{"gene":"DUSP1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1993,"finding":"CL100/DUSP1, expressed and purified from bacteria, acts as a dual-specificity phosphatase that rapidly and potently inactivates MAP kinase in vitro by concomitant dephosphorylation of both phosphothreonine and phosphotyrosine residues. It also suppresses [val12]ras-induced MAP kinase activation in Xenopus oocyte cell-free extracts. Both activities are abolished by mutagenesis of the conserved active-site Cys-258.","method":"In vitro phosphatase assay with recombinant protein; active-site mutagenesis (Cys258); cell-free Xenopus oocyte extract epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, active-site mutagenesis, and cell-free epistasis in a single rigorous study; foundational biochemical characterization","pmids":["8390041"],"is_preprint":false},{"year":1994,"finding":"The CL100 gene is present as a single locus and maps to human chromosome 5q34, and CL100-homologous sequences are conserved in mouse, chicken, Xenopus, and Drosophila genomes.","method":"PCR with human-rodent somatic cell hybrid DNA panel; fluorescence in situ hybridization (FISH)","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal mapping methods (somatic cell hybrid PCR + FISH), single lab; localization finding without functional consequence","pmids":["8168826"],"is_preprint":false},{"year":1995,"finding":"In Swiss 3T3 fibroblasts, depletion of CL100/DUSP1 with cycloheximide blocks inactivation of p42 MAP kinase after EGF stimulation; however, in adipose (3T3-L1), chromaffin (PC12), and endothelial (PAE) cells, rapid p42 MAP kinase inactivation is not catalyzed by CL100 but instead by protein phosphatase 2A (dephosphorylating Thr183) and a distinct protein tyrosine phosphatase (dephosphorylating Tyr185).","method":"Cycloheximide depletion; phospho-specific antibody western blotting; vanadate inhibition; PP2A activity assay in cell extracts","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic depletion, phosphatase inhibitors, activity assays) across multiple cell lines; negatively defines cell-type specificity of DUSP1 substrate role","pmids":["7780739"],"is_preprint":false},{"year":1995,"finding":"CL100/DUSP1 mRNA is induced ~4-fold in hippocampus and cerebral cortex within 1 h of reperfusion following transient forebrain ischemia in rats, with expression localized to neuronal cells by in situ hybridization.","method":"Northern blotting; in situ hybridization histochemistry","journal":"Journal of cerebral blood flow and metabolism","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA induction and localization only, single method, no functional consequence established","pmids":["7798338"],"is_preprint":false},{"year":1997,"finding":"In human mesangial cells, CL100/DUSP1 gene expression is induced by activation of the ERK cascade (blocked by MEK antagonist PD098059) and also by the p38/SAPK activator anisomycin (partially blocked by SB203580), demonstrating ERK-dependent and ERK-independent transcriptional induction pathways.","method":"Northern blotting; MEK inhibitor (PD098059); p38 inhibitor (SB203580); selective ERK agonists","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with two independent inhibitors; single lab","pmids":["9013447"],"is_preprint":false},{"year":1998,"finding":"Conditional expression of MKP-1 abolishes UV-induced SAPK/JNK and p38 MAPK activity, inhibits caspase-3 activation, prevents PARP cleavage, and protects U937 cells against UV-induced apoptosis in a dose-dependent manner. Cytoprotection tracks closely with JNK (not p38) inhibition, as SB203580 had no protective effect.","method":"Conditional expression system (metallothionein IIa promoter); SAPK/p38 kinase assays; caspase-3 activity; PARP western blot; DNA fragmentation; morphological apoptosis scoring","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional overexpression with dose-response, multiple orthogonal apoptosis readouts, and pharmacological dissection of SAPK vs p38 contributions","pmids":["9501207"],"is_preprint":false},{"year":2000,"finding":"Expression of CL100/MKP-1 selectively prevents SAPK/JNK (but not p38) activation by cisplatin and protects cells against cisplatin-induced apoptosis. A catalytically inactive CL100 mutant decreases the IC50 for cisplatin and increases JNK activity, indicating that phosphatase activity is required. ERK-specific phosphatase Pyst1 does not confer protection.","method":"Overexpression and dominant-negative mutant transfection; JNK/p38 kinase assays; cell viability (IC50); apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — catalytically inactive mutant confirms requirement for enzymatic activity; multiple kinase substrates tested; orthogonal death assays","pmids":["11064451"],"is_preprint":false},{"year":2000,"finding":"Glucagon induces MKP-1 mRNA and protein expression in rat hepatocytes through a cAMP/PKA-dependent mechanism (sensitive to adenylate cyclase and PKA inhibitors), and the induced MKP-1 correlates with antagonization of EGF-induced MAP kinase phosphorylation.","method":"Northern/Western blotting; pharmacological inhibitors of adenylate cyclase, PKA, PKG, PKC, Ca2+, MAPKs","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors tested in a single lab; correlative link between MKP-1 induction and MAP kinase dephosphorylation","pmids":["10784592"],"is_preprint":false},{"year":2001,"finding":"Glucocorticoids inhibit ERK-1/2 in mast cells via a dual mechanism: (1) transcriptional up-regulation of MKP-1 at the promoter level, and (2) inhibition of proteasomal degradation of MKP-1 triggered by mast cell activation. Both actions are necessary for glucocorticoid-mediated ERK-1/2 inhibition. In NIH-3T3 fibroblasts, glucocorticoids up-regulate MKP-1 but do not block its proteasomal degradation, and consequently cannot inhibit ERK-1/2.","method":"Promoter reporter assays; proteasome inhibitor experiments; Western blotting for MKP-1 protein stability; ERK-1/2 kinase assays; cell-type comparison","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (promoter reporters + proteasome inhibition + protein stability + kinase assays) in two cell types; mechanistic dissection of two independent regulatory levels","pmids":["11742987"],"is_preprint":false},{"year":2002,"finding":"PKA phosphorylates an MKP-1-GST fusion protein in vitro, and cAMP increases 32P incorporation into immunoprecipitated MKP-1 in H295R adrenocortical cells. PKA or MKP-1 overexpression increases CYP17 promoter activity; antisense silencing of MKP-1 attenuates cAMP-stimulated CYP17 expression, while silencing of ERK1/2 increases it, placing MKP-1 in the cAMP/PKA-ERK1/2-SF-1-CYP17 transcriptional axis.","method":"In vitro PKA phosphorylation of MKP-1-GST fusion protein; 32P labeling + immunoprecipitation; transient transfection reporter assays; antisense oligonucleotide knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphorylation reconstitution plus cell-based knockdown and reporter assays; single lab but multiple orthogonal methods","pmids":["12506119"],"is_preprint":false},{"year":2004,"finding":"MKP-1 abundance increases during adipocyte differentiation with timing parallel to decreased p42/p44 MAPK activity. Ectopic MKP-1 expression reduces, and MKP-1 depletion (antisense RNA) increases, p42/p44 MAPK activity. Prevention of MKP-1 up-regulation blocks adipocyte differentiation, an effect reversed by MEK inhibitor PD98059, establishing MKP-1-mediated ERK inactivation as essential for adipogenesis.","method":"Ectopic overexpression; antisense RNA knockdown; MEK inhibitor rescue (PD98059); kinase activity assays; differentiation markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function, loss-of-function, and pharmacological rescue in a single study; clearly defined cellular phenotype","pmids":["15269202"],"is_preprint":false},{"year":2004,"finding":"H2O2 induces MKP-1 expression in rat mesangial cells via the MAP kinase–AP-1 pathway; selective inhibitors of individual MAPKs or dominant-negative c-jun suppress MKP-1 expression. Wild-type MKP-1 but not catalytically inactive MKP-1CS attenuates H2O2-induced apoptosis, establishing that phosphatase activity is required for cytoprotection against oxidative stress.","method":"Northern/Western blotting; MAP kinase inhibitors; dominant-negative c-jun; transfection of wild-type vs. catalytically inactive MKP-1CS; apoptosis assay","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — active-site mutant controls, pharmacological pathway dissection, and functional apoptosis readout in a single study","pmids":["15059639"],"is_preprint":false},{"year":2004,"finding":"In normal VSMC, insulin increases MKP-1 expression and MKP-1 phosphorylation (stabilizing it), leading to MAPK inactivation and inhibition of PDGF-driven cell migration. MKP-1 siRNA abolishes insulin inhibition of migration. Adenoviral MKP-1 expression restores insulin inhibition of migration in diabetic GK rat VSMCs, where MKP-1 induction and phosphorylation are impaired.","method":"siRNA knockdown; adenoviral overexpression; PDGF-induced migration assay; MAPK phosphorylation western blotting; proteasome inhibitor experiments; cGK Ialpha adenoviral expression","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA and adenoviral rescue in two cell models with defined migration phenotype; multiple orthogonal approaches","pmids":["15355857"],"is_preprint":false},{"year":2006,"finding":"MKP-1 overexpression increases cisplatin resistance in H-1299 NSCLC cells; siRNA knockdown of MKP-1 sensitizes H-460 cells to cisplatin by enhancing JNK and p38 activation and increasing apoptosis. MKP-1 siRNA-expressing H-460 tumor xenografts grew slower and were more cisplatin-sensitive. Knockdown of the related MKP-2 had no effect, indicating specificity.","method":"siRNA knockdown; overexpression; cisplatin sensitivity assay; JNK/p38 kinase western blots; xenograft mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo gain- and loss-of-function, specificity control with MKP-2 siRNA","pmids":["16462770"],"is_preprint":false},{"year":2006,"finding":"p38 MAPK mediates MKP-1 induction at a post-transcriptional level in LPS/PGN-stimulated macrophages: pharmacological inhibition or RNAi knockdown of p38 reduces MKP-1 protein but not mRNA; depletion of the p38 substrate MK2 similarly reduces MKP-1, linking p38-MK2 signaling to MKP-1 post-transcriptional regulation and establishing a positive feedback loop.","method":"p38 inhibitor (SB203580); RNAi knockdown of p38 and MK2; Northern and Western blotting; LPS tolerance model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal approaches (pharmacological + RNAi) confirming post-transcriptional regulation; single lab","pmids":["16978838"],"is_preprint":false},{"year":2007,"finding":"ERK2 phosphorylates MKP-1 in ovarian cancer cells in response to cisplatin; inhibition of MEK1/2 (U0126) or ERK2 siRNA knockdown decreases cisplatin-induced MKP-1 phosphorylation and reduces MKP-1 protein levels, sensitizing cells to cisplatin. ERK2 knockdown also decreases basal Bcl-2 protein levels.","method":"MEK1/2 inhibitor (U0126); siRNA ERK2 knockdown; MKP-1 phosphorylation western blotting; cisplatin sensitivity/apoptosis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and siRNA confirmation of ERK2-dependent MKP-1 phosphorylation; single lab, two orthogonal methods","pmids":["18089824"],"is_preprint":false},{"year":2007,"finding":"E2F-1 directly binds to the DUSP1/CL100 promoter at an E2F-1 consensus sequence and a palindromic motif, stimulates DUSP1 promoter activity, and induces DUSP1 expression specifically in response to oxidative stress. E2F-1-induced DUSP1 expression leads to ERK1/2 dephosphorylation and mediates the apoptotic response to oxidative stress.","method":"Chromatin immunoprecipitation; luciferase reporter assay; ectopic E2F-1 expression; phospho-ERK western blotting; stress-specific induction experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP plus promoter reporter plus functional epistasis; single lab but multiple orthogonal methods","pmids":["17638884"],"is_preprint":false},{"year":2008,"finding":"MKP-1 is acetylated on a key lysine residue following TLR stimulation. Acetylation of MKP-1 promotes its interaction with substrate p38 MAPK, resulting in p38 dephosphorylation and attenuation of innate immunity.","method":"Acetylation analysis post-TLR stimulation; interaction/co-immunoprecipitation of acetylated MKP-1 with p38; p38 phosphorylation assays (reviewed/highlighted from primary study)","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification (acetylation) linked to substrate binding and functional outcome; details from primary study reviewed here; single characterization","pmids":["18922786"],"is_preprint":false},{"year":2008,"finding":"HuR and NF90 bind to the AU-rich 3' UTR of MKP-1 mRNA. H2O2 treatment increases association of MKP-1 mRNA with HuR and NF90 while decreasing association with translational repressors TIAR and TIA-1. Silencing HuR or NF90 diminishes MKP-1 mRNA stability; HuR silencing also reduces MKP-1 translation. Loss of MKP-1 in HuR-silenced cells leads to elevated phospho-JNK and phospho-p38 after H2O2.","method":"Ribonucleoprotein immunoprecipitation; biotinylated RNA pulldown; siRNA silencing of RNA-binding proteins; mRNA stability assays; western blotting for MKP-1 protein and phospho-MAPKs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple RNA-binding proteins tested, RNP-IP and siRNA knockdown with functional MAPK readout; multiple orthogonal methods in single rigorous study","pmids":["18490444"],"is_preprint":false},{"year":2008,"finding":"In pituitary gonadotrophs, overexpression of MKP-1 blocks buserelin (GnRH analogue)-induced ERK dephosphorylation in the nucleus, thereby inhibiting Egr-1 expression; MKP-1 dephosphorylates ERK specifically in the nuclear compartment to control downstream transcription factor activity.","method":"Overexpression of MKP-1; chromatin immunoprecipitation (Elk-1 binding to Egr-1 gene); dominant-negative transcription factor mutants; kinase activity assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with defined nuclear ERK phosphorylation readout and downstream gene target; single lab","pmids":["18814180"],"is_preprint":false},{"year":2008,"finding":"Pancreatic reg I protein physically interacts with MKP-1 as demonstrated by yeast two-hybrid assay and confirmed by immunoprecipitation; high intracellular reg I levels are proposed to bind and inactivate MKP-1.","method":"Yeast two-hybrid; co-immunoprecipitation; Northern analysis; microarray","journal":"The Journal of surgical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP confirmation of yeast two-hybrid result; no mutagenesis or in vitro reconstitution; single lab","pmids":["18929742"],"is_preprint":false},{"year":2009,"finding":"MKP-1 deficiency in T cells impairs activation, proliferation, and function, associated with enhanced JNK activation and reduced NFATc1 nuclear translocation. MKP-1-/- mice are defective in anti-influenza immunity in vivo and resistant to EAE, demonstrating MKP-1 as a positive regulator of T cell activation.","method":"Genetic knockout; in vitro T cell activation assays; JNK phosphorylation western blot; NFATc1 nuclear localization; in vivo influenza and EAE models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple mechanistic (JNK, NFAT) and in vivo immune phenotypes; replicated across two disease models","pmids":["19748894"],"is_preprint":false},{"year":2009,"finding":"Acquired cisplatin resistance in OV433 ovarian cancer cells is associated with increased MKP-1 expression; siRNA knockdown of MKP-1 or its pharmacological inhibitor triptolide resensitizes resistant cells to cisplatin and increases apoptosis.","method":"siRNA knockdown; triptolide inhibitor; cisplatin sensitivity and apoptosis assays; western blotting","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibitor convergently demonstrate MKP-1's role; single lab","pmids":["19755862"],"is_preprint":false},{"year":2010,"finding":"BDNF-induced MKP-1 expression in neurons causes spatiotemporal inactivation of JNK, reducing phosphorylation of JNK substrates that destabilize microtubules. Neurons from mkp-1 null mice cannot produce axon branches in response to BDNF, establishing MKP-1 as essential for BDNF-induced axon branching through JNK dephosphorylation.","method":"mkp-1 knockout mice; JNK activity assays; phosphorylation of microtubule-destabilizing JNK substrates; axon branching quantification; BDNF treatment","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with clear cellular phenotype, mechanistic substrate identification, and substrate phosphorylation assays","pmids":["20935641"],"is_preprint":false},{"year":2011,"finding":"MKP-1 restricts p38 MAPK activation in macrophages to allow the pro- to anti-inflammatory transition during muscle repair. In MKP-1-deficient macrophages, p38 hyperactivation induces miR-21, which reduces PTEN, thereby extending AKT activation. Temporal p38 inhibition reverses impaired tissue healing in MKP-1-deficient mice.","method":"MKP-1 knockout mice; p38 kinase activity assays; miR-21 and PTEN expression; AKT phosphorylation western blotting; p38 inhibitor rescue; tissue repair histology","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple biochemical pathway steps validated (p38→miR-21→PTEN→AKT) and pharmacological rescue; rigorous mechanistic study","pmids":["21987635"],"is_preprint":false},{"year":2011,"finding":"hCG/cAMP stimulation in MA-10 Leydig cells rapidly increases MKP-1 mRNA by transcriptional action and accumulates MKP-1 protein in both nuclear and mitochondrial compartments. hCG/cAMP triggers ERK1/2-dependent MKP-1 phosphorylation. MKP-1 overexpression reduces ERK1/2 phosphorylation, StAR promoter activity, StAR mRNA levels, and steroidogenesis; MKP-1 siRNA knockdown produces opposite effects.","method":"mRNA and protein time-course analysis; subcellular fractionation; flag-tagged MKP-1 immunoprecipitation; ERK1/2 phosphorylation western blotting; StAR promoter reporter; siRNA knockdown; steroid hormone measurement","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular localization determined by fractionation with functional consequence (ERK-StAR-steroidogenesis axis); gain- and loss-of-function with multiple readouts; single lab but multiple orthogonal methods","pmids":["21558315"],"is_preprint":false},{"year":2011,"finding":"Progesterone receptor (PR) acts in a ligand-dependent manner through progesterone response elements downstream of the MKP-1 transcription start site and through Sp1 sites to up-regulate MKP-1 promoter activity. PR-induced MKP-1 expression results in ERK1/2 dephosphorylation and inhibits breast cancer cell proliferation; siRNA knockdown of MKP-1 blocks progestin-mediated ERK1/2 dephosphorylation and anti-proliferative effect.","method":"ChIP; luciferase reporter assay; siRNA knockdown of MKP-1; phospho-ERK1/2 western blotting; cell proliferation assay; correlation analysis in 30 breast cancer cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP + promoter reporter + siRNA rescue + functional cell proliferation; multiple orthogonal approaches in single rigorous study","pmids":["22020934"],"is_preprint":false},{"year":2012,"finding":"MKP-1 (DUSP1) enzymatic activity is required for neuroprotection against polyglutamine-expanded huntingtin toxicity in striatal neurons: phosphatase-domain mutants lose protection. Selective MKP-1 mutants that prevent p38 or JNK binding each partially attenuate neuroprotection, demonstrating that both p38 and JNK inhibition additively contribute to MKP-1-mediated neuroprotection without affecting ERK1/2.","method":"Lentiviral overexpression of wild-type and selective binding-domain mutants of MKP-1; caspase-3 activation assay; JNK/p38/ERK phosphorylation western blotting; neuronal cell death counting; in vivo rat lentiviral HD model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic activity mutant controls, selective substrate-binding mutants, in vitro and in vivo models; multiple orthogonal approaches","pmids":["23392662"],"is_preprint":false},{"year":2012,"finding":"MKP-1 is essential for RANKL-induced osteoclastogenesis regulation: RANKL induces MKP-1 expression in osteoclast precursors; mkp-1-/- osteoclasts show increased p38 MAPK and JNK activity and hyperactive bone resorption. mkp-1-/- female mice have mildly reduced bone mass, and mkp-1-/- mice show profoundly enhanced osteoclast activation in response to local LPS injection.","method":"mkp-1 knockout mice; RANKL stimulation; p38 and JNK phosphorylation western blotting; bone resorption assay; micro-CT bone mass measurement; LPS injection model; osteoclast differentiation assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with biochemical MAPK activation data, in vitro resorption assay, and in vivo bone phenotype; multiple methods","pmids":["19762714"],"is_preprint":false},{"year":2014,"finding":"DUSP1 deficiency in mice leads to enhanced oral squamous carcinogenesis (earlier onset, advanced histologic stage) with increased proinflammatory IL-1β production and deregulated chemokines. In a syngeneic tumor model, DUSP1-deficient mice form faster-growing tumors via p38-dependent inflammation, abrogated by p38 inhibitor SB203580.","method":"Dusp1-/- mice; 4-NQO carcinogenesis model; syngeneic EO771 tumor model; p38 inhibitor rescue; IL-1β ELISA; bone marrow-derived macrophage ex vivo assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological rescue; in vivo and ex vivo mechanistic readouts; p38 pathway epistasis","pmids":["25312268"],"is_preprint":false},{"year":2016,"finding":"DUSP1 overexpression maintains IRF1 mRNA and protein stability by switching off MAPKs; MAPK inhibitors and DUSP1 overexpression prolong IRF1 expression by increasing transcription and mRNA/protein stability. DUSP1 silencing increases MAPK phosphorylation and reduces IRF1 protein levels. IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1-dependent genes (e.g., CXCL10), contributing to glucocorticoid insensitivity.","method":"DUSP1 overexpression and siRNA silencing; MAPK inhibitors; IRF1 mRNA stability assays; phospho-MAPK western blotting; ChIP at CXCL10 promoter; mRNA quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function, pharmacological confirmation, ChIP, and mRNA stability assays; multiple orthogonal methods in single study","pmids":["27551049"],"is_preprint":false},{"year":2016,"finding":"DUSP1 knockdown by shRNA increases both basal and rapamycin-stimulated autophagic flux in ovarian cancer cells and MEFs. DUSP1 knockout promotes phosphorylation of ULK1 (Ser555) and BECN1 (Ser15) and increases association of PIK3C3/VPS34, ATG14, BECN1, and MAPK, activating the class III PtdIns3K complex. DUSP1-mediated suppression of autophagy acts through inactivation of MAPK1-MAPK3 (ERK).","method":"shRNA knockdown; DUSP1 knockout MEFs; overexpression; rapamycin treatment; autophagic flux assay; ULK1/BECN1 phosphorylation western blotting; co-immunoprecipitation of autophagy initiation complex components","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, shRNA, and overexpression with multiple biochemical readouts; co-IP of autophagy initiation complex; pharmacological pathway dissection","pmids":["27459239"],"is_preprint":false},{"year":2017,"finding":"PARP-1 activation causes PARylation of ATF4, reducing its binding to the CRE sequence in the MKP-1 promoter; in vitro PARylation assay showed reduced ATF4-CRE binding. PARP inhibition or silencing increases ATF4 nuclear binding and MKP-1 expression (confirmed by ChIP-qPCR showing increased ATF4 occupancy at MKP-1 initiation site), leading to JNK/p38 inactivation, reduced mitochondrial ROS, and decreased cell death.","method":"PARP-1 inhibitor/siRNA; in vitro PARylation of ATF4 and EMSA; ChIP-qPCR; MKP-1 western blotting; JNK/p38 phosphorylation; mitochondrial membrane potential; ROS assays; multiple human cell lines","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro PARylation reconstitution, ChIP-qPCR of ATF4 occupancy, functional MAPK and mitochondrial readouts; multiple orthogonal methods","pmids":["28457938"],"is_preprint":false},{"year":2017,"finding":"Genetic deletion of Fos and Dusp1 suppresses BCR-ABL-driven CML tumor growth in mice. Pharmacological inhibition of DUSP1 (combined with BCR-ABL TKI and c-FOS inhibition) eradicates minimal residual disease in multiple in vivo and xenograft CML models, indicating that growth-factor-induced DUSP1 expression sets the threshold of TKI efficacy and confers intrinsic resistance.","method":"Genetic deletion (Fos/Dusp1 knockout mice); pharmacological DUSP1 inhibition; BCR-ABL mouse model; xenograft with patient-derived CML cells; in vivo tumor growth assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion plus pharmacological inhibition; in vivo and xenograft models with patient-derived cells; replicated across multiple tumor models","pmids":["28319094"],"is_preprint":false},{"year":2017,"finding":"MKP-1 suppresses PARP-1 degradation by inhibiting JNK1/2, which promotes PARP-1 ubiquitination: MKP-1 overexpression increases PARP-1 and PAR protein levels; silencing MKP-1 promotes PARP-1 ubiquitination and reduces PARP-1 levels; silencing JNK1/2 decreases PARP-1 ubiquitination. PARP activity inhibition restores cisplatin sensitivity in MKP-1-overexpressing cells.","method":"MKP-1 overexpression and siRNA; JNK1/2 siRNA; ubiquitination assay; PARP-1 protein western blotting; cisplatin sensitivity assay; pharmacological PARP inhibitor","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (siRNA) dissection of MKP-1→JNK→PARP-1 ubiquitination axis with functional cisplatin resistance readout; multiple orthogonal methods","pmids":["28650468"],"is_preprint":false},{"year":2018,"finding":"Mkp-1 directly interacts with the DIDLID motif of Nrf2, increasing Nrf2 stability and positively regulating constitutive and LPS-inducible Nrf2/Ho-1 expression. Conversely, Nrf2 activates Mkp-1 transcription through antioxidant response elements in the Mkp-1 promoter, forming a positive feedback loop that protects against colonic inflammation.","method":"Co-immunoprecipitation of Mkp-1-Nrf2 interaction; Mkp-1-/- mice in DSS colitis model; Nrf2/Ho-1 western blotting; ARE promoter reporter for Mkp-1; colitis histology","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction by Co-IP, domain-specific interaction (DIDLID motif), promoter ARE reporter, in vivo knockout model; multiple orthogonal methods","pmids":["30061089"],"is_preprint":false},{"year":2018,"finding":"DUSP1 deficiency activates JNK, which promotes Mff phosphorylation and excessive mitochondrial fission, leading to mitochondrial oxidative stress, mPTP opening, proapoptotic protein leakage, and mitochondria-dependent apoptosis in diabetic nephropathy. DUSP1 overexpression interrupts Mff-related mitochondrial fission and reduces hyperglycemia-mediated mitochondrial damage.","method":"DUSP1 overexpression and knockdown; JNK phosphorylation western blotting; Mff phosphorylation; mitochondrial morphology assays; mPTP opening; apoptosis assays; diabetic cell and animal models","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with DUSP1 and mechanistic pathway dissection (JNK→Mff→fission); single lab","pmids":["30191967"],"is_preprint":false},{"year":2018,"finding":"USP49 deubiquitinates DUSP1, stabilizing DUSP1 protein expression; co-immunoprecipitation confirms direct interaction between USP49 and DUSP1. USP49 overexpression increases DUSP1 levels, reduces JNK1/2 activation, and protects cardiomyocytes against I/R-induced apoptosis; these effects require DUSP1-mediated JNK dephosphorylation.","method":"Co-immunoprecipitation; ubiquitination assay; siRNA and overexpression; JNK1/2 western blotting; cell viability and apoptosis assays; in vivo rat I/R model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay confirms USP49-DUSP1 interaction and deubiquitination; functional I/R phenotype; single lab","pmids":["30246457"],"is_preprint":false},{"year":2019,"finding":"DUSP1 loss in the cochlea of Dusp1-/- mice causes premature progressive hearing loss, hair cell death, spiral neuron degeneration, macrophage infiltration, imbalanced redox status, and dysregulated cytokines, establishing DUSP1 as essential for cochlear homeostasis during aging-related stress responses.","method":"Dusp1-/- knockout mice; auditory brainstem response (ABR); histology of cochlear hair cells and spiral neurons; macrophage infiltration quantification; redox status assays; cytokine expression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with electrophysiological, histological, and biochemical readouts in a rigorous study","pmids":["30938680"],"is_preprint":false},{"year":2019,"finding":"Upregulation of MKP-1 in APP/PS1 transgenic AD mice inhibits APP and BACE1 expression by inactivating the ERK1/2/MAPK signaling pathway, reducing Aβ production and plaque formation, and improving hippocampal LTP and cognitive deficits. Aβ-induced Sp1 activation decreases MKP-1 expression via Sp1 cis-acting binding elements in the MKP-1 promoter.","method":"MKP-1 overexpression in APP/PS1 transgenic mice; ERK1/2 phosphorylation western blotting; APP and BACE1 expression; Aβ ELISA; plaque immunostaining; LTP electrophysiology; behavioral cognitive tests; Sp1 promoter analysis","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression with molecular (ERK/APP/BACE1) and functional (LTP, cognition) readouts; single lab","pmids":["31840000"],"is_preprint":false},{"year":2022,"finding":"STAMBPL1 interacts with MKP-1 and stabilizes it via deubiquitination; a genome-wide siRNA DUB screen identified STAMBPL1 as an MKP-1 deubiquitinase. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin by increasing JNK phosphorylation; ectopic MKP-1 overexpression partially rescues STAMBPL1 depletion-induced cisplatin sensitivity.","method":"Genome-wide siRNA DUB library screen; co-immunoprecipitation; deubiquitination assay; cisplatin sensitivity; JNK phosphorylation western blotting; in vitro and xenograft studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen, Co-IP, deubiquitination assay, rescue experiments; multiple orthogonal methods establishing STAMBPL1 as MKP-1 DUB","pmids":["35236965"],"is_preprint":false},{"year":2023,"finding":"DUSP1 directly binds JNK; DUSP1 deficiency leads to aberrant JNK phosphorylation and BAX translocation to mitochondria, promoting mtDNA leakage and cGAS-STING pathway activation. JNK inhibition or BAX inhibition rescues mtDNA leakage; STING knockout mitigates the adverse effects of DUSP1 deficiency in ischemic AKI.","method":"Co-immunoprecipitation of DUSP1-JNK interaction; Dusp1-/- and tubular-specific Sting-/- mice; electron microscopy of mitochondria; mitochondrial membrane potential; BAX translocation western blotting; mtDNA release assay; JNK/BAX inhibitors","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of direct DUSP1-JNK binding, genetic knockout of DUSP1 and STING, multiple mitochondrial readouts, epistasis experiments; rigorous multi-method single study","pmids":["37935658"],"is_preprint":false},{"year":2023,"finding":"DUSP1 interacts with and dephosphorylates VCP at Ser784; the DUSP1 phosphatase domain mediates the DUSP1-VCP interaction on mitochondria, preventing LPS-induced VCP Ser784 phosphorylation. A phosphomimetic VCP mutant abolishes DUSP1-mediated protection of mitochondrial quality control and cardiomyocyte contractility in LPS-induced endotoxemia.","method":"Co-immunoprecipitation; phosphomimetic VCP mutant transfection; DUSP1 transgenic mice; LPS endotoxemia model; mitochondrial dynamics and mitophagy assays; echocardiography; western blotting for phospho-VCP","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP demonstrates direct DUSP1-VCP interaction, phosphomimetic mutant confirms VCP is a DUSP1 phosphatase substrate, in vivo transgenic model with functional cardiac readout; multiple orthogonal methods","pmids":["37464072"],"is_preprint":false},{"year":2023,"finding":"MKP-1 deficiency enhances PFKFB3 expression and phosphorylation in multiple cell types during sepsis, increasing glycolysis and lactate production. Pharmacological inhibition of p38 MAPK (but not JNK) substantially attenuates PFKFB3 expression and lactate production in Mkp-1-deficient macrophages, placing p38 downstream of MKP-1 in regulation of the glycolytic program via PFKFB3.","method":"Mkp-1-/- mice; E. coli sepsis and LPS models; PFKFB3 western blotting; lactate measurement; p38 and JNK inhibitors; mRNA stability assays; multiple cell types and tissues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, pharmacological epistasis (p38 vs JNK), multiple cell types, clear metabolic phenotype; rigorous multi-method study","pmids":["36803959"],"is_preprint":false},{"year":2024,"finding":"CPT1 inhibition reduces ADP-ribosylation of DUSP1 (by decreasing PARP-1 expression), leading to decreased p38 MAPK phosphorylation and stimulation of cardiomyocyte proliferation. In cardiac-specific CPT1a/CPT1b knockout mice, cardiomyocyte proliferation and post-MI cardiac function are improved; these effects are attributed to reduced DUSP1 ADP-ribosylation and consequent p38 inactivation.","method":"Cardiac-specific Cpt1a/Cpt1b knockout mice; DUSP1 ADP-ribosylation assay; p38 MAPK phosphorylation western blotting; cardiomyocyte proliferation assay; post-MI cardiac function echocardiography; si/adRNA DUSP1 and PARP1 manipulation","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and molecular ADP-ribosylation assay; pathway epistasis established; single lab","pmids":["40041918"],"is_preprint":false},{"year":2016,"finding":"In MKP-1-deficient macrophages, LPS-induced MKP-1 absence leads to increased p38 activity and elevated HIF-1α expression (via increased ROS and decreased prolyl hydroxylase expression), which in turn drives increased IL-1β production. p38 inhibition reduces pro-IL-1β and HIF-1α in MKP-1-deficient BMDMs.","method":"MKP-1-deficient bone marrow-derived macrophages; p38 and JNK phosphorylation assays; HIF-1α western blotting; ROS measurement; prolyl hydroxylase mRNA; IL-1β ELISA; pharmacological p38 and HIF-1α inhibitors","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model with multiple biochemical intermediates tested; pharmacological inhibitors confirm p38 pathway; single lab","pmids":["28238855"],"is_preprint":false},{"year":2019,"finding":"Chronic stress in mice increases Mkp-1 expression in the hippocampus via glucocorticoid signaling; increased Mkp-1 debilitates p-CREB and PPARγ, which suppresses epigenetic factors HDAC2 and SUV39H1, which normally repress Mkp-1 transcription, creating a positive feedback loop. MKP-1 hippocampal overexpression is sufficient to induce depression-like behaviors and neuroinflammation; Mkp-1 knockdown in CUMS-exposed rats reverses these effects.","method":"Chronic unpredictable mild stress (CUMS) rat model; viral MKP-1 overexpression and siRNA knockdown in hippocampus; ChIP assay for HDAC2/SUV39H1 at Mkp-1 promoter; p-CREB and ERK/p38 western blotting; behavioral tests; microglial and cytokine analyses","journal":"Molecular neurobiology / Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at Mkp-1 promoter, gain- and loss-of-function in vivo, multiple biochemical and behavioral readouts; single lab","pmids":["31267372","38424085"],"is_preprint":false}],"current_model":"DUSP1/MKP-1 is a nuclear-localized, stress- and growth factor-inducible dual-specificity phosphatase that dephosphorylates both phosphothreonine and phosphotyrosine on ERK1/2, JNK, and p38 MAPKs (confirmed in vitro with active-site Cys258 mutagenesis), acting as a key negative feedback regulator of MAPK signaling; its expression is controlled transcriptionally (by glucocorticoids via promoter elements, by E2F-1, PR, p38-MK2 post-transcriptionally, and by ATF4 whose CRE binding is blocked by PARP-1-mediated PARylation), post-transcriptionally (mRNA stabilization and translation by RNA-binding proteins HuR and NF90), and post-translationally (phosphorylation by ERK2 and PKA stabilizes the protein; acetylation on a key lysine promotes interaction with p38; ubiquitin-proteasome degradation is counteracted by the deubiquitinase STAMBPL1 and by USP49); beyond its canonical MAPK targets, DUSP1 has been found to directly bind and dephosphorylate VCP at Ser784 and to interact with JNK to prevent BAX-mediated mtDNA release; through these mechanisms DUSP1 regulates innate and adaptive immunity, apoptosis, axon branching, adipogenesis, steroidogenesis, glycolysis (via p38→PFKFB3), mitochondrial quality control, and multiple disease contexts including cancer drug resistance, neurodegeneration, and tissue repair."},"narrative":{"mechanistic_narrative":"DUSP1 (CL100/MKP-1) is a dual-specificity phosphatase that serves as the principal inducible negative-feedback regulator of MAPK signaling, dephosphorylating both phosphothreonine and phosphotyrosine residues on ERK, JNK, and p38 in an active-site Cys258-dependent manner [PMID:8390041]. Its substrate engagement is cell-type- and stimulus-specific: in fibroblasts DUSP1 inactivates ERK following EGF, whereas in other lineages this role is filled by PP2A and distinct tyrosine phosphatases [PMID:7780739]. By selectively suppressing JNK or p38, DUSP1 controls divergent outcomes including protection from UV- and cisplatin-induced apoptosis [PMID:9501207, PMID:11064451], oxidative-stress survival [PMID:15059639], BDNF-driven axon branching through JNK-dependent microtubule stabilization [PMID:20935641], adipogenesis via ERK inactivation [PMID:15269202], and steroidogenesis through nuclear and mitochondrial ERK control of the StAR axis [PMID:21558315]. DUSP1 expression is regulated at every level: transcriptionally by glucocorticoids [PMID:11742987], E2F-1 [PMID:17638884], progesterone receptor [PMID:22020934], and ATF4 (whose CRE binding is blocked by PARP-1-mediated PARylation) [PMID:28457938]; post-transcriptionally through p38-MK2 signaling and mRNA stabilization/translation by HuR and NF90 [PMID:16978838, PMID:18490444]; and post-translationally, where ERK2 and PKA phosphorylation and acetylation modulate stability and substrate binding [PMID:18089824, PMID:12506119, PMID:18922786] while ubiquitin-proteasome degradation is opposed by the deubiquitinases STAMBPL1 and USP49 [PMID:35236965, PMID:30246457]. Beyond canonical MAPK targets, DUSP1 directly binds and dephosphorylates VCP at Ser784 on mitochondria to support mitochondrial quality control [PMID:37464072] and binds JNK to prevent BAX-mediated mtDNA release and cGAS-STING activation [PMID:37935658]. Through these mechanisms DUSP1 governs innate and adaptive immunity [PMID:19748894, PMID:25312268], tissue repair [PMID:21987635], glycolytic reprogramming via p38→PFKFB3 [PMID:36803959], and disease contexts including cancer chemoresistance [PMID:16462770, PMID:28319094], neurodegeneration [PMID:23392662, PMID:31840000], and depression-like behavior [PMID:31267372, PMID:38424085].","teleology":[{"year":1993,"claim":"Established the foundational biochemical identity of DUSP1 as a dual-specificity phosphatase that directly inactivates MAP kinase, answering whether CL100 was itself the enzyme acting on both phospho-Thr and phospho-Tyr.","evidence":"In vitro phosphatase assay with recombinant protein, active-site Cys258 mutagenesis, and cell-free Xenopus extract epistasis","pmids":["8390041"],"confidence":"High","gaps":["Did not establish which MAPK family members are physiological substrates in vivo","No structural basis for dual specificity"]},{"year":1995,"claim":"Defined the cell-type specificity and physiological scope of DUSP1's ERK-inactivating role, showing it is not the universal MAPK phosphatase since other phosphatases dominate in some lineages.","evidence":"Cycloheximide depletion, phospho-specific western blotting, and PP2A activity assays across multiple cell lines","pmids":["7780739"],"confidence":"High","gaps":["Did not resolve what determines lineage-specific phosphatase usage","Loss of DUSP1 by cycloheximide is indirect"]},{"year":2000,"claim":"Demonstrated that DUSP1 selectively targets JNK over p38 to suppress stress-induced apoptosis and that enzymatic activity is essential, distinguishing it functionally from ERK-specific phosphatases.","evidence":"Conditional and catalytically inactive mutant overexpression with JNK/p38 kinase and apoptosis assays in UV- and cisplatin-treated cells","pmids":["9501207","11064451"],"confidence":"High","gaps":["Did not explain the molecular basis of JNK substrate selectivity","Endogenous DUSP1 contribution not tested by knockout"]},{"year":2001,"claim":"Revealed that DUSP1 is regulated transcriptionally and through protein stability, with glucocorticoids acting at both the promoter and proteasomal-degradation levels in a cell-type-dependent manner.","evidence":"Promoter reporters, proteasome inhibition, protein stability and ERK kinase assays in mast cells versus fibroblasts","pmids":["11742987"],"confidence":"High","gaps":["The degradation machinery and signal controlling proteasomal turnover were unidentified","Glucocorticoid promoter elements not mapped"]},{"year":2007,"claim":"Mapped specific transcription factors controlling DUSP1 induction, establishing E2F-1, and later PR, as direct promoter-binding activators linking DUSP1 to stress-induced ERK control and proliferation outcomes.","evidence":"ChIP, luciferase reporters, ectopic factor expression with phospho-ERK readout in oxidative-stress and breast cancer cells","pmids":["17638884","22020934"],"confidence":"High","gaps":["Combinatorial control among transcription factors not integrated","Stimulus-specificity of factor recruitment unresolved"]},{"year":2008,"claim":"Defined post-transcriptional and post-translational control layers, showing HuR/NF90 stabilize DUSP1 mRNA and that acetylation reprograms substrate engagement toward p38.","evidence":"RNP-immunoprecipitation, biotinylated RNA pulldown, siRNA of RNA-binding proteins, and acetylation/Co-IP analyses with phospho-MAPK readouts","pmids":["18490444","18922786"],"confidence":"High","gaps":["The acetyltransferase/deacetylase enzymes were not identified","Crosstalk between mRNA stabilization and PTMs unexamined"]},{"year":2009,"claim":"Genetic knockout work established DUSP1 as a physiological in vivo regulator of immunity, showing it is a positive regulator of T cell activation via JNK and NFATc1 control.","evidence":"Mkp-1-/- mice with in vitro T cell assays and in vivo influenza and EAE models","pmids":["19748894"],"confidence":"High","gaps":["Cell-intrinsic versus systemic contributions not fully dissected","Mechanism linking JNK to NFAT translocation incomplete"]},{"year":2010,"claim":"Knockout neurons revealed a developmental role: DUSP1 enables BDNF-induced axon branching through spatiotemporal JNK inactivation that protects microtubules.","evidence":"mkp-1 null neurons, JNK substrate phosphorylation assays, and axon branching quantification","pmids":["20935641"],"confidence":"High","gaps":["Spatial mechanism of localized JNK inactivation unresolved","Identity of microtubule-destabilizing substrates only inferred"]},{"year":2011,"claim":"Defined DUSP1's role in tuning inflammatory timing and tissue repair, showing it restrains p38 to permit the pro- to anti-inflammatory macrophage transition via a p38→miR-21→PTEN→AKT cascade.","evidence":"MKP-1 knockout mice with p38 kinase, miR-21/PTEN/AKT readouts and pharmacological p38 rescue","pmids":["21987635"],"confidence":"High","gaps":["Macrophage-intrinsic versus other cell contributions not separated","Direct vs indirect control of miR-21 induction not resolved"]},{"year":2012,"claim":"Substrate-binding mutant analysis dissected which MAPKs mediate DUSP1 neuroprotection, showing p38 and JNK inhibition additively protect striatal neurons from polyglutamine toxicity independent of ERK.","evidence":"Lentiviral wild-type and selective binding-domain mutants with caspase and MAPK phosphorylation readouts in vitro and in an HD rat model","pmids":["23392662"],"confidence":"High","gaps":["Structural basis of selective MAPK binding not determined","Translatability to chronic disease timescales untested"]},{"year":2016,"claim":"Knockout and knockdown studies expanded DUSP1's mechanistic reach to autophagy and inflammatory gene stability, showing it suppresses the class III PtdIns3K complex via ERK and maintains IRF1-dependent gene expression.","evidence":"DUSP1 knockout MEFs and shRNA with autophagic flux, ULK1/BECN1 phosphorylation, Co-IP, and IRF1 mRNA stability/ChIP assays","pmids":["27459239","27551049"],"confidence":"High","gaps":["Direct versus MAPK-mediated effects on autophagy machinery only partially separated","How DUSP1 stabilizes IRF1 mRNA mechanistically unresolved"]},{"year":2017,"claim":"Established DUSP1 as a determinant of cancer therapy resistance and uncovered ATF4/PARP-1 transcriptional control, linking growth-factor-induced DUSP1 to TKI efficacy thresholds and chemoresistance.","evidence":"Fos/Dusp1 knockout mice, pharmacological DUSP1 inhibition, patient-derived CML xenografts, and in vitro PARylation/ChIP-qPCR of ATF4 at the promoter","pmids":["28319094","28457938","28650468"],"confidence":"High","gaps":["Selectivity and mechanism of pharmacological DUSP1 inhibitors not fully defined","Generalizability of the ATF4-PARP-1 axis across stimuli unclear"]},{"year":2018,"claim":"Identified the deubiquitinases USP49 and (later) STAMBPL1 that counteract DUSP1 degradation and uncovered a DUSP1-Nrf2 antioxidant feedback loop, resolving how DUSP1 protein abundance is set.","evidence":"Co-IP, ubiquitination assays, DUB screen, domain-mapped Nrf2 interaction, ARE reporters and knockout colitis/I-R models","pmids":["30246457","30061089","35236965"],"confidence":"High","gaps":["E3 ligases driving DUSP1 ubiquitination remain unidentified","Hierarchy among competing stability mechanisms unknown"]},{"year":2023,"claim":"Expanded DUSP1's substrate repertoire beyond MAPKs by demonstrating direct dephosphorylation of VCP at Ser784 and JNK-binding control of BAX-mediated mtDNA release/cGAS-STING activation, establishing mitochondrial quality-control functions.","evidence":"Co-IP, phosphomimetic VCP mutant, Dusp1-/- and Sting-/- mice, mitochondrial imaging and mtDNA release assays","pmids":["37464072","37935658"],"confidence":"High","gaps":["Whether VCP dephosphorylation is direct catalysis in vivo not fully isolated from MAPK effects","Stoichiometry and regulation of mitochondrial DUSP1 pool unknown"]},{"year":2023,"claim":"Connected DUSP1 to metabolic reprogramming during sepsis, placing p38 downstream of DUSP1 in control of the glycolytic enzyme PFKFB3 and lactate production.","evidence":"Mkp-1-/- mice, sepsis/LPS models, PFKFB3 western blotting, lactate measurement, and p38 versus JNK pharmacological epistasis","pmids":["36803959"],"confidence":"High","gaps":["Direct transcriptional versus post-transcriptional control of PFKFB3 not separated","Cell-type-specific metabolic contributions incompletely mapped"]},{"year":null,"claim":"It remains unresolved how DUSP1 substrate selectivity (ERK vs JNK vs p38 vs non-MAPK targets such as VCP) is dynamically encoded by localization, PTM state, and binding partners within a single cell.","evidence":"No single study in the corpus integrates the structural, spatial, and PTM determinants of substrate choice","pmids":[],"confidence":"Low","gaps":["No structural model explaining dual-specificity catalysis and substrate switching","E3 ligase(s) for DUSP1 degradation unidentified","Direct non-MAPK catalysis (VCP) not reconstituted in vitro"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,11,27,42]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,23,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19,25]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[25,41,42]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,24,29,45]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6,11,41]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[31]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11,16,32]}],"complexes":[],"partners":["MAPK1","MAPK14","JNK1","VCP","NFE2L2","USP49","STAMBPL1","ATF4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P28562","full_name":"Dual specificity protein phosphatase 1","aliases":["Dual specificity protein phosphatase hVH1","Mitogen-activated protein kinase phosphatase 1","MAP kinase phosphatase 1","MKP-1","Protein-tyrosine phosphatase CL100"],"length_aa":367,"mass_kda":39.3,"function":"Dual specificity phosphatase that dephosphorylates MAP kinase MAPK1/ERK2 on both 'Thr-183' and 'Tyr-185', regulating its activity during the meiotic cell cycle","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P28562/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DUSP1","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DUSP1","total_profiled":1310},"omim":[{"mim_id":"615165","title":"AKIRIN 2; AKIRIN2","url":"https://www.omim.org/entry/615165"},{"mim_id":"608516","title":"MAJOR DEPRESSIVE DISORDER; MDD","url":"https://www.omim.org/entry/608516"},{"mim_id":"606618","title":"DUAL-SPECIFICITY PHOSPHATASE 14; DUSP14","url":"https://www.omim.org/entry/606618"},{"mim_id":"604835","title":"DUAL-SPECIFICITY PHOSPHATASE 12; DUSP12","url":"https://www.omim.org/entry/604835"},{"mim_id":"603069","title":"DUAL-SPECIFICITY PHOSPHATASE 5; DUSP5","url":"https://www.omim.org/entry/603069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DUSP1"},"hgnc":{"alias_symbol":["HVH1","CL100","MKP-1"],"prev_symbol":["PTPN10"]},"alphafold":{"accession":"P28562","domains":[{"cath_id":"3.40.250.10","chopping":"5-137","consensus_level":"high","plddt":88.1298,"start":5,"end":137},{"cath_id":"3.90.190.10","chopping":"174-312","consensus_level":"high","plddt":96.4653,"start":174,"end":312}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28562","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28562-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28562-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DUSP1","jax_strain_url":"https://www.jax.org/strain/search?query=DUSP1"},"sequence":{"accession":"P28562","fasta_url":"https://rest.uniprot.org/uniprotkb/P28562.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28562/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28562"}},"corpus_meta":[{"pmid":"11742987","id":"PMC_11742987","title":"Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11742987","citation_count":390,"is_preprint":false},{"pmid":"8390041","id":"PMC_8390041","title":"The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8390041","citation_count":318,"is_preprint":false},{"pmid":"7780739","id":"PMC_7780739","title":"Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines.","date":"1995","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/7780739","citation_count":318,"is_preprint":false},{"pmid":"21987635","id":"PMC_21987635","title":"p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21987635","citation_count":193,"is_preprint":false},{"pmid":"18490444","id":"PMC_18490444","title":"MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18490444","citation_count":188,"is_preprint":false},{"pmid":"9501207","id":"PMC_9501207","title":"Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9501207","citation_count":154,"is_preprint":false},{"pmid":"27227569","id":"PMC_27227569","title":"Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy.","date":"2016","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27227569","citation_count":137,"is_preprint":false},{"pmid":"20935641","id":"PMC_20935641","title":"The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching.","date":"2010","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20935641","citation_count":129,"is_preprint":false},{"pmid":"11064451","id":"PMC_11064451","title":"CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11064451","citation_count":125,"is_preprint":false},{"pmid":"18089824","id":"PMC_18089824","title":"ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18089824","citation_count":117,"is_preprint":false},{"pmid":"22197448","id":"PMC_22197448","title":"Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease.","date":"2011","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22197448","citation_count":111,"is_preprint":false},{"pmid":"23392662","id":"PMC_23392662","title":"MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23392662","citation_count":97,"is_preprint":false},{"pmid":"12432554","id":"PMC_12432554","title":"Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma.","date":"2002","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12432554","citation_count":94,"is_preprint":false},{"pmid":"28457938","id":"PMC_28457938","title":"PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway.","date":"2017","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28457938","citation_count":90,"is_preprint":false},{"pmid":"20890299","id":"PMC_20890299","title":"DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20890299","citation_count":88,"is_preprint":false},{"pmid":"31840000","id":"PMC_31840000","title":"MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer's disease models.","date":"2019","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31840000","citation_count":87,"is_preprint":false},{"pmid":"28319094","id":"PMC_28319094","title":"Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.","date":"2017","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28319094","citation_count":87,"is_preprint":false},{"pmid":"16462770","id":"PMC_16462770","title":"MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16462770","citation_count":84,"is_preprint":false},{"pmid":"19748894","id":"PMC_19748894","title":"MKP-1 is necessary for T cell activation and function.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19748894","citation_count":73,"is_preprint":false},{"pmid":"18922786","id":"PMC_18922786","title":"Acetylation of MKP-1 and the control of inflammation.","date":"2008","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/18922786","citation_count":72,"is_preprint":false},{"pmid":"30191967","id":"PMC_30191967","title":"DUSP1 recuses diabetic nephropathy via repressing JNK-Mff-mitochondrial fission 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It also suppresses [val12]ras-induced MAP kinase activation in Xenopus oocyte cell-free extracts. Both activities are abolished by mutagenesis of the conserved active-site Cys-258.\",\n      \"method\": \"In vitro phosphatase assay with recombinant protein; active-site mutagenesis (Cys258); cell-free Xenopus oocyte extract epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, active-site mutagenesis, and cell-free epistasis in a single rigorous study; foundational biochemical characterization\",\n      \"pmids\": [\"8390041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The CL100 gene is present as a single locus and maps to human chromosome 5q34, and CL100-homologous sequences are conserved in mouse, chicken, Xenopus, and Drosophila genomes.\",\n      \"method\": \"PCR with human-rodent somatic cell hybrid DNA panel; fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal mapping methods (somatic cell hybrid PCR + FISH), single lab; localization finding without functional consequence\",\n      \"pmids\": [\"8168826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In Swiss 3T3 fibroblasts, depletion of CL100/DUSP1 with cycloheximide blocks inactivation of p42 MAP kinase after EGF stimulation; however, in adipose (3T3-L1), chromaffin (PC12), and endothelial (PAE) cells, rapid p42 MAP kinase inactivation is not catalyzed by CL100 but instead by protein phosphatase 2A (dephosphorylating Thr183) and a distinct protein tyrosine phosphatase (dephosphorylating Tyr185).\",\n      \"method\": \"Cycloheximide depletion; phospho-specific antibody western blotting; vanadate inhibition; PP2A activity assay in cell extracts\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic depletion, phosphatase inhibitors, activity assays) across multiple cell lines; negatively defines cell-type specificity of DUSP1 substrate role\",\n      \"pmids\": [\"7780739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CL100/DUSP1 mRNA is induced ~4-fold in hippocampus and cerebral cortex within 1 h of reperfusion following transient forebrain ischemia in rats, with expression localized to neuronal cells by in situ hybridization.\",\n      \"method\": \"Northern blotting; in situ hybridization histochemistry\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA induction and localization only, single method, no functional consequence established\",\n      \"pmids\": [\"7798338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In human mesangial cells, CL100/DUSP1 gene expression is induced by activation of the ERK cascade (blocked by MEK antagonist PD098059) and also by the p38/SAPK activator anisomycin (partially blocked by SB203580), demonstrating ERK-dependent and ERK-independent transcriptional induction pathways.\",\n      \"method\": \"Northern blotting; MEK inhibitor (PD098059); p38 inhibitor (SB203580); selective ERK agonists\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with two independent inhibitors; single lab\",\n      \"pmids\": [\"9013447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Conditional expression of MKP-1 abolishes UV-induced SAPK/JNK and p38 MAPK activity, inhibits caspase-3 activation, prevents PARP cleavage, and protects U937 cells against UV-induced apoptosis in a dose-dependent manner. Cytoprotection tracks closely with JNK (not p38) inhibition, as SB203580 had no protective effect.\",\n      \"method\": \"Conditional expression system (metallothionein IIa promoter); SAPK/p38 kinase assays; caspase-3 activity; PARP western blot; DNA fragmentation; morphological apoptosis scoring\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional overexpression with dose-response, multiple orthogonal apoptosis readouts, and pharmacological dissection of SAPK vs p38 contributions\",\n      \"pmids\": [\"9501207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Expression of CL100/MKP-1 selectively prevents SAPK/JNK (but not p38) activation by cisplatin and protects cells against cisplatin-induced apoptosis. A catalytically inactive CL100 mutant decreases the IC50 for cisplatin and increases JNK activity, indicating that phosphatase activity is required. ERK-specific phosphatase Pyst1 does not confer protection.\",\n      \"method\": \"Overexpression and dominant-negative mutant transfection; JNK/p38 kinase assays; cell viability (IC50); apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — catalytically inactive mutant confirms requirement for enzymatic activity; multiple kinase substrates tested; orthogonal death assays\",\n      \"pmids\": [\"11064451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Glucagon induces MKP-1 mRNA and protein expression in rat hepatocytes through a cAMP/PKA-dependent mechanism (sensitive to adenylate cyclase and PKA inhibitors), and the induced MKP-1 correlates with antagonization of EGF-induced MAP kinase phosphorylation.\",\n      \"method\": \"Northern/Western blotting; pharmacological inhibitors of adenylate cyclase, PKA, PKG, PKC, Ca2+, MAPKs\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors tested in a single lab; correlative link between MKP-1 induction and MAP kinase dephosphorylation\",\n      \"pmids\": [\"10784592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Glucocorticoids inhibit ERK-1/2 in mast cells via a dual mechanism: (1) transcriptional up-regulation of MKP-1 at the promoter level, and (2) inhibition of proteasomal degradation of MKP-1 triggered by mast cell activation. Both actions are necessary for glucocorticoid-mediated ERK-1/2 inhibition. In NIH-3T3 fibroblasts, glucocorticoids up-regulate MKP-1 but do not block its proteasomal degradation, and consequently cannot inhibit ERK-1/2.\",\n      \"method\": \"Promoter reporter assays; proteasome inhibitor experiments; Western blotting for MKP-1 protein stability; ERK-1/2 kinase assays; cell-type comparison\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (promoter reporters + proteasome inhibition + protein stability + kinase assays) in two cell types; mechanistic dissection of two independent regulatory levels\",\n      \"pmids\": [\"11742987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PKA phosphorylates an MKP-1-GST fusion protein in vitro, and cAMP increases 32P incorporation into immunoprecipitated MKP-1 in H295R adrenocortical cells. PKA or MKP-1 overexpression increases CYP17 promoter activity; antisense silencing of MKP-1 attenuates cAMP-stimulated CYP17 expression, while silencing of ERK1/2 increases it, placing MKP-1 in the cAMP/PKA-ERK1/2-SF-1-CYP17 transcriptional axis.\",\n      \"method\": \"In vitro PKA phosphorylation of MKP-1-GST fusion protein; 32P labeling + immunoprecipitation; transient transfection reporter assays; antisense oligonucleotide knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphorylation reconstitution plus cell-based knockdown and reporter assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12506119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MKP-1 abundance increases during adipocyte differentiation with timing parallel to decreased p42/p44 MAPK activity. Ectopic MKP-1 expression reduces, and MKP-1 depletion (antisense RNA) increases, p42/p44 MAPK activity. Prevention of MKP-1 up-regulation blocks adipocyte differentiation, an effect reversed by MEK inhibitor PD98059, establishing MKP-1-mediated ERK inactivation as essential for adipogenesis.\",\n      \"method\": \"Ectopic overexpression; antisense RNA knockdown; MEK inhibitor rescue (PD98059); kinase activity assays; differentiation markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function, loss-of-function, and pharmacological rescue in a single study; clearly defined cellular phenotype\",\n      \"pmids\": [\"15269202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"H2O2 induces MKP-1 expression in rat mesangial cells via the MAP kinase–AP-1 pathway; selective inhibitors of individual MAPKs or dominant-negative c-jun suppress MKP-1 expression. Wild-type MKP-1 but not catalytically inactive MKP-1CS attenuates H2O2-induced apoptosis, establishing that phosphatase activity is required for cytoprotection against oxidative stress.\",\n      \"method\": \"Northern/Western blotting; MAP kinase inhibitors; dominant-negative c-jun; transfection of wild-type vs. catalytically inactive MKP-1CS; apoptosis assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — active-site mutant controls, pharmacological pathway dissection, and functional apoptosis readout in a single study\",\n      \"pmids\": [\"15059639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In normal VSMC, insulin increases MKP-1 expression and MKP-1 phosphorylation (stabilizing it), leading to MAPK inactivation and inhibition of PDGF-driven cell migration. MKP-1 siRNA abolishes insulin inhibition of migration. Adenoviral MKP-1 expression restores insulin inhibition of migration in diabetic GK rat VSMCs, where MKP-1 induction and phosphorylation are impaired.\",\n      \"method\": \"siRNA knockdown; adenoviral overexpression; PDGF-induced migration assay; MAPK phosphorylation western blotting; proteasome inhibitor experiments; cGK Ialpha adenoviral expression\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA and adenoviral rescue in two cell models with defined migration phenotype; multiple orthogonal approaches\",\n      \"pmids\": [\"15355857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MKP-1 overexpression increases cisplatin resistance in H-1299 NSCLC cells; siRNA knockdown of MKP-1 sensitizes H-460 cells to cisplatin by enhancing JNK and p38 activation and increasing apoptosis. MKP-1 siRNA-expressing H-460 tumor xenografts grew slower and were more cisplatin-sensitive. Knockdown of the related MKP-2 had no effect, indicating specificity.\",\n      \"method\": \"siRNA knockdown; overexpression; cisplatin sensitivity assay; JNK/p38 kinase western blots; xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo gain- and loss-of-function, specificity control with MKP-2 siRNA\",\n      \"pmids\": [\"16462770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p38 MAPK mediates MKP-1 induction at a post-transcriptional level in LPS/PGN-stimulated macrophages: pharmacological inhibition or RNAi knockdown of p38 reduces MKP-1 protein but not mRNA; depletion of the p38 substrate MK2 similarly reduces MKP-1, linking p38-MK2 signaling to MKP-1 post-transcriptional regulation and establishing a positive feedback loop.\",\n      \"method\": \"p38 inhibitor (SB203580); RNAi knockdown of p38 and MK2; Northern and Western blotting; LPS tolerance model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal approaches (pharmacological + RNAi) confirming post-transcriptional regulation; single lab\",\n      \"pmids\": [\"16978838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ERK2 phosphorylates MKP-1 in ovarian cancer cells in response to cisplatin; inhibition of MEK1/2 (U0126) or ERK2 siRNA knockdown decreases cisplatin-induced MKP-1 phosphorylation and reduces MKP-1 protein levels, sensitizing cells to cisplatin. ERK2 knockdown also decreases basal Bcl-2 protein levels.\",\n      \"method\": \"MEK1/2 inhibitor (U0126); siRNA ERK2 knockdown; MKP-1 phosphorylation western blotting; cisplatin sensitivity/apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and siRNA confirmation of ERK2-dependent MKP-1 phosphorylation; single lab, two orthogonal methods\",\n      \"pmids\": [\"18089824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"E2F-1 directly binds to the DUSP1/CL100 promoter at an E2F-1 consensus sequence and a palindromic motif, stimulates DUSP1 promoter activity, and induces DUSP1 expression specifically in response to oxidative stress. E2F-1-induced DUSP1 expression leads to ERK1/2 dephosphorylation and mediates the apoptotic response to oxidative stress.\",\n      \"method\": \"Chromatin immunoprecipitation; luciferase reporter assay; ectopic E2F-1 expression; phospho-ERK western blotting; stress-specific induction experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP plus promoter reporter plus functional epistasis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17638884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MKP-1 is acetylated on a key lysine residue following TLR stimulation. Acetylation of MKP-1 promotes its interaction with substrate p38 MAPK, resulting in p38 dephosphorylation and attenuation of innate immunity.\",\n      \"method\": \"Acetylation analysis post-TLR stimulation; interaction/co-immunoprecipitation of acetylated MKP-1 with p38; p38 phosphorylation assays (reviewed/highlighted from primary study)\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification (acetylation) linked to substrate binding and functional outcome; details from primary study reviewed here; single characterization\",\n      \"pmids\": [\"18922786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HuR and NF90 bind to the AU-rich 3' UTR of MKP-1 mRNA. H2O2 treatment increases association of MKP-1 mRNA with HuR and NF90 while decreasing association with translational repressors TIAR and TIA-1. Silencing HuR or NF90 diminishes MKP-1 mRNA stability; HuR silencing also reduces MKP-1 translation. Loss of MKP-1 in HuR-silenced cells leads to elevated phospho-JNK and phospho-p38 after H2O2.\",\n      \"method\": \"Ribonucleoprotein immunoprecipitation; biotinylated RNA pulldown; siRNA silencing of RNA-binding proteins; mRNA stability assays; western blotting for MKP-1 protein and phospho-MAPKs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple RNA-binding proteins tested, RNP-IP and siRNA knockdown with functional MAPK readout; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18490444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In pituitary gonadotrophs, overexpression of MKP-1 blocks buserelin (GnRH analogue)-induced ERK dephosphorylation in the nucleus, thereby inhibiting Egr-1 expression; MKP-1 dephosphorylates ERK specifically in the nuclear compartment to control downstream transcription factor activity.\",\n      \"method\": \"Overexpression of MKP-1; chromatin immunoprecipitation (Elk-1 binding to Egr-1 gene); dominant-negative transcription factor mutants; kinase activity assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with defined nuclear ERK phosphorylation readout and downstream gene target; single lab\",\n      \"pmids\": [\"18814180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pancreatic reg I protein physically interacts with MKP-1 as demonstrated by yeast two-hybrid assay and confirmed by immunoprecipitation; high intracellular reg I levels are proposed to bind and inactivate MKP-1.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; Northern analysis; microarray\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP confirmation of yeast two-hybrid result; no mutagenesis or in vitro reconstitution; single lab\",\n      \"pmids\": [\"18929742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MKP-1 deficiency in T cells impairs activation, proliferation, and function, associated with enhanced JNK activation and reduced NFATc1 nuclear translocation. MKP-1-/- mice are defective in anti-influenza immunity in vivo and resistant to EAE, demonstrating MKP-1 as a positive regulator of T cell activation.\",\n      \"method\": \"Genetic knockout; in vitro T cell activation assays; JNK phosphorylation western blot; NFATc1 nuclear localization; in vivo influenza and EAE models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple mechanistic (JNK, NFAT) and in vivo immune phenotypes; replicated across two disease models\",\n      \"pmids\": [\"19748894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Acquired cisplatin resistance in OV433 ovarian cancer cells is associated with increased MKP-1 expression; siRNA knockdown of MKP-1 or its pharmacological inhibitor triptolide resensitizes resistant cells to cisplatin and increases apoptosis.\",\n      \"method\": \"siRNA knockdown; triptolide inhibitor; cisplatin sensitivity and apoptosis assays; western blotting\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibitor convergently demonstrate MKP-1's role; single lab\",\n      \"pmids\": [\"19755862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BDNF-induced MKP-1 expression in neurons causes spatiotemporal inactivation of JNK, reducing phosphorylation of JNK substrates that destabilize microtubules. Neurons from mkp-1 null mice cannot produce axon branches in response to BDNF, establishing MKP-1 as essential for BDNF-induced axon branching through JNK dephosphorylation.\",\n      \"method\": \"mkp-1 knockout mice; JNK activity assays; phosphorylation of microtubule-destabilizing JNK substrates; axon branching quantification; BDNF treatment\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with clear cellular phenotype, mechanistic substrate identification, and substrate phosphorylation assays\",\n      \"pmids\": [\"20935641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MKP-1 restricts p38 MAPK activation in macrophages to allow the pro- to anti-inflammatory transition during muscle repair. In MKP-1-deficient macrophages, p38 hyperactivation induces miR-21, which reduces PTEN, thereby extending AKT activation. Temporal p38 inhibition reverses impaired tissue healing in MKP-1-deficient mice.\",\n      \"method\": \"MKP-1 knockout mice; p38 kinase activity assays; miR-21 and PTEN expression; AKT phosphorylation western blotting; p38 inhibitor rescue; tissue repair histology\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple biochemical pathway steps validated (p38→miR-21→PTEN→AKT) and pharmacological rescue; rigorous mechanistic study\",\n      \"pmids\": [\"21987635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hCG/cAMP stimulation in MA-10 Leydig cells rapidly increases MKP-1 mRNA by transcriptional action and accumulates MKP-1 protein in both nuclear and mitochondrial compartments. hCG/cAMP triggers ERK1/2-dependent MKP-1 phosphorylation. MKP-1 overexpression reduces ERK1/2 phosphorylation, StAR promoter activity, StAR mRNA levels, and steroidogenesis; MKP-1 siRNA knockdown produces opposite effects.\",\n      \"method\": \"mRNA and protein time-course analysis; subcellular fractionation; flag-tagged MKP-1 immunoprecipitation; ERK1/2 phosphorylation western blotting; StAR promoter reporter; siRNA knockdown; steroid hormone measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular localization determined by fractionation with functional consequence (ERK-StAR-steroidogenesis axis); gain- and loss-of-function with multiple readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21558315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Progesterone receptor (PR) acts in a ligand-dependent manner through progesterone response elements downstream of the MKP-1 transcription start site and through Sp1 sites to up-regulate MKP-1 promoter activity. PR-induced MKP-1 expression results in ERK1/2 dephosphorylation and inhibits breast cancer cell proliferation; siRNA knockdown of MKP-1 blocks progestin-mediated ERK1/2 dephosphorylation and anti-proliferative effect.\",\n      \"method\": \"ChIP; luciferase reporter assay; siRNA knockdown of MKP-1; phospho-ERK1/2 western blotting; cell proliferation assay; correlation analysis in 30 breast cancer cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP + promoter reporter + siRNA rescue + functional cell proliferation; multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"22020934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MKP-1 (DUSP1) enzymatic activity is required for neuroprotection against polyglutamine-expanded huntingtin toxicity in striatal neurons: phosphatase-domain mutants lose protection. Selective MKP-1 mutants that prevent p38 or JNK binding each partially attenuate neuroprotection, demonstrating that both p38 and JNK inhibition additively contribute to MKP-1-mediated neuroprotection without affecting ERK1/2.\",\n      \"method\": \"Lentiviral overexpression of wild-type and selective binding-domain mutants of MKP-1; caspase-3 activation assay; JNK/p38/ERK phosphorylation western blotting; neuronal cell death counting; in vivo rat lentiviral HD model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic activity mutant controls, selective substrate-binding mutants, in vitro and in vivo models; multiple orthogonal approaches\",\n      \"pmids\": [\"23392662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MKP-1 is essential for RANKL-induced osteoclastogenesis regulation: RANKL induces MKP-1 expression in osteoclast precursors; mkp-1-/- osteoclasts show increased p38 MAPK and JNK activity and hyperactive bone resorption. mkp-1-/- female mice have mildly reduced bone mass, and mkp-1-/- mice show profoundly enhanced osteoclast activation in response to local LPS injection.\",\n      \"method\": \"mkp-1 knockout mice; RANKL stimulation; p38 and JNK phosphorylation western blotting; bone resorption assay; micro-CT bone mass measurement; LPS injection model; osteoclast differentiation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with biochemical MAPK activation data, in vitro resorption assay, and in vivo bone phenotype; multiple methods\",\n      \"pmids\": [\"19762714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DUSP1 deficiency in mice leads to enhanced oral squamous carcinogenesis (earlier onset, advanced histologic stage) with increased proinflammatory IL-1β production and deregulated chemokines. In a syngeneic tumor model, DUSP1-deficient mice form faster-growing tumors via p38-dependent inflammation, abrogated by p38 inhibitor SB203580.\",\n      \"method\": \"Dusp1-/- mice; 4-NQO carcinogenesis model; syngeneic EO771 tumor model; p38 inhibitor rescue; IL-1β ELISA; bone marrow-derived macrophage ex vivo assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological rescue; in vivo and ex vivo mechanistic readouts; p38 pathway epistasis\",\n      \"pmids\": [\"25312268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DUSP1 overexpression maintains IRF1 mRNA and protein stability by switching off MAPKs; MAPK inhibitors and DUSP1 overexpression prolong IRF1 expression by increasing transcription and mRNA/protein stability. DUSP1 silencing increases MAPK phosphorylation and reduces IRF1 protein levels. IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1-dependent genes (e.g., CXCL10), contributing to glucocorticoid insensitivity.\",\n      \"method\": \"DUSP1 overexpression and siRNA silencing; MAPK inhibitors; IRF1 mRNA stability assays; phospho-MAPK western blotting; ChIP at CXCL10 promoter; mRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function, pharmacological confirmation, ChIP, and mRNA stability assays; multiple orthogonal methods in single study\",\n      \"pmids\": [\"27551049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DUSP1 knockdown by shRNA increases both basal and rapamycin-stimulated autophagic flux in ovarian cancer cells and MEFs. DUSP1 knockout promotes phosphorylation of ULK1 (Ser555) and BECN1 (Ser15) and increases association of PIK3C3/VPS34, ATG14, BECN1, and MAPK, activating the class III PtdIns3K complex. DUSP1-mediated suppression of autophagy acts through inactivation of MAPK1-MAPK3 (ERK).\",\n      \"method\": \"shRNA knockdown; DUSP1 knockout MEFs; overexpression; rapamycin treatment; autophagic flux assay; ULK1/BECN1 phosphorylation western blotting; co-immunoprecipitation of autophagy initiation complex components\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, shRNA, and overexpression with multiple biochemical readouts; co-IP of autophagy initiation complex; pharmacological pathway dissection\",\n      \"pmids\": [\"27459239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PARP-1 activation causes PARylation of ATF4, reducing its binding to the CRE sequence in the MKP-1 promoter; in vitro PARylation assay showed reduced ATF4-CRE binding. PARP inhibition or silencing increases ATF4 nuclear binding and MKP-1 expression (confirmed by ChIP-qPCR showing increased ATF4 occupancy at MKP-1 initiation site), leading to JNK/p38 inactivation, reduced mitochondrial ROS, and decreased cell death.\",\n      \"method\": \"PARP-1 inhibitor/siRNA; in vitro PARylation of ATF4 and EMSA; ChIP-qPCR; MKP-1 western blotting; JNK/p38 phosphorylation; mitochondrial membrane potential; ROS assays; multiple human cell lines\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro PARylation reconstitution, ChIP-qPCR of ATF4 occupancy, functional MAPK and mitochondrial readouts; multiple orthogonal methods\",\n      \"pmids\": [\"28457938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic deletion of Fos and Dusp1 suppresses BCR-ABL-driven CML tumor growth in mice. Pharmacological inhibition of DUSP1 (combined with BCR-ABL TKI and c-FOS inhibition) eradicates minimal residual disease in multiple in vivo and xenograft CML models, indicating that growth-factor-induced DUSP1 expression sets the threshold of TKI efficacy and confers intrinsic resistance.\",\n      \"method\": \"Genetic deletion (Fos/Dusp1 knockout mice); pharmacological DUSP1 inhibition; BCR-ABL mouse model; xenograft with patient-derived CML cells; in vivo tumor growth assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion plus pharmacological inhibition; in vivo and xenograft models with patient-derived cells; replicated across multiple tumor models\",\n      \"pmids\": [\"28319094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MKP-1 suppresses PARP-1 degradation by inhibiting JNK1/2, which promotes PARP-1 ubiquitination: MKP-1 overexpression increases PARP-1 and PAR protein levels; silencing MKP-1 promotes PARP-1 ubiquitination and reduces PARP-1 levels; silencing JNK1/2 decreases PARP-1 ubiquitination. PARP activity inhibition restores cisplatin sensitivity in MKP-1-overexpressing cells.\",\n      \"method\": \"MKP-1 overexpression and siRNA; JNK1/2 siRNA; ubiquitination assay; PARP-1 protein western blotting; cisplatin sensitivity assay; pharmacological PARP inhibitor\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (siRNA) dissection of MKP-1→JNK→PARP-1 ubiquitination axis with functional cisplatin resistance readout; multiple orthogonal methods\",\n      \"pmids\": [\"28650468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mkp-1 directly interacts with the DIDLID motif of Nrf2, increasing Nrf2 stability and positively regulating constitutive and LPS-inducible Nrf2/Ho-1 expression. Conversely, Nrf2 activates Mkp-1 transcription through antioxidant response elements in the Mkp-1 promoter, forming a positive feedback loop that protects against colonic inflammation.\",\n      \"method\": \"Co-immunoprecipitation of Mkp-1-Nrf2 interaction; Mkp-1-/- mice in DSS colitis model; Nrf2/Ho-1 western blotting; ARE promoter reporter for Mkp-1; colitis histology\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction by Co-IP, domain-specific interaction (DIDLID motif), promoter ARE reporter, in vivo knockout model; multiple orthogonal methods\",\n      \"pmids\": [\"30061089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DUSP1 deficiency activates JNK, which promotes Mff phosphorylation and excessive mitochondrial fission, leading to mitochondrial oxidative stress, mPTP opening, proapoptotic protein leakage, and mitochondria-dependent apoptosis in diabetic nephropathy. DUSP1 overexpression interrupts Mff-related mitochondrial fission and reduces hyperglycemia-mediated mitochondrial damage.\",\n      \"method\": \"DUSP1 overexpression and knockdown; JNK phosphorylation western blotting; Mff phosphorylation; mitochondrial morphology assays; mPTP opening; apoptosis assays; diabetic cell and animal models\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with DUSP1 and mechanistic pathway dissection (JNK→Mff→fission); single lab\",\n      \"pmids\": [\"30191967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP49 deubiquitinates DUSP1, stabilizing DUSP1 protein expression; co-immunoprecipitation confirms direct interaction between USP49 and DUSP1. USP49 overexpression increases DUSP1 levels, reduces JNK1/2 activation, and protects cardiomyocytes against I/R-induced apoptosis; these effects require DUSP1-mediated JNK dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; siRNA and overexpression; JNK1/2 western blotting; cell viability and apoptosis assays; in vivo rat I/R model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay confirms USP49-DUSP1 interaction and deubiquitination; functional I/R phenotype; single lab\",\n      \"pmids\": [\"30246457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP1 loss in the cochlea of Dusp1-/- mice causes premature progressive hearing loss, hair cell death, spiral neuron degeneration, macrophage infiltration, imbalanced redox status, and dysregulated cytokines, establishing DUSP1 as essential for cochlear homeostasis during aging-related stress responses.\",\n      \"method\": \"Dusp1-/- knockout mice; auditory brainstem response (ABR); histology of cochlear hair cells and spiral neurons; macrophage infiltration quantification; redox status assays; cytokine expression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with electrophysiological, histological, and biochemical readouts in a rigorous study\",\n      \"pmids\": [\"30938680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Upregulation of MKP-1 in APP/PS1 transgenic AD mice inhibits APP and BACE1 expression by inactivating the ERK1/2/MAPK signaling pathway, reducing Aβ production and plaque formation, and improving hippocampal LTP and cognitive deficits. Aβ-induced Sp1 activation decreases MKP-1 expression via Sp1 cis-acting binding elements in the MKP-1 promoter.\",\n      \"method\": \"MKP-1 overexpression in APP/PS1 transgenic mice; ERK1/2 phosphorylation western blotting; APP and BACE1 expression; Aβ ELISA; plaque immunostaining; LTP electrophysiology; behavioral cognitive tests; Sp1 promoter analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression with molecular (ERK/APP/BACE1) and functional (LTP, cognition) readouts; single lab\",\n      \"pmids\": [\"31840000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAMBPL1 interacts with MKP-1 and stabilizes it via deubiquitination; a genome-wide siRNA DUB screen identified STAMBPL1 as an MKP-1 deubiquitinase. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin by increasing JNK phosphorylation; ectopic MKP-1 overexpression partially rescues STAMBPL1 depletion-induced cisplatin sensitivity.\",\n      \"method\": \"Genome-wide siRNA DUB library screen; co-immunoprecipitation; deubiquitination assay; cisplatin sensitivity; JNK phosphorylation western blotting; in vitro and xenograft studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen, Co-IP, deubiquitination assay, rescue experiments; multiple orthogonal methods establishing STAMBPL1 as MKP-1 DUB\",\n      \"pmids\": [\"35236965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUSP1 directly binds JNK; DUSP1 deficiency leads to aberrant JNK phosphorylation and BAX translocation to mitochondria, promoting mtDNA leakage and cGAS-STING pathway activation. JNK inhibition or BAX inhibition rescues mtDNA leakage; STING knockout mitigates the adverse effects of DUSP1 deficiency in ischemic AKI.\",\n      \"method\": \"Co-immunoprecipitation of DUSP1-JNK interaction; Dusp1-/- and tubular-specific Sting-/- mice; electron microscopy of mitochondria; mitochondrial membrane potential; BAX translocation western blotting; mtDNA release assay; JNK/BAX inhibitors\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of direct DUSP1-JNK binding, genetic knockout of DUSP1 and STING, multiple mitochondrial readouts, epistasis experiments; rigorous multi-method single study\",\n      \"pmids\": [\"37935658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUSP1 interacts with and dephosphorylates VCP at Ser784; the DUSP1 phosphatase domain mediates the DUSP1-VCP interaction on mitochondria, preventing LPS-induced VCP Ser784 phosphorylation. A phosphomimetic VCP mutant abolishes DUSP1-mediated protection of mitochondrial quality control and cardiomyocyte contractility in LPS-induced endotoxemia.\",\n      \"method\": \"Co-immunoprecipitation; phosphomimetic VCP mutant transfection; DUSP1 transgenic mice; LPS endotoxemia model; mitochondrial dynamics and mitophagy assays; echocardiography; western blotting for phospho-VCP\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP demonstrates direct DUSP1-VCP interaction, phosphomimetic mutant confirms VCP is a DUSP1 phosphatase substrate, in vivo transgenic model with functional cardiac readout; multiple orthogonal methods\",\n      \"pmids\": [\"37464072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MKP-1 deficiency enhances PFKFB3 expression and phosphorylation in multiple cell types during sepsis, increasing glycolysis and lactate production. Pharmacological inhibition of p38 MAPK (but not JNK) substantially attenuates PFKFB3 expression and lactate production in Mkp-1-deficient macrophages, placing p38 downstream of MKP-1 in regulation of the glycolytic program via PFKFB3.\",\n      \"method\": \"Mkp-1-/- mice; E. coli sepsis and LPS models; PFKFB3 western blotting; lactate measurement; p38 and JNK inhibitors; mRNA stability assays; multiple cell types and tissues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, pharmacological epistasis (p38 vs JNK), multiple cell types, clear metabolic phenotype; rigorous multi-method study\",\n      \"pmids\": [\"36803959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1 inhibition reduces ADP-ribosylation of DUSP1 (by decreasing PARP-1 expression), leading to decreased p38 MAPK phosphorylation and stimulation of cardiomyocyte proliferation. In cardiac-specific CPT1a/CPT1b knockout mice, cardiomyocyte proliferation and post-MI cardiac function are improved; these effects are attributed to reduced DUSP1 ADP-ribosylation and consequent p38 inactivation.\",\n      \"method\": \"Cardiac-specific Cpt1a/Cpt1b knockout mice; DUSP1 ADP-ribosylation assay; p38 MAPK phosphorylation western blotting; cardiomyocyte proliferation assay; post-MI cardiac function echocardiography; si/adRNA DUSP1 and PARP1 manipulation\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and molecular ADP-ribosylation assay; pathway epistasis established; single lab\",\n      \"pmids\": [\"40041918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In MKP-1-deficient macrophages, LPS-induced MKP-1 absence leads to increased p38 activity and elevated HIF-1α expression (via increased ROS and decreased prolyl hydroxylase expression), which in turn drives increased IL-1β production. p38 inhibition reduces pro-IL-1β and HIF-1α in MKP-1-deficient BMDMs.\",\n      \"method\": \"MKP-1-deficient bone marrow-derived macrophages; p38 and JNK phosphorylation assays; HIF-1α western blotting; ROS measurement; prolyl hydroxylase mRNA; IL-1β ELISA; pharmacological p38 and HIF-1α inhibitors\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model with multiple biochemical intermediates tested; pharmacological inhibitors confirm p38 pathway; single lab\",\n      \"pmids\": [\"28238855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chronic stress in mice increases Mkp-1 expression in the hippocampus via glucocorticoid signaling; increased Mkp-1 debilitates p-CREB and PPARγ, which suppresses epigenetic factors HDAC2 and SUV39H1, which normally repress Mkp-1 transcription, creating a positive feedback loop. MKP-1 hippocampal overexpression is sufficient to induce depression-like behaviors and neuroinflammation; Mkp-1 knockdown in CUMS-exposed rats reverses these effects.\",\n      \"method\": \"Chronic unpredictable mild stress (CUMS) rat model; viral MKP-1 overexpression and siRNA knockdown in hippocampus; ChIP assay for HDAC2/SUV39H1 at Mkp-1 promoter; p-CREB and ERK/p38 western blotting; behavioral tests; microglial and cytokine analyses\",\n      \"journal\": \"Molecular neurobiology / Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at Mkp-1 promoter, gain- and loss-of-function in vivo, multiple biochemical and behavioral readouts; single lab\",\n      \"pmids\": [\"31267372\", \"38424085\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DUSP1/MKP-1 is a nuclear-localized, stress- and growth factor-inducible dual-specificity phosphatase that dephosphorylates both phosphothreonine and phosphotyrosine on ERK1/2, JNK, and p38 MAPKs (confirmed in vitro with active-site Cys258 mutagenesis), acting as a key negative feedback regulator of MAPK signaling; its expression is controlled transcriptionally (by glucocorticoids via promoter elements, by E2F-1, PR, p38-MK2 post-transcriptionally, and by ATF4 whose CRE binding is blocked by PARP-1-mediated PARylation), post-transcriptionally (mRNA stabilization and translation by RNA-binding proteins HuR and NF90), and post-translationally (phosphorylation by ERK2 and PKA stabilizes the protein; acetylation on a key lysine promotes interaction with p38; ubiquitin-proteasome degradation is counteracted by the deubiquitinase STAMBPL1 and by USP49); beyond its canonical MAPK targets, DUSP1 has been found to directly bind and dephosphorylate VCP at Ser784 and to interact with JNK to prevent BAX-mediated mtDNA release; through these mechanisms DUSP1 regulates innate and adaptive immunity, apoptosis, axon branching, adipogenesis, steroidogenesis, glycolysis (via p38→PFKFB3), mitochondrial quality control, and multiple disease contexts including cancer drug resistance, neurodegeneration, and tissue repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DUSP1 (CL100/MKP-1) is a dual-specificity phosphatase that serves as the principal inducible negative-feedback regulator of MAPK signaling, dephosphorylating both phosphothreonine and phosphotyrosine residues on ERK, JNK, and p38 in an active-site Cys258-dependent manner [#0]. Its substrate engagement is cell-type- and stimulus-specific: in fibroblasts DUSP1 inactivates ERK following EGF, whereas in other lineages this role is filled by PP2A and distinct tyrosine phosphatases [#2]. By selectively suppressing JNK or p38, DUSP1 controls divergent outcomes including protection from UV- and cisplatin-induced apoptosis [#5, #6], oxidative-stress survival [#11], BDNF-driven axon branching through JNK-dependent microtubule stabilization [#23], adipogenesis via ERK inactivation [#10], and steroidogenesis through nuclear and mitochondrial ERK control of the StAR axis [#25]. DUSP1 expression is regulated at every level: transcriptionally by glucocorticoids [#8], E2F-1 [#16], progesterone receptor [#26], and ATF4 (whose CRE binding is blocked by PARP-1-mediated PARylation) [#32]; post-transcriptionally through p38-MK2 signaling and mRNA stabilization/translation by HuR and NF90 [#14, #18]; and post-translationally, where ERK2 and PKA phosphorylation and acetylation modulate stability and substrate binding [#15, #9, #17] while ubiquitin-proteasome degradation is opposed by the deubiquitinases STAMBPL1 and USP49 [#40, #37]. Beyond canonical MAPK targets, DUSP1 directly binds and dephosphorylates VCP at Ser784 on mitochondria to support mitochondrial quality control [#42] and binds JNK to prevent BAX-mediated mtDNA release and cGAS-STING activation [#41]. Through these mechanisms DUSP1 governs innate and adaptive immunity [#21, #29], tissue repair [#24], glycolytic reprogramming via p38\\u2192PFKFB3 [#43], and disease contexts including cancer chemoresistance [#13, #33], neurodegeneration [#27, #39], and depression-like behavior [#46].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the foundational biochemical identity of DUSP1 as a dual-specificity phosphatase that directly inactivates MAP kinase, answering whether CL100 was itself the enzyme acting on both phospho-Thr and phospho-Tyr.\",\n      \"evidence\": \"In vitro phosphatase assay with recombinant protein, active-site Cys258 mutagenesis, and cell-free Xenopus extract epistasis\",\n      \"pmids\": [\"8390041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which MAPK family members are physiological substrates in vivo\", \"No structural basis for dual specificity\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the cell-type specificity and physiological scope of DUSP1's ERK-inactivating role, showing it is not the universal MAPK phosphatase since other phosphatases dominate in some lineages.\",\n      \"evidence\": \"Cycloheximide depletion, phospho-specific western blotting, and PP2A activity assays across multiple cell lines\",\n      \"pmids\": [\"7780739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve what determines lineage-specific phosphatase usage\", \"Loss of DUSP1 by cycloheximide is indirect\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that DUSP1 selectively targets JNK over p38 to suppress stress-induced apoptosis and that enzymatic activity is essential, distinguishing it functionally from ERK-specific phosphatases.\",\n      \"evidence\": \"Conditional and catalytically inactive mutant overexpression with JNK/p38 kinase and apoptosis assays in UV- and cisplatin-treated cells\",\n      \"pmids\": [\"9501207\", \"11064451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain the molecular basis of JNK substrate selectivity\", \"Endogenous DUSP1 contribution not tested by knockout\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed that DUSP1 is regulated transcriptionally and through protein stability, with glucocorticoids acting at both the promoter and proteasomal-degradation levels in a cell-type-dependent manner.\",\n      \"evidence\": \"Promoter reporters, proteasome inhibition, protein stability and ERK kinase assays in mast cells versus fibroblasts\",\n      \"pmids\": [\"11742987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The degradation machinery and signal controlling proteasomal turnover were unidentified\", \"Glucocorticoid promoter elements not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped specific transcription factors controlling DUSP1 induction, establishing E2F-1, and later PR, as direct promoter-binding activators linking DUSP1 to stress-induced ERK control and proliferation outcomes.\",\n      \"evidence\": \"ChIP, luciferase reporters, ectopic factor expression with phospho-ERK readout in oxidative-stress and breast cancer cells\",\n      \"pmids\": [\"17638884\", \"22020934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial control among transcription factors not integrated\", \"Stimulus-specificity of factor recruitment unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined post-transcriptional and post-translational control layers, showing HuR/NF90 stabilize DUSP1 mRNA and that acetylation reprograms substrate engagement toward p38.\",\n      \"evidence\": \"RNP-immunoprecipitation, biotinylated RNA pulldown, siRNA of RNA-binding proteins, and acetylation/Co-IP analyses with phospho-MAPK readouts\",\n      \"pmids\": [\"18490444\", \"18922786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The acetyltransferase/deacetylase enzymes were not identified\", \"Crosstalk between mRNA stabilization and PTMs unexamined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic knockout work established DUSP1 as a physiological in vivo regulator of immunity, showing it is a positive regulator of T cell activation via JNK and NFATc1 control.\",\n      \"evidence\": \"Mkp-1-/- mice with in vitro T cell assays and in vivo influenza and EAE models\",\n      \"pmids\": [\"19748894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-intrinsic versus systemic contributions not fully dissected\", \"Mechanism linking JNK to NFAT translocation incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout neurons revealed a developmental role: DUSP1 enables BDNF-induced axon branching through spatiotemporal JNK inactivation that protects microtubules.\",\n      \"evidence\": \"mkp-1 null neurons, JNK substrate phosphorylation assays, and axon branching quantification\",\n      \"pmids\": [\"20935641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial mechanism of localized JNK inactivation unresolved\", \"Identity of microtubule-destabilizing substrates only inferred\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined DUSP1's role in tuning inflammatory timing and tissue repair, showing it restrains p38 to permit the pro- to anti-inflammatory macrophage transition via a p38\\u2192miR-21\\u2192PTEN\\u2192AKT cascade.\",\n      \"evidence\": \"MKP-1 knockout mice with p38 kinase, miR-21/PTEN/AKT readouts and pharmacological p38 rescue\",\n      \"pmids\": [\"21987635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Macrophage-intrinsic versus other cell contributions not separated\", \"Direct vs indirect control of miR-21 induction not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Substrate-binding mutant analysis dissected which MAPKs mediate DUSP1 neuroprotection, showing p38 and JNK inhibition additively protect striatal neurons from polyglutamine toxicity independent of ERK.\",\n      \"evidence\": \"Lentiviral wild-type and selective binding-domain mutants with caspase and MAPK phosphorylation readouts in vitro and in an HD rat model\",\n      \"pmids\": [\"23392662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selective MAPK binding not determined\", \"Translatability to chronic disease timescales untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Knockout and knockdown studies expanded DUSP1's mechanistic reach to autophagy and inflammatory gene stability, showing it suppresses the class III PtdIns3K complex via ERK and maintains IRF1-dependent gene expression.\",\n      \"evidence\": \"DUSP1 knockout MEFs and shRNA with autophagic flux, ULK1/BECN1 phosphorylation, Co-IP, and IRF1 mRNA stability/ChIP assays\",\n      \"pmids\": [\"27459239\", \"27551049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus MAPK-mediated effects on autophagy machinery only partially separated\", \"How DUSP1 stabilizes IRF1 mRNA mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established DUSP1 as a determinant of cancer therapy resistance and uncovered ATF4/PARP-1 transcriptional control, linking growth-factor-induced DUSP1 to TKI efficacy thresholds and chemoresistance.\",\n      \"evidence\": \"Fos/Dusp1 knockout mice, pharmacological DUSP1 inhibition, patient-derived CML xenografts, and in vitro PARylation/ChIP-qPCR of ATF4 at the promoter\",\n      \"pmids\": [\"28319094\", \"28457938\", \"28650468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity and mechanism of pharmacological DUSP1 inhibitors not fully defined\", \"Generalizability of the ATF4-PARP-1 axis across stimuli unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the deubiquitinases USP49 and (later) STAMBPL1 that counteract DUSP1 degradation and uncovered a DUSP1-Nrf2 antioxidant feedback loop, resolving how DUSP1 protein abundance is set.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, DUB screen, domain-mapped Nrf2 interaction, ARE reporters and knockout colitis/I-R models\",\n      \"pmids\": [\"30246457\", \"30061089\", \"35236965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases driving DUSP1 ubiquitination remain unidentified\", \"Hierarchy among competing stability mechanisms unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded DUSP1's substrate repertoire beyond MAPKs by demonstrating direct dephosphorylation of VCP at Ser784 and JNK-binding control of BAX-mediated mtDNA release/cGAS-STING activation, establishing mitochondrial quality-control functions.\",\n      \"evidence\": \"Co-IP, phosphomimetic VCP mutant, Dusp1-/- and Sting-/- mice, mitochondrial imaging and mtDNA release assays\",\n      \"pmids\": [\"37464072\", \"37935658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VCP dephosphorylation is direct catalysis in vivo not fully isolated from MAPK effects\", \"Stoichiometry and regulation of mitochondrial DUSP1 pool unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected DUSP1 to metabolic reprogramming during sepsis, placing p38 downstream of DUSP1 in control of the glycolytic enzyme PFKFB3 and lactate production.\",\n      \"evidence\": \"Mkp-1-/- mice, sepsis/LPS models, PFKFB3 western blotting, lactate measurement, and p38 versus JNK pharmacological epistasis\",\n      \"pmids\": [\"36803959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional versus post-transcriptional control of PFKFB3 not separated\", \"Cell-type-specific metabolic contributions incompletely mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DUSP1 substrate selectivity (ERK vs JNK vs p38 vs non-MAPK targets such as VCP) is dynamically encoded by localization, PTM state, and binding partners within a single cell.\",\n      \"evidence\": \"No single study in the corpus integrates the structural, spatial, and PTM determinants of substrate choice\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model explaining dual-specificity catalysis and substrate switching\", \"E3 ligase(s) for DUSP1 degradation unidentified\", \"Direct non-MAPK catalysis (VCP) not reconstituted in vitro\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 11, 27, 42]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 23, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19, 25]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [25, 41, 42]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 24, 29, 45]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6, 11, 41]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11, 16, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAPK1\", \"MAPK14\", \"JNK1\", \"VCP\", \"NFE2L2\", \"USP49\", \"STAMBPL1\", \"ATF4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}