprint":false},{"pmid":"33718185","id":"PMC_33718185","title":"Decreased DUSP26 Expression Promotes Malignant Behavior in Glioblastoma Cells via Deregulation of MAPK and Akt Signaling Pathway.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33718185","citation_count":4,"is_preprint":false},{"pmid":"11165297","id":"PMC_11165297","title":"Feeding rhythms of the green-lipped mussel, Perna viridis (Linnaeus, 1758) (Bivalvia: Mytilidae) during spring and neap tidal cycles.","date":"2001","source":"Journal of experimental marine biology and ecology","url":"https://pubmed.ncbi.nlm.nih.gov/11165297","citation_count":2,"is_preprint":false},{"pmid":"39222869","id":"PMC_39222869","title":"Overexpression of DUSP26 gene suppressed the proliferation, migration, and invasion of human prostate cancer cells.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39222869","citation_count":1,"is_preprint":false},{"pmid":"41748589","id":"PMC_41748589","title":"DUSP26 protects against acute kidney injury by dephosphorylating p53 at serine 312.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41748589","citation_count":1,"is_preprint":false},{"pmid":"33928040","id":"PMC_33928040","title":"Corrigendum: Decreased DUSP26 Expression Promotes Malignant Behavior in Glioblastoma Cells via Deregulation of MAPK and Akt Signaling Pathway.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33928040","citation_count":1,"is_preprint":false},{"pmid":"41789628","id":"PMC_41789628","title":"DUSP26: Unveiling a critical molecular mediator and therapeutic target in developmental dysplasia of the hip‑associated secondary osteoarthritis.","date":"2026","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41789628","citation_count":0,"is_preprint":false},{"pmid":"42261762","id":"PMC_42261762","title":"PRMT9 Aggravated Dopaminergic Neurodegeneration in Parkinson's Disease Model by Facilitating the Degradation of DUSP26 and Inducing Mitochondrial Dysfunction.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42261762","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14579,"output_tokens":3781,"usd":0.050226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11492,"output_tokens":4231,"usd":0.081617,"stage2_stop_reason":"end_turn"},"total_usd":0.131843,"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\": 2006,\n      \"finding\": \"DUSP26 forms a physical complex with p38 MAPK and effectively dephosphorylates p38, promoting survival of anaplastic thyroid cancer cells by inhibiting p38-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay, overexpression/knockdown in ATC cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vitro phosphatase assay, replicated across multiple ATC cell lines and primary tumor samples\",\n      \"pmids\": [\"16924234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DUSP26 interacts with HSF4b (identified by yeast two-hybrid) and controls ERK activity, leading to phosphorylation/dephosphorylation of HSF4b and altering its DNA-binding ability.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase/phosphatase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification plus functional phosphatase assays, single lab\",\n      \"pmids\": [\"16581800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DUSP26 associates with KIF3 motor subunit Kif3a (identified by yeast two-hybrid) and also with Kap3; DUSP26 dephosphorylates Kap3, promoting N-cadherin/beta-catenin distribution to cell-cell junctions and increased cell-cell adhesiveness; this requires catalytic activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, colocalization, in vitro dephosphorylation assay, catalytically inactive mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro phosphatase assay, mutagenesis) in single lab\",\n      \"pmids\": [\"19043453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NSC-87877 competitively inhibits DUSP26 phosphatase activity in vitro and blocks DUSP26-mediated dephosphorylation of p38.\",\n      \"method\": \"In vitro phosphatase assay, kinetic inhibition analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro kinetic assay but single lab, single study\",\n      \"pmids\": [\"19233143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DUSP26 does not dephosphorylate ERK, JNK, or p38 MAPKs in epithelial cells as measured by in vitro phosphatase assays and overexpression; its growth-suppressive effects on MCF10A cells depend on phosphatase activity but not MAPK dephosphorylation.\",\n      \"method\": \"In vitro phosphatase assay, overexpression and knockdown in epithelial cell lines, 3D culture\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro assay plus cell-based functional experiments with multiple lines; contradicts some earlier reports\",\n      \"pmids\": [\"20347885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Adenylate kinase 2 (AK2) forms a complex with DUSP26, stimulates DUSP26 phosphatase activity independently of AK enzymatic activity, and the AK2/DUSP26 complex dephosphorylates FADD at Ser194, suppressing cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase reconstitution, xenograft assay, AK2-deficient MEFs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of complex activity, Co-IP, in vivo xenograft, MEF genetic model, multiple orthogonal methods\",\n      \"pmids\": [\"24548998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUSP26 inhibition by NSC-87877 or shRNA knockdown in neuroblastoma cells increases p53 phosphorylation (Ser37, Ser46) and activates p38 downstream effectors (HSP27, MAPKAPK2), inducing apoptosis; p53 knockdown or p38 inhibition partially reverses this cytotoxicity.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition (NSC-87877, SB203580), Western blot, intrarenal mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (shRNA rescue) plus pharmacological validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"26247726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DUSP26 phosphatase activity is required for increased Aβ42 generation; DUSP26 induces JNK activation and stimulates anterograde axonal transport of C99-positive vesicles, shifting γ-secretase/C99 localization from cell body to axons under hypoxia.\",\n      \"method\": \"Genome-wide functional cDNA screen, live-cell vesicle trafficking assay, JNK inhibitor (SP600125), NSC-87877, catalytically inactive mutant\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen identification, trafficking assay, pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"26924229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NEAP/DUSP26 (phosphatase-competent form) suppresses EGFR expression in PC12 cells by decreasing EGFR promoter activity through downregulation of the Akt pathway and Wilms' tumor gene product (WT1); catalytic activity is required.\",\n      \"method\": \"Overexpression of WT and C152S mutant, EGFR promoter reporter assay, RNAi knockdown, EGFR inhibitor rescue\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assays, mutant analysis, and rescue experiments; single lab\",\n      \"pmids\": [\"19014381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NEAP/DUSP26 directly dephosphorylates TrkA and FGFR1 in vitro; morpholino knockdown of NEAP in zebrafish causes hyper-phosphorylation of TrkA and FGFR1 and defects in retinal differentiation and cranial motor neurons.\",\n      \"method\": \"In vitro dephosphorylation assay, RNAi knockdown in PC12 cells, zebrafish morpholino knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphatase assay combined with in vivo morpholino genetic model, single lab\",\n      \"pmids\": [\"28701747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DUSP26 antagonizes MDM2-mediated ubiquitination and degradation of DPP4 in human valvular interstitial cells, thereby stabilizing DPP4 and promoting aortic valve calcification.\",\n      \"method\": \"Immunoprecipitation, LC-MS/MS, functional calcification assays, adeno-associated virus shRNA in ApoE-/- mice\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS identification of DPP4 interaction, in vivo AAV silencing model, single lab\",\n      \"pmids\": [\"34179958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DUSP26 is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence; loss of DUSP26 increases ROS, reduces ATP production and mitochondrial motility, releases HtrA2 into cytoplasm, and activates p38 MAPK, leading to dopaminergic neuronal death in mouse substantia nigra.\",\n      \"method\": \"Subcellular fractionation, live imaging for mitochondrial targeting, Dusp26 knockout mouse model, ROS/ATP measurements\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by fractionation and imaging with functional consequence, validated in KO mouse model with defined neurodegeneration phenotype\",\n      \"pmids\": [\"35313355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP26 dephosphorylates FAK and negatively regulates the FAK-ERK signaling pathway in cardiomyocytes; DUSP26 overexpression improves mitochondrial fusion and cardiac function in diabetic db/db mice, and pharmacological FAK activation partially offsets these benefits.\",\n      \"method\": \"Overexpression in db/db mouse model, echocardiography, mitochondrial function assays, FAK activator rescue experiment\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression with pharmacological rescue epistasis, single lab\",\n      \"pmids\": [\"39510451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP26 directly binds p53 and dephosphorylates it at serine 312, dampening p53 transcriptional activity toward cell death genes and protecting kidney tubular cells from acute kidney injury.\",\n      \"method\": \"Co-immunoprecipitation, in vitro dephosphorylation assay with site-specific p53 antibodies, proximal tubule-specific knock-in mouse, pharmacological inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical demonstration of dephosphorylation at defined site, validated in cell-type-specific knock-in mouse model with multiple orthogonal approaches\",\n      \"pmids\": [\"41748589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP26 dephosphorylates HDAC1, HDAC2, and HDAC8 (identified by mass spectrometry-based proteomics), inactivating them and maintaining chondrocyte integrity; DUSP26 overexpression protects against IL-1β-induced cartilage degradation.\",\n      \"method\": \"Mass spectrometry proteomics, adenovirus-mediated overexpression and shRNA silencing, in vitro chondrocyte inflammatory model\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of substrates with genetic gain/loss-of-function validation, single lab\",\n      \"pmids\": [\"41789628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRMT9 directly interacts with DUSP26 and methylates it at arginine R29, promoting its polyubiquitination by Trim32 and proteasomal degradation, thereby reducing DUSP26 levels and exacerbating mitochondrial dysfunction in dopaminergic neurons.\",\n      \"method\": \"Co-immunoprecipitation, arginine methylation assay, ubiquitination assay, Trim32 identification, PRMT9 overexpression/KO in MPTP mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of methylation site and E3 ligase, validated in in vivo PD model, single lab\",\n      \"pmids\": [\"42261762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP26 overexpression in prostate cancer PC3 cells impairs TAK1, p38, and JNK phosphorylation, suppressing proliferation, migration, and invasion; TAK1 inhibitor treatment attenuates the effect of DUSP26.\",\n      \"method\": \"Overexpression and siRNA knockdown, Western blot, subcutaneous xenograft, RNA-seq, pharmacological TAK1 inhibition rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by pharmacological rescue, combined with in vivo xenograft, single lab\",\n      \"pmids\": [\"39222869\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DUSP26 is an atypical dual-specificity phosphatase that localizes to the mitochondrial outer membrane (via an N-terminal targeting sequence) and dephosphorylates multiple substrates including p38 MAPK, FADD (stimulated by the activator AK2), p53 at Ser312, TrkA, FGFR1, Kap3 (a KIF3 motor subunit), FAK, and HDACs 1/2/8, thereby regulating cell survival, proliferation, apoptosis, intracellular transport, mitochondrial homeostasis, and neuronal integrity; its activity is subject to post-translational regulation through PRMT9-mediated arginine methylation at R29, which triggers Trim32-dependent polyubiquitination and proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DUSP26 is an atypical dual-specificity phosphatase that dephosphorylates a broad panel of substrates to control cell survival, proliferation, apoptosis, and mitochondrial and neuronal homeostasis across diverse tissues [#0, #5, #11, #13]. In its best-defined survival role, DUSP26 forms a complex with and dephosphorylates p38 MAPK to suppress p38-mediated apoptosis in anaplastic thyroid cancer cells [#0], and its activity is potentiated by adenylate kinase 2 (AK2), which binds DUSP26 and stimulates dephosphorylation of FADD at Ser194 to restrain proliferation [#5]. DUSP26 directly binds and dephosphorylates p53 at Ser312 to dampen p53-driven cell-death transcription and protect renal tubular cells [#13], and it inactivates HDAC1, HDAC2, and HDAC8 to maintain chondrocyte integrity [#14]. The enzyme also acts on receptor and cytoskeletal substrates, dephosphorylating TrkA and FGFR1 with consequences for retinal and motor-neuron development [#9], the KIF3 motor subunit Kap3 to promote N-cadherin/beta-catenin junctional localization and cell-cell adhesion [#2], and FAK to negatively regulate FAK-ERK signaling [#12]. DUSP26 is targeted to the mitochondrial outer membrane via an N-terminal targeting sequence, where its loss elevates ROS, reduces ATP and mitochondrial motility, and triggers dopaminergic neuronal death [#11]; its abundance is controlled by PRMT9-mediated arginine methylation at R29 that licenses Trim32-dependent polyubiquitination and proteasomal degradation [#15]. The small molecule NSC-87877 competitively inhibits its catalytic activity [#3]. Substrate selectivity is context-dependent: in epithelial cells DUSP26 does not dephosphorylate ERK, JNK, or p38, yet still suppresses growth in a phosphatase-activity-dependent manner [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first DUSP26 substrate and a pro-survival function, answering whether this atypical phosphatase had a defined MAPK target relevant to cancer.\",\n      \"evidence\": \"Reciprocal Co-IP and in vitro phosphatase assay with overexpression/knockdown across anaplastic thyroid cancer lines and primary tumors\",\n      \"pmids\": [\"16924234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of p38 recognition\", \"Substrate specificity later found to be cell-context dependent\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a transcription-factor-linked interaction, showing DUSP26 can influence ERK activity and HSF4b DNA-binding.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro kinase/phosphatase assays\",\n      \"pmids\": [\"16581800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase target within the HSF4b axis not pinpointed\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended DUSP26 substrates beyond signaling kinases to cytoskeletal transport and to transcriptional control of EGFR, broadening its functional scope.\",\n      \"evidence\": \"Y2H, Co-IP, colocalization, in vitro dephosphorylation of Kap3, catalytic-mutant analysis; separately EGFR promoter reporter and C152S mutant in PC12 cells\",\n      \"pmids\": [\"19043453\", \"19014381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-sites on Kap3 not mapped\", \"Mechanistic link between phosphatase activity and WT1/EGFR promoter regulation indirect\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a pharmacological tool, establishing that NSC-87877 competitively inhibits DUSP26 and blocks p38 dephosphorylation.\",\n      \"evidence\": \"In vitro phosphatase assay with kinetic inhibition analysis\",\n      \"pmids\": [\"19233143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity against other phosphatases not established\", \"No cellular potency or off-target profile in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Challenged the universality of MAPK targeting by showing DUSP26 does not dephosphorylate ERK/JNK/p38 in epithelial cells yet still suppresses growth, establishing context-dependent substrate selection.\",\n      \"evidence\": \"In vitro phosphatase assay, overexpression/knockdown, and 3D culture in epithelial lines\",\n      \"pmids\": [\"20347885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The relevant epithelial substrate driving growth suppression not identified\", \"Contradicts MAPK-dependent models without reconciling mechanism\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed allosteric regulation of DUSP26, showing AK2 stimulates its phosphatase activity independent of kinase function and redirects it to FADD-Ser194.\",\n      \"evidence\": \"Co-IP, in vitro reconstitution, xenograft, AK2-deficient MEFs\",\n      \"pmids\": [\"24548998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AK2-induced activation not resolved\", \"How AK2 dictates substrate choice unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a DUSP26-p53/p38 survival axis in neuroblastoma, linking enzyme inhibition to apoptosis induction.\",\n      \"evidence\": \"shRNA, NSC-87877 and SB203580 epistasis, Western blot, intrarenal mouse model\",\n      \"pmids\": [\"26247726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 effects were direct not addressed here\", \"p53/p38 contributions only partially separable\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected DUSP26 catalytic activity to amyloidogenic axonal transport, implicating it in JNK-driven C99 vesicle trafficking under hypoxia.\",\n      \"evidence\": \"Genome-wide cDNA screen, live-cell trafficking assay, JNK inhibitor and catalytic-dead mutant\",\n      \"pmids\": [\"26924229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase substrate in the JNK/transport pathway not identified\", \"Mechanism of anterograde bias unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated direct receptor tyrosine kinase substrates (TrkA, FGFR1) and an in vivo developmental requirement.\",\n      \"evidence\": \"In vitro dephosphorylation, PC12 RNAi, zebrafish morpholino knockdown\",\n      \"pmids\": [\"28701747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phospho-tyrosines on TrkA/FGFR1 not mapped\", \"Morpholino specificity not genetically confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-canonical, phosphatase-independent stabilizing role, with DUSP26 antagonizing MDM2-mediated DPP4 degradation to drive valve calcification.\",\n      \"evidence\": \"Co-IP, LC-MS/MS, calcification assays, AAV-shRNA in ApoE-/- mice\",\n      \"pmids\": [\"34179958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity contributes not resolved\", \"Mechanism of MDM2 antagonism unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localized DUSP26 to the mitochondrial outer membrane via an N-terminal targeting sequence and tied its loss to mitochondrial dysfunction and dopaminergic neurodegeneration.\",\n      \"evidence\": \"Subcellular fractionation, live imaging, Dusp26 knockout mouse, ROS/ATP assays\",\n      \"pmids\": [\"35313355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mitochondrial substrate not defined\", \"HtrA2 release mechanism downstream of DUSP26 loss unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added FAK and TAK1-p38-JNK axes as functional targets, linking DUSP26 to cardiac mitochondrial fusion and prostate cancer suppression.\",\n      \"evidence\": \"In vivo overexpression in db/db mice with FAK-activator rescue; PC3 overexpression/siRNA, xenograft, RNA-seq, TAK1 inhibitor rescue\",\n      \"pmids\": [\"39510451\", \"39222869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect dephosphorylation of TAK1 not distinguished\", \"Single-lab in vivo models\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided direct, site-specific substrate definitions (p53-Ser312 and HDAC1/2/8) with cell-type-specific genetic models, anchoring DUSP26's protective roles in kidney and cartilage.\",\n      \"evidence\": \"Co-IP, site-specific in vitro dephosphorylation, proximal-tubule knock-in mouse; MS proteomics with adenoviral gain/loss in chondrocytes\",\n      \"pmids\": [\"41748589\", \"41789628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural recognition of these substrates not solved\", \"HDAC substrate work is single-lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established post-translational control of DUSP26 abundance via PRMT9 methylation at R29 driving Trim32-dependent degradation in a Parkinson's model.\",\n      \"evidence\": \"Co-IP, methylation and ubiquitination assays, PRMT9 OE/KO in MPTP mice\",\n      \"pmids\": [\"42261762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How R29 methylation recruits Trim32 mechanistically unclear\", \"Single-lab biochemical model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DUSP26 selects among its many reported substrates in different cell types and which determinants (localization, AK2 binding, methylation state) govern this specificity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Substrate repertoire varies by tissue without a unifying selectivity rule\", \"Catalytic vs scaffolding contributions not separated across functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 9, 12, 13, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 5, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 12, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAPK14\", \"AK2\", \"FADD\", \"TP53\", \"KIF3A\", \"KAP3\", \"PRMT9\", \"TRIM32\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}