{"gene":"EPPK1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2015,"finding":"Epiplakin (EPPK1) binds to keratin 8 (K8) and K18 via multiple domains in hepatocytes and cholangiocytes. Eppk1-deficient mice subjected to bile duct ligation or DDC diet developed more pronounced liver injury with larger keratin granules, indicating impaired disease-induced keratin network reorganization. Primary Eppk1-/- hepatocytes showed increased keratin aggregate formation after okadaic acid treatment, rescued by the chemical chaperone TMAO, establishing EPPK1 as a chaperone for keratin reorganization under stress.","method":"Eppk1-/- mouse liver injury models (CBDL, DDC diet), primary hepatocyte culture with phosphatase inhibitor treatment, co-immunoprecipitation/binding assays for K8/K18, TMAO rescue experiments, transfection experiments","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, Eppk1-/- mouse models with defined phenotype, multiple orthogonal methods (in vivo injury models, primary cell culture, chemical chaperone rescue), single lab but multiple independent assays","pmids":["25617501"],"is_preprint":false},{"year":2022,"finding":"EPPK1 undergoes a Ca2+-dependent switch from a diffuse cytoplasmic distribution to a keratin filament-associated state. Under standard conditions EPPK1 is not associated with keratin filaments; ER stress, oxidative stress, UV stress, or cell fixation induce rapid and reversible EPPK1 association with keratin filaments. This re-localization requires elevation of cytoplasmic Ca2+ and leads to significantly reduced keratin dynamics, suggesting EPPK1 stabilizes the keratin network during stress.","method":"Live-cell imaging of fluorescently tagged EPPK1 and keratin in epithelial cells, Ca2+ manipulation experiments, FRAP-based measurement of keratin dynamics","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional consequence (keratin dynamics), Ca2+ manipulation as mechanistic validation, multiple orthogonal stress conditions, single lab","pmids":["36231039"],"is_preprint":false},{"year":2022,"finding":"EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces and changes in cell size, shape, and filopodia characteristics, establishing EPPK1 as a regulator of mechanical properties and morphology in retinal Müller cells. EPPK1 was identified as highly expressed in macular Müller cells compared to rod-associated Müller cells.","method":"EPPK1 knockout in human Müller cell line, traction force microscopy, cell morphology analysis, comparative proteomics of human and mouse retinal regions","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined mechanical and morphological phenotypic readouts, single lab, two orthogonal methods (traction force and morphometry)","pmids":["36334068"],"is_preprint":false},{"year":2023,"finding":"DHT (dihydrotestosterone) directly binds to EPPK1 protein (established by biotinylated DHT pull-down). EPPK1 knockdown abolished DHT-promoted proliferation and invasion in bladder cancer cells. In DHT-treated high-EPPK1 cells, JUP expression was elevated and c-Jun bound the JUP promoter. DHT-induced activation of p38 MAPK and c-Jun was absent in EPPK1 knockdown cells, placing EPPK1 upstream of the p38 MAPK/c-Jun/JUP signaling axis in a non-androgen receptor pathway.","method":"Biotinylated DHT pull-down assay, siRNA knockdown, p38 inhibitor treatment, ChIP for c-Jun at JUP promoter, xenograft mouse model, in vivo BBN carcinogenesis model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding assay (biotinylated DHT pulldown), epistasis by inhibitor and KD, ChIP for transcription factor binding, in vivo validation, single lab but multiple orthogonal methods","pmids":["37328487"],"is_preprint":false},{"year":2021,"finding":"KLF5 transcription factor directly binds to the EPPK1 promoter (established by chromatin immunoprecipitation and reporter gene assay) and activates EPPK1 transcription. KLF5-mediated cell proliferation in HeLa cells is partially dependent on EPPK1 upregulation, and EPPK1 lies upstream of p38 signaling in this proliferation pathway.","method":"ChIP assay, luciferase reporter gene assay, siRNA knockdown of KLF5 and EPPK1, adenovirus-mediated overexpression, western blot for p38 signaling, CCK8 proliferation assay","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP and reporter assay establish direct transcription factor binding, epistasis by KD places EPPK1 upstream of p38, single lab with multiple orthogonal methods","pmids":["33827480"],"is_preprint":false},{"year":2022,"finding":"EPPK1 promotes esophageal squamous cell carcinoma (ESCC) cell proliferation, migration, invasion, and EMT, and suppresses apoptosis. Silencing EPPK1 reduced activation of the PI3K/AKT signaling pathway, placing EPPK1 as an upstream activator of PI3K/AKT in ESCC cells.","method":"siRNA knockdown, CCK-8 assay, colony formation, wound healing, Transwell invasion, flow cytometry apoptosis, western blot for PI3K/AKT pathway components and EMT markers","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with multiple defined cellular phenotypes and pathway readout by western blot, single lab, no rescue experiment","pmids":["35238170"],"is_preprint":false},{"year":2024,"finding":"METTL3 mediates N6-methyladenosine (m6A) modification of EPPK1 mRNA (confirmed by MeRIP assay), and EPPK1 is a direct target of METTL3. METTL3 deficiency reduces EPPK1 expression and inactivates the PI3K/AKT pathway in esophageal cancer cells. Rescue of EPPK1 expression reversed the inhibitory effects of METTL3 knockdown on proliferation, invasion, migration, and stemness.","method":"MeRIP (m6A methylation immunoprecipitation), RIP assay, dual-luciferase reporter assay, siRNA knockdown, rescue overexpression, MTT/EdU/colony/Transwell/wound-healing assays, xenograft tumor experiments, IHC","journal":"Environmental toxicology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MeRIP establishes direct m6A modification, RIP and reporter confirm METTL3-EPPK1 interaction, rescue experiment validates epistasis, multiple orthogonal methods in single lab","pmids":["38293837"],"is_preprint":false},{"year":2024,"finding":"CRISPR-Cas9 knockout of EPPK1 in lung adenocarcinoma cell lines induced a mesenchymal-to-epithelial transition (MET), diminished cell proliferation and invasion, downregulated MYC and upregulated p53 at both protein and RNA levels, and altered expression of oncogenes, anti-apoptosis, and angiogenesis genes. EPPK1 protein expression was also increased in bronchial epithelial cells after 16 weeks of cigarette smoke exposure.","method":"CRISPR-Cas9 KO, RNA sequencing, western blot, proliferation and invasion assays, cigarette smoke exposure model, GO enrichment analysis","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined cellular and transcriptional phenotypes, RNA-seq provides pathway-level mechanism, single lab","pmids":["38594604"],"is_preprint":false},{"year":2026,"finding":"EPPK1 functions as an RNA-binding protein that binds YAP mRNA and enhances its stability. EPPK1 knockdown reduced YAP expression and suppressed ovarian cancer cell proliferation, migration, invasion, and immune escape; these effects were rescued by YAP overexpression, placing EPPK1 upstream of YAP in a post-transcriptional regulatory axis.","method":"RIP assay for EPPK1-YAP mRNA interaction, mRNA stability assay, siRNA knockdown, YAP overexpression rescue, xenograft model, in vitro proliferation/migration/invasion/immune escape assays","journal":"Journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishes direct RNA binding, rescue experiment validates epistasis, single lab with multiple orthogonal methods","pmids":["41569058"],"is_preprint":false},{"year":2008,"finding":"Eppk1 is expressed in pancreatic progenitor cells (Eppk1+/Pdx1+/Sox9+ multipotent progenitor cells) in early pancreatic epithelium, later confined to endocrine/exocrine progenitors and duct cells. In the adult pancreas, Eppk1 marks centroacinar cells and duct cells. In caerulein-induced pancreatitis and partial pancreatectomy regeneration models, Eppk1-positive cells expand, identifying it as a marker of pancreatic progenitor/regenerating cell populations.","method":"Immunohistochemistry, co-expression analysis with lineage markers (Pdx1, Sox9, Ngn3, p48) in mouse embryonic and adult pancreas, acute pancreatitis and partial pancreatectomy models","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemistry co-localization with established lineage markers across multiple model systems, replicated across developmental and injury contexts, no functional perturbation","pmids":["18498355"],"is_preprint":false},{"year":2011,"finding":"Eppk1 marks hepatic progenitor cells (oval cells) in CDE diet-injured mouse liver, co-expressing the progenitor marker A6, cholangiocyte markers (cytokeratins, E-cadherin, osteopontin, Sox9), and PCNA, identifying Eppk1+ cells as transient amplifying hepatic progenitors. In normal liver, Eppk1 is confined to cholangiocytes/bile duct cells.","method":"Immunohistochemistry and co-expression analysis with multiple lineage markers in CDE diet mouse liver injury model and normal developing liver","journal":"Gene expression patterns","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immunohistochemistry co-localization only, no functional perturbation of EPPK1","pmids":["21216305"],"is_preprint":false},{"year":2025,"finding":"EPPK1 expression is specifically downregulated in the suprabasal granular layer of psoriatic epidermis compared to healthy skin. IFN-γ treatment of human ex vivo skin explants downregulates EPPK1, identifying IFN-γ as the main cytokine responsible for EPPK1 downregulation in psoriasis. Transcriptomic profiling of Eppk1-/- murine epidermis showed reduced expression of genes involved in epithelial adhesion and lipid metabolism, partially overlapping with the psoriatic keratinocyte signature.","method":"scRNA-seq of psoriatic vs healthy skin, immunofluorescence of human psoriasis samples, ex vivo cytokine treatment of human skin explants, RNA-seq of Eppk1-/- murine epidermis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, immunofluorescence, ex vivo functional cytokine experiment, KO transcriptomics), single lab","pmids":["40746860"],"is_preprint":false}],"current_model":"EPPK1 (epiplakin) is a plakin-family cytoskeletal linker protein that associates with keratin intermediate filaments in a stress-dependent, Ca2+-regulated manner — diffuse in resting cells but rapidly recruited to keratin filaments upon ER, oxidative, or UV stress — where it acts as a chaperone to stabilize keratin network organization and reduce keratin dynamics; upstream, KLF5 directly transactivates EPPK1, and METTL3 promotes EPPK1 expression via m6A mRNA modification, while IFN-γ suppresses it in inflammatory skin; downstream, EPPK1 activates the PI3K/AKT and p38 MAPK pathways (the latter via direct DHT binding and JUP/c-Jun signaling in a non-androgen-receptor pathway) and stabilizes YAP mRNA as an RNA-binding protein, collectively driving epithelial cell proliferation, invasion, EMT, and cancer progression."},"narrative":{"mechanistic_narrative":"EPPK1 (epiplakin) is a plakin-family cytoskeletal linker that organizes and protects the keratin intermediate filament network, acting as a stress-inducible keratin chaperone [PMID:25617501, PMID:36231039]. It binds keratin 8 and keratin 18 through multiple domains, and in its absence keratin aggregates form more readily under phosphatase-inhibitor or in vivo liver-injury stress—a defect rescuable by the chemical chaperone TMAO—establishing a role in disease-induced keratin reorganization [PMID:25617501]. Its engagement of the filament network is conditional: EPPK1 is diffuse in resting cells but undergoes a rapid, reversible, Ca2+-dependent switch to a keratin filament-associated state upon ER, oxidative, or UV stress, where it reduces keratin dynamics and stabilizes the network [PMID:36231039]. Consistent with a structural/mechanical role, EPPK1 loss in retinal Müller cells lowers traction forces and alters cell size, shape, and filopodia [PMID:36334068]. Beyond cytoskeletal organization, EPPK1 is repeatedly implicated as a driver of epithelial proliferation, invasion, and EMT in cancer: it is transcriptionally activated by KLF5 binding its promoter [PMID:33827480] and post-transcriptionally upregulated through METTL3-mediated m6A modification of its mRNA [PMID:38293837], and it functions downstream as an upstream activator of PI3K/AKT signaling [PMID:35238170, PMID:38293837] and of a p38 MAPK/c-Jun/JUP axis that it engages via direct dihydrotestosterone binding in a non-androgen-receptor manner [PMID:37328487]. EPPK1 also acts as an RNA-binding protein that binds and stabilizes YAP mRNA to promote tumor cell proliferation, invasion, and immune escape [PMID:41569058], and its CRISPR knockout drives mesenchymal-to-epithelial transition with MYC downregulation and p53 upregulation [PMID:38594604]. In tissue contexts, EPPK1 marks pancreatic and hepatic progenitor/regenerating cell populations [PMID:18498355], and its expression is downregulated by IFN-γ in psoriatic epidermis [PMID:40746860].","teleology":[{"year":2008,"claim":"Established EPPK1 as a marker of progenitor and regenerating epithelial cell populations, linking it to tissue renewal before any mechanistic role was known.","evidence":"Immunohistochemistry and lineage-marker co-expression in mouse embryonic/adult pancreas plus pancreatitis and partial pancreatectomy models","pmids":["18498355"],"confidence":"Medium","gaps":["Marker-only association with no functional perturbation","Does not establish whether EPPK1 contributes to progenitor identity or expansion"]},{"year":2011,"claim":"Extended the progenitor-marker observation to hepatic oval cells, suggesting a broadly shared role across epithelial regenerative compartments.","evidence":"Immunohistochemistry and lineage-marker co-localization in CDE-diet mouse liver injury","pmids":["21216305"],"confidence":"Low","gaps":["Co-localization only, no functional perturbation of EPPK1","Single lab, descriptive"]},{"year":2015,"claim":"Resolved the first molecular function—EPPK1 binds K8/K18 and acts as a chaperone for stress-induced keratin reorganization—answering what EPPK1 does at the cytoskeleton.","evidence":"Eppk1-/- mouse liver injury models, primary hepatocyte phosphatase-inhibitor treatment, K8/K18 binding assays, TMAO rescue","pmids":["25617501"],"confidence":"High","gaps":["Domain-level determinants of keratin binding not mapped to function","Chaperone mechanism inferred from TMAO rescue rather than direct biochemistry"]},{"year":2022,"claim":"Defined the regulatory logic of keratin engagement—a Ca2+-dependent, stress-triggered switch from diffuse to filament-associated state that reduces keratin dynamics.","evidence":"Live-cell imaging of tagged EPPK1/keratin, Ca2+ manipulation, FRAP under ER/oxidative/UV stress in epithelial cells","pmids":["36231039"],"confidence":"High","gaps":["Ca2+ sensor/effector that drives relocalization unidentified","Whether the same switch operates in vivo not tested"]},{"year":2022,"claim":"Showed EPPK1 sets the mechanical properties of epithelial cells, generalizing its cytoskeletal role to traction-force generation and morphology.","evidence":"EPPK1 knockout in a human Müller cell line, traction force microscopy, morphometry","pmids":["36334068"],"confidence":"Medium","gaps":["Link between traction-force change and keratin organization not established","No rescue experiment"]},{"year":2021,"claim":"Identified the first direct upstream transcriptional regulator (KLF5) and placed EPPK1 upstream of p38 in driving proliferation, opening a cancer-signaling role.","evidence":"ChIP and luciferase reporter for KLF5 at the EPPK1 promoter, siRNA epistasis, p38 western blot, proliferation assays in HeLa cells","pmids":["33827480"],"confidence":"High","gaps":["How EPPK1 mechanistically activates p38 not defined","Generality across tumor types not addressed at this stage"]},{"year":2022,"claim":"Connected EPPK1 to PI3K/AKT activation as a driver of proliferation, invasion, and EMT in esophageal squamous carcinoma.","evidence":"siRNA knockdown with proliferation/migration/invasion/apoptosis assays and PI3K/AKT and EMT marker western blots in ESCC cells","pmids":["35238170"],"confidence":"Medium","gaps":["No rescue experiment","Mechanism by which EPPK1 engages PI3K/AKT unknown"]},{"year":2023,"claim":"Revealed an unexpected ligand-sensing function—direct DHT binding by EPPK1 driving a non-androgen-receptor p38/c-Jun/JUP axis in bladder cancer.","evidence":"Biotinylated DHT pull-down, siRNA, p38 inhibitor, ChIP for c-Jun at JUP promoter, xenograft and BBN carcinogenesis models","pmids":["37328487"],"confidence":"High","gaps":["DHT-binding site/structural basis not defined","How DHT binding transduces to p38 activation unresolved"]},{"year":2024,"claim":"Defined a post-transcriptional control layer—METTL3-mediated m6A modification of EPPK1 mRNA—as an upstream driver of EPPK1 expression and PI3K/AKT signaling.","evidence":"MeRIP, RIP, dual-luciferase, siRNA, EPPK1 rescue, xenograft in esophageal cancer cells","pmids":["38293837"],"confidence":"High","gaps":["m6A reader mediating EPPK1 mRNA fate not identified","Whether m6A affects stability vs translation not separated"]},{"year":2024,"claim":"Showed EPPK1 loss reprograms transcription toward an epithelial, tumor-suppressive state (MET, MYC down, p53 up), linking it to lung adenocarcinoma and smoke exposure.","evidence":"CRISPR-Cas9 knockout, RNA-seq, western blot, proliferation/invasion assays, cigarette smoke exposure model","pmids":["38594604"],"confidence":"Medium","gaps":["Direct vs indirect control of MYC/p53 not distinguished","Mechanism connecting EPPK1 to transcriptional reprogramming unknown"]},{"year":2026,"claim":"Established a second molecular activity—EPPK1 as an RNA-binding protein that stabilizes YAP mRNA—defining a post-transcriptional oncogenic axis.","evidence":"RIP for EPPK1-YAP mRNA, mRNA stability assay, siRNA, YAP overexpression rescue, xenograft in ovarian cancer","pmids":["41569058"],"confidence":"Medium","gaps":["RNA-binding determinants within EPPK1 not mapped","Breadth of EPPK1's mRNA targets beyond YAP unknown"]},{"year":2025,"claim":"Placed EPPK1 in inflammatory skin homeostasis, identifying IFN-γ as the cytokine that suppresses it in psoriatic epidermis.","evidence":"scRNA-seq of psoriatic vs healthy skin, immunofluorescence, ex vivo IFN-γ treatment of human skin, RNA-seq of Eppk1-/- murine epidermis","pmids":["40746860"],"confidence":"Medium","gaps":["Mechanism of IFN-γ-mediated EPPK1 repression not defined","Functional consequence of EPPK1 loss for the psoriatic phenotype not established"]},{"year":null,"claim":"How EPPK1's keratin-chaperone/cytoskeletal function mechanistically connects to its cancer signaling roles (PI3K/AKT, p38, YAP mRNA stabilization) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified mechanism linking filament organization to growth-signaling outputs","Structural basis of DHT binding and RNA binding undefined","No structural model of the multidomain protein"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,6,7,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1]}],"complexes":[],"partners":["KRT8","KRT18","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P58107","full_name":"Epiplakin","aliases":["450 kDa epidermal antigen"],"length_aa":5088,"mass_kda":555.7,"function":"Cytoskeletal linker protein that connects to intermediate filaments and controls their reorganization in response to stress (PubMed:15671067, PubMed:23398049, PubMed:27206504). In response to mechanical stress like wound healing, is associated with the machinery for cellular motility by slowing down keratinocyte migration and proliferation and accelerating keratin bundling in proliferating keratinocytes thus contributing to tissue architecture (PubMed:23398049, PubMed:27206504). However in wound healing in corneal epithelium also positively regulates cell differentiation and proliferation and negatively regulates migration thereby controlling corneal epithelium morphogenesis and integrity. In response to cellular stress, plays a role in keratin filament reorganization, probably by protecting keratin filaments against disruption. During liver and pancreas injuries, plays a protective role by chaperoning disease-induced intermediate filament reorganization (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, hemidesmosome; Cell junction, tight junction; Cell projection; Apicolateral cell membrane; Basolateral cell membrane; Cell junction","url":"https://www.uniprot.org/uniprotkb/P58107/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPPK1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":9,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KRT18","stoichiometry":0.2},{"gene":"VIM","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPPK1","total_profiled":1310},"omim":[{"mim_id":"607606","title":"KERATIN 9, TYPE I; KRT9","url":"https://www.omim.org/entry/607606"},{"mim_id":"607553","title":"EPIPLAKIN 1; EPPK1","url":"https://www.omim.org/entry/607553"},{"mim_id":"144200","title":"PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, 1; EPPK1","url":"https://www.omim.org/entry/144200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Intermediate filaments","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":15.2}],"url":"https://www.proteinatlas.org/search/EPPK1"},"hgnc":{"alias_symbol":["EPIPL1"],"prev_symbol":[]},"alphafold":{"accession":"P58107","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58107","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPPK1","jax_strain_url":"https://www.jax.org/strain/search?query=EPPK1"},"sequence":{"accession":"P58107","fasta_url":"https://rest.uniprot.org/uniprotkb/P58107.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58107/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58107"}},"corpus_meta":[{"pmid":"25526346","id":"PMC_25526346","title":"Mutational landscape of intrahepatic cholangiocarcinoma.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25526346","citation_count":353,"is_preprint":false},{"pmid":"29950347","id":"PMC_29950347","title":"Quantitative Proteomic Analysis Identifies 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\"finding\": \"Epiplakin (EPPK1) binds to keratin 8 (K8) and K18 via multiple domains in hepatocytes and cholangiocytes. Eppk1-deficient mice subjected to bile duct ligation or DDC diet developed more pronounced liver injury with larger keratin granules, indicating impaired disease-induced keratin network reorganization. Primary Eppk1-/- hepatocytes showed increased keratin aggregate formation after okadaic acid treatment, rescued by the chemical chaperone TMAO, establishing EPPK1 as a chaperone for keratin reorganization under stress.\",\n      \"method\": \"Eppk1-/- mouse liver injury models (CBDL, DDC diet), primary hepatocyte culture with phosphatase inhibitor treatment, co-immunoprecipitation/binding assays for K8/K18, TMAO rescue experiments, transfection experiments\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, Eppk1-/- mouse models with defined phenotype, multiple orthogonal methods (in vivo injury models, primary cell culture, chemical chaperone rescue), single lab but multiple independent assays\",\n      \"pmids\": [\"25617501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EPPK1 undergoes a Ca2+-dependent switch from a diffuse cytoplasmic distribution to a keratin filament-associated state. Under standard conditions EPPK1 is not associated with keratin filaments; ER stress, oxidative stress, UV stress, or cell fixation induce rapid and reversible EPPK1 association with keratin filaments. This re-localization requires elevation of cytoplasmic Ca2+ and leads to significantly reduced keratin dynamics, suggesting EPPK1 stabilizes the keratin network during stress.\",\n      \"method\": \"Live-cell imaging of fluorescently tagged EPPK1 and keratin in epithelial cells, Ca2+ manipulation experiments, FRAP-based measurement of keratin dynamics\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional consequence (keratin dynamics), Ca2+ manipulation as mechanistic validation, multiple orthogonal stress conditions, single lab\",\n      \"pmids\": [\"36231039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces and changes in cell size, shape, and filopodia characteristics, establishing EPPK1 as a regulator of mechanical properties and morphology in retinal Müller cells. EPPK1 was identified as highly expressed in macular Müller cells compared to rod-associated Müller cells.\",\n      \"method\": \"EPPK1 knockout in human Müller cell line, traction force microscopy, cell morphology analysis, comparative proteomics of human and mouse retinal regions\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined mechanical and morphological phenotypic readouts, single lab, two orthogonal methods (traction force and morphometry)\",\n      \"pmids\": [\"36334068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHT (dihydrotestosterone) directly binds to EPPK1 protein (established by biotinylated DHT pull-down). EPPK1 knockdown abolished DHT-promoted proliferation and invasion in bladder cancer cells. In DHT-treated high-EPPK1 cells, JUP expression was elevated and c-Jun bound the JUP promoter. DHT-induced activation of p38 MAPK and c-Jun was absent in EPPK1 knockdown cells, placing EPPK1 upstream of the p38 MAPK/c-Jun/JUP signaling axis in a non-androgen receptor pathway.\",\n      \"method\": \"Biotinylated DHT pull-down assay, siRNA knockdown, p38 inhibitor treatment, ChIP for c-Jun at JUP promoter, xenograft mouse model, in vivo BBN carcinogenesis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding assay (biotinylated DHT pulldown), epistasis by inhibitor and KD, ChIP for transcription factor binding, in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37328487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF5 transcription factor directly binds to the EPPK1 promoter (established by chromatin immunoprecipitation and reporter gene assay) and activates EPPK1 transcription. KLF5-mediated cell proliferation in HeLa cells is partially dependent on EPPK1 upregulation, and EPPK1 lies upstream of p38 signaling in this proliferation pathway.\",\n      \"method\": \"ChIP assay, luciferase reporter gene assay, siRNA knockdown of KLF5 and EPPK1, adenovirus-mediated overexpression, western blot for p38 signaling, CCK8 proliferation assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP and reporter assay establish direct transcription factor binding, epistasis by KD places EPPK1 upstream of p38, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33827480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EPPK1 promotes esophageal squamous cell carcinoma (ESCC) cell proliferation, migration, invasion, and EMT, and suppresses apoptosis. Silencing EPPK1 reduced activation of the PI3K/AKT signaling pathway, placing EPPK1 as an upstream activator of PI3K/AKT in ESCC cells.\",\n      \"method\": \"siRNA knockdown, CCK-8 assay, colony formation, wound healing, Transwell invasion, flow cytometry apoptosis, western blot for PI3K/AKT pathway components and EMT markers\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with multiple defined cellular phenotypes and pathway readout by western blot, single lab, no rescue experiment\",\n      \"pmids\": [\"35238170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 mediates N6-methyladenosine (m6A) modification of EPPK1 mRNA (confirmed by MeRIP assay), and EPPK1 is a direct target of METTL3. METTL3 deficiency reduces EPPK1 expression and inactivates the PI3K/AKT pathway in esophageal cancer cells. Rescue of EPPK1 expression reversed the inhibitory effects of METTL3 knockdown on proliferation, invasion, migration, and stemness.\",\n      \"method\": \"MeRIP (m6A methylation immunoprecipitation), RIP assay, dual-luciferase reporter assay, siRNA knockdown, rescue overexpression, MTT/EdU/colony/Transwell/wound-healing assays, xenograft tumor experiments, IHC\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MeRIP establishes direct m6A modification, RIP and reporter confirm METTL3-EPPK1 interaction, rescue experiment validates epistasis, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"38293837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR-Cas9 knockout of EPPK1 in lung adenocarcinoma cell lines induced a mesenchymal-to-epithelial transition (MET), diminished cell proliferation and invasion, downregulated MYC and upregulated p53 at both protein and RNA levels, and altered expression of oncogenes, anti-apoptosis, and angiogenesis genes. EPPK1 protein expression was also increased in bronchial epithelial cells after 16 weeks of cigarette smoke exposure.\",\n      \"method\": \"CRISPR-Cas9 KO, RNA sequencing, western blot, proliferation and invasion assays, cigarette smoke exposure model, GO enrichment analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined cellular and transcriptional phenotypes, RNA-seq provides pathway-level mechanism, single lab\",\n      \"pmids\": [\"38594604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EPPK1 functions as an RNA-binding protein that binds YAP mRNA and enhances its stability. EPPK1 knockdown reduced YAP expression and suppressed ovarian cancer cell proliferation, migration, invasion, and immune escape; these effects were rescued by YAP overexpression, placing EPPK1 upstream of YAP in a post-transcriptional regulatory axis.\",\n      \"method\": \"RIP assay for EPPK1-YAP mRNA interaction, mRNA stability assay, siRNA knockdown, YAP overexpression rescue, xenograft model, in vitro proliferation/migration/invasion/immune escape assays\",\n      \"journal\": \"Journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishes direct RNA binding, rescue experiment validates epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41569058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Eppk1 is expressed in pancreatic progenitor cells (Eppk1+/Pdx1+/Sox9+ multipotent progenitor cells) in early pancreatic epithelium, later confined to endocrine/exocrine progenitors and duct cells. In the adult pancreas, Eppk1 marks centroacinar cells and duct cells. In caerulein-induced pancreatitis and partial pancreatectomy regeneration models, Eppk1-positive cells expand, identifying it as a marker of pancreatic progenitor/regenerating cell populations.\",\n      \"method\": \"Immunohistochemistry, co-expression analysis with lineage markers (Pdx1, Sox9, Ngn3, p48) in mouse embryonic and adult pancreas, acute pancreatitis and partial pancreatectomy models\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemistry co-localization with established lineage markers across multiple model systems, replicated across developmental and injury contexts, no functional perturbation\",\n      \"pmids\": [\"18498355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Eppk1 marks hepatic progenitor cells (oval cells) in CDE diet-injured mouse liver, co-expressing the progenitor marker A6, cholangiocyte markers (cytokeratins, E-cadherin, osteopontin, Sox9), and PCNA, identifying Eppk1+ cells as transient amplifying hepatic progenitors. In normal liver, Eppk1 is confined to cholangiocytes/bile duct cells.\",\n      \"method\": \"Immunohistochemistry and co-expression analysis with multiple lineage markers in CDE diet mouse liver injury model and normal developing liver\",\n      \"journal\": \"Gene expression patterns\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunohistochemistry co-localization only, no functional perturbation of EPPK1\",\n      \"pmids\": [\"21216305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EPPK1 expression is specifically downregulated in the suprabasal granular layer of psoriatic epidermis compared to healthy skin. IFN-γ treatment of human ex vivo skin explants downregulates EPPK1, identifying IFN-γ as the main cytokine responsible for EPPK1 downregulation in psoriasis. Transcriptomic profiling of Eppk1-/- murine epidermis showed reduced expression of genes involved in epithelial adhesion and lipid metabolism, partially overlapping with the psoriatic keratinocyte signature.\",\n      \"method\": \"scRNA-seq of psoriatic vs healthy skin, immunofluorescence of human psoriasis samples, ex vivo cytokine treatment of human skin explants, RNA-seq of Eppk1-/- murine epidermis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, immunofluorescence, ex vivo functional cytokine experiment, KO transcriptomics), single lab\",\n      \"pmids\": [\"40746860\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPPK1 (epiplakin) is a plakin-family cytoskeletal linker protein that associates with keratin intermediate filaments in a stress-dependent, Ca2+-regulated manner — diffuse in resting cells but rapidly recruited to keratin filaments upon ER, oxidative, or UV stress — where it acts as a chaperone to stabilize keratin network organization and reduce keratin dynamics; upstream, KLF5 directly transactivates EPPK1, and METTL3 promotes EPPK1 expression via m6A mRNA modification, while IFN-γ suppresses it in inflammatory skin; downstream, EPPK1 activates the PI3K/AKT and p38 MAPK pathways (the latter via direct DHT binding and JUP/c-Jun signaling in a non-androgen-receptor pathway) and stabilizes YAP mRNA as an RNA-binding protein, collectively driving epithelial cell proliferation, invasion, EMT, and cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPPK1 (epiplakin) is a plakin-family cytoskeletal linker that organizes and protects the keratin intermediate filament network, acting as a stress-inducible keratin chaperone [#0, #1]. It binds keratin 8 and keratin 18 through multiple domains, and in its absence keratin aggregates form more readily under phosphatase-inhibitor or in vivo liver-injury stress—a defect rescuable by the chemical chaperone TMAO—establishing a role in disease-induced keratin reorganization [#0]. Its engagement of the filament network is conditional: EPPK1 is diffuse in resting cells but undergoes a rapid, reversible, Ca2+-dependent switch to a keratin filament-associated state upon ER, oxidative, or UV stress, where it reduces keratin dynamics and stabilizes the network [#1]. Consistent with a structural/mechanical role, EPPK1 loss in retinal Müller cells lowers traction forces and alters cell size, shape, and filopodia [#2]. Beyond cytoskeletal organization, EPPK1 is repeatedly implicated as a driver of epithelial proliferation, invasion, and EMT in cancer: it is transcriptionally activated by KLF5 binding its promoter [#4] and post-transcriptionally upregulated through METTL3-mediated m6A modification of its mRNA [#6], and it functions downstream as an upstream activator of PI3K/AKT signaling [#5, #6] and of a p38 MAPK/c-Jun/JUP axis that it engages via direct dihydrotestosterone binding in a non-androgen-receptor manner [#3]. EPPK1 also acts as an RNA-binding protein that binds and stabilizes YAP mRNA to promote tumor cell proliferation, invasion, and immune escape [#8], and its CRISPR knockout drives mesenchymal-to-epithelial transition with MYC downregulation and p53 upregulation [#7]. In tissue contexts, EPPK1 marks pancreatic and hepatic progenitor/regenerating cell populations [#9], and its expression is downregulated by IFN-γ in psoriatic epidermis [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established EPPK1 as a marker of progenitor and regenerating epithelial cell populations, linking it to tissue renewal before any mechanistic role was known.\",\n      \"evidence\": \"Immunohistochemistry and lineage-marker co-expression in mouse embryonic/adult pancreas plus pancreatitis and partial pancreatectomy models\",\n      \"pmids\": [\"18498355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Marker-only association with no functional perturbation\", \"Does not establish whether EPPK1 contributes to progenitor identity or expansion\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the progenitor-marker observation to hepatic oval cells, suggesting a broadly shared role across epithelial regenerative compartments.\",\n      \"evidence\": \"Immunohistochemistry and lineage-marker co-localization in CDE-diet mouse liver injury\",\n      \"pmids\": [\"21216305\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-localization only, no functional perturbation of EPPK1\", \"Single lab, descriptive\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the first molecular function—EPPK1 binds K8/K18 and acts as a chaperone for stress-induced keratin reorganization—answering what EPPK1 does at the cytoskeleton.\",\n      \"evidence\": \"Eppk1-/- mouse liver injury models, primary hepatocyte phosphatase-inhibitor treatment, K8/K18 binding assays, TMAO rescue\",\n      \"pmids\": [\"25617501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain-level determinants of keratin binding not mapped to function\", \"Chaperone mechanism inferred from TMAO rescue rather than direct biochemistry\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the regulatory logic of keratin engagement—a Ca2+-dependent, stress-triggered switch from diffuse to filament-associated state that reduces keratin dynamics.\",\n      \"evidence\": \"Live-cell imaging of tagged EPPK1/keratin, Ca2+ manipulation, FRAP under ER/oxidative/UV stress in epithelial cells\",\n      \"pmids\": [\"36231039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ca2+ sensor/effector that drives relocalization unidentified\", \"Whether the same switch operates in vivo not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed EPPK1 sets the mechanical properties of epithelial cells, generalizing its cytoskeletal role to traction-force generation and morphology.\",\n      \"evidence\": \"EPPK1 knockout in a human Müller cell line, traction force microscopy, morphometry\",\n      \"pmids\": [\"36334068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between traction-force change and keratin organization not established\", \"No rescue experiment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the first direct upstream transcriptional regulator (KLF5) and placed EPPK1 upstream of p38 in driving proliferation, opening a cancer-signaling role.\",\n      \"evidence\": \"ChIP and luciferase reporter for KLF5 at the EPPK1 promoter, siRNA epistasis, p38 western blot, proliferation assays in HeLa cells\",\n      \"pmids\": [\"33827480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EPPK1 mechanistically activates p38 not defined\", \"Generality across tumor types not addressed at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected EPPK1 to PI3K/AKT activation as a driver of proliferation, invasion, and EMT in esophageal squamous carcinoma.\",\n      \"evidence\": \"siRNA knockdown with proliferation/migration/invasion/apoptosis assays and PI3K/AKT and EMT marker western blots in ESCC cells\",\n      \"pmids\": [\"35238170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment\", \"Mechanism by which EPPK1 engages PI3K/AKT unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an unexpected ligand-sensing function—direct DHT binding by EPPK1 driving a non-androgen-receptor p38/c-Jun/JUP axis in bladder cancer.\",\n      \"evidence\": \"Biotinylated DHT pull-down, siRNA, p38 inhibitor, ChIP for c-Jun at JUP promoter, xenograft and BBN carcinogenesis models\",\n      \"pmids\": [\"37328487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DHT-binding site/structural basis not defined\", \"How DHT binding transduces to p38 activation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a post-transcriptional control layer—METTL3-mediated m6A modification of EPPK1 mRNA—as an upstream driver of EPPK1 expression and PI3K/AKT signaling.\",\n      \"evidence\": \"MeRIP, RIP, dual-luciferase, siRNA, EPPK1 rescue, xenograft in esophageal cancer cells\",\n      \"pmids\": [\"38293837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A reader mediating EPPK1 mRNA fate not identified\", \"Whether m6A affects stability vs translation not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed EPPK1 loss reprograms transcription toward an epithelial, tumor-suppressive state (MET, MYC down, p53 up), linking it to lung adenocarcinoma and smoke exposure.\",\n      \"evidence\": \"CRISPR-Cas9 knockout, RNA-seq, western blot, proliferation/invasion assays, cigarette smoke exposure model\",\n      \"pmids\": [\"38594604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of MYC/p53 not distinguished\", \"Mechanism connecting EPPK1 to transcriptional reprogramming unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a second molecular activity—EPPK1 as an RNA-binding protein that stabilizes YAP mRNA—defining a post-transcriptional oncogenic axis.\",\n      \"evidence\": \"RIP for EPPK1-YAP mRNA, mRNA stability assay, siRNA, YAP overexpression rescue, xenograft in ovarian cancer\",\n      \"pmids\": [\"41569058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding determinants within EPPK1 not mapped\", \"Breadth of EPPK1's mRNA targets beyond YAP unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed EPPK1 in inflammatory skin homeostasis, identifying IFN-γ as the cytokine that suppresses it in psoriatic epidermis.\",\n      \"evidence\": \"scRNA-seq of psoriatic vs healthy skin, immunofluorescence, ex vivo IFN-γ treatment of human skin, RNA-seq of Eppk1-/- murine epidermis\",\n      \"pmids\": [\"40746860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IFN-γ-mediated EPPK1 repression not defined\", \"Functional consequence of EPPK1 loss for the psoriatic phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EPPK1's keratin-chaperone/cytoskeletal function mechanistically connects to its cancer signaling roles (PI3K/AKT, p38, YAP mRNA stabilization) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified mechanism linking filament organization to growth-signaling outputs\", \"Structural basis of DHT binding and RNA binding undefined\", \"No structural model of the multidomain protein\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT8\", \"KRT18\", \"YAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}