{"gene":"MAPK15","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1999,"finding":"ERK7 (MAPK15) has constitutive kinase activity in serum-starved cells dependent on its C-terminal domain; the C-terminal tail (not the kinase domain) regulates its nuclear localization and growth inhibition; it is not activated by extracellular stimuli that activate ERK1/2, JNK, or p38.","method":"Cloning, expression in COS cells, kinase assays, deletion mutant analysis, fluorescence localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — original characterization with multiple orthogonal methods (kinase assays, localization, deletion mutants), foundational paper with 126 citations","pmids":["9891064"],"is_preprint":false},{"year":2001,"finding":"ERK7 (MAPK15) is activated by intramolecular autophosphorylation of its TEY motif without requiring an upstream MEK; multiple regions of the C-terminal domain regulate its kinase activity; MEK inhibitors do not suppress ERK7 activity.","method":"In vitro kinase assays, MEK inhibitor treatment, autophosphorylation assays, C-terminal deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of autophosphorylation with mutagenesis, replicated domain analyses","pmids":["11287416"],"is_preprint":false},{"year":2002,"finding":"ERK8 (MAPK15) associates with the c-Src SH3 domain via two SH3-binding motifs in its C-terminal region, co-immunoprecipitates with c-Src in vivo, and is activated downstream of c-Src (v-Src or constitutively active c-Src); this activation is MEK-independent.","method":"In vitro pulldown (SH3 domain binding), co-immunoprecipitation, co-transfection with v-Src/active c-Src, MEK inhibitor U0126 treatment, Src inhibitor PP2 treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and in vitro binding plus functional epistasis with inhibitors, 98 citations","pmids":["11875070"],"is_preprint":false},{"year":2004,"finding":"ERK7 (MAPK15) protein expression is regulated by ubiquitination and rapid proteasomal turnover; the N-terminal 20 amino acids of the kinase domain are necessary and sufficient to direct ERK7 degradation; ERK7 is ubiquitinated by the SCF (Skp1-Cullin-F-box) complex.","method":"Proteasome inhibitor treatment, ERK2-ERK7 chimeric proteins, GFP fusion constructs, dominant-negative Cullin-1 mutant co-expression, pulse-chase degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple chimeric constructs and genetic epistasis with dominant-negative Cullin-1, clean mechanistic dissection","pmids":["15033983"],"is_preprint":false},{"year":2006,"finding":"ERK8 (MAPK15) phosphorylation of its TEY motif is an autophosphorylation event; dephosphorylation of Thr-175 by PP2A reduces activity >95% while dephosphorylation of Tyr-177 by PTP1B reduces activity only 15–20%; H2O2, okadaic acid, and osmotic shock activate ERK8 in cells; catalytically inactive mutants (D154A, K42A) are not phosphorylated, confirming autophosphorylation; ERK8 has a substrate specificity distinct from ERK1/2.","method":"In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, phosphosite identification by mass spectrometry, in vitro kinase assay with myelin basic protein","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified phosphatases, mutagenesis, and substrate profiling","pmids":["16336213"],"is_preprint":false},{"year":2006,"finding":"ERK8 (MAPK15) interacts with Hic-5 (ARA55) via the LIM3 and LIM4 domains of Hic-5 and the kinase-independent C-terminal region of ERK8; through this interaction, ERK8 negatively regulates glucocorticoid receptor (GRα) and androgen receptor transcriptional co-activation by Hic-5 in a kinase-independent manner.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, transcriptional reporter assays, siRNA knockdown of endogenous ERK8","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by Co-IP, functional validation by reporter assay and siRNA knockdown","pmids":["16624805"],"is_preprint":false},{"year":2006,"finding":"ERK8 (MAPK15) is activated by RET/PTC3 (an activated RET proto-oncogene) through a mechanism requiring Tyr981 of RET/PTC3 and c-Abl kinase activity (not strictly Src); ERK8 participates in RET/PTC3-dependent stimulation of the c-jun promoter; the C-terminal domain of ERK8 is the region modulated by RET/PTC3 and Abl.","method":"Co-transfection with RET/PTC3 mutants, kinase assays, c-jun promoter reporter assay, Abl inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via site-directed RET mutants and pharmacological Abl inhibition, single lab","pmids":["16484222"],"is_preprint":false},{"year":2009,"finding":"ERK8 (MAPK15) activity is induced by DNA single-strand break-generating agents (H2O2, DNA alkylating agents, cross-linking agents, PARP inhibitor KU-0058948); the DNA alkylating agent MMS induces proteasome-dependent degradation of endogenous ERK8, linking ERK8 to DNA damage response.","method":"ERK8 kinase activity assays in transfected cells after agonist treatment, proteasome inhibitor rescue experiments","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with multiple orthogonal DNA-damaging agents, single lab","pmids":["19166846"],"is_preprint":false},{"year":2010,"finding":"ERK8 (MAPK15) is chromatin-bound and interacts with PCNA via a conserved PIP box motif; chromatin-bound ERK8 prevents HDM2-mediated ubiquitination and degradation of PCNA by blocking PCNA–HDM2 association; silencing ERK8 decreases PCNA levels and increases DNA damage, which is rescued by ectopic PCNA expression.","method":"Co-immunoprecipitation (chromatin fraction), PIP-box mutant analysis, siRNA knockdown, ectopic PCNA rescue, DNA damage assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mutant, genetic epistasis rescue experiment, multiple readouts","pmids":["20733054"],"is_preprint":false},{"year":2010,"finding":"ERK8 (MAPK15) interacts with ERRα via two LXXLL motifs in ERK8; this interaction induces CRM1-dependent translocation of ERRα to the cytoplasm and inhibits ERRα transcriptional activity; ERK8 counteracts EGF receptor-induced ERRα activation in mammary cells.","method":"Co-immunoprecipitation, LXXLL mutant analysis, nuclear export (CRM1) inhibitor treatment, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis, pharmacological CRM1 inhibition, and reporter assays providing mechanistic detail","pmids":["21190936"],"is_preprint":false},{"year":2011,"finding":"ERK7 (Drosophila ortholog of MAPK15) negatively regulates protein secretion in response to serum/amino-acid starvation by phosphorylating Sec16 at its C-terminus, causing cytoplasmic dispersion of Sec16 and disassembly of ER exit sites; this response is TORC1-independent.","method":"Drosophila RNAi screen, epistasis experiments in S2 cells and human cells, Sec16 phosphorylation assays, proteasome inhibition to stabilize ERK7","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — RNAi screen with functional epistasis, validated in both Drosophila and human cells with substrate identification","pmids":["21847093"],"is_preprint":false},{"year":2012,"finding":"MAPK15 (ERK8) interacts with ATG8-family proteins (MAP1LC3B, GABARAP, GABARAPL1) via a conserved LC3-interacting region (LIR) motif; through this interaction, MAPK15 localizes to autophagic compartments and stimulates ATG8 lipidation, autophagosome formation, and SQSTM1 degradation in a kinase-dependent manner; MAPK15 activity is induced by serum and amino-acid starvation and is required for starvation-induced autophagy.","method":"Co-immunoprecipitation, LIR mutant analysis, autophagosome formation assays (LC3 lipidation, SQSTM1 degradation), confocal microscopy localization, siRNA knockdown","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis (LIR mutant), kinase-dead mutant, multiple autophagy readouts, replicated in multiple cell types","pmids":["22948227"],"is_preprint":false},{"year":2013,"finding":"ERK8 (MAPK15) localizes to the spindle fibers and microtubule asters during mouse oocyte meiotic maturation; knockdown of ERK8 by antibody microinjection or siRNA causes abnormal spindles, failed chromosome congression, and decreased polar body extrusion.","method":"Immunofluorescence localization, taxol treatment, antibody microinjection, siRNA knockdown, spindle morphology analysis","journal":"Microscopy and microanalysis","confidence":"Medium","confidence_rationale":"Tier 3 — localization and KD with specific phenotypic readout, single lab","pmids":["23351492"],"is_preprint":false},{"year":2013,"finding":"A homology model of the ERK8 kinase domain was validated experimentally; compounds identified by virtual screening were confirmed as ATP-competitive inhibitors of ERK8; a gatekeeper mutant corroborated the predicted binding mode.","method":"Homology modeling, pharmacophore screening, molecular docking, in vitro kinase inhibition assays, gatekeeper mutant","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1/3 — computational model validated by in vitro inhibition and mutagenesis, but no crystal structure","pmids":["23326322"],"is_preprint":false},{"year":2014,"finding":"ERK8 (MAPK15) is a negative regulator of O-GalNAc glycosylation; ERK8 is partially localized at the Golgi and its inhibition/knockdown induces relocation of GalNAc-transferases from the Golgi to the ER via a COPI-dependent pathway distinct from KDEL receptor trafficking; ERK8 downregulation activates cell motility.","method":"RNAi screen of 948 signaling genes, imaging of GalNAc-T subcellular localization, COPI pathway epistasis, cell motility assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genome-wide RNAi screen with mechanistic follow-up, pathway epistasis, multiple readouts","pmids":["24618899"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, ERK7 (MAPK15 ortholog) is upregulated in insulin-producing cells (IPCs) upon ribosome biogenesis impairment or starvation, acts epistatically downstream of p53, and is sufficient and essential to inhibit insulin-like peptide (dILP) secretion; this defines a p53→ERK7 axis in a cell-autonomous ribosome surveillance response.","method":"Genetic epistasis (double mutant analysis), IPC-specific RNAi, ERK7 overexpression in IPCs, body size measurements, developmental timing","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean epistasis with double mutants in defined cell type, multiple genetic tools","pmids":["25393288"],"is_preprint":false},{"year":2015,"finding":"ERK7 (Xenopus MAPK15 ortholog) regulates ciliogenesis by phosphorylating CapZIP (an actin regulator) in cooperation with Dishevelled; Dishevelled facilitates ERK7 phosphorylation of CapZIP by binding both ERK7 and CapZIP; ERK7 knockdown abolishes the apical actin meshwork, inhibits basal body apical migration, and reduces cilium number and length in multiciliated cells.","method":"Xenopus embryo knockdown (morpholino), in vitro kinase assay showing direct phosphorylation of CapZIP by ERK7, co-immunoprecipitation (Dishevelled-ERK7-CapZIP), confocal imaging of cilia and actin","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — direct substrate phosphorylation in vitro confirmed with Co-IP ternary complex and in vivo phenotype","pmids":["25823377"],"is_preprint":false},{"year":2015,"finding":"MAPK15 physically recruits BCR-ABL1 to autophagic vesicles via its LIR domain interaction with LC3-family proteins; MAPK15 mediates BCR-ABL1-induced autophagy; depletion of endogenous MAPK15 inhibits BCR-ABL1-dependent cell proliferation in vitro and tumor formation in vivo.","method":"Co-immunoprecipitation, LIR mutant analysis, autophagy assays in HeLa and K562 cells, pharmacological MAPK15 inhibition, xenograft tumor formation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — domain mutant (LIR), Co-IP, in vitro and in vivo loss-of-function with defined phenotype","pmids":["26291129"],"is_preprint":false},{"year":2015,"finding":"MAPK15 in gastric cancer cells sustains c-Jun phosphorylation and increases c-Jun protein stability/half-life; MAPK15 knockdown reduces c-Jun phosphorylation and shortens c-Jun half-life; MAPK15 overexpression increases c-Jun phosphorylation.","method":"siRNA knockdown, transient overexpression, c-Jun phosphorylation immunoblot, c-Jun half-life pulse-chase analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — functional assay showing substrate stabilization, single lab, no in vitro direct phosphorylation demonstrated","pmids":["26035356"],"is_preprint":false},{"year":2016,"finding":"ERK8 (MAPK15) phosphorylates HuR in response to H2O2; this phosphorylation prevents HuR from binding to the PDCD4 3'UTR, allowing miR-21-mediated degradation of PDCD4 mRNA, thereby downregulating the tumor suppressor PDCD4.","method":"Co-immunoprecipitation, in vitro kinase assay, RNA pulldown/RIP (HuR-PDCD4 3'UTR binding), miR-21 reporter assay, H2O2 treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay plus RNA binding assay plus functional miRNA readout, single lab","pmids":["26595526"],"is_preprint":false},{"year":2016,"finding":"MAPK15 protects germ cell tumor cells from DNA damage by sustaining autophagy; MAPK15-dependent autophagy is required for basal DNA damage management and for p53 suppression; depletion of MAPK15 triggers p53-dependent cell cycle arrest.","method":"siRNA knockdown, autophagy inhibition, DNA damage marker analysis (γH2AX), p53 activation assays, xenograft tumor formation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis (autophagy→DNA damage→p53) with multiple loss-of-function approaches","pmids":["26988910"],"is_preprint":false},{"year":2017,"finding":"MAPK15 (SWIP-13 in C. elegans) acts presynaptically to regulate DAT (dopamine transporter) surface expression and DA clearance; SWIP-13/ERK8 activates Rho GTPases to control DAT surface availability, a mechanism conserved in human ERK8.","method":"Forward genetic screen in C. elegans, in vitro Rho GTPase activation assays, in vivo DAT surface expression measurements, epistasis with Rho pathway mutants","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — forward genetic screen, in vitro and in vivo epistasis, conservation validated in human cells","pmids":["28842414"],"is_preprint":false},{"year":2017,"finding":"MAPK15 localizes to a basal body subdomain and regulates primary cilia formation in C. elegans sensory neurons and human cells; MAPK15 regulates localization of ciliary proteins involved in cilium structure, IFT transport, and signaling (including BBS7).","method":"Fluorescence localization (GFP fusions), C. elegans loss-of-function mutants, human cell knockdown, ciliary protein trafficking assays","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo localization and loss-of-function in two species with multiple ciliary protein readouts","pmids":["29021280"],"is_preprint":false},{"year":2017,"finding":"MAPK-15 in C. elegans localizes to cilia and is required for PKD-2 (polycystin-2) localization in male ray neurons; a catalytic-site mutant causes ciliary defects (dye uptake, dendrite extension, male mating); MAPK15 expression is partially DAF-19/RFX-dependent.","method":"GFP transgenic localization, catalytic mutant analysis, dye-filling assay, male mating behavior assay, rescue experiments","journal":"Cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 3 — in vivo localization and catalytic mutant with defined behavioral phenotype, single lab","pmids":["28745435"],"is_preprint":false},{"year":2018,"finding":"MAPK15 is part of the ULK1 complex and stimulates AMPK-dependent ULK1 activity toward downstream substrates; MAPK15 directly interacts with the ULK1 complex and mediates ULK1 activation induced by nutrient starvation, establishing a MAPK15→ULK1→autophagosome biogenesis cascade.","method":"Co-immunoprecipitation (MAPK15-ULK1 complex), in vitro kinase assays (ULK1 substrate phosphorylation), starvation-induced autophagy assays, ULK2 redundancy analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct complex Co-IP and in vitro kinase cascade reconstitution with multiple substrates","pmids":["30131341"],"is_preprint":false},{"year":2020,"finding":"In Toxoplasma gondii, ERK7 is regulated by AC9 (apical cap protein 9): AC9 directly binds ERK7 through a conserved C-terminal motif, is required for ERK7 localization to the apical cap, and inhibits ERK7 activity by displacing nucleotide from the active site; ERK7 is required for apical complex (conoid) biogenesis and parasite invasion/egress.","method":"Proximity biotinylation (BioID), crystal structure of ERK7-AC9 complex, genetic depletion (conditional KO), yeast two-hybrid, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation, proximity proteomics, and genetic depletion phenotype","pmids":["32409604"],"is_preprint":false},{"year":2020,"finding":"In Drosophila, ERK7 controls subcellular localization of the chromatin-binding protein PWP1 in the fat body; PWP1 maintains expression of sugarbabe (a lipogenic transcription factor); ERK7 acts as an anti-anabolic kinase inhibiting lipid storage and growth under nutrient deprivation.","method":"ERK7 loss-of-function and gain-of-function in Drosophila larvae, genetic epistasis (PWP1 and sugarbabe mutants), TAG measurement, growth rate analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple pathway components in vivo, single species","pmids":["33369866"],"is_preprint":false},{"year":2021,"finding":"In Toxoplasma, ERK7 depletion causes loss of the apical polar ring, disorganization of subpellicular microtubules, severe impairment of microneme secretion, and accumulation of microneme proteins; ERK7 depletion phenocopies AC9 and AC10 depletion, consistent with an ERK7-AC9-AC10 complex controlling apical complex integrity.","method":"Conditional knockdown (dTAG system), ultrastructure expansion microscopy (U-ExM), comparative proteomics, electron microscopy","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging modalities and proteomics confirm phenotype; replication of prior work with higher resolution","pmids":["34607461"],"is_preprint":false},{"year":2021,"finding":"MAPK15 controls primary ciliogenesis and canonical Hedgehog (HH) signaling in NIH3T3 cells; in SHH-driven medulloblastoma cells, MAPK15 regulates cancer stem cell self-renewal (medullo-sphere formation) through a cilia-dependent mechanism; pharmacological inhibition of MAPK15 prevents proliferation of SHH-driven medulloblastoma cells.","method":"siRNA knockdown, pharmacological inhibition, HH pathway reporter assays, oncogenic SMO-M2/GLI2-DN epistasis, medullo-sphere assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological approaches with pathway epistasis, single lab","pmids":["34638386"],"is_preprint":false},{"year":2022,"finding":"In Toxoplasma, AC9, AC10, and ERK7 form an essential trimeric complex with multivalent pairwise interactions; AC10 is a foundational scaffold; multiple independent interaction regions enable oligomerization that concentrates ERK7 at the apical cap cytoskeleton.","method":"Yeast two-hybrid, deletion analyses, conditional knockdown, proximity biotinylation, functional complementation","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — multiple domain deletion analyses and yeast two-hybrid define protein-protein interaction architecture","pmids":["35130732"],"is_preprint":false},{"year":2022,"finding":"MAPK15 prevents oxidative stress-induced cellular senescence by controlling mitophagy: MAPK15 stimulates ULK1-dependent PRKN (Parkin) Ser108 phosphorylation, promotes recruitment of damaged mitochondria to autophagosomes/lysosomes, and participates in mitochondrial network reorganization prior to disposal; loss of MAPK15 reduces mitochondrial respiration, increases mitochondrial ROS, and drives nuclear DNA damage-induced senescence in primary human airway epithelial cells.","method":"siRNA knockdown, MAPK15 KO/KD, mitophagy flux assays, PRKN phosphorylation immunoblot, mitochondrial function assays (respiration, ATP, ROS), senescence markers (SA-β-gal, γH2AX)","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 — direct substrate phosphorylation (PRKN Ser108), multiple mitophagy and senescence readouts, primary cells","pmids":["35642724"],"is_preprint":false},{"year":2023,"finding":"In Toxoplasma, the ERK7 interactome includes a putative E3 ligase CSAR1 that is normally localized to the residual body and responsible for maternal cytoskeleton turnover during cytokinesis; CSAR1 genetic disruption fully suppresses loss of the apical complex upon ERK7 knockdown, establishing a protein homeostasis pathway where ERK7 protects the apical complex from CSAR1-mediated degradation.","method":"Proximity biotinylation (ERK7 interactome), conditional knockdown (dTAG), genetic suppressor screen (CSAR1 disruption), immunofluorescence microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis (CSAR1 KO suppresses ERK7 KD) with interactome data and localization evidence","pmids":["37027006"],"is_preprint":false},{"year":2023,"finding":"MAPK15 interacts with NF-κB p50 subunit and enters the nucleus together; the MAPK15–NF-κB p50 complex binds the EP3 (prostaglandin E2 receptor) promoter and transcriptionally upregulates EP3 expression, promoting lung adenocarcinoma cell migration.","method":"Co-immunoprecipitation (MAPK15-p50), luciferase reporter assay (EP3 promoter), siRNA knockdown, nuclear fractionation, transwell migration assay, in vivo metastasis model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus reporter assay plus in vivo functional validation, single lab","pmids":["36900191"],"is_preprint":false},{"year":2024,"finding":"MAPK15 controls the transactivating potential of NRF2 by inducing NRF2 activating phosphorylation, increasing NRF2 expression and nuclear translocation upon oxidative stress; MAPK15 is necessary for NRF2-dependent antioxidant gene expression in response to cigarette smoke in lung epithelial cells.","method":"siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, NRF2 target gene expression analysis, cigarette smoke extract treatment","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct phosphorylation of NRF2 shown with nuclear translocation, functional target gene readout, single lab","pmids":["38555711"],"is_preprint":false},{"year":2025,"finding":"CLIC3 (chloride intracellular channel 3) interacts with ERK7 (MAPK15) at the plasma membrane and represses ERK7 activity; CLIC3-ERK7 interaction promotes cellular senescence; knockdown of CLIC3 mitigates senescence by de-repressing ERK7.","method":"Co-immunoprecipitation (CLIC3-ERK7), membrane fractionation, siRNA knockdown, senescence assays (SA-β-gal, SASP markers), ERK7 kinase activity assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and functional knockdown, single lab, mechanism not fully dissected","pmids":["39809890"],"is_preprint":false},{"year":2025,"finding":"MAPK15 suppresses IFNB1 expression by preventing oxidative stress-dependent JNK-JUN pathway activation; MAPK15 downregulation increases ROS, activates JNK-JUN signaling, and upregulates IFNB1 and interferon-stimulated genes; the antioxidant NACET blocks MAPK15 loss-induced JUN activation and IFNB1 expression.","method":"MAPK15 siRNA knockdown, luciferase reporter assays (IFNB1 promoter), JNK pharmacological inhibitor, NACET antioxidant rescue, ELISA (IFNB1 secretion), gene expression analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and antioxidant epistasis with reporter assays, single lab","pmids":["40507959"],"is_preprint":false},{"year":2026,"finding":"MAPK15 knockout mice exhibit liver steatosis (MASLD-like phenotype) due to increased expression and membrane localization of the CD36 fatty acid translocase; MAPK15 overexpression opposes lipid accumulation in hepatocellular models; Mapk15-/- mice fed a western diet accelerate to steatohepatitis.","method":"Knockout mouse model (Mapk15-/-), CD36 expression and localization analysis, western diet feeding, hepatocellular in vitro models, transcriptomic analysis of human MASLD cohorts","journal":"Hepatology communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO mouse model with defined molecular target (CD36), gain-of-function rescue, human cohort validation","pmids":["41610145"],"is_preprint":false}],"current_model":"MAPK15 (ERK7/ERK8) is an atypical, constitutively autophosphorylating MAP kinase whose activity and stability are governed by its C-terminal domain (which also directs nuclear localization) and regulated by ubiquitin-proteasome-mediated turnover; it is activated by DNA damage, oxidative stress, and nutrient starvation rather than canonical mitogen-stimulated MEK cascades, and functions through both kinase-dependent mechanisms—including direct phosphorylation of CapZIP to regulate ciliogenesis, stimulation of ULK1/AMPK-dependent autophagy/mitophagy via LIR-domain interactions with LC3/GABARAP proteins, phosphorylation of PRKN (Ser108) to promote mitophagy, activation of NRF2 to control antioxidant responses, suppression of JNK-JUN-IFNB1 signaling, maintenance of PCNA stability by blocking HDM2 access, and regulation of GalNAc-transferase Golgi localization to control O-glycosylation and cell motility—and kinase-independent mechanisms such as acting as an ERRα corepressor (inducing CRM1-dependent nuclear exclusion) and sequestering Hic-5 to suppress glucocorticoid receptor transactivation; in vivo, MAPK15 is essential for primary and motile cilia biogenesis across species, controls dopamine transporter surface expression via Rho GTPases, and limits hepatic lipid uptake by suppressing CD36 membrane localization, with its loss leading to cellular senescence, genomic instability, and metabolic liver disease."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of ERK7/MAPK15 as an atypical MAP kinase with constitutive activity and a regulatory C-terminal domain resolved the question of whether all MAPKs require extracellular mitogenic stimulation and established that the C-terminal tail governs both nuclear localization and growth inhibition.","evidence":"Cloning, kinase assays, deletion mutants, and fluorescence localization in COS cells","pmids":["9891064"],"confidence":"High","gaps":["Identity of endogenous upstream activating signals unknown","C-terminal domain structure unresolved","Physiological substrates not identified"]},{"year":2001,"claim":"Demonstration that ERK7 autophosphorylates its TEY activation motif intramolecularly, without requiring an upstream MEK, established a fundamentally different activation mechanism from classical MAPKs.","evidence":"In vitro autophosphorylation assays with kinase-dead mutants and MEK inhibitor insensitivity","pmids":["11287416"],"confidence":"High","gaps":["Crystal structure of the kinase domain not determined","Mechanism by which the C-terminal domain stimulates autophosphorylation unclear"]},{"year":2002,"claim":"Finding that c-Src activates ERK8/MAPK15 via SH3-domain binding to the C-terminal region identified the first upstream regulatory input, acting through a MEK-independent route.","evidence":"In vitro SH3-domain pulldown, reciprocal Co-IP, epistasis with Src and MEK inhibitors","pmids":["11875070"],"confidence":"High","gaps":["Whether Src phosphorylates MAPK15 directly or acts allosterically not resolved","Physiological contexts of Src–MAPK15 axis undefined"]},{"year":2004,"claim":"Revealing that MAPK15 undergoes rapid SCF-complex-mediated proteasomal degradation directed by its N-terminal 20 amino acids explained how a constitutively active kinase is kept at low steady-state levels.","evidence":"Proteasome inhibitors, ERK2–ERK7 chimeric constructs, dominant-negative Cullin-1, pulse-chase","pmids":["15033983"],"confidence":"High","gaps":["Specific F-box protein not identified","Signals that stabilize MAPK15 under stress not defined"]},{"year":2006,"claim":"Biochemical dissection of TEY autophosphorylation showed Thr-175 is the critical activating residue (PP2A dephosphorylation eliminates >95% activity), while identification of H₂O₂ and osmotic shock as activators established MAPK15 as a stress-responsive kinase with a substrate specificity distinct from ERK1/2.","evidence":"In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, mass spectrometry","pmids":["16336213"],"confidence":"High","gaps":["Endogenous stress-sensing mechanism upstream of autophosphorylation unresolved","Full substrate consensus motif not defined"]},{"year":2006,"claim":"Discovery that MAPK15 sequesters Hic-5 via its C-terminal domain to repress glucocorticoid and androgen receptor co-activation, and separately acts as an ERRα corepressor via LXXLL motifs promoting CRM1-dependent nuclear export, revealed kinase-independent transcriptional regulatory functions.","evidence":"Yeast two-hybrid, Co-IP, transcriptional reporters, siRNA, CRM1 inhibitor (for ERRα work in 2010)","pmids":["16624805","21190936"],"confidence":"High","gaps":["Physiological relevance of steroid receptor regulation in vivo not tested","Whether kinase-dependent and kinase-independent functions are coordinated is unknown"]},{"year":2009,"claim":"Showing that DNA single-strand-break-generating agents activate MAPK15 and that alkylation damage triggers its proteasomal degradation linked MAPK15 to the DNA damage response, prior to identification of specific genome-maintenance substrates.","evidence":"Kinase activity assays after H₂O₂, alkylating agents, PARP inhibitor treatment; proteasome inhibitor rescue","pmids":["19166846"],"confidence":"Medium","gaps":["Downstream DNA repair effectors not identified","Whether MAPK15 degradation is a feedback termination signal or pathological consequence unclear"]},{"year":2010,"claim":"Identification of PCNA as a chromatin-bound MAPK15 partner, whose stability MAPK15 maintains by blocking HDM2-mediated ubiquitination, provided the first direct mechanistic link between MAPK15 and genome integrity maintenance.","evidence":"Chromatin-fraction Co-IP, PIP-box mutant, siRNA with ectopic PCNA rescue, γH2AX assay","pmids":["20733054"],"confidence":"High","gaps":["Whether MAPK15 phosphorylates PCNA or acts purely as a scaffold not resolved","In vivo genome instability phenotype not examined"]},{"year":2011,"claim":"Drosophila ERK7 was shown to phosphorylate Sec16 to disassemble ER exit sites upon starvation, establishing the first direct substrate connection and placing MAPK15 as a nutrient-sensing regulator of secretory pathway organization.","evidence":"Drosophila RNAi screen, Sec16 phosphorylation assays, human cell validation, TORC1 epistasis","pmids":["21847093"],"confidence":"High","gaps":["Sec16 phosphorylation site identity not mapped in mammalian cells","Relationship to autophagy induction unclear at this stage"]},{"year":2012,"claim":"Discovery that MAPK15 binds ATG8-family proteins (LC3B, GABARAP, GABARAPL1) via a LIR motif and stimulates autophagosome formation in a kinase-dependent manner upon starvation established MAPK15 as a direct autophagy regulator.","evidence":"Co-IP, LIR mutant analysis, LC3 lipidation assays, SQSTM1 degradation, siRNA in multiple cell types","pmids":["22948227"],"confidence":"High","gaps":["Direct kinase target in the autophagy cascade not yet identified","Whether MAPK15 acts upstream or in parallel to mTOR-dependent autophagy signals unknown"]},{"year":2014,"claim":"An RNAi screen identified MAPK15 as a negative regulator of O-GalNAc glycosylation by controlling COPI-dependent Golgi retention of GalNAc-transferases, revealing an unexpected role in Golgi trafficking and cell motility.","evidence":"Genome-wide RNAi screen, GalNAc-T localization imaging, COPI epistasis, cell motility assays","pmids":["24618899"],"confidence":"High","gaps":["Direct MAPK15 substrate in the COPI retention pathway not identified","Whether this function is linked to ciliogenesis or secretion regulation is unknown"]},{"year":2015,"claim":"Identification of CapZIP as a direct MAPK15 phosphorylation substrate in Xenopus multiciliated cells, acting in cooperation with Dishevelled, established the molecular mechanism by which MAPK15 organizes the apical actin network for basal body docking and ciliogenesis.","evidence":"In vitro kinase assay (ERK7→CapZIP), Co-IP of ternary complex (Dvl–ERK7–CapZIP), morpholino knockdown, confocal imaging","pmids":["25823377"],"confidence":"High","gaps":["CapZIP phosphorylation sites not fully mapped","Whether mammalian MAPK15 uses the same substrate for primary ciliogenesis untested"]},{"year":2017,"claim":"Studies in C. elegans and human cells demonstrated that MAPK15 localizes to basal bodies and is essential for primary cilia formation, ciliary protein trafficking (including BBS7 and PKD-2), and also regulates dopamine transporter surface expression via Rho GTPases, broadening MAPK15's roles to neuronal signaling.","evidence":"C. elegans forward genetic screen, GFP localization, loss-of-function mutants, Rho GTPase activation assays, conservation in human cells","pmids":["29021280","28745435","28842414"],"confidence":"High","gaps":["Direct Rho GTPase substrate relationship not biochemically defined","How basal body localization is achieved in mammalian cells unclear"]},{"year":2018,"claim":"Placing MAPK15 within the ULK1 complex and showing it stimulates AMPK-dependent ULK1 activity identified the kinase cascade through which MAPK15 drives autophagosome biogenesis upon starvation.","evidence":"Co-IP of MAPK15–ULK1 complex, in vitro kinase cascade assay, starvation-induced autophagy readouts","pmids":["30131341"],"confidence":"High","gaps":["Whether MAPK15 directly phosphorylates ULK1 or acts via AMPK not resolved","Relative contribution versus other ULK1 activators not quantified"]},{"year":2020,"claim":"The crystal structure of the Toxoplasma ERK7–AC9 complex revealed that AC9 inhibits ERK7 by displacing nucleotide from the active site, providing the first structural understanding of MAPK15 regulation and linking it to apical complex biogenesis in apicomplexan parasites.","evidence":"X-ray crystallography, BioID, conditional KO, yeast two-hybrid","pmids":["32409604"],"confidence":"High","gaps":["Mammalian structural equivalent of AC9-mediated regulation not identified","Whether a similar allosteric inhibition occurs in metazoan MAPK15 unknown"]},{"year":2022,"claim":"MAPK15 was shown to prevent oxidative stress-induced cellular senescence by driving ULK1-dependent PRKN Ser108 phosphorylation and mitophagy, directly connecting MAPK15-regulated mitochondrial quality control to prevention of nuclear DNA damage and senescence in primary human cells.","evidence":"MAPK15 KO/KD, PRKN Ser108 phosphorylation immunoblot, mitophagy flux, respiration/ROS/ATP assays, senescence markers in primary airway epithelia","pmids":["35642724"],"confidence":"High","gaps":["Whether MAPK15 phosphorylates PRKN directly or through ULK1 not fully dissected","Tissue-specific relevance beyond airway epithelium not established"]},{"year":2024,"claim":"Demonstration that MAPK15 activates NRF2 by inducing its phosphorylation and nuclear translocation upon oxidative stress (cigarette smoke) identified an additional antioxidant effector arm complementing its mitophagy function.","evidence":"siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, target gene expression in lung epithelial cells","pmids":["38555711"],"confidence":"Medium","gaps":["NRF2 phosphorylation site by MAPK15 not mapped","Whether this is direct phosphorylation or mediated through Keap1 regulation unclear"]},{"year":2025,"claim":"MAPK15 was found to suppress IFNB1 expression and interferon-stimulated gene programs by preventing ROS-dependent JNK–JUN pathway activation, adding an anti-inflammatory dimension to its antioxidant functions.","evidence":"siRNA knockdown, IFNB1 promoter reporter, JNK inhibitor and NACET antioxidant epistasis, ELISA","pmids":["40507959"],"confidence":"Medium","gaps":["Whether MAPK15 directly inhibits JNK or acts solely through ROS suppression not resolved","In vivo inflammatory phenotype not tested"]},{"year":2025,"claim":"Mapk15 knockout mice develop liver steatosis driven by increased CD36 membrane localization and lipid uptake, validated in human MASLD cohorts, establishing the first in vivo mammalian disease phenotype for MAPK15 loss.","evidence":"Mapk15−/− mouse model, CD36 expression/localization, western diet challenge, hepatocellular gain-of-function rescue, human cohort transcriptomics","pmids":["41610145"],"confidence":"High","gaps":["Mechanism by which MAPK15 controls CD36 trafficking not defined","Whether metabolic phenotype is connected to autophagy/mitophagy functions of MAPK15 not tested"]},{"year":null,"claim":"Key open questions include: the full structural basis of mammalian MAPK15 autophosphorylation and C-terminal domain regulation, the identity of the F-box protein mediating its SCF-dependent turnover, how its diverse functions (ciliogenesis, autophagy/mitophagy, genome maintenance, Golgi trafficking, metabolic regulation) are coordinated in space and time, and whether MAPK15 loss-of-function causes human Mendelian disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian MAPK15 crystal structure exists","F-box protein identity unknown","Integrated signaling model connecting cilia, autophagy, and metabolic functions lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,16,19,30]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,4,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,14,35]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,9,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,9,32]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[14]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[16,22,23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[34]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,17,24,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,8,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,21,35]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,7,33,35]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[16,22,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[26,36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[30,34]}],"complexes":["ULK1 complex","ERK7-AC9-AC10 (Toxoplasma apical cap complex)"],"partners":["ULK1","PCNA","SRC","DVL","GABARAP","MAP1LC3B","PRKN","NRF2"],"other_free_text":[]},"mechanistic_narrative":"MAPK15 (ERK7/ERK8) is an atypical MAP kinase that functions as a stress-responsive, constitutively autophosphorylating signaling hub integrating nutrient sensing, genome maintenance, autophagy, ciliogenesis, and antioxidant defense. Its kinase activity depends on intramolecular autophosphorylation of its TEY motif—independent of upstream MEKs—and is regulated by its unique C-terminal domain, which also controls nuclear localization, protein–protein interactions (including c-Src, Dishevelled, and LC3/GABARAP family proteins), and rapid SCF-mediated proteasomal turnover [PMID:9891064, PMID:11287416, PMID:15033983, PMID:22948227]. MAPK15 promotes autophagy and mitophagy through direct engagement of the ULK1/AMPK axis and PRKN Ser108 phosphorylation, thereby preventing mitochondrial ROS accumulation, DNA damage, and cellular senescence; it also stabilizes chromatin-bound PCNA by blocking HDM2-mediated ubiquitination, activates NRF2-dependent antioxidant transcription, and suppresses JNK–JUN–IFNB1 inflammatory signaling [PMID:30131341, PMID:35642724, PMID:20733054, PMID:38555711, PMID:40507959]. Beyond genome and organelle homeostasis, MAPK15 is essential for primary and motile cilia biogenesis across species—phosphorylating CapZIP to organize the apical actin network for basal body migration—regulates GalNAc-transferase Golgi-to-ER trafficking to control O-glycosylation and cell motility, and limits hepatic lipid uptake by suppressing CD36 membrane localization, with Mapk15 knockout mice developing steatohepatitis [PMID:25823377, PMID:29021280, PMID:24618899, PMID:41610145]."},"prefetch_data":{"uniprot":{"accession":"Q8TD08","full_name":"Mitogen-activated protein kinase 15","aliases":["Extracellular signal-regulated kinase 7","ERK-7","Extracellular signal-regulated kinase 8","ERK-8"],"length_aa":544,"mass_kda":59.8,"function":"Atypical MAPK protein that regulates several process such as autophagy, ciliogenesis, protein trafficking/secretion and genome integrity, in a kinase activity-dependent manner (PubMed:20733054, PubMed:21847093, PubMed:22948227, PubMed:24618899, PubMed:29021280). Controls both, basal and starvation-induced autophagy throught its interaction with GABARAP, MAP1LC3B and GABARAPL1 leading to autophagosome formation, SQSTM1 degradation and reduced MAP1LC3B inhibitory phosphorylation (PubMed:22948227). Regulates primary cilium formation and the localization of ciliary proteins involved in cilium structure, transport, and signaling (PubMed:29021280). Prevents the relocation of the sugar-adding enzymes from the Golgi to the endoplasmic reticulum, thereby restricting the production of sugar-coated proteins (PubMed:24618899). Upon amino-acid starvation, mediates transitional endoplasmic reticulum site disassembly and inhibition of secretion (PubMed:21847093). Binds to chromatin leading to MAPK15 activation and interaction with PCNA, that which protects genomic integrity by inhibiting MDM2-mediated degradation of PCNA (PubMed:20733054). Regulates DA transporter (DAT) activity and protein expression via activation of RhoA (PubMed:28842414). In response to H(2)O(2) treatment phosphorylates ELAVL1, thus preventing it from binding to the PDCD4 3'UTR and rendering the PDCD4 mRNA accessible to miR-21 and leading to its degradation and loss of protein expression (PubMed:26595526). Also functions in a kinase activity-independent manner as a negative regulator of growth (By similarity). Phosphorylates in vitro FOS and MBP (PubMed:11875070, PubMed:16484222, PubMed:19166846, PubMed:20638370). During oocyte maturation, plays a key role in the microtubule organization and meiotic cell cycle progression in oocytes, fertilized eggs, and early embryos (By similarity). Interacts with ESRRA promoting its re-localization from the nucleus to the cytoplasm and then prevents its transcriptional activity (PubMed:21190936)","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cell junction, tight junction; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasmic vesicle, autophagosome; Golgi apparatus; Nucleus; Cytoplasm; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q8TD08/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPK15","classification":"Not Classified","n_dependent_lines":49,"n_total_lines":1208,"dependency_fraction":0.04056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAPK15","total_profiled":1310},"omim":[{"mim_id":"618616","title":"MITOGEN-ACTIVATED PROTEIN KINASE 15; MAPK15","url":"https://www.omim.org/entry/618616"},{"mim_id":"604296","title":"GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE; GRHPR","url":"https://www.omim.org/entry/604296"},{"mim_id":"260000","title":"HYPEROXALURIA, PRIMARY, TYPE II; HP2","url":"https://www.omim.org/entry/260000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":70.7},{"tissue":"fallopian tube","ntpm":36.1}],"url":"https://www.proteinatlas.org/search/MAPK15"},"hgnc":{"alias_symbol":["ERK8","ERK7"],"prev_symbol":[]},"alphafold":{"accession":"Q8TD08","domains":[{"cath_id":"3.30.200.20","chopping":"8-95_327-347","consensus_level":"high","plddt":89.3691,"start":8,"end":347},{"cath_id":"1.10.510.10","chopping":"98-308","consensus_level":"high","plddt":86.9575,"start":98,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD08","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD08-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD08-F1-predicted_aligned_error_v6.png","plddt_mean":68.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPK15","jax_strain_url":"https://www.jax.org/strain/search?query=MAPK15"},"sequence":{"accession":"Q8TD08","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TD08.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TD08/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD08"}},"corpus_meta":[{"pmid":"9891064","id":"PMC_9891064","title":"Extracellular 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safety","url":"https://pubmed.ncbi.nlm.nih.gov/40784096","citation_count":0,"is_preprint":false},{"pmid":"40396004","id":"PMC_40396004","title":"MAPK15 controls mitochondrial fitness and contributes to prevent cellular senescence.","date":"2022","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/40396004","citation_count":0,"is_preprint":false},{"pmid":"40507959","id":"PMC_40507959","title":"MAPK15 Prevents IFNB1 Expression by Suppressing Oxidative Stress-Dependent Activation of the JNK-JUN Pathway.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40507959","citation_count":0,"is_preprint":false},{"pmid":"41610145","id":"PMC_41610145","title":"MAPK15 controls intracellular lipid uptake and protects mammalian liver from steatotic disease.","date":"2026","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/41610145","citation_count":0,"is_preprint":false},{"pmid":"40938944","id":"PMC_40938944","title":"Molecular docking to homology models of human and Trypanosoma brucei ERK8 that identified ortholog-specific inhibitors.","date":"2025","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40938944","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.23.630083","title":"MAPK15 PROTECTS AGAINST THE DEVELOPMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE","date":"2024-12-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.23.630083","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26000,"output_tokens":9183,"usd":0.107872},"stage2":{"model":"claude-opus-4-6","input_tokens":13056,"output_tokens":4998,"usd":0.285345},"total_usd":0.393217,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"ERK7 (MAPK15) has constitutive kinase activity in serum-starved cells dependent on its C-terminal domain; the C-terminal tail (not the kinase domain) regulates its nuclear localization and growth inhibition; it is not activated by extracellular stimuli that activate ERK1/2, JNK, or p38.\",\n      \"method\": \"Cloning, expression in COS cells, kinase assays, deletion mutant analysis, fluorescence localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original characterization with multiple orthogonal methods (kinase assays, localization, deletion mutants), foundational paper with 126 citations\",\n      \"pmids\": [\"9891064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ERK7 (MAPK15) is activated by intramolecular autophosphorylation of its TEY motif without requiring an upstream MEK; multiple regions of the C-terminal domain regulate its kinase activity; MEK inhibitors do not suppress ERK7 activity.\",\n      \"method\": \"In vitro kinase assays, MEK inhibitor treatment, autophosphorylation assays, C-terminal deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of autophosphorylation with mutagenesis, replicated domain analyses\",\n      \"pmids\": [\"11287416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ERK8 (MAPK15) associates with the c-Src SH3 domain via two SH3-binding motifs in its C-terminal region, co-immunoprecipitates with c-Src in vivo, and is activated downstream of c-Src (v-Src or constitutively active c-Src); this activation is MEK-independent.\",\n      \"method\": \"In vitro pulldown (SH3 domain binding), co-immunoprecipitation, co-transfection with v-Src/active c-Src, MEK inhibitor U0126 treatment, Src inhibitor PP2 treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and in vitro binding plus functional epistasis with inhibitors, 98 citations\",\n      \"pmids\": [\"11875070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERK7 (MAPK15) protein expression is regulated by ubiquitination and rapid proteasomal turnover; the N-terminal 20 amino acids of the kinase domain are necessary and sufficient to direct ERK7 degradation; ERK7 is ubiquitinated by the SCF (Skp1-Cullin-F-box) complex.\",\n      \"method\": \"Proteasome inhibitor treatment, ERK2-ERK7 chimeric proteins, GFP fusion constructs, dominant-negative Cullin-1 mutant co-expression, pulse-chase degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple chimeric constructs and genetic epistasis with dominant-negative Cullin-1, clean mechanistic dissection\",\n      \"pmids\": [\"15033983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ERK8 (MAPK15) phosphorylation of its TEY motif is an autophosphorylation event; dephosphorylation of Thr-175 by PP2A reduces activity >95% while dephosphorylation of Tyr-177 by PTP1B reduces activity only 15–20%; H2O2, okadaic acid, and osmotic shock activate ERK8 in cells; catalytically inactive mutants (D154A, K42A) are not phosphorylated, confirming autophosphorylation; ERK8 has a substrate specificity distinct from ERK1/2.\",\n      \"method\": \"In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, phosphosite identification by mass spectrometry, in vitro kinase assay with myelin basic protein\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified phosphatases, mutagenesis, and substrate profiling\",\n      \"pmids\": [\"16336213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ERK8 (MAPK15) interacts with Hic-5 (ARA55) via the LIM3 and LIM4 domains of Hic-5 and the kinase-independent C-terminal region of ERK8; through this interaction, ERK8 negatively regulates glucocorticoid receptor (GRα) and androgen receptor transcriptional co-activation by Hic-5 in a kinase-independent manner.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, transcriptional reporter assays, siRNA knockdown of endogenous ERK8\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by Co-IP, functional validation by reporter assay and siRNA knockdown\",\n      \"pmids\": [\"16624805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ERK8 (MAPK15) is activated by RET/PTC3 (an activated RET proto-oncogene) through a mechanism requiring Tyr981 of RET/PTC3 and c-Abl kinase activity (not strictly Src); ERK8 participates in RET/PTC3-dependent stimulation of the c-jun promoter; the C-terminal domain of ERK8 is the region modulated by RET/PTC3 and Abl.\",\n      \"method\": \"Co-transfection with RET/PTC3 mutants, kinase assays, c-jun promoter reporter assay, Abl inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via site-directed RET mutants and pharmacological Abl inhibition, single lab\",\n      \"pmids\": [\"16484222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERK8 (MAPK15) activity is induced by DNA single-strand break-generating agents (H2O2, DNA alkylating agents, cross-linking agents, PARP inhibitor KU-0058948); the DNA alkylating agent MMS induces proteasome-dependent degradation of endogenous ERK8, linking ERK8 to DNA damage response.\",\n      \"method\": \"ERK8 kinase activity assays in transfected cells after agonist treatment, proteasome inhibitor rescue experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with multiple orthogonal DNA-damaging agents, single lab\",\n      \"pmids\": [\"19166846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERK8 (MAPK15) is chromatin-bound and interacts with PCNA via a conserved PIP box motif; chromatin-bound ERK8 prevents HDM2-mediated ubiquitination and degradation of PCNA by blocking PCNA–HDM2 association; silencing ERK8 decreases PCNA levels and increases DNA damage, which is rescued by ectopic PCNA expression.\",\n      \"method\": \"Co-immunoprecipitation (chromatin fraction), PIP-box mutant analysis, siRNA knockdown, ectopic PCNA rescue, DNA damage assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mutant, genetic epistasis rescue experiment, multiple readouts\",\n      \"pmids\": [\"20733054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERK8 (MAPK15) interacts with ERRα via two LXXLL motifs in ERK8; this interaction induces CRM1-dependent translocation of ERRα to the cytoplasm and inhibits ERRα transcriptional activity; ERK8 counteracts EGF receptor-induced ERRα activation in mammary cells.\",\n      \"method\": \"Co-immunoprecipitation, LXXLL mutant analysis, nuclear export (CRM1) inhibitor treatment, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis, pharmacological CRM1 inhibition, and reporter assays providing mechanistic detail\",\n      \"pmids\": [\"21190936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ERK7 (Drosophila ortholog of MAPK15) negatively regulates protein secretion in response to serum/amino-acid starvation by phosphorylating Sec16 at its C-terminus, causing cytoplasmic dispersion of Sec16 and disassembly of ER exit sites; this response is TORC1-independent.\",\n      \"method\": \"Drosophila RNAi screen, epistasis experiments in S2 cells and human cells, Sec16 phosphorylation assays, proteasome inhibition to stabilize ERK7\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi screen with functional epistasis, validated in both Drosophila and human cells with substrate identification\",\n      \"pmids\": [\"21847093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAPK15 (ERK8) interacts with ATG8-family proteins (MAP1LC3B, GABARAP, GABARAPL1) via a conserved LC3-interacting region (LIR) motif; through this interaction, MAPK15 localizes to autophagic compartments and stimulates ATG8 lipidation, autophagosome formation, and SQSTM1 degradation in a kinase-dependent manner; MAPK15 activity is induced by serum and amino-acid starvation and is required for starvation-induced autophagy.\",\n      \"method\": \"Co-immunoprecipitation, LIR mutant analysis, autophagosome formation assays (LC3 lipidation, SQSTM1 degradation), confocal microscopy localization, siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis (LIR mutant), kinase-dead mutant, multiple autophagy readouts, replicated in multiple cell types\",\n      \"pmids\": [\"22948227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERK8 (MAPK15) localizes to the spindle fibers and microtubule asters during mouse oocyte meiotic maturation; knockdown of ERK8 by antibody microinjection or siRNA causes abnormal spindles, failed chromosome congression, and decreased polar body extrusion.\",\n      \"method\": \"Immunofluorescence localization, taxol treatment, antibody microinjection, siRNA knockdown, spindle morphology analysis\",\n      \"journal\": \"Microscopy and microanalysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization and KD with specific phenotypic readout, single lab\",\n      \"pmids\": [\"23351492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A homology model of the ERK8 kinase domain was validated experimentally; compounds identified by virtual screening were confirmed as ATP-competitive inhibitors of ERK8; a gatekeeper mutant corroborated the predicted binding mode.\",\n      \"method\": \"Homology modeling, pharmacophore screening, molecular docking, in vitro kinase inhibition assays, gatekeeper mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/3 — computational model validated by in vitro inhibition and mutagenesis, but no crystal structure\",\n      \"pmids\": [\"23326322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERK8 (MAPK15) is a negative regulator of O-GalNAc glycosylation; ERK8 is partially localized at the Golgi and its inhibition/knockdown induces relocation of GalNAc-transferases from the Golgi to the ER via a COPI-dependent pathway distinct from KDEL receptor trafficking; ERK8 downregulation activates cell motility.\",\n      \"method\": \"RNAi screen of 948 signaling genes, imaging of GalNAc-T subcellular localization, COPI pathway epistasis, cell motility assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide RNAi screen with mechanistic follow-up, pathway epistasis, multiple readouts\",\n      \"pmids\": [\"24618899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, ERK7 (MAPK15 ortholog) is upregulated in insulin-producing cells (IPCs) upon ribosome biogenesis impairment or starvation, acts epistatically downstream of p53, and is sufficient and essential to inhibit insulin-like peptide (dILP) secretion; this defines a p53→ERK7 axis in a cell-autonomous ribosome surveillance response.\",\n      \"method\": \"Genetic epistasis (double mutant analysis), IPC-specific RNAi, ERK7 overexpression in IPCs, body size measurements, developmental timing\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean epistasis with double mutants in defined cell type, multiple genetic tools\",\n      \"pmids\": [\"25393288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERK7 (Xenopus MAPK15 ortholog) regulates ciliogenesis by phosphorylating CapZIP (an actin regulator) in cooperation with Dishevelled; Dishevelled facilitates ERK7 phosphorylation of CapZIP by binding both ERK7 and CapZIP; ERK7 knockdown abolishes the apical actin meshwork, inhibits basal body apical migration, and reduces cilium number and length in multiciliated cells.\",\n      \"method\": \"Xenopus embryo knockdown (morpholino), in vitro kinase assay showing direct phosphorylation of CapZIP by ERK7, co-immunoprecipitation (Dishevelled-ERK7-CapZIP), confocal imaging of cilia and actin\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct substrate phosphorylation in vitro confirmed with Co-IP ternary complex and in vivo phenotype\",\n      \"pmids\": [\"25823377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAPK15 physically recruits BCR-ABL1 to autophagic vesicles via its LIR domain interaction with LC3-family proteins; MAPK15 mediates BCR-ABL1-induced autophagy; depletion of endogenous MAPK15 inhibits BCR-ABL1-dependent cell proliferation in vitro and tumor formation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, LIR mutant analysis, autophagy assays in HeLa and K562 cells, pharmacological MAPK15 inhibition, xenograft tumor formation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutant (LIR), Co-IP, in vitro and in vivo loss-of-function with defined phenotype\",\n      \"pmids\": [\"26291129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAPK15 in gastric cancer cells sustains c-Jun phosphorylation and increases c-Jun protein stability/half-life; MAPK15 knockdown reduces c-Jun phosphorylation and shortens c-Jun half-life; MAPK15 overexpression increases c-Jun phosphorylation.\",\n      \"method\": \"siRNA knockdown, transient overexpression, c-Jun phosphorylation immunoblot, c-Jun half-life pulse-chase analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assay showing substrate stabilization, single lab, no in vitro direct phosphorylation demonstrated\",\n      \"pmids\": [\"26035356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERK8 (MAPK15) phosphorylates HuR in response to H2O2; this phosphorylation prevents HuR from binding to the PDCD4 3'UTR, allowing miR-21-mediated degradation of PDCD4 mRNA, thereby downregulating the tumor suppressor PDCD4.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, RNA pulldown/RIP (HuR-PDCD4 3'UTR binding), miR-21 reporter assay, H2O2 treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay plus RNA binding assay plus functional miRNA readout, single lab\",\n      \"pmids\": [\"26595526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAPK15 protects germ cell tumor cells from DNA damage by sustaining autophagy; MAPK15-dependent autophagy is required for basal DNA damage management and for p53 suppression; depletion of MAPK15 triggers p53-dependent cell cycle arrest.\",\n      \"method\": \"siRNA knockdown, autophagy inhibition, DNA damage marker analysis (γH2AX), p53 activation assays, xenograft tumor formation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis (autophagy→DNA damage→p53) with multiple loss-of-function approaches\",\n      \"pmids\": [\"26988910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAPK15 (SWIP-13 in C. elegans) acts presynaptically to regulate DAT (dopamine transporter) surface expression and DA clearance; SWIP-13/ERK8 activates Rho GTPases to control DAT surface availability, a mechanism conserved in human ERK8.\",\n      \"method\": \"Forward genetic screen in C. elegans, in vitro Rho GTPase activation assays, in vivo DAT surface expression measurements, epistasis with Rho pathway mutants\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — forward genetic screen, in vitro and in vivo epistasis, conservation validated in human cells\",\n      \"pmids\": [\"28842414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAPK15 localizes to a basal body subdomain and regulates primary cilia formation in C. elegans sensory neurons and human cells; MAPK15 regulates localization of ciliary proteins involved in cilium structure, IFT transport, and signaling (including BBS7).\",\n      \"method\": \"Fluorescence localization (GFP fusions), C. elegans loss-of-function mutants, human cell knockdown, ciliary protein trafficking assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo localization and loss-of-function in two species with multiple ciliary protein readouts\",\n      \"pmids\": [\"29021280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAPK-15 in C. elegans localizes to cilia and is required for PKD-2 (polycystin-2) localization in male ray neurons; a catalytic-site mutant causes ciliary defects (dye uptake, dendrite extension, male mating); MAPK15 expression is partially DAF-19/RFX-dependent.\",\n      \"method\": \"GFP transgenic localization, catalytic mutant analysis, dye-filling assay, male mating behavior assay, rescue experiments\",\n      \"journal\": \"Cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — in vivo localization and catalytic mutant with defined behavioral phenotype, single lab\",\n      \"pmids\": [\"28745435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAPK15 is part of the ULK1 complex and stimulates AMPK-dependent ULK1 activity toward downstream substrates; MAPK15 directly interacts with the ULK1 complex and mediates ULK1 activation induced by nutrient starvation, establishing a MAPK15→ULK1→autophagosome biogenesis cascade.\",\n      \"method\": \"Co-immunoprecipitation (MAPK15-ULK1 complex), in vitro kinase assays (ULK1 substrate phosphorylation), starvation-induced autophagy assays, ULK2 redundancy analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct complex Co-IP and in vitro kinase cascade reconstitution with multiple substrates\",\n      \"pmids\": [\"30131341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Toxoplasma gondii, ERK7 is regulated by AC9 (apical cap protein 9): AC9 directly binds ERK7 through a conserved C-terminal motif, is required for ERK7 localization to the apical cap, and inhibits ERK7 activity by displacing nucleotide from the active site; ERK7 is required for apical complex (conoid) biogenesis and parasite invasion/egress.\",\n      \"method\": \"Proximity biotinylation (BioID), crystal structure of ERK7-AC9 complex, genetic depletion (conditional KO), yeast two-hybrid, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation, proximity proteomics, and genetic depletion phenotype\",\n      \"pmids\": [\"32409604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila, ERK7 controls subcellular localization of the chromatin-binding protein PWP1 in the fat body; PWP1 maintains expression of sugarbabe (a lipogenic transcription factor); ERK7 acts as an anti-anabolic kinase inhibiting lipid storage and growth under nutrient deprivation.\",\n      \"method\": \"ERK7 loss-of-function and gain-of-function in Drosophila larvae, genetic epistasis (PWP1 and sugarbabe mutants), TAG measurement, growth rate analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple pathway components in vivo, single species\",\n      \"pmids\": [\"33369866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Toxoplasma, ERK7 depletion causes loss of the apical polar ring, disorganization of subpellicular microtubules, severe impairment of microneme secretion, and accumulation of microneme proteins; ERK7 depletion phenocopies AC9 and AC10 depletion, consistent with an ERK7-AC9-AC10 complex controlling apical complex integrity.\",\n      \"method\": \"Conditional knockdown (dTAG system), ultrastructure expansion microscopy (U-ExM), comparative proteomics, electron microscopy\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities and proteomics confirm phenotype; replication of prior work with higher resolution\",\n      \"pmids\": [\"34607461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAPK15 controls primary ciliogenesis and canonical Hedgehog (HH) signaling in NIH3T3 cells; in SHH-driven medulloblastoma cells, MAPK15 regulates cancer stem cell self-renewal (medullo-sphere formation) through a cilia-dependent mechanism; pharmacological inhibition of MAPK15 prevents proliferation of SHH-driven medulloblastoma cells.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, HH pathway reporter assays, oncogenic SMO-M2/GLI2-DN epistasis, medullo-sphere assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches with pathway epistasis, single lab\",\n      \"pmids\": [\"34638386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Toxoplasma, AC9, AC10, and ERK7 form an essential trimeric complex with multivalent pairwise interactions; AC10 is a foundational scaffold; multiple independent interaction regions enable oligomerization that concentrates ERK7 at the apical cap cytoskeleton.\",\n      \"method\": \"Yeast two-hybrid, deletion analyses, conditional knockdown, proximity biotinylation, functional complementation\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple domain deletion analyses and yeast two-hybrid define protein-protein interaction architecture\",\n      \"pmids\": [\"35130732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAPK15 prevents oxidative stress-induced cellular senescence by controlling mitophagy: MAPK15 stimulates ULK1-dependent PRKN (Parkin) Ser108 phosphorylation, promotes recruitment of damaged mitochondria to autophagosomes/lysosomes, and participates in mitochondrial network reorganization prior to disposal; loss of MAPK15 reduces mitochondrial respiration, increases mitochondrial ROS, and drives nuclear DNA damage-induced senescence in primary human airway epithelial cells.\",\n      \"method\": \"siRNA knockdown, MAPK15 KO/KD, mitophagy flux assays, PRKN phosphorylation immunoblot, mitochondrial function assays (respiration, ATP, ROS), senescence markers (SA-β-gal, γH2AX)\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct substrate phosphorylation (PRKN Ser108), multiple mitophagy and senescence readouts, primary cells\",\n      \"pmids\": [\"35642724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Toxoplasma, the ERK7 interactome includes a putative E3 ligase CSAR1 that is normally localized to the residual body and responsible for maternal cytoskeleton turnover during cytokinesis; CSAR1 genetic disruption fully suppresses loss of the apical complex upon ERK7 knockdown, establishing a protein homeostasis pathway where ERK7 protects the apical complex from CSAR1-mediated degradation.\",\n      \"method\": \"Proximity biotinylation (ERK7 interactome), conditional knockdown (dTAG), genetic suppressor screen (CSAR1 disruption), immunofluorescence microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (CSAR1 KO suppresses ERK7 KD) with interactome data and localization evidence\",\n      \"pmids\": [\"37027006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAPK15 interacts with NF-κB p50 subunit and enters the nucleus together; the MAPK15–NF-κB p50 complex binds the EP3 (prostaglandin E2 receptor) promoter and transcriptionally upregulates EP3 expression, promoting lung adenocarcinoma cell migration.\",\n      \"method\": \"Co-immunoprecipitation (MAPK15-p50), luciferase reporter assay (EP3 promoter), siRNA knockdown, nuclear fractionation, transwell migration assay, in vivo metastasis model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus reporter assay plus in vivo functional validation, single lab\",\n      \"pmids\": [\"36900191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAPK15 controls the transactivating potential of NRF2 by inducing NRF2 activating phosphorylation, increasing NRF2 expression and nuclear translocation upon oxidative stress; MAPK15 is necessary for NRF2-dependent antioxidant gene expression in response to cigarette smoke in lung epithelial cells.\",\n      \"method\": \"siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, NRF2 target gene expression analysis, cigarette smoke extract treatment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct phosphorylation of NRF2 shown with nuclear translocation, functional target gene readout, single lab\",\n      \"pmids\": [\"38555711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLIC3 (chloride intracellular channel 3) interacts with ERK7 (MAPK15) at the plasma membrane and represses ERK7 activity; CLIC3-ERK7 interaction promotes cellular senescence; knockdown of CLIC3 mitigates senescence by de-repressing ERK7.\",\n      \"method\": \"Co-immunoprecipitation (CLIC3-ERK7), membrane fractionation, siRNA knockdown, senescence assays (SA-β-gal, SASP markers), ERK7 kinase activity assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional knockdown, single lab, mechanism not fully dissected\",\n      \"pmids\": [\"39809890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAPK15 suppresses IFNB1 expression by preventing oxidative stress-dependent JNK-JUN pathway activation; MAPK15 downregulation increases ROS, activates JNK-JUN signaling, and upregulates IFNB1 and interferon-stimulated genes; the antioxidant NACET blocks MAPK15 loss-induced JUN activation and IFNB1 expression.\",\n      \"method\": \"MAPK15 siRNA knockdown, luciferase reporter assays (IFNB1 promoter), JNK pharmacological inhibitor, NACET antioxidant rescue, ELISA (IFNB1 secretion), gene expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and antioxidant epistasis with reporter assays, single lab\",\n      \"pmids\": [\"40507959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAPK15 knockout mice exhibit liver steatosis (MASLD-like phenotype) due to increased expression and membrane localization of the CD36 fatty acid translocase; MAPK15 overexpression opposes lipid accumulation in hepatocellular models; Mapk15-/- mice fed a western diet accelerate to steatohepatitis.\",\n      \"method\": \"Knockout mouse model (Mapk15-/-), CD36 expression and localization analysis, western diet feeding, hepatocellular in vitro models, transcriptomic analysis of human MASLD cohorts\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO mouse model with defined molecular target (CD36), gain-of-function rescue, human cohort validation\",\n      \"pmids\": [\"41610145\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPK15 (ERK7/ERK8) is an atypical, constitutively autophosphorylating MAP kinase whose activity and stability are governed by its C-terminal domain (which also directs nuclear localization) and regulated by ubiquitin-proteasome-mediated turnover; it is activated by DNA damage, oxidative stress, and nutrient starvation rather than canonical mitogen-stimulated MEK cascades, and functions through both kinase-dependent mechanisms—including direct phosphorylation of CapZIP to regulate ciliogenesis, stimulation of ULK1/AMPK-dependent autophagy/mitophagy via LIR-domain interactions with LC3/GABARAP proteins, phosphorylation of PRKN (Ser108) to promote mitophagy, activation of NRF2 to control antioxidant responses, suppression of JNK-JUN-IFNB1 signaling, maintenance of PCNA stability by blocking HDM2 access, and regulation of GalNAc-transferase Golgi localization to control O-glycosylation and cell motility—and kinase-independent mechanisms such as acting as an ERRα corepressor (inducing CRM1-dependent nuclear exclusion) and sequestering Hic-5 to suppress glucocorticoid receptor transactivation; in vivo, MAPK15 is essential for primary and motile cilia biogenesis across species, controls dopamine transporter surface expression via Rho GTPases, and limits hepatic lipid uptake by suppressing CD36 membrane localization, with its loss leading to cellular senescence, genomic instability, and metabolic liver disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAPK15 (ERK7/ERK8) is an atypical MAP kinase that functions as a stress-responsive, constitutively autophosphorylating signaling hub integrating nutrient sensing, genome maintenance, autophagy, ciliogenesis, and antioxidant defense. Its kinase activity depends on intramolecular autophosphorylation of its TEY motif—independent of upstream MEKs—and is regulated by its unique C-terminal domain, which also controls nuclear localization, protein–protein interactions (including c-Src, Dishevelled, and LC3/GABARAP family proteins), and rapid SCF-mediated proteasomal turnover [PMID:9891064, PMID:11287416, PMID:15033983, PMID:22948227]. MAPK15 promotes autophagy and mitophagy through direct engagement of the ULK1/AMPK axis and PRKN Ser108 phosphorylation, thereby preventing mitochondrial ROS accumulation, DNA damage, and cellular senescence; it also stabilizes chromatin-bound PCNA by blocking HDM2-mediated ubiquitination, activates NRF2-dependent antioxidant transcription, and suppresses JNK–JUN–IFNB1 inflammatory signaling [PMID:30131341, PMID:35642724, PMID:20733054, PMID:38555711, PMID:40507959]. Beyond genome and organelle homeostasis, MAPK15 is essential for primary and motile cilia biogenesis across species—phosphorylating CapZIP to organize the apical actin network for basal body migration—regulates GalNAc-transferase Golgi-to-ER trafficking to control O-glycosylation and cell motility, and limits hepatic lipid uptake by suppressing CD36 membrane localization, with Mapk15 knockout mice developing steatohepatitis [PMID:25823377, PMID:29021280, PMID:24618899, PMID:41610145].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of ERK7/MAPK15 as an atypical MAP kinase with constitutive activity and a regulatory C-terminal domain resolved the question of whether all MAPKs require extracellular mitogenic stimulation and established that the C-terminal tail governs both nuclear localization and growth inhibition.\",\n      \"evidence\": \"Cloning, kinase assays, deletion mutants, and fluorescence localization in COS cells\",\n      \"pmids\": [\"9891064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of endogenous upstream activating signals unknown\", \"C-terminal domain structure unresolved\", \"Physiological substrates not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that ERK7 autophosphorylates its TEY activation motif intramolecularly, without requiring an upstream MEK, established a fundamentally different activation mechanism from classical MAPKs.\",\n      \"evidence\": \"In vitro autophosphorylation assays with kinase-dead mutants and MEK inhibitor insensitivity\",\n      \"pmids\": [\"11287416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the kinase domain not determined\", \"Mechanism by which the C-terminal domain stimulates autophosphorylation unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Finding that c-Src activates ERK8/MAPK15 via SH3-domain binding to the C-terminal region identified the first upstream regulatory input, acting through a MEK-independent route.\",\n      \"evidence\": \"In vitro SH3-domain pulldown, reciprocal Co-IP, epistasis with Src and MEK inhibitors\",\n      \"pmids\": [\"11875070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Src phosphorylates MAPK15 directly or acts allosterically not resolved\", \"Physiological contexts of Src–MAPK15 axis undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealing that MAPK15 undergoes rapid SCF-complex-mediated proteasomal degradation directed by its N-terminal 20 amino acids explained how a constitutively active kinase is kept at low steady-state levels.\",\n      \"evidence\": \"Proteasome inhibitors, ERK2–ERK7 chimeric constructs, dominant-negative Cullin-1, pulse-chase\",\n      \"pmids\": [\"15033983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific F-box protein not identified\", \"Signals that stabilize MAPK15 under stress not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Biochemical dissection of TEY autophosphorylation showed Thr-175 is the critical activating residue (PP2A dephosphorylation eliminates >95% activity), while identification of H₂O₂ and osmotic shock as activators established MAPK15 as a stress-responsive kinase with a substrate specificity distinct from ERK1/2.\",\n      \"evidence\": \"In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, mass spectrometry\",\n      \"pmids\": [\"16336213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stress-sensing mechanism upstream of autophosphorylation unresolved\", \"Full substrate consensus motif not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that MAPK15 sequesters Hic-5 via its C-terminal domain to repress glucocorticoid and androgen receptor co-activation, and separately acts as an ERRα corepressor via LXXLL motifs promoting CRM1-dependent nuclear export, revealed kinase-independent transcriptional regulatory functions.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, transcriptional reporters, siRNA, CRM1 inhibitor (for ERRα work in 2010)\",\n      \"pmids\": [\"16624805\", \"21190936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of steroid receptor regulation in vivo not tested\", \"Whether kinase-dependent and kinase-independent functions are coordinated is unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that DNA single-strand-break-generating agents activate MAPK15 and that alkylation damage triggers its proteasomal degradation linked MAPK15 to the DNA damage response, prior to identification of specific genome-maintenance substrates.\",\n      \"evidence\": \"Kinase activity assays after H₂O₂, alkylating agents, PARP inhibitor treatment; proteasome inhibitor rescue\",\n      \"pmids\": [\"19166846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream DNA repair effectors not identified\", \"Whether MAPK15 degradation is a feedback termination signal or pathological consequence unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of PCNA as a chromatin-bound MAPK15 partner, whose stability MAPK15 maintains by blocking HDM2-mediated ubiquitination, provided the first direct mechanistic link between MAPK15 and genome integrity maintenance.\",\n      \"evidence\": \"Chromatin-fraction Co-IP, PIP-box mutant, siRNA with ectopic PCNA rescue, γH2AX assay\",\n      \"pmids\": [\"20733054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAPK15 phosphorylates PCNA or acts purely as a scaffold not resolved\", \"In vivo genome instability phenotype not examined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Drosophila ERK7 was shown to phosphorylate Sec16 to disassemble ER exit sites upon starvation, establishing the first direct substrate connection and placing MAPK15 as a nutrient-sensing regulator of secretory pathway organization.\",\n      \"evidence\": \"Drosophila RNAi screen, Sec16 phosphorylation assays, human cell validation, TORC1 epistasis\",\n      \"pmids\": [\"21847093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sec16 phosphorylation site identity not mapped in mammalian cells\", \"Relationship to autophagy induction unclear at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that MAPK15 binds ATG8-family proteins (LC3B, GABARAP, GABARAPL1) via a LIR motif and stimulates autophagosome formation in a kinase-dependent manner upon starvation established MAPK15 as a direct autophagy regulator.\",\n      \"evidence\": \"Co-IP, LIR mutant analysis, LC3 lipidation assays, SQSTM1 degradation, siRNA in multiple cell types\",\n      \"pmids\": [\"22948227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase target in the autophagy cascade not yet identified\", \"Whether MAPK15 acts upstream or in parallel to mTOR-dependent autophagy signals unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"An RNAi screen identified MAPK15 as a negative regulator of O-GalNAc glycosylation by controlling COPI-dependent Golgi retention of GalNAc-transferases, revealing an unexpected role in Golgi trafficking and cell motility.\",\n      \"evidence\": \"Genome-wide RNAi screen, GalNAc-T localization imaging, COPI epistasis, cell motility assays\",\n      \"pmids\": [\"24618899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MAPK15 substrate in the COPI retention pathway not identified\", \"Whether this function is linked to ciliogenesis or secretion regulation is unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of CapZIP as a direct MAPK15 phosphorylation substrate in Xenopus multiciliated cells, acting in cooperation with Dishevelled, established the molecular mechanism by which MAPK15 organizes the apical actin network for basal body docking and ciliogenesis.\",\n      \"evidence\": \"In vitro kinase assay (ERK7→CapZIP), Co-IP of ternary complex (Dvl–ERK7–CapZIP), morpholino knockdown, confocal imaging\",\n      \"pmids\": [\"25823377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CapZIP phosphorylation sites not fully mapped\", \"Whether mammalian MAPK15 uses the same substrate for primary ciliogenesis untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Studies in C. elegans and human cells demonstrated that MAPK15 localizes to basal bodies and is essential for primary cilia formation, ciliary protein trafficking (including BBS7 and PKD-2), and also regulates dopamine transporter surface expression via Rho GTPases, broadening MAPK15's roles to neuronal signaling.\",\n      \"evidence\": \"C. elegans forward genetic screen, GFP localization, loss-of-function mutants, Rho GTPase activation assays, conservation in human cells\",\n      \"pmids\": [\"29021280\", \"28745435\", \"28842414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Rho GTPase substrate relationship not biochemically defined\", \"How basal body localization is achieved in mammalian cells unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placing MAPK15 within the ULK1 complex and showing it stimulates AMPK-dependent ULK1 activity identified the kinase cascade through which MAPK15 drives autophagosome biogenesis upon starvation.\",\n      \"evidence\": \"Co-IP of MAPK15–ULK1 complex, in vitro kinase cascade assay, starvation-induced autophagy readouts\",\n      \"pmids\": [\"30131341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAPK15 directly phosphorylates ULK1 or acts via AMPK not resolved\", \"Relative contribution versus other ULK1 activators not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The crystal structure of the Toxoplasma ERK7–AC9 complex revealed that AC9 inhibits ERK7 by displacing nucleotide from the active site, providing the first structural understanding of MAPK15 regulation and linking it to apical complex biogenesis in apicomplexan parasites.\",\n      \"evidence\": \"X-ray crystallography, BioID, conditional KO, yeast two-hybrid\",\n      \"pmids\": [\"32409604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian structural equivalent of AC9-mediated regulation not identified\", \"Whether a similar allosteric inhibition occurs in metazoan MAPK15 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MAPK15 was shown to prevent oxidative stress-induced cellular senescence by driving ULK1-dependent PRKN Ser108 phosphorylation and mitophagy, directly connecting MAPK15-regulated mitochondrial quality control to prevention of nuclear DNA damage and senescence in primary human cells.\",\n      \"evidence\": \"MAPK15 KO/KD, PRKN Ser108 phosphorylation immunoblot, mitophagy flux, respiration/ROS/ATP assays, senescence markers in primary airway epithelia\",\n      \"pmids\": [\"35642724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAPK15 phosphorylates PRKN directly or through ULK1 not fully dissected\", \"Tissue-specific relevance beyond airway epithelium not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that MAPK15 activates NRF2 by inducing its phosphorylation and nuclear translocation upon oxidative stress (cigarette smoke) identified an additional antioxidant effector arm complementing its mitophagy function.\",\n      \"evidence\": \"siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, target gene expression in lung epithelial cells\",\n      \"pmids\": [\"38555711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NRF2 phosphorylation site by MAPK15 not mapped\", \"Whether this is direct phosphorylation or mediated through Keap1 regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MAPK15 was found to suppress IFNB1 expression and interferon-stimulated gene programs by preventing ROS-dependent JNK–JUN pathway activation, adding an anti-inflammatory dimension to its antioxidant functions.\",\n      \"evidence\": \"siRNA knockdown, IFNB1 promoter reporter, JNK inhibitor and NACET antioxidant epistasis, ELISA\",\n      \"pmids\": [\"40507959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAPK15 directly inhibits JNK or acts solely through ROS suppression not resolved\", \"In vivo inflammatory phenotype not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapk15 knockout mice develop liver steatosis driven by increased CD36 membrane localization and lipid uptake, validated in human MASLD cohorts, establishing the first in vivo mammalian disease phenotype for MAPK15 loss.\",\n      \"evidence\": \"Mapk15−/− mouse model, CD36 expression/localization, western diet challenge, hepatocellular gain-of-function rescue, human cohort transcriptomics\",\n      \"pmids\": [\"41610145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MAPK15 controls CD36 trafficking not defined\", \"Whether metabolic phenotype is connected to autophagy/mitophagy functions of MAPK15 not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the full structural basis of mammalian MAPK15 autophosphorylation and C-terminal domain regulation, the identity of the F-box protein mediating its SCF-dependent turnover, how its diverse functions (ciliogenesis, autophagy/mitophagy, genome maintenance, Golgi trafficking, metabolic regulation) are coordinated in space and time, and whether MAPK15 loss-of-function causes human Mendelian disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian MAPK15 crystal structure exists\", \"F-box protein identity unknown\", \"Integrated signaling model connecting cilia, autophagy, and metabolic functions lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 16, 19, 30]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 4, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 14, 35]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 9, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 9, 32]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [16, 22, 23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 17, 24, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 8, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 21, 35]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 7, 33, 35]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [16, 22, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [26, 36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [30, 34]}\n    ],\n    \"complexes\": [\n      \"ULK1 complex\",\n      \"ERK7-AC9-AC10 (Toxoplasma apical cap complex)\"\n    ],\n    \"partners\": [\n      \"ULK1\",\n      \"PCNA\",\n      \"SRC\",\n      \"DVL\",\n      \"GABARAP\",\n      \"MAP1LC3B\",\n      \"PRKN\",\n      \"NRF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}