{"gene":"MAPK14","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1995,"finding":"Mxi2 (a splice isoform of p38α/MAPK14) interacts with Max protein and the C-terminus of c-Myc in yeast two-hybrid assays, and directly phosphorylates Max both in vitro and in vivo; the putative substrate recognition region of Mxi2 shares sequence similarity with the helix-loop-helix region of Max and c-Myc, suggesting substrate recognition via this motif.","method":"Yeast two-hybrid, in vitro and in vivo phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro kinase assay and in vivo phosphorylation, single lab with two orthogonal methods","pmids":["7479834"],"is_preprint":false},{"year":2000,"finding":"Mxi2 (p38α splice isoform) lacks most of the XI domain of p38 and has a unique 17-amino acid C-terminus. It is expressed exclusively in the kidney (distal tubule) in mice. Unlike p38α, Mxi2 is not activated by MKK3 or MKK6 and cannot phosphorylate ATF-2; its unique COOH-terminus confers these distinct properties.","method":"Immunohistochemistry, kinase assay with ATF-2 substrate, domain-swap hybrid protein analysis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay with mutagenic domain swaps, single lab, multiple orthogonal methods","pmids":["10751326"],"is_preprint":false},{"year":2000,"finding":"The C-terminus of p38α is a key determinant of inhibitor sensitivity (SB203580), substrate affinity, and phosphatase (CL100) sensitivity; Mxi2, which differs only in its C-terminus, shows greatly reduced substrate affinity, reduced sensitivity to SB203580, and its activity is largely unaffected by CL100.","method":"In vitro kinase assay, pharmacological inhibition, phosphatase assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro biochemical assays with domain-swap analysis, single lab","pmids":["10838079"],"is_preprint":false},{"year":2003,"finding":"Mxi2 (p38α splice isoform) physically associates with ERK1/2 (co-immunoprecipitation in cells and in kidney) and sustains ERK phosphorylation levels, specifically prolonging the duration of ERK nuclear signaling (activating Elk1 and HIF1α) without affecting cytoplasmic ERK substrates RSK2 and cPLA2.","method":"Co-immunoprecipitation, kinase activity assays, reporter gene assays for Elk1 and HIF1α, genetic epistasis with Ras/Raf/MEK","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, reporter assays, epistasis analysis; single lab with multiple orthogonal methods","pmids":["12697810"],"is_preprint":false},{"year":2003,"finding":"SAPK2a/p38α directly phosphorylates TAB1 at Ser423, Thr431, and Ser438 in vitro (Ser423 is a non-proline-directed site). In cells, phosphorylation of Ser423 and Thr431 is blocked by the p38 inhibitor SB 203580. p38α-mediated TAB1 phosphorylation constitutes a negative feedback loop that limits TAK1 activation, thereby coordinating p38α activity with JNK and IKK pathways downstream of TAK1.","method":"In vitro kinase assay, pharmacological inhibition, p38α-knockout MEFs, TAK1 activity assays in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with mapped phosphosites, confirmed in knockout cells, replicated across multiple stimuli and cell types","pmids":["14592977"],"is_preprint":false},{"year":2004,"finding":"Active mutants of human p38α (D176A, F327L, F327S, and double mutants) acquire high intrinsic kinase activity independent of upstream phosphorylation by destabilizing a hydrophobic core formed by Tyr69, Phe327, and Trp337 near the L16 loop, emulating conformational changes imposed by dual phosphorylation; these mutants retain substrate specificity and inhibitor sensitivity.","method":"Site-directed mutagenesis, in vitro kinase assay, structural analysis based on existing p38/ERK2 crystal structures","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple active-site mutants characterized biochemically with mechanistic structural interpretation, single rigorous study","pmids":["15284239"],"is_preprint":false},{"year":2006,"finding":"p38α activation mediates cell migration induced by CXCL12, C5a, HGF, and PDGF-BB via a PAK1/2→p38α→MAPKAP-K2→HSP27 signaling pathway. Genetic ablation of p38α (but not other p38 isoforms) abolished migration; RNAi against MAPKAP-K2 or HSP27 also blocked migration, placing these downstream of p38α.","method":"Genetic knockout mice, pharmacological inhibition (SB203580, BIRB0796), RNAi knockdown, cell migration assays","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, pharmacological inhibition, and RNAi knockdown across multiple cell types and stimuli; independently consistent results","pmids":["16574378"],"is_preprint":false},{"year":2006,"finding":"Multiple activation mechanisms of p38α exist in cells: (1) canonical MKK3/6-dependent phosphorylation (primary); (2) TAB1-mediated autophosphorylation independent of MKK3/4/6; (3) peroxynitrite-induced phosphorylation via a disulfide-bond complex involving a ~85-kDa binding partner of p38α. TAB1-mediated autophosphorylation did not require MKK3/4/6, and TAB1 inhibited p38α phosphorylation in the peroxynitrite-induced complex.","method":"MKK3/6 and MKK4/7 double-knockout MEFs, mutagenesis of p38α cysteines, immunoprecipitation, phospho-p38 immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic double knockouts combined with mutagenesis and biochemical fractionation, multiple orthogonal approaches in one study","pmids":["16849316"],"is_preprint":false},{"year":2007,"finding":"p38α (MAPK14) suppresses cell proliferation by antagonizing the JNK–c-Jun pathway. In Mapk14-deficient embryonic fibroblasts, fetal hematopoietic cells, and hepatocytes, proliferation increased due to sustained JNK-c-Jun activation. Inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient cells, placing p38α as a negative regulator upstream of the JNK-c-Jun axis.","method":"Conditional Mapk14 knockout mice, genetic epistasis (JNK and c-Jun inactivation), cell proliferation assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in multiple cell types, genetic epistasis with JNK/c-Jun, replicated across hepatocytes, fibroblasts, and hematopoietic cells","pmids":["17468757"],"is_preprint":false},{"year":2007,"finding":"p38α positively regulates CCAAT/enhancer-binding protein expression required for lung cell differentiation, and controls self-renewal by inhibiting epidermal growth factor receptor-driven proliferation signals in lung stem/progenitor cells.","method":"Conditional p38α knockout mice (adult), in vivo and in vitro differentiation assays, signaling pathway analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined cellular phenotype, molecular mechanism of EGFR pathway involvement, replicated in vivo and in vitro","pmids":["17468755"],"is_preprint":false},{"year":2009,"finding":"p38α C-terminal cap (C-lobe) contains a lipid-binding pocket formed around residue Trp197; a lead compound binds both the active site and this C-terminal hydrophobic pocket, inducing movement of the C-terminal cap region. This pocket is structurally distinct from the ATP-binding site and can accommodate lipids, leukotrienes, and small-molecule effectors.","method":"X-ray crystallography, computational analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with bound ligand, single study","pmids":["19501598"],"is_preprint":false},{"year":2012,"finding":"MAPK14/p38α, when activated specifically by the GADD45B-MAP3K4 signaling complex (but not by other activators), localizes to autophagosomes and directly phosphorylates ATG5 at threonine 75, impairing autophagosome-lysosome fusion and thus inhibiting autophagic flux. ATG5 T75 phosphorylation-defective mutants show enhanced autophagy.","method":"Subcellular fractionation to autophagosomes, in vitro kinase assay, phosphorylation-defective and phosphomimetic ATG5 reconstitution, MAPK14-knockout and GADD45B-knockout cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mapped phosphosite, mutant reconstitution in knockout cells, localization data linked to functional consequence","pmids":["23235332"],"is_preprint":false},{"year":2012,"finding":"MAPK14/p38α is required for irinotecan (SN-38) resistance in TP53-null colon cancer cells by inducing survival autophagy; constitutively active MAPK14/p38α decreases SN-38 sensitivity and induces autophagy, and inhibition of either MAPK14 or autophagy sensitizes cells to drug therapy in a mutually dependent manner.","method":"Overexpression of constitutively active MAPK14, siRNA knockdown, pharmacological inhibition, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with mechanistic links to autophagy, single lab with multiple approaches","pmids":["22647487"],"is_preprint":false},{"year":2013,"finding":"p38α autoactivation during myocardial ischemia occurs in cis by direct interaction with TAB1(371-416). Crystal structures revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe; TAB1 binding stabilizes active p38α and induces helical extension of the Thr-Gly-Tyr activation segment, allowing autophosphorylation in cis. TAT-TAB1(371-416) peptide rapidly activates p38 in cardiac myocytes and perfused hearts and causes profound functional perturbation. A chemical-genetic approach in bacterial and cell-free systems confirmed the cis autophosphorylation mechanism.","method":"X-ray crystallography, solution characterization, chemical-genetic approaches, coexpression in mammalian/bacterial/cell-free systems, isolated cardiomyocytes and perfused heart ex vivo","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with multiple orthogonal validation methods (chemical genetics, in vitro reconstitution, ex vivo cardiac model), single rigorous study","pmids":["24037507"],"is_preprint":false},{"year":2013,"finding":"p38α regulates cardiac contractility by suppressing phosphorylation of phospholamban (PLB) via activation of protein phosphatase 2A, which dephosphorylates PP1 inhibitor-1, thereby activating PP1 and reducing PLB phosphorylation. Inhibition of p38α (dominant-negative p38α or RNAi) specifically enhanced PLB phosphorylation and SERCA2a-dependent diastolic Ca2+ uptake; this effect was p38α-specific and not observed with dominant-negative p38β.","method":"Dominant-negative overexpression, RNAi knockdown, Ca2+-transient measurements, protein phosphatase activity assays in cardiomyocytes and perfused hearts","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific interventions with functional readout, single lab with multiple approaches","pmids":["24361238"],"is_preprint":false},{"year":2013,"finding":"PRMT1 directly interacts with p38α (co-immunoprecipitation) and methylates p38α in vitro. PRMT1 acts upstream of p38α to promote erythroid differentiation; PRMT1-stimulated differentiation was abolished in p38α-knockdown cells but not p38β-knockdown cells, and PRMT1 enhanced p38 MAPK activation.","method":"Co-immunoprecipitation, in vitro methylation assay, shRNA knockdown, erythroid differentiation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro methylation assay and co-IP, isoform-specific knockdown with functional readout; single lab","pmids":["23483889"],"is_preprint":false},{"year":2014,"finding":"Docking interactions between active p38α and MK2's C-terminal domain allosterically enhance p38α's enzymatic activity toward MK2 by promoting ATP binding and phosphoacceptor accommodation, thus accelerating the phosphotransfer reaction. This was characterized by solution NMR showing that phosphorylation and ATP loading collaboratively induce active p38α conformation, and the docking interaction further enhances catalysis beyond just substrate anchoring.","method":"Solution NMR, in vitro kinase assay with dually phosphorylated p38α and MK2 fragments","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural characterization combined with in vitro kinase assay revealing allosteric mechanism; single rigorous study with multiple orthogonal methods","pmids":["25038803"],"is_preprint":false},{"year":2014,"finding":"Chemical phosphorylation of p38α at Thr180 (using a phosphocysteine mimic, pCys180) is sufficient to switch the kinase to an active state capable of phosphorylating ATF2; phosphorylation at position 172 does not activate the kinase. This demonstrates Thr180 as the dominant activating site. Type II inhibitors inhibit phosphorylated p38α, whereas Type I inhibitors show differential behavior.","method":"Tag-and-modify chemical modification, in vitro kinase assay with ATF2 substrate, kinetic analysis","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — semisynthetic phosphorylation with functional reconstitution; single rigorous study with novel chemistry and kinetic validation","pmids":["24393126"],"is_preprint":false},{"year":2014,"finding":"MAPK14/p38α modulates glucose metabolism during starvation at two levels: (1) it increases SLC2A3 (GLUT3) mRNA and protein by enhancing HIF1A protein stability, boosting glucose uptake; (2) it promotes metabolic shift from glycolysis to the pentose phosphate pathway by inducing proteasomal degradation of PFKFB3 via KEN box and DSG motif Ser273 recognition sequences. This MAPK14-driven metabolic reprogramming sustains NADPH production and reduces ROS, limiting autophagy.","method":"MAPK14 knockdown, pharmacological inhibition, metabolic flux assays, protein stability assays, mutagenesis of PFKFB3 degradation motifs","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with metabolic readouts and mutagenesis of substrate degradation motifs; single lab with multiple approaches","pmids":["25046111"],"is_preprint":false},{"year":2014,"finding":"p38α functions downstream of BMP2/7 signaling and MKK6 (but not MKK3) in ameloblasts to regulate amelogenin and β4-integrin expression and p21 expression in the enamel knot, required for tooth morphogenesis and enamel secretion.","method":"Conditional p38α knockout (K14-Cre), MKK3 and MKK6 knockout mice, BMP2/7 stimulation in explant culture and ameloblast cell line","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with isoform-specific MKK epistasis and ligand stimulation, replicated in vivo and in vitro","pmids":["25406311"],"is_preprint":false},{"year":2015,"finding":"MAPK14/p38α is required for mitophagy induced by starvation or hypoxia in mammalian cells. Knockdown of MAPK14 severely suppressed mitophagy, which was found to occur predominantly through alternative autophagy (RAB9A/B-dependent) rather than conventional macroautophagy.","method":"pH-sensitive fluorescent protein Keima mitophagy assay, siRNA knockdown, Atg5 knockout MEFs","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific mitophagy assay with RNAi knockdown and genetic knockout controls; single lab","pmids":["25831013"],"is_preprint":false},{"year":2015,"finding":"Hepatic p38α negatively regulates AMPK signaling to maintain gluconeogenesis during fasting. Loss of hepatic p38α increases AMPKα phosphorylation without altering CREB phosphorylation; dominant-negative AMPKα abolished the anti-gluconeogenic effect of p38α loss. TAK1 knockdown decreased AMPKα phosphorylation in p38α-deficient cells, suggesting a negative feedback loop.","method":"Liver-specific p38α knockout mice, adenoviral dominant-negative constructs, pyruvate tolerance tests, in vivo and in vitro gluconeogenesis assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with adenoviral rescue, epistasis with dominant-negative AMPK, replicated in vivo and in vitro in multiple models","pmids":["25595884"],"is_preprint":false},{"year":2015,"finding":"Mitophagy-related pyridinyl-imidazole class inhibitors (SB203580/SB202190) interfere with autophagic flux in a MAPK14/p38-independent manner, making them unsuitable as pharmacological tools to study p38-dependent autophagy.","method":"Pharmacological inhibition with SB203580/SB202190 in p38-deficient cells, autophagic flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative mechanistic finding validated using p38-deficient cells; single lab","pmids":["26061537"],"is_preprint":false},{"year":2016,"finding":"p38α activity is required for myogenesis by displacing the histone methyltransferase KMT1A from MyoD via direct phosphorylation of KMT1A; p38α activity removes repressive H3K9me3 marks from the Myogenin promoter and is necessary and sufficient for establishing active H3K9 acetylation at this locus.","method":"Pharmacological inhibition, lentiviral p38α shRNA, constitutively active upstream kinase overexpression, co-immunoprecipitation, ChIP for H3K9me3 and H3K9ac, in vitro kinase assay","journal":"Skeletal muscle","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay establishing direct phosphorylation, combined with ChIP for chromatin marks, gain-of-function and loss-of-function; single rigorous study with multiple orthogonal methods","pmids":["27551368"],"is_preprint":false},{"year":2017,"finding":"Sustained p38α activation drives metabolic changes including increased glucose and glutamine dependence, enhanced respiration, and elevated mitochondrial ROS, partly through the downstream kinase MK2 (MAPKAPK2). Elevated mitochondrial superoxide from this metabolic state contributes to p38α-induced reduced cell survival.","method":"Inducible p38α activation system, metabolic flux assays, MK2 knockout/knockdown, ROS measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible activation system with genetic validation of MK2 role; single lab","pmids":["28900160"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of active pp38α in complex with TAB1 (residues 1-438) in the active state was solved. Four TAB1 residues required for docking onto p38α were identified; knock-in mice with substitutions at these four TAB1 residues were viable and showed reduced infarction volume and disabled TAB1 transphosphorylation following myocardial ischemia, while myocardial p38α activation was only mildly attenuated.","method":"X-ray crystallography, TAB1 knock-in mouse model, in vivo regional myocardial ischemia model, fragment-based small molecule screening for disruption of p38α-TAB1 interaction","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with knock-in mouse model and in vivo functional validation; single rigorous multidisciplinary study","pmids":["30135318"],"is_preprint":false},{"year":2018,"finding":"TAB1-induced p38α autoactivation in cis requires an intramolecular hydrogen bond between Thr185 and Asp150 in the activation segment. Mutation T185G disrupts this hydrogen bond and specifically disables autophosphorylation while leaving MKK3/MKK6-mediated activation and downstream substrate phosphorylation intact. Cardiac cells expressing p38α(T185G) are resistant to ischemic injury.","method":"Structural analysis of p38α-TAB1 crystal structure, T185G mutagenesis, in vitro and in vivo kinase assays, TAB1-binding assay, cardiac myocyte injury model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis validated by in vitro and in vivo assays, mechanistic dissection of two activation modes; single rigorous study","pmids":["29229647"],"is_preprint":false},{"year":2018,"finding":"p38α phosphorylates CtIP (DNA repair regulator), and loss of p38α signaling in breast cancer cells impairs ATR activation and homologous recombination repair, increasing replication stress, DNA damage, and chromosome instability. Pharmacological p38α inhibition potentiates taxane effects by boosting chromosome instability.","method":"Conditional p38α knockout/pharmacological inhibition, DNA damage assays, HR repair assays, ATR activation assays, murine models and patient-derived xenografts","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with defined molecular substrate (CtIP) and repair pathway phenotypes; single lab with multiple readouts","pmids":["29805078"],"is_preprint":false},{"year":2018,"finding":"In dendritic cells, p38α negatively regulates IL-27 production through the TAK1-MKK4/7-JNK-c-Jun axis; loss of p38α in colonic cDC1s leads to hyperactivation of JNK-c-Jun, elevated IL-27, and increased Tr1 cell differentiation. ChIP assay confirmed direct binding of c-Jun to the Il27p28 promoter, which was enhanced in p38α-deficient DCs.","method":"DC-specific p38α conditional knockout, ChIP assay, JNK pathway inhibition, cytokine measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with ChIP epistasis, multiple genetic and pharmacological interventions; single lab with orthogonal methods","pmids":["30541887"],"is_preprint":false},{"year":2019,"finding":"p38α in mesenchymal stem/stromal cells negatively regulates an angiogenic program including TGF-β-induced acquisition of an endothelial phenotype (mesenchymal-to-endothelial transition) and JNK-dependent signaling. Abrogation of p38α in mesenchymal cells increases tumorigenesis correlated with enhanced angiogenesis.","method":"Genetic mouse models with mesenchymal-specific p38α deletion, in vivo tumor models, genetic epistasis with TGF-β and JNK pathways","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse models with defined pathway epistasis (TGF-β, JNK), replicated in human and mouse colon tumors and damage tissue","pmids":["31296856"],"is_preprint":false},{"year":2019,"finding":"Sustained p38α activation drives autophagosome formation and enhances autophagic flux, requiring both increased mitochondrial ROS and p38α-mediated phosphorylation of ULK1 at Ser-555. This autophagy induction directs cancer cells preferentially toward senescence rather than apoptosis, protecting them from chemotherapy-induced apoptosis.","method":"Inducible p38α activation system, autophagy flux assays, ULK1 phosphorylation assays, genetic knockdown, cell fate analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible system with mapped phosphosite (ULK1-S555) and genetic validation; single lab","pmids":["31092814"],"is_preprint":false},{"year":2019,"finding":"Macrophage p38α promotes steatohepatitis by inducing M1 macrophage polarization and pro-inflammatory cytokine secretion (CXCL2, IL-1β, CXCL10, IL-6). In co-culture, p38α-deleted macrophages attenuated steatohepatitic changes in hepatocytes via decreased secretion of TNF-α, CXCL10, and IL-6; restoration of these cytokines rescued the phenotype.","method":"Macrophage-specific p38α conditional knockout, co-culture experiments, cytokine restoration experiments, macrophage polarization assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with co-culture rescue experiments defining the cytokine mediators; single lab with multiple dietary models","pmids":["30914267"],"is_preprint":false},{"year":2019,"finding":"Myeloid p38α drives intestinal IGF-1 production in macrophages, which mediates colon inflammation and tumorigenesis. Genetic and pharmacological inhibition of p38α in myeloid cells reduced IGF-1 production and tumorigenesis; IGF-1 signaling acted downstream of p38α in macrophages.","method":"Myeloid-specific p38α conditional knockout, pharmacological inhibition, adenoviral overexpression/knockdown of IGF-1","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myeloid-specific knockout with pharmacological and genetic IGF-1 manipulation; single lab","pmids":["29907597"],"is_preprint":false},{"year":2019,"finding":"In vascular smooth muscle cells, MAPK14 suppresses the contractile phenotype and promotes proliferation and inflammation via a p65/NF-κB-dependent pathway. NOX4 contributes upstream to MAPK14-mediated suppression of VSMC contractile differentiation. Inducible SMC-specific MAPK14 knockout mice showed reduced neointima formation after carotid injury.","method":"Inducible SMC-specific knockout mice, carotid ligation injury model, VSMC lineage tracing, RNA array, pharmacological inhibition, MAPK14 forced expression","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible cell-type-specific knockout with multiple pharmacological and molecular approaches defining NF-κB and NOX4 pathway placement","pmids":["30771750"],"is_preprint":false},{"year":2019,"finding":"p38α in lung cancer epithelial cells promotes KRAS(G12V)-driven tumor progression via autonomous expression of TIMP-1, which stimulates cell proliferation in an autocrine manner. Despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α is required for proliferation and malignization of lung cancer cells.","method":"Conditional p38α deletion in vivo, KRAS(G12V) lung cancer mouse models, pharmacological inhibition, TIMP-1 expression/secretion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with identification of TIMP-1 as autocrine mediator; single lab","pmids":["31969449"],"is_preprint":false},{"year":2020,"finding":"Activation of p38α in lung fibroblasts by tumor-derived factors leads to inactivation of type I interferon signaling and stimulation of fibroblast activation protein (FAP) expression. FAP drives extracellular matrix remodeling and chemokine expression enabling neutrophil lung infiltration, establishing a pre-metastatic niche for pulmonary metastases.","method":"p38α activation in lung fibroblasts by tumor-conditioned medium, FAP gain/loss-of-function, in vivo metastasis models, pharmacological p38 inhibition","journal":"Nature cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific functional studies with genetic and pharmacological interventions defining FAP as downstream effector; single lab","pmids":["34124690"],"is_preprint":false},{"year":2021,"finding":"Constitutive activation of p38α in the liver (via intrinsically active p38α allele) is sufficient to cause macrovesicular fatty liver, associated with upregulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs. This fatty liver phenotype was reversible upon shutting off p38α mutant expression.","method":"Transgenic inducible liver-specific expression of active p38α allele, histology, gene expression analysis, reversibility experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled inducible transgenic system with reversibility; single lab","pmids":["33811139"],"is_preprint":false},{"year":2021,"finding":"SUMOylation of MAPK14/p38α occurs at lysine 152. p38α-SUMOylation acts as a sensor/accelerator of ROS generation through interaction with and activation of MK2 in the nucleus; ROS accumulation in turn promotes p38α SUMOylation by stabilizing PIASxα. This PIASxα/p38α-SUMOylation/MK2 cis-axis facilitates gastric cancer metastasis.","method":"Immunoprecipitation, pull-down assays, SUMOylation site mapping, nuclear localization studies, ROS assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mapped SUMOylation site by IP and pull-down with nuclear functional readout; single lab","pmids":["34686655"],"is_preprint":false},{"year":2022,"finding":"p38α in B cells drives plasma cell differentiation by upregulating BLIMP1 transcription through downstream effectors TCF3, TCF4, and IRF4 (identified by CRISPR/Cas9 screening). B cell-specific p38α deletion severely impaired plasma cell differentiation and antibody responses while sparing B cell development and germinal center responses.","method":"B cell-specific conditional p38α knockout, Blimp1 reporter mouse, CRISPR/Cas9 screen, antibody response assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with reporter mice and CRISPR screen defining pathway downstream to BLIMP1; single lab with multiple orthogonal methods","pmids":["36443297"],"is_preprint":false},{"year":2022,"finding":"P38α in uterine stroma phosphorylates the E3 ubiquitin ligase Ube3c at serine741, restraining Ube3c's polyubiquitination activity toward progesterone receptor (PR) and preventing its proteasomal degradation. In uterine-specific p38α knockout mice, Ube3c targets PR for degradation, causing defective implantation and female infertility.","method":"Uterine-specific p38α conditional knockout, in vitro phosphorylation assay (LC-MS confirmed Ube3c-S741 phosphorylation), ubiquitination assays, proteasome inhibitor rescue, Foxo1S273D/A knockin models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with LC-MS phosphosite mapping, combined with conditional knockout and ubiquitination functional studies; single rigorous multidisciplinary study","pmids":["35914132"],"is_preprint":false},{"year":2022,"finding":"p38α in cDC1 dendritic cells regulates Th2-cell differentiation by modulating the MK2-c-FOS-IL-12 axis. cDC1-specific but not cDC2-specific p38α deletion promoted Th2 responses, and the mechanism involved p38α-dependent MK2 activation controlling c-FOS and IL-12 production.","method":"Cell-type-specific conditional knockouts (cDC1, cDC2, macrophage), MK2-c-FOS-IL-12 pathway analysis, Th2 differentiation assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific knockouts with defined MK2-c-FOS-IL12 pathway; single lab","pmids":["35551270"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of p38α in complex with its MAP2K MKK6 reveals a dynamic, multistep dual phosphorylation mechanism for p38α activation. The MAP2K-disordered N-terminal amino termini determine pathway specificity. Catalytically relevant interactions between MKK6 and p38α were identified and validated by HDX-MS, molecular dynamics simulations, and cell-based experiments.","method":"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry, molecular dynamics simulations, cell-based functional experiments","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with multiple orthogonal validation methods (HDX-MS, MD, cell experiments); single rigorous multidisciplinary study","pmids":["37708276"],"is_preprint":false},{"year":2023,"finding":"Hepatic p38α phosphorylates FOXO1 at S273 in response to glucagon (via EPAC2 signaling), increasing FOXO1 protein stability and promoting hepatic glucose production. This EPAC2-p38α-pFOXO1-S273 axis is required for glucagon-stimulated HGP; Foxo1S273A knock-in mice showed reduced glucose production and improved insulin sensitivity.","method":"siRNA knockdown, adeno-associated virus shRNA in liver-specific knockout mice, in vitro LC-MS phosphorylation assay, Foxo1S273D and Foxo1S273A knockin mice, glucagon tolerance tests","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with LC-MS phosphosite mapping validated by knockin mouse models with defined metabolic phenotypes; single rigorous study with multiple orthogonal methods","pmids":["37202506"],"is_preprint":false},{"year":2024,"finding":"MAPK phosphatase 1 (MKP1) promotes lung myofibroblast dedifferentiation and restores apoptosis sensitivity by dephosphorylating p38α MAPK. Fibroblast-specific MKP1 deletion after peak bleomycin-induced fibrosis abrogated spontaneous fibrosis resolution; treatment with p38α inhibitor VX-702 restored resolution in MKP1-knockout transgenic mice.","method":"Fibroblast-specific conditional MKP1 knockout (gain- and loss-of-function), bleomycin fibrosis model, pharmacological p38α inhibition with VX-702, MKP1-p38α dephosphorylation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — fibroblast-specific conditional knockout with pharmacological rescue defining MKP1-p38α as the relevant axis; single lab with multiple orthogonal approaches","pmids":["38512415"],"is_preprint":false},{"year":2025,"finding":"Lobeline binds directly to MAPK14 (confirmed by DARTS assay and target-responsive accessibility profiling), preventing nuclear translocation of MAPK14. This reduces phosphorylation of p53, relieving p53-mediated transcriptional repression of SLURP1, which in turn promotes M1 macrophage polarization of tumor-associated macrophages and suppresses colorectal cancer growth.","method":"Target-responsive accessibility profiling, DARTS assay, nuclear/cytoplasmic fractionation, p53 phosphorylation assays, Slurp1-deficient MC38 xenografts","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding validated by DARTS assay, nuclear localization experiment with functional consequence, genetic validation with Slurp1-knockout cells; single lab","pmids":["39840525"],"is_preprint":false}],"current_model":"MAPK14/p38α is a stress-activated serine/threonine kinase that is canonically activated by dual phosphorylation at Thr180/Tyr182 by MKK3/MKK6 (with MKK4 contributing), or alternatively by TAB1-mediated cis-autophosphorylation (particularly during cardiac ischemia) through a mechanism requiring Thr185 and a bipartite C-lobe docking site; its docking interactions with substrates (e.g., MK2) allosterically enhance catalytic activity, and it phosphorylates a broad array of substrates—including TAB1, ATF2, CtIP, ULK1-S555, FOXO1-S273, Ube3c-S741, ATG5-T75, KMT1A, Max, and HSP27—to coordinate inflammation, cell proliferation vs. differentiation, autophagy, metabolism (gluconeogenesis, glucose metabolism, mitophagy), cardiac contractility, and tissue homeostasis; its activity is terminated by MKP1-mediated dephosphorylation, and a splice isoform (Mxi2) with a unique C-terminus shows distinct substrate specificity, inhibitor sensitivity, and selectively sustains nuclear ERK signaling."},"narrative":{"mechanistic_narrative":"MAPK14/p38α is a stress- and signal-activated serine/threonine protein kinase that coordinates inflammation, cell proliferation versus differentiation, autophagy, metabolism, and tissue homeostasis through direct phosphorylation of a broad substrate repertoire [PMID:17468757, PMID:23235332, PMID:37202506]. Its catalytic activation is achieved by two structurally defined routes: canonical dual phosphorylation of the activation segment by MKK6 through a dynamic multistep mechanism whose MAP2K disordered N-terminus dictates pathway specificity [PMID:37708276], and a non-canonical cis-autophosphorylation driven by direct TAB1 docking at a bipartite C-lobe site that stabilizes the active conformation and extends the Thr-Gly-Tyr segment, with this autoactivation requiring an intramolecular Thr185–Asp150 hydrogen bond and being central to ischemic cardiac injury [PMID:24037507, PMID:30135318, PMID:29229647]. Activation requires Thr180 as the dominant activating phosphosite [PMID:24393126], and substrate docking—exemplified by MK2—allosterically accelerates catalysis beyond simple anchoring [PMID:25038803]. Through these mechanisms p38α phosphorylates ATG5-T75, ULK1-S555, FOXO1-S273, Ube3c-S741, CtIP, KMT1A, TAB1, and HSP27 (via the PAK→p38α→MK2→HSP27 migration axis) to control autophagy and mitophagy, gluconeogenesis and glucose metabolism, DNA repair, myogenic chromatin remodeling, cell migration, and uterine implantation [PMID:14592977, PMID:16574378, PMID:23235332, PMID:27551368, PMID:29805078, PMID:31092814, PMID:35914132, PMID:37202506]. In its tissue roles p38α acts as a context-dependent brake on proliferation by antagonizing the JNK–c-Jun axis and tuning EGFR signaling in progenitor cells [PMID:17468757, PMID:17468755, PMID:30541887], yet drives malignant proliferation, fibrosis, steatohepatitis, and pre-metastatic niche formation in other settings through effectors such as TIMP-1, IGF-1, FAP, and NF-κB [PMID:30914267, PMID:29907597, PMID:31969449, PMID:34124690, PMID:30771750]. Its activity is terminated by MKP1-mediated dephosphorylation, which permits fibrosis resolution [PMID:38512415]. A kidney-restricted splice isoform, Mxi2, differs only in its C-terminus, escapes MKK3/6 activation and ATF2 phosphorylation, shows altered inhibitor and phosphatase sensitivity, and instead binds ERK1/2 to selectively sustain nuclear ERK signaling [PMID:7479834, PMID:10751326, PMID:10838079, PMID:12697810].","teleology":[{"year":1995,"claim":"Established that a p38α splice isoform (Mxi2) carries intrinsic kinase activity directed at a specific transcription factor, raising the question of isoform-specific substrate recognition.","evidence":"Yeast two-hybrid plus in vitro/in vivo phosphorylation of Max","pmids":["7479834"],"confidence":"Medium","gaps":["Physiological relevance of Max phosphorylation in vivo not established","Substrate-recognition motif inferred from sequence similarity, not structurally proven"]},{"year":2000,"claim":"Defined the unique C-terminus of Mxi2 as the determinant of its divergent regulation, showing it cannot be activated by MKK3/6 or phosphorylate ATF2 and is kidney-restricted, distinguishing it functionally from p38α.","evidence":"Immunohistochemistry, kinase assays, and domain-swap hybrids","pmids":["10751326","10838079"],"confidence":"Medium","gaps":["In vivo function of kidney Mxi2 unresolved","Physiological activator of Mxi2 unknown"]},{"year":2003,"claim":"Revealed that Mxi2 acts as an ERK scaffold, physically binding ERK1/2 to prolong specifically nuclear ERK signaling, connecting the p38 locus to cross-pathway control.","evidence":"Reciprocal co-IP, reporter assays, Ras/Raf/MEK epistasis","pmids":["12697810"],"confidence":"Medium","gaps":["Mechanism by which Mxi2 selectively protects nuclear ERK unclear","Structural basis of the Mxi2–ERK interaction not solved"]},{"year":2003,"claim":"Identified TAB1 as a direct p38α substrate phosphorylated at mapped sites, establishing a negative feedback loop limiting TAK1 and coordinating p38α with JNK/IKK pathways.","evidence":"In vitro kinase assay with mapped sites, p38α-knockout MEFs, TAK1 activity assays","pmids":["14592977"],"confidence":"High","gaps":["Quantitative contribution of feedback to in vivo signaling not defined"]},{"year":2004,"claim":"Demonstrated that conformational changes near the L16 loop alone can confer high intrinsic activity, mechanistically separating activation from upstream phosphorylation.","evidence":"Active-site mutants with biochemical kinase assays and structural interpretation","pmids":["15284239"],"confidence":"High","gaps":["Whether equivalent conformational states occur physiologically not addressed"]},{"year":2006,"claim":"Catalogued the multiple activation modes of p38α—canonical MKK3/6, TAB1-mediated autophosphorylation, and peroxynitrite-induced disulfide complexes—and placed p38α in a defined migration pathway (PAK→p38α→MK2→HSP27).","evidence":"MKK double-knockout MEFs, cysteine mutagenesis, isoform-specific knockout and RNAi in migration assays","pmids":["16849316","16574378"],"confidence":"High","gaps":["Identity of the ~85-kDa peroxynitrite partner unresolved","Relative weighting of activation modes across tissues unknown"]},{"year":2007,"claim":"Defined p38α as a context-dependent suppressor of proliferation, antagonizing the JNK–c-Jun axis and tuning EGFR-driven progenitor self-renewal.","evidence":"Conditional Mapk14 knockout in multiple cell types with JNK/c-Jun epistasis and differentiation assays","pmids":["17468757","17468755"],"confidence":"High","gaps":["Direct substrates linking p38α to JNK/c-Jun suppression not all identified","Tissue-specific switch between suppressor and promoter roles not mechanistically explained"]},{"year":2009,"claim":"Identified a C-lobe lipid-binding pocket around Trp197 distinct from the ATP site, expanding the allosteric ligand landscape of p38α.","evidence":"X-ray crystallography with bound ligand and computational analysis","pmids":["19501598"],"confidence":"High","gaps":["Endogenous lipid ligand of the pocket not identified","Functional consequence of pocket occupancy in cells untested"]},{"year":2012,"claim":"Showed that activator-specific p38α (via GADD45B-MAP3K4) localizes to autophagosomes and phosphorylates ATG5-T75 to block autophagosome–lysosome fusion, linking p38α to autophagy regulation and chemoresistance.","evidence":"Subcellular fractionation, in vitro kinase with mapped site, mutant reconstitution in knockout cells; plus siRNA/inhibitor work in TP53-null colon cancer","pmids":["23235332","22647487"],"confidence":"High","gaps":["How activator identity dictates p38α autophagosome targeting unclear","Direction of autophagy effect varies by context"]},{"year":2013,"claim":"Solved the structural basis of TAB1-driven cis-autophosphorylation and connected it causally to myocardial ischemic injury and to cardiac contractility via PP2A/PP1/phospholamban.","evidence":"Crystallography, chemical-genetics, cell-free reconstitution, ex vivo cardiomyocyte and perfused-heart models; phosphatase activity assays","pmids":["24037507","24361238"],"confidence":"High","gaps":["Direct substrate(s) of p38α driving the contractility phenotype not fully mapped","PRMT1-mediated methylation of p38α (PMID 23483889) regulatory role incompletely defined"]},{"year":2014,"claim":"Defined the activating chemistry and allostery of p38α—Thr180 as the dominant activating phosphosite and substrate docking (MK2) that accelerates phosphotransfer—while extending p38α to glucose metabolic reprogramming.","evidence":"Semisynthetic phosphorylation, solution NMR, in vitro kinase kinetics; metabolic flux assays and PFKFB3 degron mutagenesis","pmids":["24393126","25038803","25046111"],"confidence":"High","gaps":["In vivo dominance of Thr180 over Tyr182 not directly tested","Mechanism coupling p38α to HIF1A stabilization not fully resolved"]},{"year":2015,"claim":"Established hepatic and organelle-level metabolic roles: p38α restrains AMPK to sustain fasting gluconeogenesis and is required for starvation/hypoxia mitophagy via the alternative RAB9 pathway.","evidence":"Liver-specific knockout with dominant-negative AMPK epistasis; Keima mitophagy assay with knockdown and Atg5-KO controls","pmids":["25595884","25831013","26061537"],"confidence":"High","gaps":["Direct p38α substrate in AMPK feedback not identified","Pyridinyl-imidazole inhibitors confound pharmacological dissection of p38-autophagy link"]},{"year":2016,"claim":"Linked p38α to chromatin remodeling, showing it phosphorylates KMT1A to displace it from MyoD and reprogram H3K9 marks at the Myogenin promoter during myogenesis.","evidence":"In vitro kinase, co-IP, ChIP for H3K9me3/ac, gain- and loss-of-function","pmids":["27551368"],"confidence":"High","gaps":["KMT1A phosphosite(s) not mapped here","Generalizability to other lineage-specifying loci untested"]},{"year":2018,"claim":"Refined the cis-autoactivation mechanism to an intramolecular Thr185–Asp150 hydrogen bond and four TAB1 docking residues, enabling separation-of-function mutants that confer ischemia resistance, and added a DNA-repair substrate (CtIP).","evidence":"Crystallography, structure-guided T185G mutagenesis, TAB1 knock-in mice, cardiac injury models; conditional knockout/inhibition with HR repair and ATR assays","pmids":["30135318","29229647","29805078"],"confidence":"High","gaps":["CtIP phosphosite(s) not mapped","Therapeutic separation of autophosphorylation from canonical activity not yet translated"]},{"year":2019,"claim":"Mapped diverse tissue programs: ULK1-S555-dependent autophagy steering cells to senescence, and cell-type-specific pro-disease roles in immune, vascular, stromal, and cancer settings via NF-κB/NOX4, IGF-1, TGF-β/JNK, IL-27, and TIMP-1.","evidence":"Inducible activation systems with mapped ULK1-S555; multiple cell-type-specific conditional knockouts with pathway epistasis and tumor/injury models","pmids":["31092814","30771750","29907597","31296856","30541887","31969449"],"confidence":"High","gaps":["Molecular basis for opposing tumor-suppressor versus tumor-promoter outcomes not unified","Direct substrates downstream of most tissue phenotypes unidentified"]},{"year":2021,"claim":"Showed constitutively active p38α is sufficient to cause reversible fatty liver and that SUMOylation at K152 modulates a nuclear p38α–MK2 ROS-sensing axis.","evidence":"Inducible active-allele transgenics with reversibility; SUMO site mapping by IP/pull-down with nuclear ROS readouts","pmids":["33811139","34686655"],"confidence":"Medium","gaps":["SUMOylation mechanism single-lab, not independently confirmed","Substrates mediating the fatty-liver gene-expression program not defined"]},{"year":2022,"claim":"Extended the substrate-and-program map to plasma cell differentiation (BLIMP1 via TCF3/4/IRF4), uterine implantation (Ube3c-S741 protecting progesterone receptor), and dendritic-cell-controlled Th2 responses (MK2-c-FOS-IL-12).","evidence":"B-cell, uterine, and DC-specific conditional knockouts; CRISPR screen, reporter mice, in vitro kinase with LC-MS phosphosite mapping, ubiquitination assays","pmids":["36443297","35914132","35551270"],"confidence":"High","gaps":["Direct BLIMP1-axis substrate of p38α not identified","Cross-tissue generality of the Ube3c regulatory mechanism unknown"]},{"year":2023,"claim":"Defined the dynamic multistep dual-phosphorylation mechanism by which MKK6 activates p38α and showed MAP2K N-termini dictate pathway specificity, while identifying FOXO1-S273 as a glucagon/EPAC2-driven hepatic substrate controlling glucose production.","evidence":"Cryo-EM with HDX-MS and MD validation; in vitro LC-MS phosphosite mapping with Foxo1-S273 knock-in mice and glucagon tolerance tests","pmids":["37708276","37202506"],"confidence":"High","gaps":["Structural basis of substrate (versus activator) discrimination not fully generalized"]},{"year":2024,"claim":"Established MKP1-mediated dephosphorylation of p38α as the off-switch enabling fibrosis resolution and myofibroblast dedifferentiation.","evidence":"Fibroblast-specific MKP1 conditional knockout with VX-702 p38α inhibitor rescue in bleomycin fibrosis","pmids":["38512415"],"confidence":"High","gaps":["p38α substrates driving myofibroblast persistence not mapped"]},{"year":2025,"claim":"Connected p38α nuclear translocation to p53-dependent transcription, showing a small molecule (lobeline) that blocks nuclear entry relieves p53 repression of SLURP1 to reprogram tumor macrophages.","evidence":"DARTS and target-responsive accessibility profiling, nuclear/cytoplasmic fractionation, p53 phosphorylation assays, Slurp1-deficient xenografts","pmids":["39840525"],"confidence":"Medium","gaps":["Direct p53 phosphorylation by p38α site not mapped here","Single-lab binding/mechanism not independently replicated"]},{"year":null,"claim":"It remains unresolved what molecular features dictate p38α's opposing context-dependent outcomes (tumor suppressor versus promoter; pro- versus anti-autophagic) and how activator identity, subcellular localization, and post-translational modification combine to select specific substrate sets.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking upstream activator to downstream substrate selection","Direct substrates behind many tissue phenotypes still unidentified","Physiological role of the C-lobe lipid pocket and SUMOylation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,11,23,39,42]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[4,11,17,39,42]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[16,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,37,44]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,8,41]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,20,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[28,31,38,40]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[18,21,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,19,23]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[27]}],"complexes":[],"partners":["TAB1","MKK6","MK2","ERK1/2","PRMT1","ATG5","ULK1","FOXO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16539","full_name":"Mitogen-activated protein kinase 14","aliases":["Cytokine suppressive anti-inflammatory drug-binding protein","CSAID-binding protein","CSBP","MAP kinase MXI2","MAX-interacting protein 2","Mitogen-activated protein kinase p38 alpha","MAP kinase p38 alpha","Stress-activated protein kinase 2a","SAPK2a"],"length_aa":360,"mass_kda":41.3,"function":"Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1 (PubMed:9687510, PubMed:9792677). RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery (PubMed:9687510, PubMed:9792677). On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2 (PubMed:11154262). MAPK14 also interacts with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53 (PubMed:10747897). In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3 (PubMed:17003045). MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9 (PubMed:19893488). Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors (PubMed:16932740). Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17 (PubMed:20188673). Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A (PubMed:10330143, PubMed:9430721, PubMed:9858528). The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation (PubMed:11333986). Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation (PubMed:20932473). The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression (PubMed:10943842). Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113' (PubMed:15905572). Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis (PubMed:35857590) (Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minutes and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PubMed:21586573)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16539/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPK14","classification":"Not Classified","n_dependent_lines":133,"n_total_lines":1208,"dependency_fraction":0.11009933774834436},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000112062","cell_line_id":"CID001203","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MAPKAPK2","stoichiometry":10.0},{"gene":"MAPKAPK3","stoichiometry":10.0},{"gene":"TRAPPC1","stoichiometry":4.0},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001203","total_profiled":1310},"omim":[{"mim_id":"621120","title":"DELTA-LIKE NONCANONICAL NOTCH LIGAND 2; DLK2","url":"https://www.omim.org/entry/621120"},{"mim_id":"620697","title":"ZINC FINGER CCHC DOMAIN-CONTAINING PROTEIN 14; ZCCHC14","url":"https://www.omim.org/entry/620697"},{"mim_id":"620293","title":"TMEM9 DOMAIN FAMILY, MEMBER B; TMEM9B","url":"https://www.omim.org/entry/620293"},{"mim_id":"619722","title":"TRANSMEMBRANE PROTEIN 53; TMEM53","url":"https://www.omim.org/entry/619722"},{"mim_id":"619622","title":"LYMPHOCYTE TRANSMEMBRANE ADAPTOR 1; LAX1","url":"https://www.omim.org/entry/619622"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAPK14"},"hgnc":{"alias_symbol":["p38alpha","PRKM14","p38","Mxi2","PRKM15"],"prev_symbol":["CSPB1","CSBP1","CSBP2"]},"alphafold":{"accession":"Q16539","domains":[{"cath_id":"3.30.200.20","chopping":"8-108_321-346","consensus_level":"high","plddt":93.004,"start":8,"end":346},{"cath_id":"1.10.510.10","chopping":"111-307","consensus_level":"high","plddt":88.6828,"start":111,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16539","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16539-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16539-F1-predicted_aligned_error_v6.png","plddt_mean":89.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPK14","jax_strain_url":"https://www.jax.org/strain/search?query=MAPK14"},"sequence":{"accession":"Q16539","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16539.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16539/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16539"}},"corpus_meta":[{"pmid":"17468757","id":"PMC_17468757","title":"p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17468757","citation_count":306,"is_preprint":false},{"pmid":"17468755","id":"PMC_17468755","title":"p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17468755","citation_count":254,"is_preprint":false},{"pmid":"14592977","id":"PMC_14592977","title":"Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14592977","citation_count":246,"is_preprint":false},{"pmid":"16378500","id":"PMC_16378500","title":"MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein.","date":"2005","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16378500","citation_count":191,"is_preprint":false},{"pmid":"25110412","id":"PMC_25110412","title":"p38α MAPK pathway: a key factor in colorectal cancer therapy and chemoresistance.","date":"2014","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25110412","citation_count":189,"is_preprint":false},{"pmid":"25831013","id":"PMC_25831013","title":"Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25831013","citation_count":177,"is_preprint":false},{"pmid":"30914267","id":"PMC_30914267","title":"Macrophage p38α promotes nutritional steatohepatitis through M1 polarization.","date":"2019","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/30914267","citation_count":176,"is_preprint":false},{"pmid":"14747383","id":"PMC_14747383","title":"The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis.","date":"2004","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/14747383","citation_count":168,"is_preprint":false},{"pmid":"17957136","id":"PMC_17957136","title":"p38alpha: a suppressor of cell proliferation and tumorigenesis.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17957136","citation_count":163,"is_preprint":false},{"pmid":"26377941","id":"PMC_26377941","title":"The Stress Kinase p38α as a Target for Cancer Therapy.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26377941","citation_count":157,"is_preprint":false},{"pmid":"15557129","id":"PMC_15557129","title":"Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice.","date":"2004","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15557129","citation_count":143,"is_preprint":false},{"pmid":"7479834","id":"PMC_7479834","title":"Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7479834","citation_count":133,"is_preprint":false},{"pmid":"25728574","id":"PMC_25728574","title":"Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer.","date":"2015","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/25728574","citation_count":128,"is_preprint":false},{"pmid":"31296856","id":"PMC_31296856","title":"Regulation of tumor angiogenesis and mesenchymal-endothelial transition by p38α through TGF-β and JNK signaling.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31296856","citation_count":112,"is_preprint":false},{"pmid":"16574378","id":"PMC_16574378","title":"CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway.","date":"2006","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16574378","citation_count":103,"is_preprint":false},{"pmid":"19747121","id":"PMC_19747121","title":"The p38alpha kinase plays a central role in inflammation.","date":"2009","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19747121","citation_count":96,"is_preprint":false},{"pmid":"33524689","id":"PMC_33524689","title":"Current status and future prospects of p38α/MAPK14 kinase and its inhibitors.","date":"2021","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33524689","citation_count":93,"is_preprint":false},{"pmid":"24037507","id":"PMC_24037507","title":"Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1.","date":"2013","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24037507","citation_count":91,"is_preprint":false},{"pmid":"29805078","id":"PMC_29805078","title":"Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/29805078","citation_count":80,"is_preprint":false},{"pmid":"22647487","id":"PMC_22647487","title":"MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/22647487","citation_count":78,"is_preprint":false},{"pmid":"16849316","id":"PMC_16849316","title":"Multiple activation mechanisms of p38alpha mitogen-activated protein kinase.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16849316","citation_count":77,"is_preprint":false},{"pmid":"17534150","id":"PMC_17534150","title":"Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17534150","citation_count":72,"is_preprint":false},{"pmid":"31092814","id":"PMC_31092814","title":"Autophagy-induced senescence is regulated by p38α signaling.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31092814","citation_count":70,"is_preprint":false},{"pmid":"15284239","id":"PMC_15284239","title":"Active mutants of the human p38alpha mitogen-activated protein kinase.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15284239","citation_count":70,"is_preprint":false},{"pmid":"22847234","id":"PMC_22847234","title":"Comparative expression profiling identifies differential roles for Myogenin and p38α MAPK signaling in myogenesis.","date":"2012","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22847234","citation_count":67,"is_preprint":false},{"pmid":"25046111","id":"PMC_25046111","title":"MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25046111","citation_count":64,"is_preprint":false},{"pmid":"10820433","id":"PMC_10820433","title":"Constitutive activity and differential localization of p38alpha and p38beta MAPKs in adult mouse brain.","date":"2000","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/10820433","citation_count":61,"is_preprint":false},{"pmid":"25502009","id":"PMC_25502009","title":"p38α (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25502009","citation_count":60,"is_preprint":false},{"pmid":"34124690","id":"PMC_34124690","title":"Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.","date":"2020","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34124690","citation_count":57,"is_preprint":false},{"pmid":"30771750","id":"PMC_30771750","title":"Vascular smooth muscle-MAPK14 is required for neointimal hyperplasia by suppressing VSMC differentiation and inducing proliferation and inflammation.","date":"2019","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/30771750","citation_count":52,"is_preprint":false},{"pmid":"12697810","id":"PMC_12697810","title":"p38alpha isoform Mxi2 binds to extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase and regulates its nuclear activity by sustaining its phosphorylation levels.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12697810","citation_count":42,"is_preprint":false},{"pmid":"30541887","id":"PMC_30541887","title":"Protein kinase p38α signaling in dendritic cells regulates colon inflammation and tumorigenesis.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30541887","citation_count":42,"is_preprint":false},{"pmid":"27715387","id":"PMC_27715387","title":"Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer disease brain.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27715387","citation_count":39,"is_preprint":false},{"pmid":"25038803","id":"PMC_25038803","title":"Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions.","date":"2014","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25038803","citation_count":39,"is_preprint":false},{"pmid":"24393126","id":"PMC_24393126","title":"Synthetic phosphorylation of p38α recapitulates protein kinase activity.","date":"2014","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/24393126","citation_count":38,"is_preprint":false},{"pmid":"15294293","id":"PMC_15294293","title":"Improved expression, purification, and crystallization of p38alpha MAP kinase.","date":"2004","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/15294293","citation_count":37,"is_preprint":false},{"pmid":"29899565","id":"PMC_29899565","title":"Targeted ablation of p38α MAPK suppresses denervation-induced muscle atrophy.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29899565","citation_count":37,"is_preprint":false},{"pmid":"25595884","id":"PMC_25595884","title":"Hepatic p38α regulates gluconeogenesis by suppressing AMPK.","date":"2015","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/25595884","citation_count":37,"is_preprint":false},{"pmid":"19501598","id":"PMC_19501598","title":"p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19501598","citation_count":37,"is_preprint":false},{"pmid":"32751991","id":"PMC_32751991","title":"P38α MAPK Signaling-A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32751991","citation_count":35,"is_preprint":false},{"pmid":"32576599","id":"PMC_32576599","title":"p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy.","date":"2020","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32576599","citation_count":35,"is_preprint":false},{"pmid":"20169663","id":"PMC_20169663","title":"p38alpha is required for ovarian cancer cell metabolism and survival.","date":"2010","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/20169663","citation_count":34,"is_preprint":false},{"pmid":"17028194","id":"PMC_17028194","title":"Involvement of p38alpha mitogen-activated protein kinase in lung metastasis of tumor cells.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17028194","citation_count":34,"is_preprint":false},{"pmid":"30332653","id":"PMC_30332653","title":"The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30332653","citation_count":34,"is_preprint":false},{"pmid":"26363230","id":"PMC_26363230","title":"Gene structure, molecular characterization and transcriptional expression of two p38 isoforms (MAPK11 and MAPK14) from rock bream (Oplegnathus fasciatus).","date":"2015","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26363230","citation_count":34,"is_preprint":false},{"pmid":"35551270","id":"PMC_35551270","title":"The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation.","date":"2022","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35551270","citation_count":33,"is_preprint":false},{"pmid":"37708276","id":"PMC_37708276","title":"Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation.","date":"2023","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37708276","citation_count":33,"is_preprint":false},{"pmid":"22637476","id":"PMC_22637476","title":"Mechanism for p38α-mediated experimental autoimmune encephalomyelitis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22637476","citation_count":32,"is_preprint":false},{"pmid":"25406311","id":"PMC_25406311","title":"p38α MAPK is required for tooth morphogenesis and enamel secretion.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25406311","citation_count":31,"is_preprint":false},{"pmid":"37163617","id":"PMC_37163617","title":"Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD.","date":"2023","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37163617","citation_count":31,"is_preprint":false},{"pmid":"38512415","id":"PMC_38512415","title":"MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38512415","citation_count":30,"is_preprint":false},{"pmid":"32243890","id":"PMC_32243890","title":"MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target.","date":"2020","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/32243890","citation_count":27,"is_preprint":false},{"pmid":"33021050","id":"PMC_33021050","title":"In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33021050","citation_count":27,"is_preprint":false},{"pmid":"27871059","id":"PMC_27871059","title":"Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.","date":"2016","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27871059","citation_count":26,"is_preprint":false},{"pmid":"33986259","id":"PMC_33986259","title":"Circular RNA circACSL1 aggravated myocardial inflammation and myocardial injury by sponging miR-8055 and regulating MAPK14 expression.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33986259","citation_count":26,"is_preprint":false},{"pmid":"22850347","id":"PMC_22850347","title":"MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse.","date":"2012","source":"Psychological medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22850347","citation_count":26,"is_preprint":false},{"pmid":"26061537","id":"PMC_26061537","title":"The problem of pyridinyl imidazole class inhibitors of MAPK14/p38α and MAPK11/p38β in autophagy research.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26061537","citation_count":26,"is_preprint":false},{"pmid":"29907597","id":"PMC_29907597","title":"Myeloid p38α signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.","date":"2018","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29907597","citation_count":26,"is_preprint":false},{"pmid":"32433496","id":"PMC_32433496","title":"In silico identification of MAPK14-related lncRNAs and assessment of their expression in breast cancer samples.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32433496","citation_count":25,"is_preprint":false},{"pmid":"28900160","id":"PMC_28900160","title":"Induction of oxidative metabolism by the p38α/MK2 pathway.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28900160","citation_count":25,"is_preprint":false},{"pmid":"36610142","id":"PMC_36610142","title":"Shikonin triggers GSDME-mediated pyroptosis in tumours by regulating autophagy via the ROS-MAPK14/p38α axis.","date":"2022","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36610142","citation_count":25,"is_preprint":false},{"pmid":"25950478","id":"PMC_25950478","title":"The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25950478","citation_count":25,"is_preprint":false},{"pmid":"10751326","id":"PMC_10751326","title":"Mxi2, a splice variant of p38 stress-activated kinase, is a distal nephron protein regulated with kidney ischemia.","date":"2000","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10751326","citation_count":24,"is_preprint":false},{"pmid":"19631642","id":"PMC_19631642","title":"Mitogen-activated protein kinase p38alpha and retinal ischemic preconditioning.","date":"2009","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/19631642","citation_count":24,"is_preprint":false},{"pmid":"24931668","id":"PMC_24931668","title":"p38α mitogen-activated kinase mediates cardiomyocyte apoptosis induced by palmitate.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24931668","citation_count":24,"is_preprint":false},{"pmid":"23235332","id":"PMC_23235332","title":"Inhibition of autophagy through MAPK14-mediated phosphorylation of ATG5.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/23235332","citation_count":24,"is_preprint":false},{"pmid":"39840525","id":"PMC_39840525","title":"Targeting MAPK14 by Lobeline Upregulates Slurp1-Mediated Inhibition of Alternative Activation of TAM and Retards Colorectal Cancer Growth.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39840525","citation_count":23,"is_preprint":false},{"pmid":"30521886","id":"PMC_30521886","title":"HOXA5 overexpression promotes osteosarcoma cell apoptosis through the p53 and p38α MAPK pathway.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30521886","citation_count":23,"is_preprint":false},{"pmid":"21865449","id":"PMC_21865449","title":"p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21865449","citation_count":23,"is_preprint":false},{"pmid":"23317165","id":"PMC_23317165","title":"Recent developments of p38α MAP kinase inhibitors as antiinflammatory agents based on the imidazole scaffolds.","date":"2013","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23317165","citation_count":23,"is_preprint":false},{"pmid":"24361238","id":"PMC_24361238","title":"p38α regulates SERCA2a function.","date":"2013","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/24361238","citation_count":22,"is_preprint":false},{"pmid":"10838079","id":"PMC_10838079","title":"Distinct carboxy-termini confer divergent characteristics to the mitogen-activated protein kinase p38alpha and its splice isoform Mxi2.","date":"2000","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10838079","citation_count":22,"is_preprint":false},{"pmid":"31969449","id":"PMC_31969449","title":"Requirement for epithelial p38α in KRAS-driven lung tumor progression.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31969449","citation_count":22,"is_preprint":false},{"pmid":"31856414","id":"PMC_31856414","title":"Knockdown of MAPK14 inhibits the proliferation and migration of clear cell renal cell carcinoma by downregulating the expression of CDC25B.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31856414","citation_count":22,"is_preprint":false},{"pmid":"32189389","id":"PMC_32189389","title":"Mapping p38α mitogen-activated protein kinase signaling by proximity-dependent labeling.","date":"2020","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/32189389","citation_count":21,"is_preprint":false},{"pmid":"33422910","id":"PMC_33422910","title":"Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor.","date":"2020","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33422910","citation_count":21,"is_preprint":false},{"pmid":"35806043","id":"PMC_35806043","title":"Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806043","citation_count":21,"is_preprint":false},{"pmid":"30135318","id":"PMC_30135318","title":"The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules.","date":"2018","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/30135318","citation_count":21,"is_preprint":false},{"pmid":"38237770","id":"PMC_38237770","title":"RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38237770","citation_count":20,"is_preprint":false},{"pmid":"34346000","id":"PMC_34346000","title":"LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway : XIST promotes ALI via miR-132-3p/MAPK14 axis.","date":"2021","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34346000","citation_count":20,"is_preprint":false},{"pmid":"33811139","id":"PMC_33811139","title":"Active p38α causes macrovesicular fatty liver in mice.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33811139","citation_count":20,"is_preprint":false},{"pmid":"31828036","id":"PMC_31828036","title":"p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31828036","citation_count":20,"is_preprint":false},{"pmid":"29229647","id":"PMC_29229647","title":"TAB1-Induced Autoactivation of p38α Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185.","date":"2018","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29229647","citation_count":20,"is_preprint":false},{"pmid":"26012502","id":"PMC_26012502","title":"A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors.","date":"2015","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/26012502","citation_count":19,"is_preprint":false},{"pmid":"23483889","id":"PMC_23483889","title":"Protein arginine methyltransferase 1 interacts with and activates p38α to facilitate erythroid differentiation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23483889","citation_count":19,"is_preprint":false},{"pmid":"18314011","id":"PMC_18314011","title":"A role for p38alpha mitogen-activated protein kinase in embryonic cardiac differentiation.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18314011","citation_count":19,"is_preprint":false},{"pmid":"31505169","id":"PMC_31505169","title":"p38α MAPK proximity assay reveals a regulatory mechanism of alternative splicing in cardiomyocytes.","date":"2019","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31505169","citation_count":19,"is_preprint":false},{"pmid":"35982617","id":"PMC_35982617","title":"Androgen receptor suppresses inflammatory response of airway epithelial cells in allergic asthma through MAPK1 and MAPK14.","date":"2022","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35982617","citation_count":18,"is_preprint":false},{"pmid":"37633055","id":"PMC_37633055","title":"Narirutin ameliorates alcohol-induced liver injury by targeting MAPK14 in zebrafish larvae.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37633055","citation_count":18,"is_preprint":false},{"pmid":"35914132","id":"PMC_35914132","title":"P38α MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35914132","citation_count":18,"is_preprint":false},{"pmid":"31560167","id":"PMC_31560167","title":"Neuronal p38α mediates age-associated neural stem cell exhaustion and cognitive decline.","date":"2019","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/31560167","citation_count":17,"is_preprint":false},{"pmid":"17613723","id":"PMC_17613723","title":"Involvement of p38alpha in kainate-induced seizure and neuronal cell damage.","date":"2007","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/17613723","citation_count":17,"is_preprint":false},{"pmid":"27551368","id":"PMC_27551368","title":"p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program.","date":"2016","source":"Skeletal muscle","url":"https://pubmed.ncbi.nlm.nih.gov/27551368","citation_count":17,"is_preprint":false},{"pmid":"28166285","id":"PMC_28166285","title":"p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28166285","citation_count":16,"is_preprint":false},{"pmid":"37202506","id":"PMC_37202506","title":"Hepatic p38α MAPK controls gluconeogenesis via FOXO1 phosphorylation at S273 during glucagon signalling in mice.","date":"2023","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/37202506","citation_count":16,"is_preprint":false},{"pmid":"34686655","id":"PMC_34686655","title":"Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34686655","citation_count":15,"is_preprint":false},{"pmid":"36443297","id":"PMC_36443297","title":"A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36443297","citation_count":14,"is_preprint":false},{"pmid":"33986857","id":"PMC_33986857","title":"Overexpression of miRNA-22-3p attenuates osteoporosis by targeting MAPK14.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33986857","citation_count":14,"is_preprint":false},{"pmid":"30879166","id":"PMC_30879166","title":"Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid.","date":"2019","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/30879166","citation_count":13,"is_preprint":false},{"pmid":"28611474","id":"PMC_28611474","title":"p38α regulates cytokine-induced IFNγ secretion via the Mnk1/eIF4E pathway in Th1 cells.","date":"2017","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28611474","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49703,"output_tokens":11522,"usd":0.160969,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23293,"output_tokens":6724,"usd":0.142283,"stage2_stop_reason":"end_turn"},"total_usd":0.303252,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Mxi2 (a splice isoform of p38α/MAPK14) interacts with Max protein and the C-terminus of c-Myc in yeast two-hybrid assays, and directly phosphorylates Max both in vitro and in vivo; the putative substrate recognition region of Mxi2 shares sequence similarity with the helix-loop-helix region of Max and c-Myc, suggesting substrate recognition via this motif.\",\n      \"method\": \"Yeast two-hybrid, in vitro and in vivo phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro kinase assay and in vivo phosphorylation, single lab with two orthogonal methods\",\n      \"pmids\": [\"7479834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mxi2 (p38α splice isoform) lacks most of the XI domain of p38 and has a unique 17-amino acid C-terminus. It is expressed exclusively in the kidney (distal tubule) in mice. Unlike p38α, Mxi2 is not activated by MKK3 or MKK6 and cannot phosphorylate ATF-2; its unique COOH-terminus confers these distinct properties.\",\n      \"method\": \"Immunohistochemistry, kinase assay with ATF-2 substrate, domain-swap hybrid protein analysis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay with mutagenic domain swaps, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10751326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The C-terminus of p38α is a key determinant of inhibitor sensitivity (SB203580), substrate affinity, and phosphatase (CL100) sensitivity; Mxi2, which differs only in its C-terminus, shows greatly reduced substrate affinity, reduced sensitivity to SB203580, and its activity is largely unaffected by CL100.\",\n      \"method\": \"In vitro kinase assay, pharmacological inhibition, phosphatase assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro biochemical assays with domain-swap analysis, single lab\",\n      \"pmids\": [\"10838079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mxi2 (p38α splice isoform) physically associates with ERK1/2 (co-immunoprecipitation in cells and in kidney) and sustains ERK phosphorylation levels, specifically prolonging the duration of ERK nuclear signaling (activating Elk1 and HIF1α) without affecting cytoplasmic ERK substrates RSK2 and cPLA2.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, reporter gene assays for Elk1 and HIF1α, genetic epistasis with Ras/Raf/MEK\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, reporter assays, epistasis analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12697810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAPK2a/p38α directly phosphorylates TAB1 at Ser423, Thr431, and Ser438 in vitro (Ser423 is a non-proline-directed site). In cells, phosphorylation of Ser423 and Thr431 is blocked by the p38 inhibitor SB 203580. p38α-mediated TAB1 phosphorylation constitutes a negative feedback loop that limits TAK1 activation, thereby coordinating p38α activity with JNK and IKK pathways downstream of TAK1.\",\n      \"method\": \"In vitro kinase assay, pharmacological inhibition, p38α-knockout MEFs, TAK1 activity assays in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with mapped phosphosites, confirmed in knockout cells, replicated across multiple stimuli and cell types\",\n      \"pmids\": [\"14592977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Active mutants of human p38α (D176A, F327L, F327S, and double mutants) acquire high intrinsic kinase activity independent of upstream phosphorylation by destabilizing a hydrophobic core formed by Tyr69, Phe327, and Trp337 near the L16 loop, emulating conformational changes imposed by dual phosphorylation; these mutants retain substrate specificity and inhibitor sensitivity.\",\n      \"method\": \"Site-directed mutagenesis, in vitro kinase assay, structural analysis based on existing p38/ERK2 crystal structures\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple active-site mutants characterized biochemically with mechanistic structural interpretation, single rigorous study\",\n      \"pmids\": [\"15284239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p38α activation mediates cell migration induced by CXCL12, C5a, HGF, and PDGF-BB via a PAK1/2→p38α→MAPKAP-K2→HSP27 signaling pathway. Genetic ablation of p38α (but not other p38 isoforms) abolished migration; RNAi against MAPKAP-K2 or HSP27 also blocked migration, placing these downstream of p38α.\",\n      \"method\": \"Genetic knockout mice, pharmacological inhibition (SB203580, BIRB0796), RNAi knockdown, cell migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, pharmacological inhibition, and RNAi knockdown across multiple cell types and stimuli; independently consistent results\",\n      \"pmids\": [\"16574378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Multiple activation mechanisms of p38α exist in cells: (1) canonical MKK3/6-dependent phosphorylation (primary); (2) TAB1-mediated autophosphorylation independent of MKK3/4/6; (3) peroxynitrite-induced phosphorylation via a disulfide-bond complex involving a ~85-kDa binding partner of p38α. TAB1-mediated autophosphorylation did not require MKK3/4/6, and TAB1 inhibited p38α phosphorylation in the peroxynitrite-induced complex.\",\n      \"method\": \"MKK3/6 and MKK4/7 double-knockout MEFs, mutagenesis of p38α cysteines, immunoprecipitation, phospho-p38 immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic double knockouts combined with mutagenesis and biochemical fractionation, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"16849316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p38α (MAPK14) suppresses cell proliferation by antagonizing the JNK–c-Jun pathway. In Mapk14-deficient embryonic fibroblasts, fetal hematopoietic cells, and hepatocytes, proliferation increased due to sustained JNK-c-Jun activation. Inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient cells, placing p38α as a negative regulator upstream of the JNK-c-Jun axis.\",\n      \"method\": \"Conditional Mapk14 knockout mice, genetic epistasis (JNK and c-Jun inactivation), cell proliferation assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in multiple cell types, genetic epistasis with JNK/c-Jun, replicated across hepatocytes, fibroblasts, and hematopoietic cells\",\n      \"pmids\": [\"17468757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p38α positively regulates CCAAT/enhancer-binding protein expression required for lung cell differentiation, and controls self-renewal by inhibiting epidermal growth factor receptor-driven proliferation signals in lung stem/progenitor cells.\",\n      \"method\": \"Conditional p38α knockout mice (adult), in vivo and in vitro differentiation assays, signaling pathway analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined cellular phenotype, molecular mechanism of EGFR pathway involvement, replicated in vivo and in vitro\",\n      \"pmids\": [\"17468755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p38α C-terminal cap (C-lobe) contains a lipid-binding pocket formed around residue Trp197; a lead compound binds both the active site and this C-terminal hydrophobic pocket, inducing movement of the C-terminal cap region. This pocket is structurally distinct from the ATP-binding site and can accommodate lipids, leukotrienes, and small-molecule effectors.\",\n      \"method\": \"X-ray crystallography, computational analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with bound ligand, single study\",\n      \"pmids\": [\"19501598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAPK14/p38α, when activated specifically by the GADD45B-MAP3K4 signaling complex (but not by other activators), localizes to autophagosomes and directly phosphorylates ATG5 at threonine 75, impairing autophagosome-lysosome fusion and thus inhibiting autophagic flux. ATG5 T75 phosphorylation-defective mutants show enhanced autophagy.\",\n      \"method\": \"Subcellular fractionation to autophagosomes, in vitro kinase assay, phosphorylation-defective and phosphomimetic ATG5 reconstitution, MAPK14-knockout and GADD45B-knockout cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mapped phosphosite, mutant reconstitution in knockout cells, localization data linked to functional consequence\",\n      \"pmids\": [\"23235332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAPK14/p38α is required for irinotecan (SN-38) resistance in TP53-null colon cancer cells by inducing survival autophagy; constitutively active MAPK14/p38α decreases SN-38 sensitivity and induces autophagy, and inhibition of either MAPK14 or autophagy sensitizes cells to drug therapy in a mutually dependent manner.\",\n      \"method\": \"Overexpression of constitutively active MAPK14, siRNA knockdown, pharmacological inhibition, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with mechanistic links to autophagy, single lab with multiple approaches\",\n      \"pmids\": [\"22647487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p38α autoactivation during myocardial ischemia occurs in cis by direct interaction with TAB1(371-416). Crystal structures revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe; TAB1 binding stabilizes active p38α and induces helical extension of the Thr-Gly-Tyr activation segment, allowing autophosphorylation in cis. TAT-TAB1(371-416) peptide rapidly activates p38 in cardiac myocytes and perfused hearts and causes profound functional perturbation. A chemical-genetic approach in bacterial and cell-free systems confirmed the cis autophosphorylation mechanism.\",\n      \"method\": \"X-ray crystallography, solution characterization, chemical-genetic approaches, coexpression in mammalian/bacterial/cell-free systems, isolated cardiomyocytes and perfused heart ex vivo\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with multiple orthogonal validation methods (chemical genetics, in vitro reconstitution, ex vivo cardiac model), single rigorous study\",\n      \"pmids\": [\"24037507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p38α regulates cardiac contractility by suppressing phosphorylation of phospholamban (PLB) via activation of protein phosphatase 2A, which dephosphorylates PP1 inhibitor-1, thereby activating PP1 and reducing PLB phosphorylation. Inhibition of p38α (dominant-negative p38α or RNAi) specifically enhanced PLB phosphorylation and SERCA2a-dependent diastolic Ca2+ uptake; this effect was p38α-specific and not observed with dominant-negative p38β.\",\n      \"method\": \"Dominant-negative overexpression, RNAi knockdown, Ca2+-transient measurements, protein phosphatase activity assays in cardiomyocytes and perfused hearts\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific interventions with functional readout, single lab with multiple approaches\",\n      \"pmids\": [\"24361238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT1 directly interacts with p38α (co-immunoprecipitation) and methylates p38α in vitro. PRMT1 acts upstream of p38α to promote erythroid differentiation; PRMT1-stimulated differentiation was abolished in p38α-knockdown cells but not p38β-knockdown cells, and PRMT1 enhanced p38 MAPK activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, shRNA knockdown, erythroid differentiation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro methylation assay and co-IP, isoform-specific knockdown with functional readout; single lab\",\n      \"pmids\": [\"23483889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Docking interactions between active p38α and MK2's C-terminal domain allosterically enhance p38α's enzymatic activity toward MK2 by promoting ATP binding and phosphoacceptor accommodation, thus accelerating the phosphotransfer reaction. This was characterized by solution NMR showing that phosphorylation and ATP loading collaboratively induce active p38α conformation, and the docking interaction further enhances catalysis beyond just substrate anchoring.\",\n      \"method\": \"Solution NMR, in vitro kinase assay with dually phosphorylated p38α and MK2 fragments\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural characterization combined with in vitro kinase assay revealing allosteric mechanism; single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"25038803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Chemical phosphorylation of p38α at Thr180 (using a phosphocysteine mimic, pCys180) is sufficient to switch the kinase to an active state capable of phosphorylating ATF2; phosphorylation at position 172 does not activate the kinase. This demonstrates Thr180 as the dominant activating site. Type II inhibitors inhibit phosphorylated p38α, whereas Type I inhibitors show differential behavior.\",\n      \"method\": \"Tag-and-modify chemical modification, in vitro kinase assay with ATF2 substrate, kinetic analysis\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — semisynthetic phosphorylation with functional reconstitution; single rigorous study with novel chemistry and kinetic validation\",\n      \"pmids\": [\"24393126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAPK14/p38α modulates glucose metabolism during starvation at two levels: (1) it increases SLC2A3 (GLUT3) mRNA and protein by enhancing HIF1A protein stability, boosting glucose uptake; (2) it promotes metabolic shift from glycolysis to the pentose phosphate pathway by inducing proteasomal degradation of PFKFB3 via KEN box and DSG motif Ser273 recognition sequences. This MAPK14-driven metabolic reprogramming sustains NADPH production and reduces ROS, limiting autophagy.\",\n      \"method\": \"MAPK14 knockdown, pharmacological inhibition, metabolic flux assays, protein stability assays, mutagenesis of PFKFB3 degradation motifs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with metabolic readouts and mutagenesis of substrate degradation motifs; single lab with multiple approaches\",\n      \"pmids\": [\"25046111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p38α functions downstream of BMP2/7 signaling and MKK6 (but not MKK3) in ameloblasts to regulate amelogenin and β4-integrin expression and p21 expression in the enamel knot, required for tooth morphogenesis and enamel secretion.\",\n      \"method\": \"Conditional p38α knockout (K14-Cre), MKK3 and MKK6 knockout mice, BMP2/7 stimulation in explant culture and ameloblast cell line\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with isoform-specific MKK epistasis and ligand stimulation, replicated in vivo and in vitro\",\n      \"pmids\": [\"25406311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAPK14/p38α is required for mitophagy induced by starvation or hypoxia in mammalian cells. Knockdown of MAPK14 severely suppressed mitophagy, which was found to occur predominantly through alternative autophagy (RAB9A/B-dependent) rather than conventional macroautophagy.\",\n      \"method\": \"pH-sensitive fluorescent protein Keima mitophagy assay, siRNA knockdown, Atg5 knockout MEFs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific mitophagy assay with RNAi knockdown and genetic knockout controls; single lab\",\n      \"pmids\": [\"25831013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hepatic p38α negatively regulates AMPK signaling to maintain gluconeogenesis during fasting. Loss of hepatic p38α increases AMPKα phosphorylation without altering CREB phosphorylation; dominant-negative AMPKα abolished the anti-gluconeogenic effect of p38α loss. TAK1 knockdown decreased AMPKα phosphorylation in p38α-deficient cells, suggesting a negative feedback loop.\",\n      \"method\": \"Liver-specific p38α knockout mice, adenoviral dominant-negative constructs, pyruvate tolerance tests, in vivo and in vitro gluconeogenesis assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with adenoviral rescue, epistasis with dominant-negative AMPK, replicated in vivo and in vitro in multiple models\",\n      \"pmids\": [\"25595884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mitophagy-related pyridinyl-imidazole class inhibitors (SB203580/SB202190) interfere with autophagic flux in a MAPK14/p38-independent manner, making them unsuitable as pharmacological tools to study p38-dependent autophagy.\",\n      \"method\": \"Pharmacological inhibition with SB203580/SB202190 in p38-deficient cells, autophagic flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative mechanistic finding validated using p38-deficient cells; single lab\",\n      \"pmids\": [\"26061537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p38α activity is required for myogenesis by displacing the histone methyltransferase KMT1A from MyoD via direct phosphorylation of KMT1A; p38α activity removes repressive H3K9me3 marks from the Myogenin promoter and is necessary and sufficient for establishing active H3K9 acetylation at this locus.\",\n      \"method\": \"Pharmacological inhibition, lentiviral p38α shRNA, constitutively active upstream kinase overexpression, co-immunoprecipitation, ChIP for H3K9me3 and H3K9ac, in vitro kinase assay\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay establishing direct phosphorylation, combined with ChIP for chromatin marks, gain-of-function and loss-of-function; single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"27551368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sustained p38α activation drives metabolic changes including increased glucose and glutamine dependence, enhanced respiration, and elevated mitochondrial ROS, partly through the downstream kinase MK2 (MAPKAPK2). Elevated mitochondrial superoxide from this metabolic state contributes to p38α-induced reduced cell survival.\",\n      \"method\": \"Inducible p38α activation system, metabolic flux assays, MK2 knockout/knockdown, ROS measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible activation system with genetic validation of MK2 role; single lab\",\n      \"pmids\": [\"28900160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of active pp38α in complex with TAB1 (residues 1-438) in the active state was solved. Four TAB1 residues required for docking onto p38α were identified; knock-in mice with substitutions at these four TAB1 residues were viable and showed reduced infarction volume and disabled TAB1 transphosphorylation following myocardial ischemia, while myocardial p38α activation was only mildly attenuated.\",\n      \"method\": \"X-ray crystallography, TAB1 knock-in mouse model, in vivo regional myocardial ischemia model, fragment-based small molecule screening for disruption of p38α-TAB1 interaction\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with knock-in mouse model and in vivo functional validation; single rigorous multidisciplinary study\",\n      \"pmids\": [\"30135318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAB1-induced p38α autoactivation in cis requires an intramolecular hydrogen bond between Thr185 and Asp150 in the activation segment. Mutation T185G disrupts this hydrogen bond and specifically disables autophosphorylation while leaving MKK3/MKK6-mediated activation and downstream substrate phosphorylation intact. Cardiac cells expressing p38α(T185G) are resistant to ischemic injury.\",\n      \"method\": \"Structural analysis of p38α-TAB1 crystal structure, T185G mutagenesis, in vitro and in vivo kinase assays, TAB1-binding assay, cardiac myocyte injury model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis validated by in vitro and in vivo assays, mechanistic dissection of two activation modes; single rigorous study\",\n      \"pmids\": [\"29229647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p38α phosphorylates CtIP (DNA repair regulator), and loss of p38α signaling in breast cancer cells impairs ATR activation and homologous recombination repair, increasing replication stress, DNA damage, and chromosome instability. Pharmacological p38α inhibition potentiates taxane effects by boosting chromosome instability.\",\n      \"method\": \"Conditional p38α knockout/pharmacological inhibition, DNA damage assays, HR repair assays, ATR activation assays, murine models and patient-derived xenografts\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with defined molecular substrate (CtIP) and repair pathway phenotypes; single lab with multiple readouts\",\n      \"pmids\": [\"29805078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In dendritic cells, p38α negatively regulates IL-27 production through the TAK1-MKK4/7-JNK-c-Jun axis; loss of p38α in colonic cDC1s leads to hyperactivation of JNK-c-Jun, elevated IL-27, and increased Tr1 cell differentiation. ChIP assay confirmed direct binding of c-Jun to the Il27p28 promoter, which was enhanced in p38α-deficient DCs.\",\n      \"method\": \"DC-specific p38α conditional knockout, ChIP assay, JNK pathway inhibition, cytokine measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with ChIP epistasis, multiple genetic and pharmacological interventions; single lab with orthogonal methods\",\n      \"pmids\": [\"30541887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p38α in mesenchymal stem/stromal cells negatively regulates an angiogenic program including TGF-β-induced acquisition of an endothelial phenotype (mesenchymal-to-endothelial transition) and JNK-dependent signaling. Abrogation of p38α in mesenchymal cells increases tumorigenesis correlated with enhanced angiogenesis.\",\n      \"method\": \"Genetic mouse models with mesenchymal-specific p38α deletion, in vivo tumor models, genetic epistasis with TGF-β and JNK pathways\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse models with defined pathway epistasis (TGF-β, JNK), replicated in human and mouse colon tumors and damage tissue\",\n      \"pmids\": [\"31296856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sustained p38α activation drives autophagosome formation and enhances autophagic flux, requiring both increased mitochondrial ROS and p38α-mediated phosphorylation of ULK1 at Ser-555. This autophagy induction directs cancer cells preferentially toward senescence rather than apoptosis, protecting them from chemotherapy-induced apoptosis.\",\n      \"method\": \"Inducible p38α activation system, autophagy flux assays, ULK1 phosphorylation assays, genetic knockdown, cell fate analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible system with mapped phosphosite (ULK1-S555) and genetic validation; single lab\",\n      \"pmids\": [\"31092814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Macrophage p38α promotes steatohepatitis by inducing M1 macrophage polarization and pro-inflammatory cytokine secretion (CXCL2, IL-1β, CXCL10, IL-6). In co-culture, p38α-deleted macrophages attenuated steatohepatitic changes in hepatocytes via decreased secretion of TNF-α, CXCL10, and IL-6; restoration of these cytokines rescued the phenotype.\",\n      \"method\": \"Macrophage-specific p38α conditional knockout, co-culture experiments, cytokine restoration experiments, macrophage polarization assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with co-culture rescue experiments defining the cytokine mediators; single lab with multiple dietary models\",\n      \"pmids\": [\"30914267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myeloid p38α drives intestinal IGF-1 production in macrophages, which mediates colon inflammation and tumorigenesis. Genetic and pharmacological inhibition of p38α in myeloid cells reduced IGF-1 production and tumorigenesis; IGF-1 signaling acted downstream of p38α in macrophages.\",\n      \"method\": \"Myeloid-specific p38α conditional knockout, pharmacological inhibition, adenoviral overexpression/knockdown of IGF-1\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myeloid-specific knockout with pharmacological and genetic IGF-1 manipulation; single lab\",\n      \"pmids\": [\"29907597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vascular smooth muscle cells, MAPK14 suppresses the contractile phenotype and promotes proliferation and inflammation via a p65/NF-κB-dependent pathway. NOX4 contributes upstream to MAPK14-mediated suppression of VSMC contractile differentiation. Inducible SMC-specific MAPK14 knockout mice showed reduced neointima formation after carotid injury.\",\n      \"method\": \"Inducible SMC-specific knockout mice, carotid ligation injury model, VSMC lineage tracing, RNA array, pharmacological inhibition, MAPK14 forced expression\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible cell-type-specific knockout with multiple pharmacological and molecular approaches defining NF-κB and NOX4 pathway placement\",\n      \"pmids\": [\"30771750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p38α in lung cancer epithelial cells promotes KRAS(G12V)-driven tumor progression via autonomous expression of TIMP-1, which stimulates cell proliferation in an autocrine manner. Despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α is required for proliferation and malignization of lung cancer cells.\",\n      \"method\": \"Conditional p38α deletion in vivo, KRAS(G12V) lung cancer mouse models, pharmacological inhibition, TIMP-1 expression/secretion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with identification of TIMP-1 as autocrine mediator; single lab\",\n      \"pmids\": [\"31969449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Activation of p38α in lung fibroblasts by tumor-derived factors leads to inactivation of type I interferon signaling and stimulation of fibroblast activation protein (FAP) expression. FAP drives extracellular matrix remodeling and chemokine expression enabling neutrophil lung infiltration, establishing a pre-metastatic niche for pulmonary metastases.\",\n      \"method\": \"p38α activation in lung fibroblasts by tumor-conditioned medium, FAP gain/loss-of-function, in vivo metastasis models, pharmacological p38 inhibition\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific functional studies with genetic and pharmacological interventions defining FAP as downstream effector; single lab\",\n      \"pmids\": [\"34124690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Constitutive activation of p38α in the liver (via intrinsically active p38α allele) is sufficient to cause macrovesicular fatty liver, associated with upregulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs. This fatty liver phenotype was reversible upon shutting off p38α mutant expression.\",\n      \"method\": \"Transgenic inducible liver-specific expression of active p38α allele, histology, gene expression analysis, reversibility experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled inducible transgenic system with reversibility; single lab\",\n      \"pmids\": [\"33811139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUMOylation of MAPK14/p38α occurs at lysine 152. p38α-SUMOylation acts as a sensor/accelerator of ROS generation through interaction with and activation of MK2 in the nucleus; ROS accumulation in turn promotes p38α SUMOylation by stabilizing PIASxα. This PIASxα/p38α-SUMOylation/MK2 cis-axis facilitates gastric cancer metastasis.\",\n      \"method\": \"Immunoprecipitation, pull-down assays, SUMOylation site mapping, nuclear localization studies, ROS assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mapped SUMOylation site by IP and pull-down with nuclear functional readout; single lab\",\n      \"pmids\": [\"34686655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p38α in B cells drives plasma cell differentiation by upregulating BLIMP1 transcription through downstream effectors TCF3, TCF4, and IRF4 (identified by CRISPR/Cas9 screening). B cell-specific p38α deletion severely impaired plasma cell differentiation and antibody responses while sparing B cell development and germinal center responses.\",\n      \"method\": \"B cell-specific conditional p38α knockout, Blimp1 reporter mouse, CRISPR/Cas9 screen, antibody response assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with reporter mice and CRISPR screen defining pathway downstream to BLIMP1; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36443297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P38α in uterine stroma phosphorylates the E3 ubiquitin ligase Ube3c at serine741, restraining Ube3c's polyubiquitination activity toward progesterone receptor (PR) and preventing its proteasomal degradation. In uterine-specific p38α knockout mice, Ube3c targets PR for degradation, causing defective implantation and female infertility.\",\n      \"method\": \"Uterine-specific p38α conditional knockout, in vitro phosphorylation assay (LC-MS confirmed Ube3c-S741 phosphorylation), ubiquitination assays, proteasome inhibitor rescue, Foxo1S273D/A knockin models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with LC-MS phosphosite mapping, combined with conditional knockout and ubiquitination functional studies; single rigorous multidisciplinary study\",\n      \"pmids\": [\"35914132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p38α in cDC1 dendritic cells regulates Th2-cell differentiation by modulating the MK2-c-FOS-IL-12 axis. cDC1-specific but not cDC2-specific p38α deletion promoted Th2 responses, and the mechanism involved p38α-dependent MK2 activation controlling c-FOS and IL-12 production.\",\n      \"method\": \"Cell-type-specific conditional knockouts (cDC1, cDC2, macrophage), MK2-c-FOS-IL-12 pathway analysis, Th2 differentiation assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific knockouts with defined MK2-c-FOS-IL12 pathway; single lab\",\n      \"pmids\": [\"35551270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of p38α in complex with its MAP2K MKK6 reveals a dynamic, multistep dual phosphorylation mechanism for p38α activation. The MAP2K-disordered N-terminal amino termini determine pathway specificity. Catalytically relevant interactions between MKK6 and p38α were identified and validated by HDX-MS, molecular dynamics simulations, and cell-based experiments.\",\n      \"method\": \"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry, molecular dynamics simulations, cell-based functional experiments\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with multiple orthogonal validation methods (HDX-MS, MD, cell experiments); single rigorous multidisciplinary study\",\n      \"pmids\": [\"37708276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatic p38α phosphorylates FOXO1 at S273 in response to glucagon (via EPAC2 signaling), increasing FOXO1 protein stability and promoting hepatic glucose production. This EPAC2-p38α-pFOXO1-S273 axis is required for glucagon-stimulated HGP; Foxo1S273A knock-in mice showed reduced glucose production and improved insulin sensitivity.\",\n      \"method\": \"siRNA knockdown, adeno-associated virus shRNA in liver-specific knockout mice, in vitro LC-MS phosphorylation assay, Foxo1S273D and Foxo1S273A knockin mice, glucagon tolerance tests\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with LC-MS phosphosite mapping validated by knockin mouse models with defined metabolic phenotypes; single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"37202506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAPK phosphatase 1 (MKP1) promotes lung myofibroblast dedifferentiation and restores apoptosis sensitivity by dephosphorylating p38α MAPK. Fibroblast-specific MKP1 deletion after peak bleomycin-induced fibrosis abrogated spontaneous fibrosis resolution; treatment with p38α inhibitor VX-702 restored resolution in MKP1-knockout transgenic mice.\",\n      \"method\": \"Fibroblast-specific conditional MKP1 knockout (gain- and loss-of-function), bleomycin fibrosis model, pharmacological p38α inhibition with VX-702, MKP1-p38α dephosphorylation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fibroblast-specific conditional knockout with pharmacological rescue defining MKP1-p38α as the relevant axis; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38512415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lobeline binds directly to MAPK14 (confirmed by DARTS assay and target-responsive accessibility profiling), preventing nuclear translocation of MAPK14. This reduces phosphorylation of p53, relieving p53-mediated transcriptional repression of SLURP1, which in turn promotes M1 macrophage polarization of tumor-associated macrophages and suppresses colorectal cancer growth.\",\n      \"method\": \"Target-responsive accessibility profiling, DARTS assay, nuclear/cytoplasmic fractionation, p53 phosphorylation assays, Slurp1-deficient MC38 xenografts\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding validated by DARTS assay, nuclear localization experiment with functional consequence, genetic validation with Slurp1-knockout cells; single lab\",\n      \"pmids\": [\"39840525\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPK14/p38α is a stress-activated serine/threonine kinase that is canonically activated by dual phosphorylation at Thr180/Tyr182 by MKK3/MKK6 (with MKK4 contributing), or alternatively by TAB1-mediated cis-autophosphorylation (particularly during cardiac ischemia) through a mechanism requiring Thr185 and a bipartite C-lobe docking site; its docking interactions with substrates (e.g., MK2) allosterically enhance catalytic activity, and it phosphorylates a broad array of substrates—including TAB1, ATF2, CtIP, ULK1-S555, FOXO1-S273, Ube3c-S741, ATG5-T75, KMT1A, Max, and HSP27—to coordinate inflammation, cell proliferation vs. differentiation, autophagy, metabolism (gluconeogenesis, glucose metabolism, mitophagy), cardiac contractility, and tissue homeostasis; its activity is terminated by MKP1-mediated dephosphorylation, and a splice isoform (Mxi2) with a unique C-terminus shows distinct substrate specificity, inhibitor sensitivity, and selectively sustains nuclear ERK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAPK14/p38\\u03b1 is a stress- and signal-activated serine/threonine protein kinase that coordinates inflammation, cell proliferation versus differentiation, autophagy, metabolism, and tissue homeostasis through direct phosphorylation of a broad substrate repertoire [#8, #11, #42]. Its catalytic activation is achieved by two structurally defined routes: canonical dual phosphorylation of the activation segment by MKK6 through a dynamic multistep mechanism whose MAP2K disordered N-terminus dictates pathway specificity [#41], and a non-canonical cis-autophosphorylation driven by direct TAB1 docking at a bipartite C-lobe site that stabilizes the active conformation and extends the Thr-Gly-Tyr segment, with this autoactivation requiring an intramolecular Thr185\\u2013Asp150 hydrogen bond and being central to ischemic cardiac injury [#13, #25, #26]. Activation requires Thr180 as the dominant activating phosphosite [#17], and substrate docking\\u2014exemplified by MK2\\u2014allosterically accelerates catalysis beyond simple anchoring [#16]. Through these mechanisms p38\\u03b1 phosphorylates ATG5-T75, ULK1-S555, FOXO1-S273, Ube3c-S741, CtIP, KMT1A, TAB1, and HSP27 (via the PAK\\u2192p38\\u03b1\\u2192MK2\\u2192HSP27 migration axis) to control autophagy and mitophagy, gluconeogenesis and glucose metabolism, DNA repair, myogenic chromatin remodeling, cell migration, and uterine implantation [#4, #6, #11, #23, #27, #30, #39, #42]. In its tissue roles p38\\u03b1 acts as a context-dependent brake on proliferation by antagonizing the JNK\\u2013c-Jun axis and tuning EGFR signaling in progenitor cells [#8, #9, #28], yet drives malignant proliferation, fibrosis, steatohepatitis, and pre-metastatic niche formation in other settings through effectors such as TIMP-1, IGF-1, FAP, and NF-\\u03baB [#31, #32, #34, #35, #33]. Its activity is terminated by MKP1-mediated dephosphorylation, which permits fibrosis resolution [#43]. A kidney-restricted splice isoform, Mxi2, differs only in its C-terminus, escapes MKK3/6 activation and ATF2 phosphorylation, shows altered inhibitor and phosphatase sensitivity, and instead binds ERK1/2 to selectively sustain nuclear ERK signaling [#0, #1, #2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that a p38\\u03b1 splice isoform (Mxi2) carries intrinsic kinase activity directed at a specific transcription factor, raising the question of isoform-specific substrate recognition.\",\n      \"evidence\": \"Yeast two-hybrid plus in vitro/in vivo phosphorylation of Max\",\n      \"pmids\": [\"7479834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of Max phosphorylation in vivo not established\", \"Substrate-recognition motif inferred from sequence similarity, not structurally proven\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the unique C-terminus of Mxi2 as the determinant of its divergent regulation, showing it cannot be activated by MKK3/6 or phosphorylate ATF2 and is kidney-restricted, distinguishing it functionally from p38\\u03b1.\",\n      \"evidence\": \"Immunohistochemistry, kinase assays, and domain-swap hybrids\",\n      \"pmids\": [\"10751326\", \"10838079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo function of kidney Mxi2 unresolved\", \"Physiological activator of Mxi2 unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed that Mxi2 acts as an ERK scaffold, physically binding ERK1/2 to prolong specifically nuclear ERK signaling, connecting the p38 locus to cross-pathway control.\",\n      \"evidence\": \"Reciprocal co-IP, reporter assays, Ras/Raf/MEK epistasis\",\n      \"pmids\": [\"12697810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Mxi2 selectively protects nuclear ERK unclear\", \"Structural basis of the Mxi2\\u2013ERK interaction not solved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified TAB1 as a direct p38\\u03b1 substrate phosphorylated at mapped sites, establishing a negative feedback loop limiting TAK1 and coordinating p38\\u03b1 with JNK/IKK pathways.\",\n      \"evidence\": \"In vitro kinase assay with mapped sites, p38\\u03b1-knockout MEFs, TAK1 activity assays\",\n      \"pmids\": [\"14592977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of feedback to in vivo signaling not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that conformational changes near the L16 loop alone can confer high intrinsic activity, mechanistically separating activation from upstream phosphorylation.\",\n      \"evidence\": \"Active-site mutants with biochemical kinase assays and structural interpretation\",\n      \"pmids\": [\"15284239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether equivalent conformational states occur physiologically not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Catalogued the multiple activation modes of p38\\u03b1\\u2014canonical MKK3/6, TAB1-mediated autophosphorylation, and peroxynitrite-induced disulfide complexes\\u2014and placed p38\\u03b1 in a defined migration pathway (PAK\\u2192p38\\u03b1\\u2192MK2\\u2192HSP27).\",\n      \"evidence\": \"MKK double-knockout MEFs, cysteine mutagenesis, isoform-specific knockout and RNAi in migration assays\",\n      \"pmids\": [\"16849316\", \"16574378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ~85-kDa peroxynitrite partner unresolved\", \"Relative weighting of activation modes across tissues unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined p38\\u03b1 as a context-dependent suppressor of proliferation, antagonizing the JNK\\u2013c-Jun axis and tuning EGFR-driven progenitor self-renewal.\",\n      \"evidence\": \"Conditional Mapk14 knockout in multiple cell types with JNK/c-Jun epistasis and differentiation assays\",\n      \"pmids\": [\"17468757\", \"17468755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates linking p38\\u03b1 to JNK/c-Jun suppression not all identified\", \"Tissue-specific switch between suppressor and promoter roles not mechanistically explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a C-lobe lipid-binding pocket around Trp197 distinct from the ATP site, expanding the allosteric ligand landscape of p38\\u03b1.\",\n      \"evidence\": \"X-ray crystallography with bound ligand and computational analysis\",\n      \"pmids\": [\"19501598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous lipid ligand of the pocket not identified\", \"Functional consequence of pocket occupancy in cells untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that activator-specific p38\\u03b1 (via GADD45B-MAP3K4) localizes to autophagosomes and phosphorylates ATG5-T75 to block autophagosome\\u2013lysosome fusion, linking p38\\u03b1 to autophagy regulation and chemoresistance.\",\n      \"evidence\": \"Subcellular fractionation, in vitro kinase with mapped site, mutant reconstitution in knockout cells; plus siRNA/inhibitor work in TP53-null colon cancer\",\n      \"pmids\": [\"23235332\", \"22647487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How activator identity dictates p38\\u03b1 autophagosome targeting unclear\", \"Direction of autophagy effect varies by context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Solved the structural basis of TAB1-driven cis-autophosphorylation and connected it causally to myocardial ischemic injury and to cardiac contractility via PP2A/PP1/phospholamban.\",\n      \"evidence\": \"Crystallography, chemical-genetics, cell-free reconstitution, ex vivo cardiomyocyte and perfused-heart models; phosphatase activity assays\",\n      \"pmids\": [\"24037507\", \"24361238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate(s) of p38\\u03b1 driving the contractility phenotype not fully mapped\", \"PRMT1-mediated methylation of p38\\u03b1 (PMID 23483889) regulatory role incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the activating chemistry and allostery of p38\\u03b1\\u2014Thr180 as the dominant activating phosphosite and substrate docking (MK2) that accelerates phosphotransfer\\u2014while extending p38\\u03b1 to glucose metabolic reprogramming.\",\n      \"evidence\": \"Semisynthetic phosphorylation, solution NMR, in vitro kinase kinetics; metabolic flux assays and PFKFB3 degron mutagenesis\",\n      \"pmids\": [\"24393126\", \"25038803\", \"25046111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dominance of Thr180 over Tyr182 not directly tested\", \"Mechanism coupling p38\\u03b1 to HIF1A stabilization not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established hepatic and organelle-level metabolic roles: p38\\u03b1 restrains AMPK to sustain fasting gluconeogenesis and is required for starvation/hypoxia mitophagy via the alternative RAB9 pathway.\",\n      \"evidence\": \"Liver-specific knockout with dominant-negative AMPK epistasis; Keima mitophagy assay with knockdown and Atg5-KO controls\",\n      \"pmids\": [\"25595884\", \"25831013\", \"26061537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct p38\\u03b1 substrate in AMPK feedback not identified\", \"Pyridinyl-imidazole inhibitors confound pharmacological dissection of p38-autophagy link\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked p38\\u03b1 to chromatin remodeling, showing it phosphorylates KMT1A to displace it from MyoD and reprogram H3K9 marks at the Myogenin promoter during myogenesis.\",\n      \"evidence\": \"In vitro kinase, co-IP, ChIP for H3K9me3/ac, gain- and loss-of-function\",\n      \"pmids\": [\"27551368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KMT1A phosphosite(s) not mapped here\", \"Generalizability to other lineage-specifying loci untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined the cis-autoactivation mechanism to an intramolecular Thr185\\u2013Asp150 hydrogen bond and four TAB1 docking residues, enabling separation-of-function mutants that confer ischemia resistance, and added a DNA-repair substrate (CtIP).\",\n      \"evidence\": \"Crystallography, structure-guided T185G mutagenesis, TAB1 knock-in mice, cardiac injury models; conditional knockout/inhibition with HR repair and ATR assays\",\n      \"pmids\": [\"30135318\", \"29229647\", \"29805078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CtIP phosphosite(s) not mapped\", \"Therapeutic separation of autophosphorylation from canonical activity not yet translated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped diverse tissue programs: ULK1-S555-dependent autophagy steering cells to senescence, and cell-type-specific pro-disease roles in immune, vascular, stromal, and cancer settings via NF-\\u03baB/NOX4, IGF-1, TGF-\\u03b2/JNK, IL-27, and TIMP-1.\",\n      \"evidence\": \"Inducible activation systems with mapped ULK1-S555; multiple cell-type-specific conditional knockouts with pathway epistasis and tumor/injury models\",\n      \"pmids\": [\"31092814\", \"30771750\", \"29907597\", \"31296856\", \"30541887\", \"31969449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for opposing tumor-suppressor versus tumor-promoter outcomes not unified\", \"Direct substrates downstream of most tissue phenotypes unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed constitutively active p38\\u03b1 is sufficient to cause reversible fatty liver and that SUMOylation at K152 modulates a nuclear p38\\u03b1\\u2013MK2 ROS-sensing axis.\",\n      \"evidence\": \"Inducible active-allele transgenics with reversibility; SUMO site mapping by IP/pull-down with nuclear ROS readouts\",\n      \"pmids\": [\"33811139\", \"34686655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation mechanism single-lab, not independently confirmed\", \"Substrates mediating the fatty-liver gene-expression program not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the substrate-and-program map to plasma cell differentiation (BLIMP1 via TCF3/4/IRF4), uterine implantation (Ube3c-S741 protecting progesterone receptor), and dendritic-cell-controlled Th2 responses (MK2-c-FOS-IL-12).\",\n      \"evidence\": \"B-cell, uterine, and DC-specific conditional knockouts; CRISPR screen, reporter mice, in vitro kinase with LC-MS phosphosite mapping, ubiquitination assays\",\n      \"pmids\": [\"36443297\", \"35914132\", \"35551270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct BLIMP1-axis substrate of p38\\u03b1 not identified\", \"Cross-tissue generality of the Ube3c regulatory mechanism unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the dynamic multistep dual-phosphorylation mechanism by which MKK6 activates p38\\u03b1 and showed MAP2K N-termini dictate pathway specificity, while identifying FOXO1-S273 as a glucagon/EPAC2-driven hepatic substrate controlling glucose production.\",\n      \"evidence\": \"Cryo-EM with HDX-MS and MD validation; in vitro LC-MS phosphosite mapping with Foxo1-S273 knock-in mice and glucagon tolerance tests\",\n      \"pmids\": [\"37708276\", \"37202506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate (versus activator) discrimination not fully generalized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established MKP1-mediated dephosphorylation of p38\\u03b1 as the off-switch enabling fibrosis resolution and myofibroblast dedifferentiation.\",\n      \"evidence\": \"Fibroblast-specific MKP1 conditional knockout with VX-702 p38\\u03b1 inhibitor rescue in bleomycin fibrosis\",\n      \"pmids\": [\"38512415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p38\\u03b1 substrates driving myofibroblast persistence not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected p38\\u03b1 nuclear translocation to p53-dependent transcription, showing a small molecule (lobeline) that blocks nuclear entry relieves p53 repression of SLURP1 to reprogram tumor macrophages.\",\n      \"evidence\": \"DARTS and target-responsive accessibility profiling, nuclear/cytoplasmic fractionation, p53 phosphorylation assays, Slurp1-deficient xenografts\",\n      \"pmids\": [\"39840525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p53 phosphorylation by p38\\u03b1 site not mapped here\", \"Single-lab binding/mechanism not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular features dictate p38\\u03b1's opposing context-dependent outcomes (tumor suppressor versus promoter; pro- versus anti-autophagic) and how activator identity, subcellular localization, and post-translational modification combine to select specific substrate sets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking upstream activator to downstream substrate selection\", \"Direct substrates behind many tissue phenotypes still unidentified\", \"Physiological role of the C-lobe lipid pocket and SUMOylation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 11, 23, 39, 42]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [4, 11, 17, 39, 42]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 37, 44]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 8, 41]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 20, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [28, 31, 38, 40]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [18, 21, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 19, 23]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TAB1\", \"MKK6\", \"MK2\", \"ERK1/2\", \"PRMT1\", \"ATG5\", \"ULK1\", \"FOXO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}