{"gene":"DUSP10","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1999,"finding":"MKP-5 (DUSP10) is a dual-specificity phosphatase that binds to p38 and SAPK/JNK but not MAPK/ERK, and selectively inactivates p38 and SAPK/JNK (with p38 as preferred substrate), while being present evenly in both cytoplasm and nucleus.","method":"Binding assays, in vitro phosphatase activity assays, subcellular fractionation/immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct enzymatic activity demonstrated in vitro, substrate specificity confirmed by binding and dephosphorylation assays, replicated independently in same year by Theodosiou et al. (PMID:10597297)","pmids":["10391943","10597297"],"is_preprint":false},{"year":1999,"finding":"MKP5 substrate selectivity (p38 ≈ JNK/SAPK >> ERK) is determined at least in part at the level of substrate binding, as demonstrated by immunoprecipitation of endogenous MAPKs with catalytically inactive MKP5.","method":"Immunoprecipitation using catalytically inactive MKP5 mutant expressed in mammalian cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytically inactive mutant used for binding specificity, single lab, two complementary approaches (IP and activity assay)","pmids":["10597297"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of the MAP kinase binding domain (BD) and catalytic domain (CD) of human MKP5 were solved at up to 2.2 Å resolution. The BD of MKP5 differs dramatically from MKP3: the cluster of positively charged residues critical for MAPK binding is alpha-helical in MKP5 (vs. loop/beta-strand in MKP3), located 25 Å apart, consistent with distinct substrate preferences. The CD is in an active conformation.","method":"X-ray crystallography","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution with structural comparison to functional implications for substrate specificity","pmids":["17400920"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of p38α in complex with the MAPK binding domain (KBD) of MKP5 at 2.7 Å resolution revealed a bipartite binding mode in which two distinct helical regions of KBD engage the p38α docking site (on the back of the active site), distinct from the classical linear docking motif. The KBD of MKP7 closely resembles MKP5 KBD, suggesting this mechanism is conserved in the cytoplasmic p38/JNK-specific MKP subgroup.","method":"X-ray crystallography (2.7 Å resolution crystal structure of p38α–MKP5 KBD complex)","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure with functional validation of a novel bipartite docking mechanism","pmids":["22375048"],"is_preprint":false},{"year":2009,"finding":"MKP5 has a non-redundant role in restraining p38 MAPK-mediated neutrophil superoxide production: Mkp5-/- (but not Mkp1-/-) mice showed augmented p38 MAPK activation and increased superoxide generation in neutrophils; p38 MAPK phosphorylated p47phox, and p47phox gene deletion ablated LPS-induced vascular injury in Mkp5-/- mice.","method":"Genetic knockout mouse model, neutrophil depletion, adoptive transfer, p38 MAPK inhibitor (SB203580), p47phox phosphorylation assay, in vitro kinase assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including KO mice, adoptive transfer, pharmacological inhibition, and in vitro kinase assay demonstrating mechanistic pathway","pmids":["19696743"],"is_preprint":false},{"year":2013,"finding":"MKP-5 (DUSP10) negatively regulates muscle stem cell function by controlling JNK (to coordinate proliferation) and p38 MAPK (to control differentiation); genetic loss of Mkp5 improved regenerative myogenesis and attenuated dystrophic muscle phenotype in mdx mice.","method":"Genetic knockout mouse model (Mkp5-/- and mdx/Mkp5-/- double-knockout), primary satellite cell assays, MAPK signaling analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with specific phenotypic readout in two disease-relevant mouse models, dual MAPK pathway dissection","pmids":["23543058"],"is_preprint":false},{"year":2014,"finding":"mTORC2 binds DUSP10 and phosphorylates it on serine residues 224 and 230, blocking DUSP10 turnover (stabilizing it), resulting in inactivation of p38 MAPK signaling. Nonphosphorylatable or phosphomimetic DUSP10 mutants confer differential mTOR kinase inhibitor responses in GBM cells.","method":"Co-immunoprecipitation, site-directed mutagenesis, ectopic overexpression of DUSP10 mutants, in vitro and xenograft cellular assays","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and mutagenesis in a single lab, supported by in vivo xenograft data","pmids":["25568665"],"is_preprint":false},{"year":2015,"finding":"DUSP10 knockout mice exhibited increased intestinal epithelial cell (IEC) proliferation and migration associated with increased ERK1/2 activation and KLF5 expression, and developed more colon tumors in the AOM/DSS model, identifying DUSP10 as a negative regulator of IEC growth and a colorectal cancer suppressor.","method":"Genetic knockout mouse model, AOM/DSS colorectal cancer model, MAPK phosphorylation analysis, cell proliferation and migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined phenotypic readout and MAPK mechanistic link, single lab","pmids":["25772234"],"is_preprint":false},{"year":2015,"finding":"AGR2 oncoprotein upregulates DUSP10, which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation, defining a novel AGR2→DUSP10→p38→p53 regulatory axis in human cancer cells.","method":"Gene expression manipulation, western blot for p38 MAPK and p53 phosphorylation, pathway analysis in breast cancer cells","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway established by loss/gain-of-function with phosphorylation readouts in single lab","pmids":["26733232"],"is_preprint":false},{"year":2016,"finding":"High molecular weight hyaluronic acid (HA) induces DUSP10/MKP5 expression via CD44 binding, which inhibits TNF-α-induced p38 MAPK and JNK phosphorylation and AP-1 transcriptional activity, thereby suppressing MMP13 expression in chondrocytes.","method":"CD44 function-blocking antibody, siRNA knockdown, reporter assay, western blotting, immunofluorescence in human chondrocytic C28/I2 cells","journal":"Journal of orthopaedic research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic pathway established with blocking antibody, siRNA, and reporter assay in single lab","pmids":["27101204"],"is_preprint":false},{"year":2017,"finding":"Loss of MKP-5 in skeletal muscle during regeneration activates STAT3/Bcl-2 anti-apoptotic signaling, increases catalase expression improving anti-oxidant capacity, and reduces mitochondrial apoptotic pathway activation, promoting myofiber survival.","method":"Genetic knockout mice, cardiotoxin injury model, TUNEL assay, western blot for STAT3, Bcl-2, and apoptosis markers","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with mechanistic pathway defined, single lab","pmids":["29047406"],"is_preprint":false},{"year":2017,"finding":"TP53INP1 downregulation promotes HCC metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway; the DUSP10 promoter contains p73 binding sites directly implicated in modulation by TP53INP1.","method":"Mechanistic investigations in HCC cell lines, promoter analysis, ERK pathway activation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway placement by epistasis-type experiments in cell lines, single lab","pmids":["28674078"],"is_preprint":false},{"year":2017,"finding":"Andrographolide inhibits hypoxia-induced HIF-1α and ET-1 expression through a HO-1/CO/cGMP/MKP-5 pathway: andrographolide induces HO-1 and MKP-5 expression; CO and cGMP increase MKP-5 expression; MKP-5 silencing abrogates andrographolide's suppression of p38 MAPK activation and HIF-1α expression.","method":"siRNA knockdown, pharmacological inhibitors, HO-1 inhibitor, guanylate cyclase inhibitor, western blotting in EA.hy926 endothelial cells","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway defined by siRNA and pharmacological inhibitors, single lab with multiple approaches","pmids":["29165873"],"is_preprint":false},{"year":2018,"finding":"DUSP10 is expressed in ST2hi pathogenic Th2 cells but not ILC2; DUSP10 inhibits IL-33-induced cytokine production in Th2 cells by dephosphorylating and inactivating p38 MAPK, resulting in reduced GATA3 activity. Dusp10 deletion renders ST2hi Th2 cells capable of producing IL-5 upon IL-33 stimulation.","method":"Genetic knockout mice, DUSP10 overexpression in Th2 cells, p38 MAPK phosphorylation assays, GATA3 activity assays, cytokine production measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and overexpression with defined mechanistic pathway (DUSP10→p38→GATA3→IL-5), multiple orthogonal approaches in single rigorous study","pmids":["30315197"],"is_preprint":false},{"year":2019,"finding":"MKP-5-deficient mice are protected from bleomycin-induced pulmonary fibrosis; MKP-5-deficient lung fibroblasts show enhanced p38 MAPK activity, impaired Smad3 phosphorylation, increased Smad7 levels, and decreased fibrogenic gene expression, coupling MKP-5 to the TGF-β1 signaling machinery.","method":"Genetic knockout mice, bleomycin fibrosis model, fibroblast cultures, western blot for Smad3/Smad7/p38, hydroxyproline assay, fibrogenic gene expression","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with mechanistic readouts in primary fibroblasts, single lab","pmids":["31483681"],"is_preprint":false},{"year":2019,"finding":"DUSP10 negatively regulates inflammatory cytokine production in bronchial epithelial cells in response to IL-1β stimulation (alone and in combination with rhinovirus), without affecting rhinovirus replication, as demonstrated by siRNA-mediated knockdown.","method":"siRNA knockdown, rhinovirus infection model, cytokine production assays in primary bronchial epithelial cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA loss-of-function with specific cytokine phenotype, single lab","pmids":["30333178"],"is_preprint":false},{"year":2019,"finding":"DUSP10 co-immunoprecipitates with YAP1, and their interaction is dependent on YAP1 Ser397. DUSP10 nuclear localization increases at high cell density and correlates with YAP1 activity, suggesting DUSP10 acts as a regulator of YAP1 in colorectal cancer.","method":"Co-immunoprecipitation, DUSP10 overexpression/silencing, xenograft mouse model, Drosophila transgenic model, nuclear localization imaging","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP with mutagenesis of YAP1 binding site, supported by in vivo data, single lab","pmids":["31717606"],"is_preprint":false},{"year":2020,"finding":"An allosteric binding pocket on MKP5 (distinct from the active site) was identified; a small-molecule inhibitor binding to this pocket collapses the MKP5 active site and limits MAPK binding. Crystal structure of MKP5 in complex with the inhibitor was solved. The inhibitor recapitulates MKP5 deficiency (activating p38 MAPK and JNK) and blocks TGF-β1-mediated Smad2 phosphorylation in muscle.","method":"X-ray crystallography (MKP5–inhibitor complex), phosphopeptide-based small-molecule screen, p38 MAPK/JNK activation assays, TGF-β1/Smad2 signaling assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of enzyme-inhibitor complex with functional validation by pharmacological and genetic approaches","pmids":["32843541"],"is_preprint":false},{"year":2020,"finding":"SETD8 interacts with STAT3 and recruits SETD8 to the DUSP10 promoter region, leading to epigenetic silencing of DUSP10 expression via H4K20 methylation, resulting in constitutive ERK1/2 activation in pancreatic cancer.","method":"RNA sequencing, dual-luciferase assay, ChIP assay, mass spectrometry, SETD8 gain/loss-of-function, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase, and MS establish SETD8-STAT3-DUSP10 axis; single lab with multiple orthogonal methods","pmids":["33232789"],"is_preprint":false},{"year":2021,"finding":"Bone marrow macrophage-derived exosomal miR-143-5p targets the 3'UTR of MKP5/DUSP10 mRNA (validated by dual-luciferase reporter assay), reducing MKP5 protein levels in hepatocytes and inducing insulin resistance (decreased AKT and GSK phosphorylation); MKP5 overexpression rescues miR-143-5p-induced insulin resistance.","method":"Dual-luciferase reporter assay, western blot, miR-143-5p mimic transfection, MKP5 overexpression rescue experiment in Hep1-6 cells","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — luciferase validation of miRNA-target binding with functional rescue experiment, single lab","pmids":["34647385"],"is_preprint":false},{"year":2022,"finding":"Six X-ray crystal structures of MKP5 in complex with allosteric inhibitor derivatives were solved, establishing that a parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating inhibitor potency, and that modifications to the C-9 position are essential for proper positioning.","method":"X-ray crystallography (six enzyme-inhibitor crystal structures), structure-activity relationship analysis","journal":"European journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with SAR validation identifying critical active-site residue","pmids":["36116232"],"is_preprint":false},{"year":2025,"finding":"Residue Y435 in MKP5 is required to maintain the structural integrity of the allosteric pocket; changes in this pocket propagate conformational flexibility to reorganize catalytically crucial residues in the active site. Y435 is also required for interaction with p38 MAPK and JNK, promoting their dephosphorylation.","method":"X-ray crystallography, NMR spectroscopy, molecular dynamics simulations, mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, NMR, and mutagenesis in single rigorous study establishing allosteric mechanism and MAPK binding requirement","pmids":["40745179"],"is_preprint":false},{"year":2025,"finding":"E3 ligase TRIM7 interacts with DUSP10, catalyzes its ubiquitination and proteasomal degradation, leading to hyperactivation of IKKβ-NF-κB and JNK/p38 MAPK signaling pathways in the context of NAFLD. DUSP10 silencing abrogates the protective effects of TRIM7 deficiency.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, hepatic-specific TRIM7 KO, DUSP10 silencing, gain/loss-of-function in mouse NAFLD models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing TRIM7-DUSP10 interaction, ubiquitination assay, and epistasis via DUSP10 silencing rescue, multiple orthogonal approaches","pmids":["41290618"],"is_preprint":false},{"year":2011,"finding":"ASC suppresses DUSP10/MKP5 expression in pathogen-infected macrophages (independent of caspase-1 and NLRP3), and ASC-dependent suppression of DUSP10 leads to increased MAPK (ERK) phosphorylation; MAPK activation by pathogen was abrogated in Asc-/- but not Nlrp3-/-, Nlrc4-/-, or Casp1-/- macrophages.","method":"shRNA knockdown, microarray, genetic KO macrophages (Asc-/-, Nlrp3-/-, Nlrc4-/-, Casp1-/-), TLR agonist treatment, MAPK phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using multiple KO macrophage lines with DUSP10 as mechanistic target, single lab","pmids":["21487011"],"is_preprint":false},{"year":2012,"finding":"MKP5 deficiency blocks ox-LDL uptake and foam cell formation in macrophages by reducing ox-LDL-induced NF-κB activation; MKP5 deficiency also inhibits TNF-α production and enhances TGF-β1 levels in ox-LDL-stimulated macrophages.","method":"Genetic knockout macrophages, foam cell formation assay, NF-κB activation assay (p65 RNAi), cytokine ELISA","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KO macrophages with NF-κB pathway mechanistic link confirmed by p65 RNAi epistasis, single lab","pmids":["22683306"],"is_preprint":false},{"year":2024,"finding":"MKP-5-deficient fibroblasts are impaired in TGF-β-stimulated SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and fibrogenic gene transcriptional activation; pharmacological inhibition of MKP5 blocks TGF-β signaling; this regulation occurs through a JNK-dependent pathway, as identified by RNA sequencing and transcriptomic analysis.","method":"Genetic KO fibroblasts, pharmacological MKP5 inhibitor, RNA sequencing, SMAD2 phosphorylation/nuclear translocation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches with transcriptomic mechanism, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"MKP5 inhibits hepatic stellate cell activation and hepatocyte apoptosis through regulation of the IRE1/XBP1 ER stress pathway; MKP5 knockout mice exhibited more pronounced hepatic fibrosis, and RNA-seq confirmed activation of endoplasmic reticulum protein processing pathway in MKP5-deficient fibrotic liver.","method":"Genetic knockout mice, CCl4 fibrosis model, RNA-seq, IRE1/XBP1 pathway analysis, HSC activation assays","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with RNA-seq and defined ER stress pathway mechanism, single lab","pmids":["39609656"],"is_preprint":false},{"year":2025,"finding":"HMW-HA binding to CD44 activates PI3K/Akt signaling and RhoA-associated protein kinase (ROK) signaling to induce DUSP10/MKP5 expression in chondrocytes; miR-92a, miR-181a, and miR-181d negatively regulate DUSP10/MKP5 expression and are suppressed by HMW-HA.","method":"PI3K/Akt inhibitors, miRNA mimic/inhibitor transfection (gain/loss-of-function), western blot for Akt phosphorylation, qRT-PCR in C28/I2 chondrocytes","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple miRNAs and signaling inhibitors defining upstream regulation, single lab","pmids":["40002789"],"is_preprint":false}],"current_model":"DUSP10/MKP-5 is a dual-specificity MAPK phosphatase that selectively dephosphorylates and inactivates p38 MAPK and JNK (with minimal activity toward ERK) via a bipartite kinase binding domain that engages the MAPK docking site in a novel helical mode; its catalytic domain harbors an allosteric pocket centered on residue Y435 that coordinates MAPK binding, active-site conformation, and susceptibility to small-molecule inhibition; DUSP10 activity is post-translationally regulated by mTORC2-mediated stabilizing phosphorylation (Ser224/Ser230) and by TRIM7-mediated ubiquitination and proteasomal degradation; upstream, DUSP10 expression is regulated by ASC, AGR2, SETD8/STAT3 epigenetic silencing, HMW-HA/CD44/PI3K-Akt signaling, and multiple miRNAs (miR-92a, miR-143-5p, miR-363-3p, miR-450a-5p); in muscle, DUSP10 negatively regulates satellite cell proliferation (via JNK) and differentiation (via p38) and promotes fibrosis through a JNK-dependent pathway that supports TGF-β/SMAD2 signaling; in immune cells, DUSP10 restrains neutrophil oxidant production (p38→p47phox axis), suppresses IL-33-induced IL-5 production in Th2 cells (p38→GATA3), and modulates macrophage NF-κB-dependent foam cell formation; in colorectal cancer cells DUSP10 also interacts with and regulates YAP1 in a nuclear context, and is regulated by the E3 ligase TRIM7 in the liver."},"narrative":{"mechanistic_narrative":"DUSP10 (MKP-5) is a dual-specificity MAP kinase phosphatase that selectively binds and inactivates p38 MAPK and JNK/SAPK, with p38 as the preferred substrate and minimal activity toward ERK [PMID:10391943, PMID:10597297]. Substrate selectivity is structurally encoded: its MAPK-binding domain presents an alpha-helical cluster of positively charged residues distinct from MKP3 [PMID:17400920], and it engages the p38α docking site through a non-canonical bipartite helical mode conserved across the cytoplasmic p38/JNK-specific MKP subgroup [PMID:22375048]. The catalytic domain harbors an allosteric pocket whose integrity depends on residue Y435; this residue couples pocket conformation to active-site organization and is itself required for p38 and JNK binding, and a small molecule occupying this pocket collapses the active site and recapitulates DUSP10 loss [PMID:32843541, PMID:36116232, PMID:40745179]. Through suppression of p38 and JNK, DUSP10 acts as a brake on inflammatory and stress signaling in multiple tissues: it restrains neutrophil p38→p47phox-driven superoxide production [PMID:19696743], limits IL-33→p38→GATA3-dependent IL-5 production in pathogenic Th2 cells [PMID:30315197], and negatively regulates muscle satellite cell proliferation (via JNK) and differentiation (via p38) [PMID:23543058]. DUSP10 promotes tissue fibrosis by supporting TGF-β/SMAD signaling through a JNK-dependent mechanism, and its loss protects against pulmonary and hepatic fibrosis [PMID:31483681, PMID:39609656]. DUSP10 protein abundance is set post-translationally by opposing modifications: mTORC2 binds and phosphorylates it on Ser224/Ser230 to block turnover [PMID:25568665], whereas the E3 ligase TRIM7 ubiquitinates it to drive proteasomal degradation, relieving inhibition of IKKβ-NF-κB and JNK/p38 in fatty liver disease [PMID:41290618]. Its expression is further constrained by epigenetic silencing (STAT3/SETD8) and multiple miRNAs and induced by HMW-HA/CD44 signaling [PMID:33232789, PMID:40002789].","teleology":[{"year":1999,"claim":"Established DUSP10's core biochemical identity: that it is a phosphatase with defined MAPK substrate selectivity, distinguishing it from the broad family of phosphatases.","evidence":"In vitro phosphatase and binding assays plus immunoprecipitation with catalytically inactive mutant in mammalian cells","pmids":["10391943","10597297"],"confidence":"High","gaps":["Structural basis of p38/JNK vs ERK selectivity not resolved","Physiological substrates in vivo not yet addressed"]},{"year":2007,"claim":"Resolved why DUSP10's substrate preference differs from related MKPs by showing its MAPK-binding domain uses an alpha-helical positive-charge cluster rather than the loop/beta-strand arrangement of MKP3.","evidence":"X-ray crystallography of isolated binding and catalytic domains of human MKP5","pmids":["17400920"],"confidence":"High","gaps":["Domain structures solved in isolation, not in complex with a MAPK","Allosteric regulation of the catalytic domain not described"]},{"year":2011,"claim":"Defined the docking mechanism by capturing how the binding domain engages p38α, revealing a bipartite helical mode distinct from the classical linear docking motif and conserved across the p38/JNK-specific MKP subgroup.","evidence":"2.7 Å co-crystal structure of p38α with the MKP5 KBD","pmids":["22375048"],"confidence":"High","gaps":["Does not address how docking couples to catalytic turnover","JNK docking not directly visualized"]},{"year":2009,"claim":"Provided the first non-redundant in vivo function, showing DUSP10 specifically restrains a p38→p47phox superoxide axis in neutrophils that MKP1 does not cover.","evidence":"Mkp5-/- vs Mkp1-/- mice, neutrophil adoptive transfer, p38 inhibitor, p47phox phosphorylation and gene deletion","pmids":["19696743"],"confidence":"High","gaps":["Mechanism of DUSP10 recruitment to neutrophil signaling not defined","Whether JNK contributes was not dissected"]},{"year":2013,"claim":"Showed DUSP10 partitions its two substrates to distinct cellular outputs, using JNK to gate satellite cell proliferation and p38 to gate differentiation.","evidence":"Mkp5-/- and mdx/Mkp5-/- mice, primary satellite cell assays, MAPK signaling analysis","pmids":["23543058"],"confidence":"High","gaps":["How DUSP10 selects JNK vs p38 in a given context unresolved","No structural correlate of context-specific substrate choice"]},{"year":2014,"claim":"Identified a post-translational stabilization mechanism, placing DUSP10 abundance under mTORC2 control via Ser224/Ser230 phosphorylation.","evidence":"Co-IP, site-directed mutagenesis, phospho-mutant overexpression, xenografts in GBM cells","pmids":["25568665"],"confidence":"Medium","gaps":["Single lab; kinase-substrate relationship not validated in vitro","Degradation machinery counteracting stabilization not identified here"]},{"year":2015,"claim":"Extended DUSP10's tumor-suppressive role to the intestine and linked it to ERK/KLF5, while parallel work placed it in oncogenic regulatory circuits (AGR2→DUSP10→p38→p53).","evidence":"Dusp10-/- mice in AOM/DSS model; gain/loss-of-function with phospho-readouts in cancer cell lines","pmids":["25772234","26733232"],"confidence":"Medium","gaps":["ERK regulation by DUSP10 contrasts with its weak in vitro ERK activity and is not biochemically reconciled","Tissue-context determinants of tumor-suppressive vs oncogenic behavior unclear"]},{"year":2017,"claim":"Defined upstream transcriptional and signaling inputs (TP53INP1/p73 promoter regulation; HO-1/CO/cGMP induction) and added anti-apoptotic/anti-oxidant outputs in muscle, broadening the regulatory network around DUSP10.","evidence":"Cardiotoxin injury KO mice (STAT3/Bcl-2/catalase); HCC promoter analysis; endothelial siRNA and pharmacological pathway dissection","pmids":["29047406","28674078","29165873"],"confidence":"Medium","gaps":["Direct binding of regulators to DUSP10 promoter not always demonstrated","Single-lab pathway placements"]},{"year":2019,"claim":"Consolidated DUSP10 as a tissue-protective brake on inflammation and fibrosis (Th2 IL-5 suppression, bronchial cytokine control, TGF-β/Smad coupling in lung fibroblasts) and identified a nuclear DUSP10–YAP1 interaction in colorectal cancer.","evidence":"Dusp10-/- mice and overexpression in Th2 cells; siRNA in bronchial epithelium; bleomycin fibrosis KO with Smad readouts; reciprocal Co-IP with YAP1 S397 mutant","pmids":["30315197","30333178","31483681","31717606"],"confidence":"High","gaps":["Whether DUSP10 dephosphorylates YAP1 directly is not established","Mechanism coupling p38/JNK suppression to TGF-β enhancement not fully defined"]},{"year":2020,"claim":"Discovered an allosteric pocket distinct from the active site whose inhibitor occupancy collapses catalysis, giving both a druggable mechanism and a tool to recapitulate DUSP10 deficiency.","evidence":"MKP5–inhibitor co-crystal structure, phosphopeptide screen, p38/JNK activation and TGF-β1/Smad2 assays","pmids":["32843541"],"confidence":"High","gaps":["Endogenous ligand for the allosteric pocket, if any, unknown","Selectivity against other MKPs not fully addressed"]},{"year":2022,"claim":"Mapped the chemical determinants of allosteric inhibition to a π-π interaction with Tyr435, pinpointing a single residue as the structural hinge of the pocket.","evidence":"Six MKP5–inhibitor crystal structures with structure-activity relationship analysis","pmids":["36116232"],"confidence":"High","gaps":["Functional requirement of Y435 for catalysis not yet tested at this stage","Inhibitor in vivo efficacy not addressed"]},{"year":2025,"claim":"Unified the allosteric and catalytic story by showing Y435 maintains pocket integrity, propagates conformational changes to active-site residues, and is itself required for p38 and JNK binding and dephosphorylation.","evidence":"X-ray crystallography, NMR, molecular dynamics, and mutagenesis","pmids":["40745179"],"confidence":"High","gaps":["How physiological inputs exploit this allosteric axis is unknown","Whether substrate-binding defect of Y435 mutants is independent of catalytic collapse not fully separated"]},{"year":2025,"claim":"Identified TRIM7 as the E3 ligase driving DUSP10 ubiquitination and degradation, providing the destabilizing counterpart to mTORC2 stabilization and linking DUSP10 turnover to NF-κB/MAPK hyperactivation in NAFLD.","evidence":"Co-IP, ubiquitination assay, proteasome inhibition, hepatic TRIM7 KO with DUSP10-silencing epistasis in mouse NAFLD","pmids":["41290618"],"confidence":"High","gaps":["Ubiquitin linkage type and target residues on DUSP10 not specified","Coordination with mTORC2 phosphorylation not examined"]},{"year":null,"claim":"How DUSP10 reconciles its biochemically defined p38/JNK selectivity with reported ERK-dependent phenotypes, and how its multi-tissue context determines tumor-suppressive versus oncogenic or fibrogenic output, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No biochemical basis for ERK regulation despite weak in vitro ERK activity","Context determinants of opposing physiological roles unknown","Direct vs indirect nature of the YAP1 interaction unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,17,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,13,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,13,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,22]}],"complexes":[],"partners":["MAPK14","MAPK8","MTOR","TRIM7","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6W6","full_name":"Dual specificity protein phosphatase 10","aliases":["Mitogen-activated protein kinase phosphatase 5","MAP kinase phosphatase 5","MKP-5"],"length_aa":482,"mass_kda":52.6,"function":"Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily. It preferably dephosphorylates p38","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y6W6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DUSP10","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DUSP10","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"611176","title":"JNK/MAPK8-ASSOCIATED MEMBRANE PROTEIN; JKAMP","url":"https://www.omim.org/entry/611176"},{"mim_id":"608867","title":"DUAL-SPECIFICITY PHOSPHATASE 10; DUSP10","url":"https://www.omim.org/entry/608867"},{"mim_id":"607175","title":"DUAL-SPECIFICITY PHOSPHATASE 16; DUSP16","url":"https://www.omim.org/entry/607175"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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fractionation/immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct enzymatic activity demonstrated in vitro, substrate specificity confirmed by binding and dephosphorylation assays, replicated independently in same year by Theodosiou et al. (PMID:10597297)\",\n      \"pmids\": [\"10391943\", \"10597297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MKP5 substrate selectivity (p38 ≈ JNK/SAPK >> ERK) is determined at least in part at the level of substrate binding, as demonstrated by immunoprecipitation of endogenous MAPKs with catalytically inactive MKP5.\",\n      \"method\": \"Immunoprecipitation using catalytically inactive MKP5 mutant expressed in mammalian cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytically inactive mutant used for binding specificity, single lab, two complementary approaches (IP and activity assay)\",\n      \"pmids\": [\"10597297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of the MAP kinase binding domain (BD) and catalytic domain (CD) of human MKP5 were solved at up to 2.2 Å resolution. The BD of MKP5 differs dramatically from MKP3: the cluster of positively charged residues critical for MAPK binding is alpha-helical in MKP5 (vs. loop/beta-strand in MKP3), located 25 Å apart, consistent with distinct substrate preferences. The CD is in an active conformation.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution with structural comparison to functional implications for substrate specificity\",\n      \"pmids\": [\"17400920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of p38α in complex with the MAPK binding domain (KBD) of MKP5 at 2.7 Å resolution revealed a bipartite binding mode in which two distinct helical regions of KBD engage the p38α docking site (on the back of the active site), distinct from the classical linear docking motif. The KBD of MKP7 closely resembles MKP5 KBD, suggesting this mechanism is conserved in the cytoplasmic p38/JNK-specific MKP subgroup.\",\n      \"method\": \"X-ray crystallography (2.7 Å resolution crystal structure of p38α–MKP5 KBD complex)\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure with functional validation of a novel bipartite docking mechanism\",\n      \"pmids\": [\"22375048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MKP5 has a non-redundant role in restraining p38 MAPK-mediated neutrophil superoxide production: Mkp5-/- (but not Mkp1-/-) mice showed augmented p38 MAPK activation and increased superoxide generation in neutrophils; p38 MAPK phosphorylated p47phox, and p47phox gene deletion ablated LPS-induced vascular injury in Mkp5-/- mice.\",\n      \"method\": \"Genetic knockout mouse model, neutrophil depletion, adoptive transfer, p38 MAPK inhibitor (SB203580), p47phox phosphorylation assay, in vitro kinase assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including KO mice, adoptive transfer, pharmacological inhibition, and in vitro kinase assay demonstrating mechanistic pathway\",\n      \"pmids\": [\"19696743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MKP-5 (DUSP10) negatively regulates muscle stem cell function by controlling JNK (to coordinate proliferation) and p38 MAPK (to control differentiation); genetic loss of Mkp5 improved regenerative myogenesis and attenuated dystrophic muscle phenotype in mdx mice.\",\n      \"method\": \"Genetic knockout mouse model (Mkp5-/- and mdx/Mkp5-/- double-knockout), primary satellite cell assays, MAPK signaling analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with specific phenotypic readout in two disease-relevant mouse models, dual MAPK pathway dissection\",\n      \"pmids\": [\"23543058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"mTORC2 binds DUSP10 and phosphorylates it on serine residues 224 and 230, blocking DUSP10 turnover (stabilizing it), resulting in inactivation of p38 MAPK signaling. Nonphosphorylatable or phosphomimetic DUSP10 mutants confer differential mTOR kinase inhibitor responses in GBM cells.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, ectopic overexpression of DUSP10 mutants, in vitro and xenograft cellular assays\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and mutagenesis in a single lab, supported by in vivo xenograft data\",\n      \"pmids\": [\"25568665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUSP10 knockout mice exhibited increased intestinal epithelial cell (IEC) proliferation and migration associated with increased ERK1/2 activation and KLF5 expression, and developed more colon tumors in the AOM/DSS model, identifying DUSP10 as a negative regulator of IEC growth and a colorectal cancer suppressor.\",\n      \"method\": \"Genetic knockout mouse model, AOM/DSS colorectal cancer model, MAPK phosphorylation analysis, cell proliferation and migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined phenotypic readout and MAPK mechanistic link, single lab\",\n      \"pmids\": [\"25772234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AGR2 oncoprotein upregulates DUSP10, which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation, defining a novel AGR2→DUSP10→p38→p53 regulatory axis in human cancer cells.\",\n      \"method\": \"Gene expression manipulation, western blot for p38 MAPK and p53 phosphorylation, pathway analysis in breast cancer cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway established by loss/gain-of-function with phosphorylation readouts in single lab\",\n      \"pmids\": [\"26733232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"High molecular weight hyaluronic acid (HA) induces DUSP10/MKP5 expression via CD44 binding, which inhibits TNF-α-induced p38 MAPK and JNK phosphorylation and AP-1 transcriptional activity, thereby suppressing MMP13 expression in chondrocytes.\",\n      \"method\": \"CD44 function-blocking antibody, siRNA knockdown, reporter assay, western blotting, immunofluorescence in human chondrocytic C28/I2 cells\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic pathway established with blocking antibody, siRNA, and reporter assay in single lab\",\n      \"pmids\": [\"27101204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of MKP-5 in skeletal muscle during regeneration activates STAT3/Bcl-2 anti-apoptotic signaling, increases catalase expression improving anti-oxidant capacity, and reduces mitochondrial apoptotic pathway activation, promoting myofiber survival.\",\n      \"method\": \"Genetic knockout mice, cardiotoxin injury model, TUNEL assay, western blot for STAT3, Bcl-2, and apoptosis markers\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with mechanistic pathway defined, single lab\",\n      \"pmids\": [\"29047406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TP53INP1 downregulation promotes HCC metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway; the DUSP10 promoter contains p73 binding sites directly implicated in modulation by TP53INP1.\",\n      \"method\": \"Mechanistic investigations in HCC cell lines, promoter analysis, ERK pathway activation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway placement by epistasis-type experiments in cell lines, single lab\",\n      \"pmids\": [\"28674078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Andrographolide inhibits hypoxia-induced HIF-1α and ET-1 expression through a HO-1/CO/cGMP/MKP-5 pathway: andrographolide induces HO-1 and MKP-5 expression; CO and cGMP increase MKP-5 expression; MKP-5 silencing abrogates andrographolide's suppression of p38 MAPK activation and HIF-1α expression.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors, HO-1 inhibitor, guanylate cyclase inhibitor, western blotting in EA.hy926 endothelial cells\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway defined by siRNA and pharmacological inhibitors, single lab with multiple approaches\",\n      \"pmids\": [\"29165873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DUSP10 is expressed in ST2hi pathogenic Th2 cells but not ILC2; DUSP10 inhibits IL-33-induced cytokine production in Th2 cells by dephosphorylating and inactivating p38 MAPK, resulting in reduced GATA3 activity. Dusp10 deletion renders ST2hi Th2 cells capable of producing IL-5 upon IL-33 stimulation.\",\n      \"method\": \"Genetic knockout mice, DUSP10 overexpression in Th2 cells, p38 MAPK phosphorylation assays, GATA3 activity assays, cytokine production measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and overexpression with defined mechanistic pathway (DUSP10→p38→GATA3→IL-5), multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"30315197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MKP-5-deficient mice are protected from bleomycin-induced pulmonary fibrosis; MKP-5-deficient lung fibroblasts show enhanced p38 MAPK activity, impaired Smad3 phosphorylation, increased Smad7 levels, and decreased fibrogenic gene expression, coupling MKP-5 to the TGF-β1 signaling machinery.\",\n      \"method\": \"Genetic knockout mice, bleomycin fibrosis model, fibroblast cultures, western blot for Smad3/Smad7/p38, hydroxyproline assay, fibrogenic gene expression\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with mechanistic readouts in primary fibroblasts, single lab\",\n      \"pmids\": [\"31483681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP10 negatively regulates inflammatory cytokine production in bronchial epithelial cells in response to IL-1β stimulation (alone and in combination with rhinovirus), without affecting rhinovirus replication, as demonstrated by siRNA-mediated knockdown.\",\n      \"method\": \"siRNA knockdown, rhinovirus infection model, cytokine production assays in primary bronchial epithelial cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA loss-of-function with specific cytokine phenotype, single lab\",\n      \"pmids\": [\"30333178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP10 co-immunoprecipitates with YAP1, and their interaction is dependent on YAP1 Ser397. DUSP10 nuclear localization increases at high cell density and correlates with YAP1 activity, suggesting DUSP10 acts as a regulator of YAP1 in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, DUSP10 overexpression/silencing, xenograft mouse model, Drosophila transgenic model, nuclear localization imaging\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP with mutagenesis of YAP1 binding site, supported by in vivo data, single lab\",\n      \"pmids\": [\"31717606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An allosteric binding pocket on MKP5 (distinct from the active site) was identified; a small-molecule inhibitor binding to this pocket collapses the MKP5 active site and limits MAPK binding. Crystal structure of MKP5 in complex with the inhibitor was solved. The inhibitor recapitulates MKP5 deficiency (activating p38 MAPK and JNK) and blocks TGF-β1-mediated Smad2 phosphorylation in muscle.\",\n      \"method\": \"X-ray crystallography (MKP5–inhibitor complex), phosphopeptide-based small-molecule screen, p38 MAPK/JNK activation assays, TGF-β1/Smad2 signaling assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of enzyme-inhibitor complex with functional validation by pharmacological and genetic approaches\",\n      \"pmids\": [\"32843541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD8 interacts with STAT3 and recruits SETD8 to the DUSP10 promoter region, leading to epigenetic silencing of DUSP10 expression via H4K20 methylation, resulting in constitutive ERK1/2 activation in pancreatic cancer.\",\n      \"method\": \"RNA sequencing, dual-luciferase assay, ChIP assay, mass spectrometry, SETD8 gain/loss-of-function, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase, and MS establish SETD8-STAT3-DUSP10 axis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33232789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bone marrow macrophage-derived exosomal miR-143-5p targets the 3'UTR of MKP5/DUSP10 mRNA (validated by dual-luciferase reporter assay), reducing MKP5 protein levels in hepatocytes and inducing insulin resistance (decreased AKT and GSK phosphorylation); MKP5 overexpression rescues miR-143-5p-induced insulin resistance.\",\n      \"method\": \"Dual-luciferase reporter assay, western blot, miR-143-5p mimic transfection, MKP5 overexpression rescue experiment in Hep1-6 cells\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — luciferase validation of miRNA-target binding with functional rescue experiment, single lab\",\n      \"pmids\": [\"34647385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Six X-ray crystal structures of MKP5 in complex with allosteric inhibitor derivatives were solved, establishing that a parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating inhibitor potency, and that modifications to the C-9 position are essential for proper positioning.\",\n      \"method\": \"X-ray crystallography (six enzyme-inhibitor crystal structures), structure-activity relationship analysis\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with SAR validation identifying critical active-site residue\",\n      \"pmids\": [\"36116232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Residue Y435 in MKP5 is required to maintain the structural integrity of the allosteric pocket; changes in this pocket propagate conformational flexibility to reorganize catalytically crucial residues in the active site. Y435 is also required for interaction with p38 MAPK and JNK, promoting their dephosphorylation.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, molecular dynamics simulations, mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, NMR, and mutagenesis in single rigorous study establishing allosteric mechanism and MAPK binding requirement\",\n      \"pmids\": [\"40745179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E3 ligase TRIM7 interacts with DUSP10, catalyzes its ubiquitination and proteasomal degradation, leading to hyperactivation of IKKβ-NF-κB and JNK/p38 MAPK signaling pathways in the context of NAFLD. DUSP10 silencing abrogates the protective effects of TRIM7 deficiency.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, hepatic-specific TRIM7 KO, DUSP10 silencing, gain/loss-of-function in mouse NAFLD models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing TRIM7-DUSP10 interaction, ubiquitination assay, and epistasis via DUSP10 silencing rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"41290618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ASC suppresses DUSP10/MKP5 expression in pathogen-infected macrophages (independent of caspase-1 and NLRP3), and ASC-dependent suppression of DUSP10 leads to increased MAPK (ERK) phosphorylation; MAPK activation by pathogen was abrogated in Asc-/- but not Nlrp3-/-, Nlrc4-/-, or Casp1-/- macrophages.\",\n      \"method\": \"shRNA knockdown, microarray, genetic KO macrophages (Asc-/-, Nlrp3-/-, Nlrc4-/-, Casp1-/-), TLR agonist treatment, MAPK phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using multiple KO macrophage lines with DUSP10 as mechanistic target, single lab\",\n      \"pmids\": [\"21487011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MKP5 deficiency blocks ox-LDL uptake and foam cell formation in macrophages by reducing ox-LDL-induced NF-κB activation; MKP5 deficiency also inhibits TNF-α production and enhances TGF-β1 levels in ox-LDL-stimulated macrophages.\",\n      \"method\": \"Genetic knockout macrophages, foam cell formation assay, NF-κB activation assay (p65 RNAi), cytokine ELISA\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KO macrophages with NF-κB pathway mechanistic link confirmed by p65 RNAi epistasis, single lab\",\n      \"pmids\": [\"22683306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MKP-5-deficient fibroblasts are impaired in TGF-β-stimulated SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and fibrogenic gene transcriptional activation; pharmacological inhibition of MKP5 blocks TGF-β signaling; this regulation occurs through a JNK-dependent pathway, as identified by RNA sequencing and transcriptomic analysis.\",\n      \"method\": \"Genetic KO fibroblasts, pharmacological MKP5 inhibitor, RNA sequencing, SMAD2 phosphorylation/nuclear translocation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches with transcriptomic mechanism, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MKP5 inhibits hepatic stellate cell activation and hepatocyte apoptosis through regulation of the IRE1/XBP1 ER stress pathway; MKP5 knockout mice exhibited more pronounced hepatic fibrosis, and RNA-seq confirmed activation of endoplasmic reticulum protein processing pathway in MKP5-deficient fibrotic liver.\",\n      \"method\": \"Genetic knockout mice, CCl4 fibrosis model, RNA-seq, IRE1/XBP1 pathway analysis, HSC activation assays\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with RNA-seq and defined ER stress pathway mechanism, single lab\",\n      \"pmids\": [\"39609656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMW-HA binding to CD44 activates PI3K/Akt signaling and RhoA-associated protein kinase (ROK) signaling to induce DUSP10/MKP5 expression in chondrocytes; miR-92a, miR-181a, and miR-181d negatively regulate DUSP10/MKP5 expression and are suppressed by HMW-HA.\",\n      \"method\": \"PI3K/Akt inhibitors, miRNA mimic/inhibitor transfection (gain/loss-of-function), western blot for Akt phosphorylation, qRT-PCR in C28/I2 chondrocytes\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple miRNAs and signaling inhibitors defining upstream regulation, single lab\",\n      \"pmids\": [\"40002789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DUSP10/MKP-5 is a dual-specificity MAPK phosphatase that selectively dephosphorylates and inactivates p38 MAPK and JNK (with minimal activity toward ERK) via a bipartite kinase binding domain that engages the MAPK docking site in a novel helical mode; its catalytic domain harbors an allosteric pocket centered on residue Y435 that coordinates MAPK binding, active-site conformation, and susceptibility to small-molecule inhibition; DUSP10 activity is post-translationally regulated by mTORC2-mediated stabilizing phosphorylation (Ser224/Ser230) and by TRIM7-mediated ubiquitination and proteasomal degradation; upstream, DUSP10 expression is regulated by ASC, AGR2, SETD8/STAT3 epigenetic silencing, HMW-HA/CD44/PI3K-Akt signaling, and multiple miRNAs (miR-92a, miR-143-5p, miR-363-3p, miR-450a-5p); in muscle, DUSP10 negatively regulates satellite cell proliferation (via JNK) and differentiation (via p38) and promotes fibrosis through a JNK-dependent pathway that supports TGF-β/SMAD2 signaling; in immune cells, DUSP10 restrains neutrophil oxidant production (p38→p47phox axis), suppresses IL-33-induced IL-5 production in Th2 cells (p38→GATA3), and modulates macrophage NF-κB-dependent foam cell formation; in colorectal cancer cells DUSP10 also interacts with and regulates YAP1 in a nuclear context, and is regulated by the E3 ligase TRIM7 in the liver.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DUSP10 (MKP-5) is a dual-specificity MAP kinase phosphatase that selectively binds and inactivates p38 MAPK and JNK/SAPK, with p38 as the preferred substrate and minimal activity toward ERK [#0, #1]. Substrate selectivity is structurally encoded: its MAPK-binding domain presents an alpha-helical cluster of positively charged residues distinct from MKP3 [#2], and it engages the p38\\u03b1 docking site through a non-canonical bipartite helical mode conserved across the cytoplasmic p38/JNK-specific MKP subgroup [#3]. The catalytic domain harbors an allosteric pocket whose integrity depends on residue Y435; this residue couples pocket conformation to active-site organization and is itself required for p38 and JNK binding, and a small molecule occupying this pocket collapses the active site and recapitulates DUSP10 loss [#17, #20, #21]. Through suppression of p38 and JNK, DUSP10 acts as a brake on inflammatory and stress signaling in multiple tissues: it restrains neutrophil p38\\u2192p47phox-driven superoxide production [#4], limits IL-33\\u2192p38\\u2192GATA3-dependent IL-5 production in pathogenic Th2 cells [#13], and negatively regulates muscle satellite cell proliferation (via JNK) and differentiation (via p38) [#5]. DUSP10 promotes tissue fibrosis by supporting TGF-\\u03b2/SMAD signaling through a JNK-dependent mechanism, and its loss protects against pulmonary and hepatic fibrosis [#14, #26]. DUSP10 protein abundance is set post-translationally by opposing modifications: mTORC2 binds and phosphorylates it on Ser224/Ser230 to block turnover [#6], whereas the E3 ligase TRIM7 ubiquitinates it to drive proteasomal degradation, relieving inhibition of IKK\\u03b2-NF-\\u03baB and JNK/p38 in fatty liver disease [#22]. Its expression is further constrained by epigenetic silencing (STAT3/SETD8) and multiple miRNAs and induced by HMW-HA/CD44 signaling [#18, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established DUSP10's core biochemical identity: that it is a phosphatase with defined MAPK substrate selectivity, distinguishing it from the broad family of phosphatases.\",\n      \"evidence\": \"In vitro phosphatase and binding assays plus immunoprecipitation with catalytically inactive mutant in mammalian cells\",\n      \"pmids\": [\"10391943\", \"10597297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p38/JNK vs ERK selectivity not resolved\", \"Physiological substrates in vivo not yet addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved why DUSP10's substrate preference differs from related MKPs by showing its MAPK-binding domain uses an alpha-helical positive-charge cluster rather than the loop/beta-strand arrangement of MKP3.\",\n      \"evidence\": \"X-ray crystallography of isolated binding and catalytic domains of human MKP5\",\n      \"pmids\": [\"17400920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain structures solved in isolation, not in complex with a MAPK\", \"Allosteric regulation of the catalytic domain not described\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the docking mechanism by capturing how the binding domain engages p38\\u03b1, revealing a bipartite helical mode distinct from the classical linear docking motif and conserved across the p38/JNK-specific MKP subgroup.\",\n      \"evidence\": \"2.7 \\u00c5 co-crystal structure of p38\\u03b1 with the MKP5 KBD\",\n      \"pmids\": [\"22375048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how docking couples to catalytic turnover\", \"JNK docking not directly visualized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the first non-redundant in vivo function, showing DUSP10 specifically restrains a p38\\u2192p47phox superoxide axis in neutrophils that MKP1 does not cover.\",\n      \"evidence\": \"Mkp5-/- vs Mkp1-/- mice, neutrophil adoptive transfer, p38 inhibitor, p47phox phosphorylation and gene deletion\",\n      \"pmids\": [\"19696743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DUSP10 recruitment to neutrophil signaling not defined\", \"Whether JNK contributes was not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed DUSP10 partitions its two substrates to distinct cellular outputs, using JNK to gate satellite cell proliferation and p38 to gate differentiation.\",\n      \"evidence\": \"Mkp5-/- and mdx/Mkp5-/- mice, primary satellite cell assays, MAPK signaling analysis\",\n      \"pmids\": [\"23543058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DUSP10 selects JNK vs p38 in a given context unresolved\", \"No structural correlate of context-specific substrate choice\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a post-translational stabilization mechanism, placing DUSP10 abundance under mTORC2 control via Ser224/Ser230 phosphorylation.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, phospho-mutant overexpression, xenografts in GBM cells\",\n      \"pmids\": [\"25568665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; kinase-substrate relationship not validated in vitro\", \"Degradation machinery counteracting stabilization not identified here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended DUSP10's tumor-suppressive role to the intestine and linked it to ERK/KLF5, while parallel work placed it in oncogenic regulatory circuits (AGR2\\u2192DUSP10\\u2192p38\\u2192p53).\",\n      \"evidence\": \"Dusp10-/- mice in AOM/DSS model; gain/loss-of-function with phospho-readouts in cancer cell lines\",\n      \"pmids\": [\"25772234\", \"26733232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERK regulation by DUSP10 contrasts with its weak in vitro ERK activity and is not biochemically reconciled\", \"Tissue-context determinants of tumor-suppressive vs oncogenic behavior unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined upstream transcriptional and signaling inputs (TP53INP1/p73 promoter regulation; HO-1/CO/cGMP induction) and added anti-apoptotic/anti-oxidant outputs in muscle, broadening the regulatory network around DUSP10.\",\n      \"evidence\": \"Cardiotoxin injury KO mice (STAT3/Bcl-2/catalase); HCC promoter analysis; endothelial siRNA and pharmacological pathway dissection\",\n      \"pmids\": [\"29047406\", \"28674078\", \"29165873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of regulators to DUSP10 promoter not always demonstrated\", \"Single-lab pathway placements\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Consolidated DUSP10 as a tissue-protective brake on inflammation and fibrosis (Th2 IL-5 suppression, bronchial cytokine control, TGF-\\u03b2/Smad coupling in lung fibroblasts) and identified a nuclear DUSP10\\u2013YAP1 interaction in colorectal cancer.\",\n      \"evidence\": \"Dusp10-/- mice and overexpression in Th2 cells; siRNA in bronchial epithelium; bleomycin fibrosis KO with Smad readouts; reciprocal Co-IP with YAP1 S397 mutant\",\n      \"pmids\": [\"30315197\", \"30333178\", \"31483681\", \"31717606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DUSP10 dephosphorylates YAP1 directly is not established\", \"Mechanism coupling p38/JNK suppression to TGF-\\u03b2 enhancement not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovered an allosteric pocket distinct from the active site whose inhibitor occupancy collapses catalysis, giving both a druggable mechanism and a tool to recapitulate DUSP10 deficiency.\",\n      \"evidence\": \"MKP5\\u2013inhibitor co-crystal structure, phosphopeptide screen, p38/JNK activation and TGF-\\u03b21/Smad2 assays\",\n      \"pmids\": [\"32843541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand for the allosteric pocket, if any, unknown\", \"Selectivity against other MKPs not fully addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the chemical determinants of allosteric inhibition to a \\u03c0-\\u03c0 interaction with Tyr435, pinpointing a single residue as the structural hinge of the pocket.\",\n      \"evidence\": \"Six MKP5\\u2013inhibitor crystal structures with structure-activity relationship analysis\",\n      \"pmids\": [\"36116232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional requirement of Y435 for catalysis not yet tested at this stage\", \"Inhibitor in vivo efficacy not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Unified the allosteric and catalytic story by showing Y435 maintains pocket integrity, propagates conformational changes to active-site residues, and is itself required for p38 and JNK binding and dephosphorylation.\",\n      \"evidence\": \"X-ray crystallography, NMR, molecular dynamics, and mutagenesis\",\n      \"pmids\": [\"40745179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How physiological inputs exploit this allosteric axis is unknown\", \"Whether substrate-binding defect of Y435 mutants is independent of catalytic collapse not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified TRIM7 as the E3 ligase driving DUSP10 ubiquitination and degradation, providing the destabilizing counterpart to mTORC2 stabilization and linking DUSP10 turnover to NF-\\u03baB/MAPK hyperactivation in NAFLD.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteasome inhibition, hepatic TRIM7 KO with DUSP10-silencing epistasis in mouse NAFLD\",\n      \"pmids\": [\"41290618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type and target residues on DUSP10 not specified\", \"Coordination with mTORC2 phosphorylation not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DUSP10 reconciles its biochemically defined p38/JNK selectivity with reported ERK-dependent phenotypes, and how its multi-tissue context determines tumor-suppressive versus oncogenic or fibrogenic output, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical basis for ERK regulation despite weak in vitro ERK activity\", \"Context determinants of opposing physiological roles unknown\", \"Direct vs indirect nature of the YAP1 interaction unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 17, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 13, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 13, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAPK14\", \"MAPK8\", \"MTOR\", \"TRIM7\", \"YAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}